WO2016133160A1 - Sulfonamide derivative or pharmaceutically acceptable acid addition salt thereof - Google Patents

Sulfonamide derivative or pharmaceutically acceptable acid addition salt thereof Download PDF

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WO2016133160A1
WO2016133160A1 PCT/JP2016/054700 JP2016054700W WO2016133160A1 WO 2016133160 A1 WO2016133160 A1 WO 2016133160A1 JP 2016054700 W JP2016054700 W JP 2016054700W WO 2016133160 A1 WO2016133160 A1 WO 2016133160A1
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alkyl
hydrogen atom
pharmaceutically acceptable
acid addition
addition salt
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PCT/JP2016/054700
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French (fr)
Japanese (ja)
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正史 柳沢
博 長瀬
毅 斉藤
容子 入鹿山
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国立大学法人筑波大学
ボード・オブ・リージエンツ，ザ・ユニバーシテイ・オブ・テキサス・システム
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Priority to JP2017500731A priority Critical patent/JP6746107B2/en
Publication of WO2016133160A1 publication Critical patent/WO2016133160A1/en

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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • 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
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Definitions

  • An object of the present invention is to provide a novel compound useful as an excellent orexin receptor agonist.
  • Narcolepsy is a sleep disorder caused by the brain's inability to control the sleep / wake cycle. Symptoms of narcolepsy include unbearable sleepiness during the day, weakness-induced seizures (cataplexy) induced by emotions (especially strong joy and surprise), hallucinations during sleep, and paralysis during sleep. In general, it is seriously affected. The prevalence of narcolepsy is estimated to be 0.05-0.2% (0.16-0.18% in Japan), which is not a rare disease.
  • Narcolepsy treatment is mainly pharmacotherapy and lifestyle guidance.
  • methylphenidate, modafinil and pemoline are used to control daytime sleepiness, and tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI) and serotonin to control cataplexy.
  • SSRI selective serotonin reuptake inhibitor
  • SNRI -Noradrenaline reuptake inhibitor
  • Orexin is a neuropeptide present in the lateral area of the hypothalamus, and there are two types of peptides: orexin-A and orexin-B (hypolectin 1 and hypolectin 2 (Non-patent Document 1)). These bind to orexin 1 receptor (hereinafter also referred to as OX1R) and orexin 2 receptor (hereinafter also referred to as OX2R), which are G protein-coupled receptors (Non-patent Document 2).
  • OX1R orexin 1 receptor
  • OX2R orexin 2 receptor
  • Non-patent Document 3 mouse model experiments suggested that the function of OX2R is important for maintaining arousal (Non-Patent Documents 4 and 5).
  • Orexin receptors are widely present in the brain. Orexin is a peptide and is not useful for pharmaceutical use because of its extremely low permeability through the blood brain barrier. Therefore, it is desired to reduce the molecular weight of orexin receptor agonists.
  • a compound having a cyclic guanidine skeleton has been disclosed as a low molecular weight OX2R agonist (Patent Document 1).
  • the orexin system is considered not only to regulate sleep / wakefulness as described above, but also to appropriately control feeding behavior according to emotion and energy balance. Fasted mice increase the amount of behavior to search for food by increasing wake time and decreasing sleep time. On the other hand, in orexin receptor-deficient mice, it has been clarified that the awakening time and the amount of behavior do not increase (Non-patent Document 7). Furthermore, OX2R has been shown to be involved in body weight homeostasis by improving leptin sensitivity (Non-patent Document 8). From these facts, orexin receptor (especially OX2R) agonists may become not only narcolepsy but also therapeutic agents for diabetes, obesity and metabolic syndrome, feeding inhibitors or weight gain inhibitors.
  • Non-patent Document 9 spontaneous activity was reduced in septic rats, and it was reported that orexin-containing nerve activity in the hypothalamic periarch area was reduced. There is a report that body temperature increased and recovery of cardiac function was observed after administration (Non-patent Document 10). From these facts, orexin receptor agonists may be therapeutic agents for sepsis.
  • An object of the present invention is to provide a novel low molecular weight compound exhibiting orexin receptor agonist activity, which is expected to be useful as an excellent preventive or therapeutic agent such as narcolepsy.
  • R 1 represents a hydrogen atom
  • R 2 represents —OH or C 1-4 alkoxy
  • R 1 and R 2 together represent —NR a R b (wherein R a represents a hydrogen atom or C 1-4 alkyl, and R b represents a hydrogen atom or C 1-4 alkyl).
  • R 3 is C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl (where C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl is optionally Optionally substituted with 1 to 4 R 4 selected, R 4 is a hydrogen atom, C 1-4 alkyl, C 1-4 alkoxy, Phenyl (wherein phenyl is C 1-4 alkyl, C 1-4 alkoxy or —C (O) NR 4x R 4y (where R 4x represents C 1-4 alkyl, R 4y represents C 1-4 Represents alkyl.) And may be substituted with 5-10 membered heteroaryl, halogen, -OH, —NR 4a R 4b (wherein R 4a represents a hydrogen atom, C 1-4 alkyl
  • R 4e represents a hydrogen atom or C 1-4 alkyl. Alternatively, two R 4 together form methylenedioxy.
  • W represents — (CH 2 ) n —C (O) NR Wa R Wb (where n represents an integer of 0 to 2, R Wa represents a hydrogen atom, C 1-4 alkyl (where C 1-4 Alkyl may be substituted with phenyl, pyridyl or C 1-4 alkoxy-carbonylamino optionally substituted with C 1-4 alkyl or C 1-4 alkoxy, or phenyl (where phenyl is C And optionally substituted with 1-4 alkoxy, —NO 2 or C 1-4 alkoxy-carbonylamino.), R Wb represents a hydrogen atom or C 1-4 alkyl)) or the general formula (II) :
  • R 5 is a hydrogen atom, C 1-4 alkoxy, —NR 5a R 5b (where R 5a represents a hydrogen atom or C 1-4 alkyl, and R 5b represents a hydrogen atom or C 1-4 alkyl) Or —C (O) NR 5c R 5d (where R 5c represents a hydrogen atom or C 1-4 alkyl, and R 5d represents a hydrogen atom or C 1-4 alkyl);
  • R 6 is a hydrogen atom, C 1-4 alkoxy, —OCF 3 , —NR 6a R 6b (where R 6a represents a hydrogen atom or C 1-4 alkyl, and R 6b represents a hydrogen atom or C 1-4 alkyl) Or —C (O) NR 6c R 6d (where R 6c represents a hydrogen atom or C 1-4 alkyl, and R 6d represents a hydrogen atom or C 1-4 alkyl),
  • R 7 represents a hydrogen atom, C 1-4 alkoxy or —OC
  • R 2 ′ represents phenyl substituted with —NR 3a ′ R 3b ′ (where R 3a ′ represents C 1-4 alkyl and R 3b ′ represents C 1-4 alkyl).
  • R 3a ′ represents C 1-4 alkyl and R 3b ′ represents C 1-4 alkyl.
  • W is — (CH 2 ) n —C (O) NR Wa R Wb (where n represents an integer of 0 to 2;
  • R Wa is a hydrogen atom, C 1-4 alkyl (where C 1-4 alkyl is phenyl, pyridyl or C 1-4 alkoxy-carbonyl optionally substituted with
  • R 5 is C 1-4 alkoxy, —NR 5a R 5b (where R 5a represents a hydrogen atom or C 1-4 alkyl, and R 5b represents a hydrogen atom or C 1-4 alkyl) or —C (O) NR 5c R 5d (wherein R 5c represents a hydrogen atom or C 1-4 alkyl, and R 5d represents a hydrogen atom or C 1-4 alkyl), R 6 is a hydrogen atom, C 1-4 alkoxy, —OCF 3 , —NR 6a R 6b (where R 6a represents a hydrogen atom or C 1-4 alkyl, and R 6b represents a hydrogen atom or C 1-4 alkyl) Or —C (O) NR 6c R 6d (where R 6c represents a hydrogen atom or C 1-4 alkyl, and R 6d represents a hydrogen atom or C 1-4 alkyl), R 7 represents a hydrogen atom, C 1-4 alkoxy or —OCF 3 , and
  • R 5 and R 6 together form methylenedioxy.
  • R 3 is C 1-6 alkyl, C 2-6 alkenyl or C 3-10 cycloalkyl, wherein C 1-6 alkyl, C 2-6 alkenyl or C 3-10 cycloalkyl is optionally substituted with 1 to 4 R 4
  • R 4 is a hydrogen atom, C 1-4 alkyl, C 1-4 alkoxy, Phenyl (wherein phenyl is C 1-4 alkyl, C 1-4 alkoxy, methylenedioxy or —C (O) NR 4x R 4y (where R 4x represents C 1-4 alkyl and R 4y represents Represents C 1-4 alkyl.) And may be substituted.
  • R 3 is C 6-10 aryl or 5- to 10-membered heteroaryl (where C 6-10 aryl or 5- to 10-membered heteroaryl may be optionally substituted with 1 to 4 R 4)
  • R 4 is phenyl (wherein phenyl is C 1-4 alkyl, C 1-4 alkoxy or —C (O) NR 4x R 4y (where R 4x represents C 1-4 alkyl and R 4y represents C 4 1-4 represents an alkyl group, which may be substituted with 5-10 membered heteroaryl, —C (O) OR 4c (where R 4c represents C 1-4 alkyl) or —C (O) NR 4d R 4e (where R 4d represents C 1-4 alkyl and R 4e Represents C 1-4 alkyl.
  • R 2 is —OH, or R 1 and R 2 are taken together to form —NR a R b (where R a represents a hydrogen atom or C 1-4 alkyl, and R b represents a hydrogen atom or C 1 1-4 represents a alkyl), or a pharmaceutically acceptable acid addition salt thereof, which forms a benzene ring which may be further substituted with [8]
  • a pharmaceutical comprising the compound according to any one of [1] to [7] above or a pharmaceutically acceptable acid addition salt thereof, [9] An orexin receptor agonist containing the compound according to any one of [1] to [7] above or a pharmaceutically acceptable acid addition salt thereof, [10] An anti-narcolepsy containing the compound according to any one of [1] to [7] above or a pharmaceutically acceptable acid addition salt thereof, [11]
  • a sleepiness improving agent comprising the compound according to any one of the above [1]
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable acid addition salt thereof has excellent OX2R agonist activity.
  • FIG. 1 shows that a control substance (physiological saline) or a test compound (the compound of Example 7 (dihydrochloride)) is administered to a wild-type mouse (WT mouse) or orexin receptor-deficient mouse (DKO mouse) in the light ventricle. The cumulative awakening time of 2 hours after is shown.
  • FIG. 2 shows that a control substance (physiological saline) or a test compound (compound of Example 7 (dihydrochloride)) was intraperitoneally administered to a wild type mouse (WT mouse) or orexin receptor-deficient mouse (DKO mouse). The cumulative awakening time of 2 hours after is shown.
  • FIG. 1 shows that a control substance (physiological saline) or a test compound (the compound of Example 7 (dihydrochloride)) is administered to a wild-type mouse (WT mouse) or orexin receptor-deficient mouse (DKO mouse). The cumulative awakening time of 2 hours after is shown.
  • WT mouse wild-type mouse
  • FIG. 3 shows a hypnogram for 6 hours after intraventricular administration of a control substance (saline) or a test compound (the compound of Example 7 (dihydrochloride)) to orexin-deficient mice (OXKO mice).
  • ⁇ down arrow indicates sleep onset REM sleep (SOREM), which is a catalepoxy-like symptom.
  • FIG. 4 shows a hypnogram for 6 hours after intraventricular administration of a control substance (saline) or a test compound (the compound of Example 7 (dihydrochloride)) to orexin receptor-deficient mice (DKO mice).
  • ⁇ (down arrow) in the figure indicates SOREM.
  • FIG. 5 shows the cumulative number of occurrences of SOREM when a control substance (physiological saline) or a test compound (the compound of Example 7 (dihydrochloride)) is administered into dark ventricles in orexin-deficient mice (OXKO mice).
  • FIG. 6 shows a hypnogram for 6 hours after intraperitoneal administration of the control substance (saline) or the test compound (the compound of Example 7 (dihydrochloride)) to orexin-deficient mice (OXKO mice).
  • ⁇ (down arrow) indicates SOREM.
  • FIG. 7 shows that a control substance (physiological saline) or a test compound (compound of Example 7 (dihydrochloride)) was intraperitoneally administered during dark period to orexin-deficient mice (OXKO mice) or orexin receptor-deficient mice (DKO mice). The cumulative number of SOREMs for the next 3 hours is shown.
  • FIG. 8 shows the cumulative arousal time of 2 hours after the oral administration of the control substance (physiological saline) or the test compound (the compound of Example 7 (dihydrochloride)) to wild-type mice (WT mice).
  • FIG. 9 shows a hypnogram for 6 hours after intraperitoneal administration of the control substance (saline) or the test compound (the compound of Example 7 (dihydrochloride)) to orexin neurodegenerative mice (orexin / ataxin 3 mice).
  • ⁇ down arrow in the figure indicates SOREM.
  • FIG. 10 shows that the control substance (saline) or the test compound (the compound of Example 7 (dihydrochloride)) was administered to orexin neurodegenerative mice (orexin / ataxin 3 mice) for 3 hours after intraperitoneal administration in the dark period. Indicates the cumulative number of times.
  • FIG. 10 shows that the control substance (saline) or the test compound (the compound of Example 7 (dihydrochloride) was administered to orexin neurodegenerative mice (orexin / ataxin 3 mice) for 3 hours after intraperitoneal administration in the dark period. Indicates the cumulative number of times.
  • FIG. 11-a shows the body weight of orexin-deficient mice (OXKO mice) before administration of a control substance (saline) or a test compound (compound of Example 7 (dihydrochloride)).
  • FIG. 11-b shows changes in body weight when a control substance (physiological saline) or a test compound (compound of Example 7 (dihydrochloride)) is continuously administered to OXKO mice.
  • FIG. 11-c shows the average daily food intake (per body weight) when a control substance (saline) or a test compound (the compound of Example 7 (dihydrochloride)) is continuously administered to OXKO mice.
  • FIG. 11-b shows changes in body weight when a control substance (physiological saline) or a test compound (compound of Example 7 (dihydrochloride)) is continuously administered to OXKO mice.
  • FIG. 11-c shows the average daily food intake (per body weight) when a control substance (saline) or a test compound (
  • FIG. 11-d shows the change in body weight of OXKO mice 2 weeks after the administration of the test compound (compound of Example 7 (dihydrochloride)) was discontinued.
  • FIG. 11-e shows the body weight of orexin receptor-deficient mice (DKO mice) before administration of a control substance (saline) or a test compound (the compound of Example 7 (dihydrochloride)).
  • FIG. 11-f shows changes in body weight when a control substance (saline) or a test compound (the compound of Example 7 (dihydrochloride)) was continuously administered to DKO mice.
  • FIG. 11-e shows the body weight of orexin receptor-deficient mice (DKO mice) before administration of a control substance (saline) or a test compound (the compound of Example 7 (dihydrochloride)).
  • FIG. 11-f shows changes in body weight when a control substance (saline) or a test compound (the compound of Example 7 (dihydrochloride)) was continuously administered to D
  • FIG. 11-g shows the average daily food intake (per body weight) when a control substance (physiological saline) or a test compound (the compound of Example 7 (dihydrochloride)) was continuously administered to DKO mice.
  • FIG. 11-h shows the change in body weight of DKO mice 2 weeks after the administration of the test compound (the compound of Example 7 (dihydrochloride)) was discontinued.
  • C 1-6 alkyl means a monovalent linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, consisting of a carbon atom and a hydrogen atom. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl and the like.
  • C 1-4 alkyl means a monovalent straight-chain or branched saturated hydrocarbon group having 1 to 4 carbon atoms, comprising a carbon atom and a hydrogen atom.
  • methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like can be mentioned.
  • C 1-4 alkoxy means an oxy group to which the above “C 1-4 alkyl” is bonded. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
  • halogen in the present specification means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 2-6 alkenyl refers to an unsaturated hydrocarbon having at least one monovalent linear or branched double bond having 2 to 6 carbon atoms, comprising a carbon atom and a hydrogen atom. Means group.
  • C 3-10 cycloalkyl means a monocyclic aliphatic carbocyclic group having 3 to 10 carbon atoms.
  • C 6-10 aryl means a monocyclic or condensed aromatic carbocyclic group having 6 to 10 carbon atoms.
  • phenyl, 1-naphthyl, 2-naphthyl and the like can be mentioned.
  • the “5- to 10-membered heteroaryl” is, as a ring-constituting atom, from 1 or 2 selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atom, from 5 containing 1 to 4 hetero atoms Means a 10-membered monocyclic or bicyclic aromatic heterocyclic group.
  • anti-narcolepsy agent means a therapeutic or prophylactic agent for narcolepsy.
  • the “sleep improvement agent” in the present specification means an agent that improves daytime sleepiness due to shift work, jet lag, insomnia, sleep apnea syndrome or the like.
  • R 1 represents a hydrogen atom.
  • R 2 represents —OH or C 1-4 alkoxy; Alternatively, R 1 and R 2 together represent —NR a R b (where R a represents a hydrogen atom or C 1-4 alkyl, and R b represents a hydrogen atom or C 1-4 alkyl). Further, an optionally substituted benzene ring is formed.
  • R 2 is —OH, or R 1 and R 2 together represent —NR a R b (where R a represents a hydrogen atom or C 1-4 alkyl (eg, methyl); R b preferably represents a hydrogen atom or a C 1-4 alkyl (eg, methyl), which may be further substituted to form a benzene ring.
  • R 2 is preferably C 1-4 alkoxy (eg, methoxy), particularly preferably methoxy.
  • R 3 is C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl (where C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl is optionally Optionally substituted with 1 to 4 R 4 selected, R 4 is a hydrogen atom, C 1-4 alkyl, C 1-4 alkoxy, Phenyl (wherein phenyl is C 1-4 alkyl, C 1-4 alkoxy or —C (O) NR 4x R 4y (where R 4x represents C 1-4 alkyl, R 4y represents C 1-4 Represents alkyl.) And may be substituted with 5-10 membered heteroaryl, halogen, -OH, —NR 4a R 4b (wherein R 4a represents a hydrogen atom, C 1-4 alkyl or C 1-4 alkoxy-carbonyl, and R
  • R 3 includes C 1-6 alkyl (eg, methyl, ethyl, propyl, isobutyl, neopentyl), C 2-6 alkenyl (eg, ethenyl) or C 3-10 cycloalkyl (eg, adamantyl) (Wherein C 1-6 alkyl, C 2-6 alkenyl or C 3-10 cycloalkyl may be optionally substituted with 1 to 4 R 4 , R 4 is a hydrogen atom, C 1-4 alkyl (eg methyl), C 1-4 alkoxy (eg, methoxy), Phenyl (wherein phenyl is C 1-4 alkyl (eg, methyl), C 1-4 alkoxy (eg, methoxy) or —C (O) NR 4x R 4y (where R 4x is C 1-4 alkyl) (Eg, methyl), R 4y may be substituted with C 1-4 alkyl (eg, methyl)).
  • heteroaryl eg, furyl, pyridyl, indolyl
  • Halogen fluorine atom, bromine atom
  • —NR 4a R 4b where R 4a represents a hydrogen atom, C 1-4 alkyl (eg, methyl) or C 1-4 alkoxy-carbonyl (eg, tert-butoxycarbonyl), and R 4b represents a hydrogen atom or Represents C 1-4 alkyl (eg, methyl)), —C (O) OR 4c (where R 4c represents C 1-4 alkyl (eg, methyl)) or —C (O) NR 4d R 4e (where R 4d is a hydrogen atom or C 1 -4 alkyl (eg, methyl), R 4e represents a hydrogen atom or C 1-4 alkyl (eg, methyl).
  • two R 4 together form methylenedioxy. ) Is preferred.
  • R 3 includes C 6-10 aryl (eg, phenyl, naphthyl) or 5- to 10-membered heteroaryl (eg, thiazolyl, quinolyl, isoquinolyl, quinoxalinyl) (wherein C 6-10 aryl or The 5- to 10-membered heteroaryl may be optionally substituted with 1 to 4 R 4 , R 4 is phenyl (wherein phenyl is C 1-4 alkyl (eg, methyl), C 1-4 alkoxy (eg, methoxy) or —C (O) NR 4x R 4y (where R 4x is C 1 -4 alkyl (eg, methyl), R 4y may be substituted with C 1-4 alkyl (eg, methyl)).
  • R 4 is phenyl (wherein phenyl is C 1-4 alkyl (eg, methyl), C 1-4 alkoxy (eg, methoxy) or —C (O) NR 4x R 4y (where
  • heteroaryl eg, furyl, pyridyl, indolyl
  • —C (O) OR 4c where R 4c represents C 1-4 alkyl (eg, methyl)) or —C (O) NR 4d R 4e (where R 4d is a hydrogen atom or C 1 -4 alkyl (eg, methyl), R 4e represents a hydrogen atom or C 1-4 alkyl (eg, methyl).
  • two R 4 together form methylenedioxy. ) Is preferred.
  • R 3 represents —NR 4a R 4b (where R 4a represents C 1-4 alkyl (eg, methyl), and R 4b represents C 1-4 alkyl (eg, methyl). Represents a substituted phenyl.
  • W represents — (CH 2 ) n —C (O) NR Wa R Wb (where n represents an integer of 0 to 2; R Wa is a hydrogen atom, C 1-4 alkyl (where C 1-4 alkyl is phenyl, pyridyl or C 1-4 alkoxy-carbonyl optionally substituted with C 1-4 alkyl or C 1-4 alkoxy) Or phenyl (wherein the phenyl may be substituted with C 1-4 alkoxy, —NO 2 or C 1-4 alkoxy-carbonylamino), and R Wb Represents a hydrogen atom or C 1-4 alkyl. ) Or general formula (II):
  • R 5 is a hydrogen atom, C 1-4 alkoxy, —NR 5a R 5b (where R 5a represents a hydrogen atom or C 1-4 alkyl, and R 5b represents a hydrogen atom or C 1-4 alkyl) Or —C (O) NR 5c R 5d (where R 5c represents a hydrogen atom or C 1-4 alkyl, and R 5d represents a hydrogen atom or C 1-4 alkyl);
  • R 6 is a hydrogen atom, C 1-4 alkoxy, —OCF 3 , —NR 6a R 6b (where R 6a represents a hydrogen atom or C 1-4 alkyl, and R 6b represents a hydrogen atom or C 1-4 alkyl) Or —C (O) NR 6c R 6d (where R 6c represents a hydrogen atom or C 1-4 alkyl, and R 6d represents a hydrogen atom or C 1-4 alkyl),
  • R 7 represents a hydrogen atom, C 1-4 alkoxy or —OC
  • W represents — (CH 2 ) n —C (O) NR Wa R Wb (where n represents an integer of 0 to 2, R Wa represents a hydrogen atom, C 1-4 alkyl (eg, methyl) ( Where C 1-4 alkyl is phenyl, pyridyl or C 1-4 alkoxy-carbonylamino (eg, methyl) or C 1-4 alkoxy (eg, methoxy) optionally substituted with C 1-4 alkyl (eg, methyl).
  • R 5 represents C 1-4 alkoxy (eg, methoxy)
  • —NR 5a R 5b where R 5a represents a hydrogen atom or C 1-4 alkyl (eg, methyl), and R 5b represents a hydrogen atom or C 1 -4 alkyl (eg, methyl)) or -C (O) NR 5c R 5d
  • R 5c represents a hydrogen atom or C 1-4 alkyl (eg, methyl)
  • R 5d represents a hydrogen atom
  • R 6 represents a hydrogen atom, C 1-4 alkoxy (eg, methoxy), —OCF 3
  • —NR 6a R 6b where R 6a represents a hydrogen atom or C 1-4 alkyl (eg, methyl)
  • R 6b represents a hydrogen atom or C 1-4 alkyl (eg, methyl)) or —C (O) NR 6c R 6d (where R 6c represents a hydrogen atom or a hydrogen atom or C 1-4 alky
  • R 6d represents a hydrogen atom or C 1-4 alkyl (eg, methyl)
  • R 7 represents a hydrogen atom, C 1-4 alkoxy (eg, methoxy) or —OCF 3
  • X represents —CH ⁇ .
  • R 5 and R 6 together form methylenedioxy. ).
  • n is preferably 0 or 2, and 0 is particularly preferable.
  • R 5 represents a hydrogen atom
  • R 6 represents —C (O) NR 6c R 6d
  • R 6c represents C 1-4 alkyl (eg, methyl)
  • R 6d represents C 1-4 alkyl (eg, methyl)
  • R 7 represents a hydrogen atom
  • X represents —CH ⁇ .
  • R 2 ′ represents —NR 3a ′ R 3b ′ (where R 3a ′ represents C 1-4 alkyl (eg, methyl) and R 3b ′ represents C 1-4 alkyl (eg, methyl)). Represents phenyl substituted with ] Or a pharmaceutically acceptable acid addition salt thereof.
  • Specific examples of the compound represented by the general formula (I ′) include 3 ′-(N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4′-methoxy-N, N-dimethyl- [1,1′-biphenyl] -3-carboxamide, 3 ′-(N- (3-((2- (3- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4′-methoxy-N, N-dimethyl- [1,1′-biphenyl] -3-carboxamide, and 3 '-(N- (3-((2- (4- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4'-methoxy-N, N-dimethyl- [1
  • Examples of the pharmaceutically acceptable acid addition salt of the compound of the general formula (I) of the present invention include inorganic acids such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate.
  • Organic carboxyl such as salt, acetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, phthalate
  • Examples thereof include, but are not limited to, organic sulfonates such as acid salts, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, camphorsulfonates, and the like.
  • hydrochloride hydrobromide, phosphate, tartrate, methanesulfonate, camphorsulfonate are preferable, hydrochloride, tartrate or methanesulfonate is more preferable, and hydrochloride is particularly preferably used. These are also not limiting.
  • the compound of the present invention represented by the general formula (I) can be produced by an appropriate method based on the characteristics derived from the basic skeleton and the substituent.
  • the starting materials and reagents used in the production of these compounds are generally available or described in references such as Organic Reactions (Wiley & Sons), Fieser and Fieser's Reagent for Organic Synthesis (Wiley & Sons), etc. And can be synthesized by methods known to those skilled in the art.
  • Specific examples of the method for producing the compound of the present invention represented by the general formula (I) include the methods shown in Schemes 1 to 5.
  • R 1 , R 2 , R 3 and W are the same as defined above. ].
  • the compound represented by the general formula (I) is obtained, for example, by amidating an amine derivative represented by the general formula (III) with a carboxylic acid represented by the general formula (IV). be able to.
  • Solvents include halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane, ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane (DME) and dioxane, N, N-dimethylformamide
  • aprotic polar solvent such as (DMF), dimethyl sulfoxide (DMSO) or ethyl acetate, an alcohol solvent such as methanol, ethanol or propanol or a mixed solvent thereof can be used.
  • dichloromethane or THF is preferably used.
  • the carboxylic acid (IV) is used in an amount of 0.5 to 20 equivalents, preferably 0.5 to 10 equivalents, relative to the amine derivative (III).
  • the condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), N, N′-carbonyldiimidazole (CDI), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM), ⁇ [ (1-Cyano-2-ethoxy-2-oxoethylidene) amino] oxy ⁇ -4-morpholinomethylene ⁇ dimethylammonium hexafluorophosphate (COMU), O- (7-azabenzotriazol-1-
  • the condensing agent is used in an amount of 1.0 to 100 equivalents, preferably 1.0 to 10 equivalents, relative to the amine derivative (III).
  • a base triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine and the like can be used, and triethylamine or diisopropylethylamine is preferably used.
  • the base is used in an amount of 3.0 to 100 equivalents, preferably 3.0 to 10 equivalents, relative to the amine derivative (III).
  • the reaction temperature is usually ⁇ 40 to 150 ° C., preferably 0 to 60 ° C.
  • the reaction time is appropriately selected depending on the reaction temperature and other conditions, but is usually about 20 minutes to 48 hours. Further, the concentration of the substrate (III) in the reaction system is not particularly limited, but usually 0.001 mmol / L to 1 mol / L is preferable.
  • X is a hydrogen atom or a benzyl group
  • R 1 , R 2 , R 3 and W are as defined above.
  • the derivative represented by the general formula (V) is Suzuki-coupled with the boronic acid derivative represented by the general formula (VI). Can be obtained.
  • the Suzuki coupling reaction is performed in a suitable solvent in the presence of a palladium catalyst and a base, and in the presence or absence of a phosphine ligand.
  • Solvents include ether solvents such as THF, DME and dioxane, aprotic polar solvents such as DMF and DMSO, alcohol solvents such as methanol, ethanol and propanol, aromatic solvents such as benzene, toluene and xylene, water Alternatively, a mixed solvent thereof can be used. Usually, a mixed solvent of dioxane, DME, dioxane and water or a mixed solvent of DME and water is preferably used.
  • boronic acid derivative (VI) not only boronic acid but also boronic acid esters such as boronic acid pinacol ester, boronic acid N-methyliminodiacetic acid (MIDA) ester, or potassium trifluoroborate can be used.
  • boronic acid or boronic acid pinacol ester is preferably used.
  • the boronic acid derivative (VI) is used in an amount of 1.0 to 20 equivalents, preferably 1.0 to 10 equivalents, relative to the derivative of formula (V).
  • the palladium catalyst examples include tetrakis (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride, bis (dibenzylideneacetone) palladium, bis (diphenylphosphino) ferrocenepalladium dichloride, and the like.
  • (Triphenylphosphine) palladium or bis (diphenylphosphino) ferrocenepalladium dichloride is preferably used.
  • the palladium catalyst is used in an amount of 0.001 to 1 equivalent, preferably 0.005 to 0.5 equivalent, relative to the derivative of formula (V).
  • Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, barium hydroxide, triethylamine, diisopropylethylamine, and sodium carbonate or potassium carbonate is preferably used.
  • the reaction temperature is usually ⁇ 40 to 150 ° C., preferably 20 to 110 ° C.
  • the reaction time is appropriately selected depending on the reaction temperature and other conditions, but is usually about 20 minutes to 48 hours.
  • the concentration of the substrate (V) in the reaction system is not particularly limited, but usually 0.001 mmol / L to 1 mol / L is preferable.
  • the compound represented by the general formula (I) can be obtained, for example, by deprotecting the benzyl group of the compound represented by the general formula (VII) by a hydrogenolysis reaction or the like.
  • the hydrogenolysis reaction is carried out in a suitable solvent in the presence of a palladium catalyst and in an atmosphere of hydrogen.
  • Solvents include ether solvents such as THF, DME and dioxane, aprotic polar solvents such as DMF, DMSO and ethyl acetate, alcohol solvents such as methanol, ethanol and propanol, and aromatic solvents such as benzene, toluene and xylene.
  • a solvent, acetic acid, water, or a mixed solvent thereof can be used.
  • toluene, THF, and methanol are preferably used.
  • the palladium catalyst include palladium (Pd), palladium carbon (Pd / C), palladium hydroxide (Pd (OH) 2 ), palladium hydroxide carbon (Pd (OH) 2 / C), and the like.
  • Palladium carbon (Pd / C) is preferably used.
  • the palladium catalyst is used in an amount of 0.001 to 1 equivalent, preferably 0.005 to 0.5 equivalent, relative to the derivative of formula (VII).
  • the reaction temperature is usually ⁇ 40 to 150 ° C., preferably 20 to 110 ° C.
  • the reaction time is appropriately selected depending on the reaction temperature and other conditions, but is usually about 20 minutes to 48 hours. Further, the concentration of the substrate (VII) in the reaction system is not particularly limited, but is usually preferably 0.001 mmol / L to 1 mol / L.
  • the compound represented by the general formula (I) can be obtained, for example, by amidating a sulfonic acid chloride derivative of the general formula (VIII) with an amine derivative of the general formula (IX).
  • a solvent halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, ether solvents such as diethyl ether, THF, DME, dioxane, aprotic polar solvents such as DMF, DMSO, or a mixed solvent thereof are used. be able to.
  • dichloromethane or THF is preferably used.
  • the sulfonic acid chloride derivative (VIII) is used in an amount of 0.5 to 20 equivalents, preferably 1.0 to 10 equivalents, relative to the amine derivative (IX).
  • the base include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, barium hydroxide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and the like. Pyridine is preferably used.
  • the reaction temperature is usually ⁇ 40 to 150 ° C., preferably 0 to 80 ° C.
  • the reaction time is appropriately selected depending on the reaction temperature and other conditions, but is usually about 10 minutes to 48 hours.
  • the concentration of the substrate (VIII) in the reaction system is not particularly limited, but usually 0.001 mmol / L to 1 mol / L is preferable.
  • Solvents include halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane, ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane (DME) and dioxane, N, N-dimethylformamide
  • aprotic polar solvent such as (DMF), dimethyl sulfoxide (DMSO) or ethyl acetate, an alcohol solvent such as methanol, ethanol or propanol or a mixed solvent thereof can be used.
  • dichloromethane or THF is preferably used.
  • the amine (XI) is used in an amount of 0.5 to 20 equivalents, preferably 0.5 to 10 equivalents, relative to the carboxylic acid derivative (X).
  • the condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), N, N′-carbonyldiimidazole (CDI), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM), ⁇ [ (1-Cyano-2-ethoxy-2-oxoethylidene) amino] oxy ⁇ -4-morpholinomethylene ⁇ dimethylammonium hexafluorophosphate (COMU), O- (7-azabenzotriazol-1
  • the condensing agent is used in an amount of 1.0 to 100 equivalents, preferably 1.0 to 10 equivalents, relative to the carboxylic acid derivative (X).
  • a base triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine and the like can be used, and triethylamine or diisopropylethylamine is preferably used.
  • the base is used in an amount of 3.0 to 100 equivalents, preferably 3.0 to 10 equivalents, relative to the carboxylic acid derivative (X).
  • the reaction temperature is usually ⁇ 40 to 150 ° C., preferably 0 to 60 ° C.
  • the reaction time is appropriately selected depending on the reaction temperature and other conditions, but is usually about 20 minutes to 48 hours.
  • the concentration of the substrate (X) in the reaction system is not particularly limited, but is usually preferably 0.001 mmol / L to 1 mol / L.
  • Orexin receptor agonists (especially OX2R agonists) containing the compounds of the present invention are not only effective against humans but also non-human mammals such as mice, rats, hamsters, rabbits, cats, dogs, cows , Effective against sheep, monkeys, etc.
  • the compound of the present invention is not only used as a preventive or therapeutic agent for narcolepsy as described above, but also can be used for the prevention or treatment of narcolepsy or the manufacture of a medicament for preventing or treating narcolepsy.
  • the compound of the present invention can be used as a prophylactic or therapeutic agent for sleepiness improving agent, antifeedant, weight gain inhibitor or obesity, diabetes, depression, sepsis, severe sepsis or septic shock.
  • the drug may be a free form of the compound of the present invention or its acid addition salt itself, and also excipients, stabilizers, preservatives, buffers, solubilizers, emulsifiers, diluents. Additives such as tonicity agents may be mixed as appropriate.
  • Administration forms include oral preparations such as tablets, capsules, granules, powders, syrups, parenteral preparations such as injections, suppositories, and liquids, or topical administration such as ointments, creams, patches, etc. Can be mentioned.
  • the preventive or therapeutic agent for narcolepsy of the present invention sleepiness improving agent, antifeedant, weight gain inhibitor or obesity, diabetes, depression, sepsis, severe sepsis or septic shock or the like, It is desirable to contain 0.001 to 90% by weight, preferably 0.01 to 70% by weight of the above active ingredient.
  • the amount to be used is appropriately selected according to symptoms, age, body weight, and administration method.
  • the narcolepsy preventive or therapeutic agent or sleepiness improving agent of the present invention includes a prophylactic or therapeutic agent for strong daytime sleepiness and dozing, a prophylactic or therapeutic agent for deep sleep disorder, a prophylactic or therapeutic agent for cataplexy, and It can also be used in combination.
  • the preventive or therapeutic agent for strong daytime sleepiness and doze include central nervous system stimulants such as methylphenidate, pemoline, and modafinil.
  • prophylactic or therapeutic agent for deep sleep disorder examples include sleeping drugs such as triazolam and begetamine B, and anxiolytic drugs.
  • prophylactic or therapeutic agents for cataplexy include tricyclic antidepressants such as clomipramine hydrochloride, brotizolam, imipramine hydrochloride, selective serotonin reuptake inhibitors (SSRI) such as fluvoxamine maleate, paroxetine hydrochloride, mil hydrochloride
  • SSRI selective serotonin reuptake inhibitors
  • SNRI noradrenaline reuptake inhibitors
  • Boc tert-butoxycarbonyl
  • Bn benzyl COMU: ⁇ [(1-cyano-2-ethoxy-2-oxoethylidene) amino] oxy ⁇ -4-morpholinomethylene ⁇ dimethylammonium hexafluorophosphate
  • DME 1,2 -Dimethoxyethane
  • DMF N, N-dimethylformamide
  • DIPEA N, N-diisopropylethylamine
  • HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexa Fluorophosphate Me: Methyl TFA: 2,2,2-trifluoroacetic acid
  • the compound name is ChemBioDraw Ultra ver. Manufactured by Cambridge. Named using 12.0.3. “Room temperature” in the following production examples usually indicates about 10
  • tert-butyl (2-((3-aminophenyl) (benzyl) amino) ethyl) carbamate (1.59 g) in dichloromethane (20.0 mL) was added to pyridine (413 ⁇ L) and 5-bromo-2- Methoxybenzenesulfonyl chloride (1.33 g) was added and stirred overnight at room temperature.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated.
  • the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) and tert-butyl (2-((3- (3 ′-(dimethylaminocarbamoyl) -4-methoxy [1,1′-biphenyl] ] -3-ylsulfonamido) phenyl) amino) ethyl) carbamate (950.0 mg) was obtained.
  • N- (2-(((3 ′-(dimethylcarbamoyl) -4-methoxy- [1,1′-biphenyl] -3-sulfonyl chloride (236.0 mg) in dichloromethane (4.0 mL)) was added.
  • 3-Aminophenyl) amino) ethyl) -2- (dimethylamino) benzamide (210.0 mg) and DIPEA (350 ⁇ L) were added, and the mixture was stirred at room temperature overnight.
  • pure water was added and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated.
  • N- (2-((3-aminophenyl) amino) ethyl) -2- (dimethylamino) benzamide (307.0 mg) in dichloromethane (10.0 mL) was added to pyridine (3.0 mL) and 3 -(Chlorosulfonyl) -4-methoxybenzoic acid (350.0 mg) was added, and the mixture was stirred overnight at room temperature.
  • 1.0 M hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the organic layer, and the product was extracted into the aqueous layer.
  • Test example 1 Evaluation of agonistic activity against OX2R A cell line (CHOOX2R) was established in which NAFT-luciferase gene and human OX2R gene were constantly expressed in CHO cells, a Chinese hamster ovary-derived cell line. These cells were seeded in a 96-well multiplate at 10,000 cells / well and cultured in DMEM medium (Sigma Aldrich) supplemented with 5% FBS (Thermo Scientific) for 48 hours.
  • DMEM medium Sigma Aldrich
  • FBS Thermo Scientific
  • assay buffer containing 20 ⁇ M Fura-2AM (Cayman Chemical) (20 mM HEPES (Sigma Aldrich), Hanks' balanced salt solution (Gibco), 0.1% BSA (Sigma Aldrich), 2.5 mM probenecid 100 ⁇ L of acid (Wako Pure Chemical Industries) was added and incubated for 60 minutes. After removing the buffer containing Fura-2AM, 75 ⁇ L of assay buffer was added. Thereto was added 25 ⁇ L of assay buffer containing the test compound, and the reaction was started.
  • the change in intracellular calcium ion concentration due to the reaction was measured by measuring the fluorescence intensity ratio by excitation at two wavelengths of 340 and 380 nm using FDSS7000 (Hamamatsu Photonics).
  • the test compound was dissolved in DMSO so that the concentration was 10 mM, and diluted with an assay buffer so that the final concentration was 10 ⁇ 7 M to 10 ⁇ 5 M (the final concentration of DMSO was 1%).
  • Tables 8 and 9 show the activity values of each compound.
  • Test example 2 Awakening effect of the compound of the present invention by intracerebroventricular administration to wild-type mice
  • C57BL / 6 strain WT mice and oregrin control orexin receptor-deficient mice (DKO mice) both male
  • DKO mice oregrin control orexin receptor-deficient mice
  • ZT0 9 o'clock
  • ZT12 21 o'clock
  • 6 ⁇ L of a test compound the compound of Example 7 (dihydrochloride)
  • 32 nmol, 130 nmol, 260 nmol; dissolved in physiological saline was added to ZT6 under isoflurane anesthesia using a microsyringe pump.
  • test compound prolongs the awakening time in a dose-dependent manner.
  • DKO mice there was no significant difference in the arousal time after administration of physiological saline and after administration of the test compound.
  • the cumulative wake-up time of 2 hours after administration of the control and test compounds (32 nmol, 130 nmol, 260 nmol) was evaluated by the ANOVA-Bonferoni method.
  • Test example 3 Awakening effect by intraperitoneal administration of the compound of the present invention to wild-type mice
  • C57BL / 6 strain WT mice and negative control orexin receptor-deficient mice (DKO mice) both male
  • DKO mice negative control orexin receptor-deficient mice
  • Administration and electroencephalogram measurement were started 2 weeks later.
  • the experiment was performed in a light-dark cycle environment in which the beginning of the light period was 9 o'clock (ZT0) and the beginning of the dark period was 21 o'clock (ZT12).
  • 100 ⁇ L of control (pH, osmolality adjusted saline) or test compound (compound of Example 7 (dihydrochloric acid) in ZIP6 using a syringe with a needle (29 gauge) Salt)) 40 mg / kg; dissolved in physiological saline
  • Administration was performed in the order of the control and the test compound, and one day after administration was the recovery period. The results are shown in FIG.
  • Test example 4 Inhibitory effect of cataplexy by intraventricular administration of the compound of the present invention to orexin-deficient mice (OXKO mice) In the vicinity of ZT10, under an isoflurane anesthesia, a cannula embedded in the skull of a mouse and a microsyringe pump Connected and programmed to inject 6 ⁇ L into ZT15 at a flow rate of 0.6 ⁇ L / min, and then resumed electroencephalogram electromyogram measurement in mice, and 6 ⁇ L control (pH, osmolality adjusted saline) in ZT15, or A test compound (the compound of Example 7 (dihydrochloride)) (260 nmol; dissolved in physiological saline) was automatically administered under electroencephalogram electromyogram measurement.
  • Cataplex which is one of the symptoms of narcolepsy, is known to increase in the active period (dark period) in narcolepsy model mice and increase when chocolate is given. Therefore, in this experiment, in order to induce cataplexy, chocolate (Hershey's) was given to the mouse and electroencephalogram was measured. Intraventricular administration of the test compound to OXKO mice was performed in the dark period (ZT15) in which cataplexy was observed in narcolepsy model mice, and the cataplexy was observed after administration of physiological saline as a control. Was confirmed, but cataplexy was suppressed after administration of the test compound (FIG.
  • DKO mice were also narcolepsy model mice, and cataplexy was observed, but cataplexy after test compound administration was not suppressed (FIG. 4).
  • the cumulative number of cataplexy occurrences up to 6 hours after administration of the control and test compounds (260 nmol) was evaluated by a corresponding t-test. Transition from wakefulness to REM sleep was counted as cataplexy (FIG. 5).
  • Test Example 5 Inhibitory effect of cataplexy by intraperitoneal administration of the compound of the present invention to orexin-deficient mice (OXKO mice)
  • the experimental animals are orexin-deficient mice (OXKO mice) and orexin receptor-deficient mice (DKO mice) as negative controls (both male) )
  • OXKO mice orexin-deficient mice
  • DKO mice orexin receptor-deficient mice
  • Administration and electroencephalogram measurement were started 2 weeks later.
  • the experiment was performed in a light-dark cycle environment in which the beginning of the light period was 9 o'clock (ZT0) and the beginning of the dark period was 21 o'clock (ZT12).
  • ZT0 9 o'clock
  • ZT12 21 o'clock
  • Test Example 6 Awakening effect by oral administration of the compound of the present invention to wild-type mice
  • Experimental animals are C57BL / 6 strain wild-type (WT) mice, negative control orexin receptor-deficient mice (DKO mice) (both male) It was.
  • WT strain wild-type mice
  • DKO mice negative control orexin receptor-deficient mice
  • Administration and electroencephalogram measurement were started 2 weeks later.
  • the experiment was performed in a light-dark cycle environment in which the beginning of the light period was 9 o'clock (ZT0) and the beginning of the dark period was 21 o'clock (ZT12).
  • ZT0 9 o'clock
  • ZT12 21 o'clock
  • test compound compound of Example 7 (dihydrochloride), 100 mg; physiological 100 ⁇ L (100 mg / body) was orally administered, and the subsequent electroencephalogram electromyogram was measured.
  • the results are shown in FIG.
  • the wakefulness time was significantly increased in WT mice compared to physiological saline administration.
  • the cumulative wake-up time 2 hours after administration of physiological saline and test compound was evaluated by a corresponding t test.
  • Test Example 7 Inhibitory effect of cataplexy by intraperitoneal administration of the compound of the present invention to orexin neurodegenerative mice (orexin / ataxin 3 mice) in the dark period
  • the experimental animals are orexin / ataxin 3 mice (Hara et al., Neuron, 30, 345-54, 2001). ), Orexin receptor-deficient mice (DKO mice) (both males) were used as negative controls.
  • Orexin / Ataxin 3 mice DKO mice, dark phase ZT15 intraperitoneal pH, osmolality adjusted saline, or test compound (Compound of Example 7 (dihydrochloride), 1 mg; dissolved in saline) 100 ⁇ L (40 mg / kg) was administered, and the subsequent electroencephalogram electromyogram was measured.
  • mice were given chocolate (Hershey's) to induce cataplexy. The results are shown in FIGS.
  • Test Example 8 Effect of inhibiting body weight gain by continuous administration of the compound of the present invention to orexin-deficient mice (OXKO mice)
  • Mice around 24 weeks old ( ⁇ 1 week) were bred for 1 week in a light-dark cycle environment where the beginning of the light period was 9 o'clock (ZT0) and the beginning of the dark period was 21 o'clock (ZT12). In order to relieve the stress caused by this, I practiced needle stick once a day.
  • the food was bred with normal feed (Oriental Yeast Co., Ltd., lipid 5.1%).
  • the compound of the present invention exhibits orexin receptor agonist activity and is useful as a prophylactic or therapeutic agent such as narcolepsy.
  • This application is based on a patent application No. 2015-31041 filed on Feb. 19, 2015 in Japan, the contents of which are incorporated in full herein.

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Abstract

The purpose of the present invention is to provide a novel low molecular weight compound that exhibits orexin receptor agonist activity and is expected to be useful as an excellent preventative or therapeutic agent for narcolepsy or the like. The present invention provides a sulfonamide derivative represented by general formula (I) that has excellent orexin receptor agonist activity (wherein each symbol has the same definition as that described in the specification) and a pharmaceutically acceptable acid addition salt thereof, as well as an orexin receptor agonist comprising the derivative or the pharmaceutically acceptable acid addition salt thereof.

Description

スルホンアミド誘導体またはその薬学的に許容される酸付加塩Sulfonamide derivatives or pharmaceutically acceptable acid addition salts thereof
　本発明は、優れたオレキシン受容体作動薬として有用な新規化合物を提供することを目的とする。 An object of the present invention is to provide a novel compound useful as an excellent orexin receptor agonist.
　ナルコレプシーは脳が睡眠・覚醒サイクルをコントロールできないために引き起こされる睡眠障害である。ナルコレプシーの主な症状として、日中の耐え難い眠気、情動（特に強い喜びや驚き）に誘発される脱力発作（カタプレキシー）、入眠時幻覚、および入眠時における麻痺が挙げられ、ナルコレプシー罹患者は社会生活全般において、深刻な影響を受けている。ナルコレプシーの有病率は０．０５～０．２％（日本では０．１６～０．１８％）と推定され、珍しい病気とは言えない有病率である。 Narcolepsy is a sleep disorder caused by the brain's inability to control the sleep / wake cycle. Symptoms of narcolepsy include unbearable sleepiness during the day, weakness-induced seizures (cataplexy) induced by emotions (especially strong joy and surprise), hallucinations during sleep, and paralysis during sleep. In general, it is seriously affected. The prevalence of narcolepsy is estimated to be 0.05-0.2% (0.16-0.18% in Japan), which is not a rare disease.
　ナルコレプシーの治療は薬物療法と生活指導が主流である。薬物療法としては、日中の眠気の抑制のためにメチルフェニデート、モダフィニルやペモリンが用いられ、カタプレキシーをコントロールするために三環性抗うつ薬、選択的セロトニン再取り込み阻害薬（ＳＳＲＩ）やセロトニン・ノルアドレナリン再取り込み阻害薬（ＳＮＲＩ）が用いられる。これらの治療法はナルコレプシーの対症療法ではあるが、根本治療法ではない。 Narcolepsy treatment is mainly pharmacotherapy and lifestyle guidance. For drug therapy, methylphenidate, modafinil and pemoline are used to control daytime sleepiness, and tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI) and serotonin to control cataplexy. -Noradrenaline reuptake inhibitor (SNRI) is used. These treatments are symptomatic treatments for narcolepsy, but are not fundamental treatments.
　近年、ナルコレプシーとオレキシン系機能障害の関連性が注目されている。オレキシンは視床下部外側野に存在する神経ペプチドであり、オレキシン－Ａとオレキシン－Ｂ（ヒポレクチン１、ヒポレクチン２（非特許文献１））の２種のペプチドがある。これらはＧタンパク質共役型受容体であるオレキシン１受容体（以下、ＯＸ１Ｒともいう。）およびオレキシン２受容体（以下、ＯＸ２Ｒともいう。）に結合する（非特許文献２）。マウスおよびイヌのモデル実験から、オレキシン受容体（ＯＸ１ＲとＯＸ２Ｒの両方が発現）の欠損、あるいはＯＸ２Ｒの欠損がナルコレプシーを引き起こすことが示唆された（非特許文献３）。さらに、マウスモデル実験により、ＯＸ２Ｒの機能が覚醒を維持するために重要であることが示唆された（非特許文献４、非特許文献５）。 In recent years, the relationship between narcolepsy and orexin dysfunction has attracted attention. Orexin is a neuropeptide present in the lateral area of the hypothalamus, and there are two types of peptides: orexin-A and orexin-B (hypolectin 1 and hypolectin 2 (Non-patent Document 1)). These bind to orexin 1 receptor (hereinafter also referred to as OX1R) and orexin 2 receptor (hereinafter also referred to as OX2R), which are G protein-coupled receptors (Non-patent Document 2). From mouse and dog model experiments, it was suggested that orexin receptor deficiency (expressed in both OX1R and OX2R) or OX2R deficiency causes narcolepsy (Non-patent Document 3). Furthermore, mouse model experiments suggested that the function of OX2R is important for maintaining arousal (Non-Patent Documents 4 and 5).
　一方、多くのナルコレプシー患者では、オレキシン神経の消失、およびオレキシン濃度の低下が確認された（非特許文献６）。このように、ナルコレプシーはオレキシンの欠損によって引き起こされる可能性が高いことが強く示唆される。 On the other hand, in many patients with narcolepsy, orexin nerve disappearance and orexin concentration decreased (Non-patent Document 6). Thus, it is strongly suggested that narcolepsy is likely to be caused by orexin deficiency.
　オレキシン受容体は脳内に広範に存在する。オレキシンはペプチドであり、血液脳関門の透過性が極めて低いため、医薬用途として有用ではない。そのため、オレキシン受容体作動薬の低分子化が望まれている。近年、低分子のＯＸ２Ｒ作動薬として、環状グアニジン骨格を有する化合物が開示された（特許文献１）。 Orexin receptors are widely present in the brain. Orexin is a peptide and is not useful for pharmaceutical use because of its extremely low permeability through the blood brain barrier. Therefore, it is desired to reduce the molecular weight of orexin receptor agonists. In recent years, a compound having a cyclic guanidine skeleton has been disclosed as a low molecular weight OX2R agonist (Patent Document 1).
　また、オレキシン系は上記のような睡眠・覚醒を調節するだけでなく、情動やエネルギーバランスに応じ、摂食行動もまた適切に制御すると考えられている。絶食下のマウスは、覚醒時間を増加し、睡眠時間を減少させることにより、えさを探索する行動量を増加する。一方、オレキシン受容体欠損マウスでは、覚醒時間・行動量が増加しないことが明らかになった（非特許文献７）。さらに、ＯＸ２Ｒはレプチン感受性を向上させることにより、体重の恒常性に関与することが示された（非特許文献８）。これらのことから、オレキシン受容体（特にＯＸ２Ｒ）作動薬は、ナルコレプシーだけでなく、糖尿病、肥満およびメタボリックシンドローム治療薬、摂食抑制剤または体重増加抑制剤になる可能性もある。 In addition, the orexin system is considered not only to regulate sleep / wakefulness as described above, but also to appropriately control feeding behavior according to emotion and energy balance. Fasted mice increase the amount of behavior to search for food by increasing wake time and decreasing sleep time. On the other hand, in orexin receptor-deficient mice, it has been clarified that the awakening time and the amount of behavior do not increase (Non-patent Document 7). Furthermore, OX2R has been shown to be involved in body weight homeostasis by improving leptin sensitivity (Non-patent Document 8). From these facts, orexin receptor (especially OX2R) agonists may become not only narcolepsy but also therapeutic agents for diabetes, obesity and metabolic syndrome, feeding inhibitors or weight gain inhibitors.
　さらに、敗血症ラットでは自発活動が低下しており、視床下部の脳弓周囲領域でのオレキシン含有神経活動が低下していることが報告され（非特許文献９）、敗血症モデルマウスにオレキシンを脳室内投与すると体温上昇と心機能の回復が見られたという報告がある（非特許文献１０）。これらのことから、オレキシン受容体作動薬は敗血症の治療薬になる可能性もある。 Furthermore, spontaneous activity was reduced in septic rats, and it was reported that orexin-containing nerve activity in the hypothalamic periarch area was reduced (Non-patent Document 9). There is a report that body temperature increased and recovery of cardiac function was observed after administration (Non-patent Document 10). From these facts, orexin receptor agonists may be therapeutic agents for sepsis.
米国特許８，２５８，１６３号明細書US Pat. No. 8,258,163
　本発明は、優れたナルコレプシー等の予防剤または治療剤として有用であると期待される、オレキシン受容体作動活性を示す新規低分子化合物を提供することを目的とする。 An object of the present invention is to provide a novel low molecular weight compound exhibiting orexin receptor agonist activity, which is expected to be useful as an excellent preventive or therapeutic agent such as narcolepsy.
　本発明者らは上記目的を達成するため鋭意検討した結果、優れたＯＸ２Ｒ作動活性を持つ後記一般式（Ｉ）で表される化合物を見出し、本発明を完成した。
　すなわち、本発明は、
［１］
一般式（Ｉ） As a result of intensive studies to achieve the above object, the present inventors have found a compound represented by the following general formula (I) having excellent OX2R agonist activity and completed the present invention.
That is, the present invention
[1]
Formula (I)
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
［式中、
Ｒ１は水素原子を表し、
Ｒ２は－ＯＨまたは
Ｃ１－４アルコキシを表し、
あるいはＲ１とＲ２は一緒になって－ＮＲａＲｂ（ここで、Ｒａは水素原子またはＣ１－４アルキルを表し、Ｒｂは水素原子またはＣ１－４アルキルを表す。）でさらに置換されていてもよいベンゼン環を形成し、
Ｒ３はＣ１－６アルキル、
Ｃ２－６アルケニル、
Ｃ３－１０シクロアルキル、
Ｃ６－１０アリールまたは
５～１０員ヘテロアリール
（ここで、Ｃ１－６アルキル、Ｃ２－６アルケニル、Ｃ３－１０シクロアルキル、Ｃ６－１０アリールまたは５～１０員ヘテロアリールは任意に選択される１から４個のＲ４で置換されていてもよく、
Ｒ４は水素原子、
Ｃ１－４アルキル、
Ｃ１－４アルコキシ、
フェニル（ここで、フェニルはＣ１－４アルキル、Ｃ１－４アルコキシまたは－Ｃ（Ｏ）ＮＲ４ｘＲ４ｙ（ここで、Ｒ４ｘはＣ１－４アルキルを表し、Ｒ４ｙはＣ１－４アルキルを表す。）で置換されていてもよい。）、
５～１０員ヘテロアリール、
ハロゲン、
－ＯＨ、
－ＮＲ４ａＲ４ｂ（ここで、Ｒ４ａは水素原子、Ｃ１－４アルキルまたはＣ１－４アルコキシ－カルボニルを表し、Ｒ４ｂは水素原子またはＣ１－４アルキルを表す。）、
－Ｃ（Ｏ）ＯＲ４ｃ（ここで、Ｒ４ｃはＣ１－４アルキルを表す。）または
－Ｃ（Ｏ）ＮＲ４ｄＲ４ｅ（ここで、Ｒ４ｄは水素原子またはＣ１－４アルキルを表し、Ｒ４ｅは水素原子またはＣ１－４アルキルを表す。）を表す。
あるいは２個のＲ４は一緒になってメチレンジオキシを形成する。）を表し、
Ｗは－（ＣＨ２）ｎ－Ｃ（Ｏ）ＮＲＷａＲＷｂ（ここで、ｎは０から２の整数を表し、ＲＷａは水素原子、Ｃ１－４アルキル（ここで、Ｃ１－４アルキルはＣ１－４アルキルもしくはＣ１－４アルコキシで置換されていてもよいフェニル、ピリジルまたはＣ１－４アルコキシ－カルボニルアミノで置換されていてもよい。）またはフェニル（ここで、フェニルはＣ１－４アルコキシ、－ＮＯ２またはＣ１－４アルコキシ－カルボニルアミノで置換されていてもよい。）を表し、ＲＷｂは水素原子またはＣ１－４アルキルを表す。）または
一般式（ＩＩ）： [Where:
R 1 represents a hydrogen atom,
R 2 represents —OH or C 1-4 alkoxy;
Alternatively, R 1 and R 2 together represent —NR a R b (wherein R a represents a hydrogen atom or C 1-4 alkyl, and R b represents a hydrogen atom or C 1-4 alkyl). Furthermore, an optionally substituted benzene ring is formed,
R 3 is C 1-6 alkyl,
C 2-6 alkenyl,
C 3-10 cycloalkyl,
C 6-10 aryl or 5-10 membered heteroaryl (where C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl is optionally Optionally substituted with 1 to 4 R 4 selected,
R 4 is a hydrogen atom,
C 1-4 alkyl,
C 1-4 alkoxy,
Phenyl (wherein phenyl is C 1-4 alkyl, C 1-4 alkoxy or —C (O) NR 4x R 4y (where R 4x represents C 1-4 alkyl, R 4y represents C 1-4 Represents alkyl.) And may be substituted with
5-10 membered heteroaryl,
halogen,
-OH,
—NR 4a R 4b (wherein R 4a represents a hydrogen atom, C 1-4 alkyl or C 1-4 alkoxy-carbonyl, and R 4b represents a hydrogen atom or C 1-4 alkyl),
—C (O) OR 4c (wherein R 4c represents C 1-4 alkyl) or —C (O) NR 4d R 4e (where R 4d represents a hydrogen atom or C 1-4 alkyl). , R 4e represents a hydrogen atom or C 1-4 alkyl.
Alternatively, two R 4 together form methylenedioxy. )
W represents — (CH 2 ) n —C (O) NR Wa R Wb (where n represents an integer of 0 to 2, R Wa represents a hydrogen atom, C 1-4 alkyl (where C 1-4 Alkyl may be substituted with phenyl, pyridyl or C 1-4 alkoxy-carbonylamino optionally substituted with C 1-4 alkyl or C 1-4 alkoxy, or phenyl (where phenyl is C And optionally substituted with 1-4 alkoxy, —NO 2 or C 1-4 alkoxy-carbonylamino.), R Wb represents a hydrogen atom or C 1-4 alkyl)) or the general formula (II) :
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
（ここで、
Ｒ５は水素原子、Ｃ１－４アルコキシ、－ＮＲ５ａＲ５ｂ（ここで、Ｒ５ａは水素原子またはＣ１－４アルキルを表し、Ｒ５ｂは水素原子またはＣ１－４アルキルを表す。）または－Ｃ（Ｏ）ＮＲ５ｃＲ５ｄ（ここで、Ｒ５ｃは水素原子またはＣ１－４アルキルを表し、Ｒ５ｄは水素原子またはＣ１－４アルキルを表す。）を表し、
Ｒ６は水素原子、Ｃ１－４アルコキシ、－ＯＣＦ３、－ＮＲ６ａＲ６ｂ（ここで、Ｒ６ａは水素原子またはＣ１－４アルキルを表し、Ｒ６ｂは水素原子またはＣ１－４アルキルを表す。）または－Ｃ（Ｏ）ＮＲ６ｃＲ６ｄ（ここで、Ｒ６ｃは水素原子またはＣ１－４アルキルを表し、Ｒ６ｄは水素原子またはＣ１－４アルキルを表す。）を表し、
Ｒ７は水素原子、Ｃ１－４アルコキシまたは－ＯＣＦ３を表し、かつ
Ｘは－Ｎ＝または－ＣＨ＝を表す。
あるいはＲ５およびＲ６は一緒になってメチレンジオキシを形成する。）を表す。］
で示される化合物またはその薬学的に許容される酸付加塩、
［２］
　一般式（Ｉ’） (here,
R 5 is a hydrogen atom, C 1-4 alkoxy, —NR 5a R 5b (where R 5a represents a hydrogen atom or C 1-4 alkyl, and R 5b represents a hydrogen atom or C 1-4 alkyl) Or —C (O) NR 5c R 5d (where R 5c represents a hydrogen atom or C 1-4 alkyl, and R 5d represents a hydrogen atom or C 1-4 alkyl);
R 6 is a hydrogen atom, C 1-4 alkoxy, —OCF 3 , —NR 6a R 6b (where R 6a represents a hydrogen atom or C 1-4 alkyl, and R 6b represents a hydrogen atom or C 1-4 alkyl) Or —C (O) NR 6c R 6d (where R 6c represents a hydrogen atom or C 1-4 alkyl, and R 6d represents a hydrogen atom or C 1-4 alkyl),
R 7 represents a hydrogen atom, C 1-4 alkoxy or —OCF 3 , and X represents —N═ or —CH═.
Alternatively, R 5 and R 6 together form methylenedioxy. ). ]
Or a pharmaceutically acceptable acid addition salt thereof,
[2]
Formula (I ')
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
［式中、
Ｒ２’は－ＮＲ３ａ’Ｒ３ｂ’（ここで、Ｒ３ａ’はＣ１－４アルキルを表し、Ｒ３ｂ’はＣ１－４アルキルを表す。）で置換されたフェニルを表す。］
で示される化合物またはその薬学的に許容される酸付加塩、
［３］
　３’－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミドまたはその薬学的に許容される酸付加塩、
［４］
　Ｗが－（ＣＨ２）ｎ－Ｃ（Ｏ）ＮＲＷａＲＷｂ（ここで、ｎは０から２の整数を表し、
ＲＷａは水素原子、Ｃ１－４アルキル（ここで、Ｃ１－４アルキルはＣ１－４アルキルもしくはＣ１－４アルコキシで置換されていてもよいフェニル、ピリジルまたはＣ１－４アルコキシ－カルボニルアミノで置換されていてもよい。）またはフェニル（ここで、フェニルはＣ１－４アルコキシ、－ＮＯ２またはＣ１－４アルコキシ－カルボニルアミノで置換されていてもよい。）を表し、ＲＷｂは水素原子またはＣ１－４アルキルを表す。）または
一般式（ＩＩ）： [Where:
R 2 ′ represents phenyl substituted with —NR 3a ′ R 3b ′ (where R 3a ′ represents C 1-4 alkyl and R 3b ′ represents C 1-4 alkyl). ]
Or a pharmaceutically acceptable acid addition salt thereof,
[3]
3 ′-(N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4′-methoxy-N, N-dimethyl- [1,1′-biphenyl] -3-carboxamide or a pharmaceutically acceptable acid addition salt thereof,
[4]
W is — (CH 2 ) n —C (O) NR Wa R Wb (where n represents an integer of 0 to 2;
R Wa is a hydrogen atom, C 1-4 alkyl (where C 1-4 alkyl is phenyl, pyridyl or C 1-4 alkoxy-carbonyl optionally substituted with C 1-4 alkyl or C 1-4 alkoxy) Or phenyl (wherein the phenyl may be substituted with C 1-4 alkoxy, —NO 2 or C 1-4 alkoxy-carbonylamino), and R Wb Represents a hydrogen atom or C 1-4 alkyl. ) Or general formula (II):
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
（ここで、
Ｒ５はＣ１－４アルコキシ、－ＮＲ５ａＲ５ｂ（ここで、Ｒ５ａは水素原子またはＣ１－４アルキルを表し、Ｒ５ｂは水素原子またはＣ１－４アルキルを表す。）または－Ｃ（Ｏ）ＮＲ５ｃＲ５ｄ（ここで、Ｒ５ｃは水素原子またはＣ１－４アルキルを表し、Ｒ５ｄは水素原子またはＣ１－４アルキルを表す。）を表し、
Ｒ６は水素原子、Ｃ１－４アルコキシ、－ＯＣＦ３、－ＮＲ６ａＲ６ｂ（ここで、Ｒ６ａは水素原子またはＣ１－４アルキルを表し、Ｒ６ｂは水素原子またはＣ１－４アルキルを表す。）または－Ｃ（Ｏ）ＮＲ６ｃＲ６ｄ（ここで、Ｒ６ｃは水素原子またはＣ１－４アルキルを表し、Ｒ６ｄは水素原子またはＣ１－４アルキルを表す。）を表し、
Ｒ７は水素原子、Ｃ１－４アルコキシまたは－ＯＣＦ３を表し、かつ
Ｘは－ＣＨ＝を表す。
あるいはＲ５およびＲ６は一緒になってメチレンジオキシを形成する。）である、上記［１］記載の化合物またはその薬学的に許容される酸付加塩、
［５］
　Ｒ３がＣ１－６アルキル、
Ｃ２－６アルケニルまたは
Ｃ３－１０シクロアルキル
（ここで、Ｃ１－６アルキル、Ｃ２－６アルケニルまたはＣ３－１０シクロアルキルは任意に選択される１から４個のＲ４で置換されていてもよく、
Ｒ４は水素原子、
Ｃ１－４アルキル、
Ｃ１－４アルコキシ、
フェニル（ここで、フェニルはＣ１－４アルキル、Ｃ１－４アルコキシ、メチレンジオキシまたは－Ｃ（Ｏ）ＮＲ４ｘＲ４ｙ（ここで、Ｒ４ｘはＣ１－４アルキルを表し、Ｒ４ｙはＣ１－４アルキルを表す。）で置換されていてもよい。）、
５～１０員ヘテロアリール、
ハロゲン、
－ＯＨ、
－ＮＲ４ａＲ４ｂ（ここで、Ｒ４ａは水素原子、Ｃ１－４アルキルまたはＣ１－４アルコキシ－カルボニルを表し、Ｒ４ｂは水素原子またはＣ１－４アルキルを表す。）、
－Ｃ（Ｏ）ＯＲ４ｃ（ここで、Ｒ４ｃはＣ１－４アルキルを表す。）または
－Ｃ（Ｏ）ＮＲ４ｄＲ４ｅ（ここで、Ｒ４ｄはＣ１－４アルキルを表し、Ｒ４ｅはＣ１－４アルキルを表す。）
を表す。
あるいは２個のＲ４は一緒になってメチレンジオキシを形成する。）である、上記［１］記載の化合物またはその薬学的に許容される酸付加塩、
［６］
　Ｒ３がＣ６－１０アリールまたは
５～１０員ヘテロアリール
（ここで、Ｃ６－１０アリールまたは５～１０員ヘテロアリールは任意に選択される１から４個のＲ４で置換されていてもよく、
Ｒ４はフェニル（ここで、フェニルはＣ１－４アルキル、Ｃ１－４アルコキシまたは－Ｃ（Ｏ）ＮＲ４ｘＲ４ｙ（ここで、Ｒ４ｘはＣ１－４アルキルを表し、Ｒ４ｙはＣ１－４アルキルを表す。）で置換されていてもよい。）、
５～１０員ヘテロアリール、
－Ｃ（Ｏ）ＯＲ４ｃ（ここで、Ｒ４ｃはＣ１－４アルキルを表す。）または
－Ｃ（Ｏ）ＮＲ４ｄＲ４ｅ（ここで、Ｒ４ｄはＣ１－４アルキルを表し、Ｒ４ｅはＣ１－４アルキルを表す。
あるいは２個のＲ４は一緒になってメチレンジオキシを形成する。）である、上記［１］記載の化合物またはその薬学的に許容される酸付加塩、
［７］
　Ｒ２が－ＯＨであるか、あるいは
Ｒ１とＲ２が一緒になって－ＮＲａＲｂ（ここで、Ｒａは水素原子またはＣ１－４アルキルを表し、Ｒｂは水素原子またはＣ１－４アルキルを表す。）でさらに置換されていてもよいベンゼン環を形成する、上記［１］記載の化合物またはその薬学的に許容される酸付加塩、
［８］
　上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩を含有する医薬、
［９］
　上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩を含有するオレキシン受容体作動薬、
［１０］
　上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩を含有する抗ナルコレプシー剤、
［１１］
　上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩を含有する眠気改善剤、
［１２］
　上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩を含有する、肥満症、糖尿病またはうつ病の予防剤または治療剤、
［１３］
　上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩を含有する、敗血症、重症敗血症または敗血症性ショックの予防剤または治療剤、
［１４］
　上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩を含有する、摂食抑制剤または体重増加抑制剤、
［１５］
　上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩の有効量を投与することを含むナルコレプシーの治療または予防方法、
［１６］
　上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩の有効量を投与することを含む眠気の改善方法、
［１７］
　上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩の有効量を投与することを含む、肥満症、糖尿病またはうつ病の治療または予防方法、
［１８］
　上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩の有効量を投与することを含む、敗血症、重症敗血症または敗血症性ショックの治療または予防方法、
［１９］
　上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩の有効量を投与することを含む、摂食または体重増加を抑制する方法、
［２０］
　ナルコレプシーを治療または予防するための、上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩、
［２１］
　眠気を改善するための、上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩、
［２２］
　肥満症、糖尿病またはうつ病を治療または予防するための、上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩、
［２３］
　敗血症、重症敗血症または敗血症性ショックを治療または予防するための、上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩、
［２４］
　摂食または体重増加を抑制するための、上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩、および
［２５］
　オレキシン受容体作動薬；抗ナルコレプシー剤；眠気改善剤；肥満症、糖尿病またはうつ病の予防剤または治療剤；敗血症、重症敗血症または敗血症性ショックの予防剤または治療剤；摂食抑制剤または体重増加抑制剤を製造するための、上記［１］から［７］のいずれかに記載の化合物またはその薬学的に許容される酸付加塩の使用
を提供する。 (here,
R 5 is C 1-4 alkoxy, —NR 5a R 5b (where R 5a represents a hydrogen atom or C 1-4 alkyl, and R 5b represents a hydrogen atom or C 1-4 alkyl) or —C (O) NR 5c R 5d (wherein R 5c represents a hydrogen atom or C 1-4 alkyl, and R 5d represents a hydrogen atom or C 1-4 alkyl),
R 6 is a hydrogen atom, C 1-4 alkoxy, —OCF 3 , —NR 6a R 6b (where R 6a represents a hydrogen atom or C 1-4 alkyl, and R 6b represents a hydrogen atom or C 1-4 alkyl) Or —C (O) NR 6c R 6d (where R 6c represents a hydrogen atom or C 1-4 alkyl, and R 6d represents a hydrogen atom or C 1-4 alkyl),
R 7 represents a hydrogen atom, C 1-4 alkoxy or —OCF 3 , and X represents —CH═.
Alternatively, R 5 and R 6 together form methylenedioxy. Or a pharmaceutically acceptable acid addition salt thereof,
[5]
R 3 is C 1-6 alkyl,
C 2-6 alkenyl or C 3-10 cycloalkyl, wherein C 1-6 alkyl, C 2-6 alkenyl or C 3-10 cycloalkyl is optionally substituted with 1 to 4 R 4 You may,
R 4 is a hydrogen atom,
C 1-4 alkyl,
C 1-4 alkoxy,
Phenyl (wherein phenyl is C 1-4 alkyl, C 1-4 alkoxy, methylenedioxy or —C (O) NR 4x R 4y (where R 4x represents C 1-4 alkyl and R 4y represents Represents C 1-4 alkyl.) And may be substituted.
5-10 membered heteroaryl,
halogen,
-OH,
—NR 4a R 4b (wherein R 4a represents a hydrogen atom, C 1-4 alkyl or C 1-4 alkoxy-carbonyl, and R 4b represents a hydrogen atom or C 1-4 alkyl),
—C (O) OR 4c (where R 4c represents C 1-4 alkyl) or —C (O) NR 4d R 4e (where R 4d represents C 1-4 alkyl and R 4e Represents C 1-4 alkyl.)
Represents.
Alternatively, two R 4 together form methylenedioxy. Or a pharmaceutically acceptable acid addition salt thereof,
[6]
R 3 is C 6-10 aryl or 5- to 10-membered heteroaryl (where C 6-10 aryl or 5- to 10-membered heteroaryl may be optionally substituted with 1 to 4 R 4) Often,
R 4 is phenyl (wherein phenyl is C 1-4 alkyl, C 1-4 alkoxy or —C (O) NR 4x R 4y (where R 4x represents C 1-4 alkyl and R 4y represents C 4 1-4 represents an alkyl group, which may be substituted with
5-10 membered heteroaryl,
—C (O) OR 4c (where R 4c represents C 1-4 alkyl) or —C (O) NR 4d R 4e (where R 4d represents C 1-4 alkyl and R 4e Represents C 1-4 alkyl.
Alternatively, two R 4 together form methylenedioxy. Or a pharmaceutically acceptable acid addition salt thereof,
[7]
R 2 is —OH, or R 1 and R 2 are taken together to form —NR a R b (where R a represents a hydrogen atom or C 1-4 alkyl, and R b represents a hydrogen atom or C 1 1-4 represents a alkyl), or a pharmaceutically acceptable acid addition salt thereof, which forms a benzene ring which may be further substituted with
[8]
A pharmaceutical comprising the compound according to any one of [1] to [7] above or a pharmaceutically acceptable acid addition salt thereof,
[9]
An orexin receptor agonist containing the compound according to any one of [1] to [7] above or a pharmaceutically acceptable acid addition salt thereof,
[10]
An anti-narcolepsy containing the compound according to any one of [1] to [7] above or a pharmaceutically acceptable acid addition salt thereof,
[11]
A sleepiness improving agent comprising the compound according to any one of the above [1] to [7] or a pharmaceutically acceptable acid addition salt thereof,
[12]
A prophylactic or therapeutic agent for obesity, diabetes or depression, comprising the compound according to any one of [1] to [7] above or a pharmaceutically acceptable acid addition salt thereof;
[13]
A prophylactic or therapeutic agent for sepsis, severe sepsis or septic shock, comprising the compound according to any one of [1] to [7] above or a pharmaceutically acceptable acid addition salt thereof,
[14]
An antifeedant or an inhibitor of weight gain, comprising the compound according to any one of [1] to [7] above or a pharmaceutically acceptable acid addition salt thereof,
[15]
A method for treating or preventing narcolepsy, comprising administering an effective amount of the compound according to any one of [1] to [7] above or a pharmaceutically acceptable acid addition salt thereof,
[16]
A method for improving drowsiness, comprising administering an effective amount of the compound according to any one of [1] to [7] above or a pharmaceutically acceptable acid addition salt thereof,
[17]
A method for treating or preventing obesity, diabetes or depression, comprising administering an effective amount of the compound according to any one of [1] to [7] above or a pharmaceutically acceptable acid addition salt thereof,
[18]
A method for treating or preventing sepsis, severe sepsis or septic shock, comprising administering an effective amount of the compound according to any one of [1] to [7] above or a pharmaceutically acceptable acid addition salt thereof,
[19]
A method for suppressing food intake or body weight gain, comprising administering an effective amount of the compound according to any one of [1] to [7] above or a pharmaceutically acceptable acid addition salt thereof,
[20]
The compound or a pharmaceutically acceptable acid addition salt thereof according to any one of the above [1] to [7] for treating or preventing narcolepsy,
[21]
The compound according to any one of the above [1] to [7] or a pharmaceutically acceptable acid addition salt thereof for improving drowsiness,
[22]
A compound or a pharmaceutically acceptable acid addition salt thereof according to any one of the above [1] to [7] for treating or preventing obesity, diabetes or depression,
[23]
A compound or a pharmaceutically acceptable acid addition salt thereof according to any one of [1] to [7] above for treating or preventing sepsis, severe sepsis or septic shock,
[24]
The compound according to any one of the above [1] to [7] or a pharmaceutically acceptable acid addition salt thereof for suppressing feeding or weight gain, and [25]
Orexin receptor agonist; Antinarcolepsy agent; Sleepiness ameliorating agent; Preventive or therapeutic agent for obesity, diabetes or depression; Preventive or therapeutic agent for sepsis, severe sepsis or septic shock; Antifeedant or weight gain There is provided use of the compound according to any one of the above [1] to [7] or a pharmaceutically acceptable acid addition salt thereof for producing an inhibitor.
　本発明の一般式（Ｉ）で示される化合物またはその薬学的に許容される酸付加塩は、優れたＯＸ２Ｒ作動活性を有する。 The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable acid addition salt thereof has excellent OX2R agonist activity.
図１は、野生型マウス（ＷＴマウス）またはオレキシン受容体欠損マウス（ＤＫＯマウス）に対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））を明期脳室内投与後２時間の累積覚醒時間を示す。FIG. 1 shows that a control substance (physiological saline) or a test compound (the compound of Example 7 (dihydrochloride)) is administered to a wild-type mouse (WT mouse) or orexin receptor-deficient mouse (DKO mouse) in the light ventricle. The cumulative awakening time of 2 hours after is shown. 図２は、野生型マウス（ＷＴマウス）またはオレキシン受容体欠損マウス（ＤＫＯマウス）に対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））を明期腹腔内投与後２時間の累積覚醒時間を示す。FIG. 2 shows that a control substance (physiological saline) or a test compound (compound of Example 7 (dihydrochloride)) was intraperitoneally administered to a wild type mouse (WT mouse) or orexin receptor-deficient mouse (DKO mouse). The cumulative awakening time of 2 hours after is shown. 図３は、オレキシン欠損マウス（ＯＸＫＯマウス）に対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））を暗期脳室内投与後６時間のヒプノグラムを示し、図中の↓（下矢印）はカタレプキシー様症状である入眠時ＲＥＭ睡眠（ＳＯＲＥＭ）を示す。FIG. 3 shows a hypnogram for 6 hours after intraventricular administration of a control substance (saline) or a test compound (the compound of Example 7 (dihydrochloride)) to orexin-deficient mice (OXKO mice). ↓ (down arrow) indicates sleep onset REM sleep (SOREM), which is a catalepoxy-like symptom. 図４は、オレキシン受容体欠損マウス（ＤＫＯマウス）に対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））を暗期脳室内投与後６時間のヒプノグラムを示し、図中の↓（下矢印）はＳＯＲＥＭを示す。FIG. 4 shows a hypnogram for 6 hours after intraventricular administration of a control substance (saline) or a test compound (the compound of Example 7 (dihydrochloride)) to orexin receptor-deficient mice (DKO mice). ↓ (down arrow) in the figure indicates SOREM. 図５は、オレキシン欠損マウス（ＯＸＫＯマウス）に対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））を暗期脳室内投与したときの、ＳＯＲＥＭの累積発生回数を示す。FIG. 5 shows the cumulative number of occurrences of SOREM when a control substance (physiological saline) or a test compound (the compound of Example 7 (dihydrochloride)) is administered into dark ventricles in orexin-deficient mice (OXKO mice). Show. 図６は、オレキシン欠損マウス（ＯＸＫＯマウス）に対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））を暗期腹腔内投与後６時間のヒプノグラムを示し、図中の↓（下矢印）はＳＯＲＥＭを示す。FIG. 6 shows a hypnogram for 6 hours after intraperitoneal administration of the control substance (saline) or the test compound (the compound of Example 7 (dihydrochloride)) to orexin-deficient mice (OXKO mice). ↓ (down arrow) indicates SOREM. 図７は、オレキシン欠損マウス（ＯＸＫＯマウス）またはオレキシン受容体欠損マウス（ＤＫＯマウス）に対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））を暗期腹腔内投与後３時間のＳＯＲＥＭの累積回数を示す。FIG. 7 shows that a control substance (physiological saline) or a test compound (compound of Example 7 (dihydrochloride)) was intraperitoneally administered during dark period to orexin-deficient mice (OXKO mice) or orexin receptor-deficient mice (DKO mice). The cumulative number of SOREMs for the next 3 hours is shown. 図８は、野生型マウス（ＷＴマウス）に対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））を明期経口投与後２時間の累積覚醒時間を示す。FIG. 8 shows the cumulative arousal time of 2 hours after the oral administration of the control substance (physiological saline) or the test compound (the compound of Example 7 (dihydrochloride)) to wild-type mice (WT mice). 図９は、オレキシン神経変性マウス（オレキシン／アタキシン３マウス）に対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））を暗期腹腔内投与後６時間のヒプノグラムを示し、図中の↓（下矢印）はＳＯＲＥＭを示す。FIG. 9 shows a hypnogram for 6 hours after intraperitoneal administration of the control substance (saline) or the test compound (the compound of Example 7 (dihydrochloride)) to orexin neurodegenerative mice (orexin / ataxin 3 mice). In the figure, ↓ (down arrow) in the figure indicates SOREM. 図１０は、オレキシン神経変性マウス（オレキシン／アタキシン３マウス）に対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））を暗期腹腔内投与後３時間のＳＯＲＥＭの累積回数を示す。FIG. 10 shows that the control substance (saline) or the test compound (the compound of Example 7 (dihydrochloride)) was administered to orexin neurodegenerative mice (orexin / ataxin 3 mice) for 3 hours after intraperitoneal administration in the dark period. Indicates the cumulative number of times. 図１１－ａは、対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））の投与前のオレキシン欠損マウス（ＯＸＫＯマウス）の体重を示す。FIG. 11-a shows the body weight of orexin-deficient mice (OXKO mice) before administration of a control substance (saline) or a test compound (compound of Example 7 (dihydrochloride)). 図１１－ｂは、ＯＸＫＯマウスに対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））を連続投与したときの体重変化を示す。FIG. 11-b shows changes in body weight when a control substance (physiological saline) or a test compound (compound of Example 7 (dihydrochloride)) is continuously administered to OXKO mice. 図１１－ｃは、ＯＸＫＯマウスに対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））を連続投与したときの一日平均摂餌量（体重あたり）を示す。FIG. 11-c shows the average daily food intake (per body weight) when a control substance (saline) or a test compound (the compound of Example 7 (dihydrochloride)) is continuously administered to OXKO mice. 図１１－ｄは、被験化合物（実施例７の化合物（二塩酸塩））の投与中止後２週間のＯＸＫＯマウスの体重変化を示す。FIG. 11-d shows the change in body weight of OXKO mice 2 weeks after the administration of the test compound (compound of Example 7 (dihydrochloride)) was discontinued. 図１１－ｅは、対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））の投与前のオレキシン受容体欠損マウス（ＤＫＯマウス）の体重を示す。FIG. 11-e shows the body weight of orexin receptor-deficient mice (DKO mice) before administration of a control substance (saline) or a test compound (the compound of Example 7 (dihydrochloride)). 図１１－ｆは、ＤＫＯマウスに対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））を連続投与したときの体重変化を示す。FIG. 11-f shows changes in body weight when a control substance (saline) or a test compound (the compound of Example 7 (dihydrochloride)) was continuously administered to DKO mice. 図１１－ｇは、ＤＫＯマウスに対照物質（生理食塩水）または被験化合物（実施例７の化合物（二塩酸塩））を連続投与したときの一日平均摂餌量（体重あたり）を示す。FIG. 11-g shows the average daily food intake (per body weight) when a control substance (physiological saline) or a test compound (the compound of Example 7 (dihydrochloride)) was continuously administered to DKO mice. 図１１－ｈは、被験化合物（実施例７の化合物（二塩酸塩））の投与中止後２週間のＤＫＯマウスの体重変化を示す。FIG. 11-h shows the change in body weight of DKO mice 2 weeks after the administration of the test compound (the compound of Example 7 (dihydrochloride)) was discontinued.
　本明細書で使用する次の用語は、特に断りのない限り、下記の定義の通りである。
　本明細書中の「ハロゲン」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子等が挙げられる。
　本明細書中の「Ｃ１－６アルキル」は、炭素原子および水素原子からなる、炭素数１から６の一価の直鎖または分岐状の飽和炭化水素基を意味する。例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ネオペンチル、ヘキシル等が挙げられる。
　本明細書中の「Ｃ１－４アルキル」は、炭素原子および水素原子からなる、炭素数１から４の一価の直鎖または分岐状の飽和炭化水素基を意味する。例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル等が挙げられる。
　本明細書中の「Ｃ１－４アルコキシ」は、上記「Ｃ１－４アルキル」が結合したオキシ基を意味する。例えば、メトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、イソブトキシ、ｔｅｒｔ－ブトキシ等が挙げられる。
　本明細書中の「ハロゲン」は、フッ素原子、塩素原子、臭素原子またはヨウ素原子を意味する。
　本明細書中の「Ｃ２－６アルケニル」は、炭素原子および水素原子からなる、炭素数２から６の一価の直鎖または分岐状の少なくとも１個の二重結合を有する不飽和炭化水素基を意味する。例えば、エテニル、１－プロペニル、２－プロペニル、２－メチル－１－プロペニル、１－ブテニル、２－ブテニル、３－ブテニル、３－メチル－２－ブテニル、１－ペンテニル、２－ペンテニル、３－ペンテニル、４－ペンテニル、４－メチル－３－ペンテニル、１－ヘキセニル、３－ヘキセニル、５－ヘキセニル等が挙げられる。
　本明細書中の「Ｃ３－１０シクロアルキル」は、炭素数３から１０個の単環の脂肪族炭素環式基を意味する。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、アダマンチル等が挙げられる。
　本明細書中の「Ｃ６－１０アリール」は、炭素数６から１０個の単環または縮合の芳香族炭素環式基を意味する。例えば、フェニル、１－ナフチル、２－ナフチル等が挙げられる。
　本明細書中の「５～１０員ヘテロアリール」は環構成原子として、炭素原子以外に酸素原子、硫黄原子および窒素原子から選ばれる１または２種、１ないし４個のヘテロ原子を含む５から１０員の単環または二環の芳香族ヘテロ環式基を意味する。例えば、チエニル、フリル、ピロリル、イミダゾリル、ピラゾリル、トリアゾリル、テトラゾリル、オキサゾリル、イソキサゾリル、チアゾリル、イソチアゾリル、ピリジル、ピリダジニル、ピリミジニル、フラザニル、ピラジニル、チアジアゾリル、オキサジアゾリル、ベンゾフリル、ベンゾチエニル、ベンズイミダゾリル、ベンゾチアゾリル、キノリル、イソキノリル、シンノリニル、キナゾリニル、キノキサリニル、フタラジニル、１Ｈ－インダゾリル、インドリル等が挙げられる。
　本明細書中の「抗ナルコレプシー剤」は、ナルコレプシーの治療または予防剤を意味する。
　本明細書中の「睡眠改善剤」は、シフトワーク、ジェットラグ、不眠症または睡眠時無呼吸症候群等による日中の眠気を改善する薬剤を意味する。 The following terms used in this specification are defined as follows unless otherwise specified.
Examples of the “halogen” in the present specification include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
In the present specification, “C 1-6 alkyl” means a monovalent linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, consisting of a carbon atom and a hydrogen atom. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl and the like.
In the present specification, “C 1-4 alkyl” means a monovalent straight-chain or branched saturated hydrocarbon group having 1 to 4 carbon atoms, comprising a carbon atom and a hydrogen atom. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like can be mentioned.
In the present specification, “C 1-4 alkoxy” means an oxy group to which the above “C 1-4 alkyl” is bonded. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
The “halogen” in the present specification means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The term “C 2-6 alkenyl” as used herein refers to an unsaturated hydrocarbon having at least one monovalent linear or branched double bond having 2 to 6 carbon atoms, comprising a carbon atom and a hydrogen atom. Means group. For example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3- Examples include pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl and the like.
As used herein, “C 3-10 cycloalkyl” means a monocyclic aliphatic carbocyclic group having 3 to 10 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like.
As used herein, “C 6-10 aryl” means a monocyclic or condensed aromatic carbocyclic group having 6 to 10 carbon atoms. For example, phenyl, 1-naphthyl, 2-naphthyl and the like can be mentioned.
In the present specification, the “5- to 10-membered heteroaryl” is, as a ring-constituting atom, from 1 or 2 selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atom, from 5 containing 1 to 4 hetero atoms Means a 10-membered monocyclic or bicyclic aromatic heterocyclic group. For example, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, furazanyl, pyrazinyl, thiadiazolyl, oxadiazolyl, benzofuryl, benzothiazoyl, benzimidazolyl, benzimidazolyl, Examples thereof include isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1H-indazolyl, indolyl and the like.
As used herein, “anti-narcolepsy agent” means a therapeutic or prophylactic agent for narcolepsy.
The “sleep improvement agent” in the present specification means an agent that improves daytime sleepiness due to shift work, jet lag, insomnia, sleep apnea syndrome or the like.
　以下に、一般式（Ｉ）の各記号の定義と好ましい態様について説明する。 Hereinafter, the definitions and preferred embodiments of the symbols of the general formula (I) will be described.
　Ｒ１は水素原子を表す。 R 1 represents a hydrogen atom.
　Ｒ２は－ＯＨまたは
Ｃ１－４アルコキシを表し、
あるいはＲ１とＲ２は一緒になって－ＮＲａＲｂ（ここで、Ｒａは水素原子またはＣ１－４アルキルを表し、Ｒｂは水素原子またはＣ１－４アルキルを表す。）でさらに置換されていてもよいベンゼン環を形成する。 R 2 represents —OH or C 1-4 alkoxy;
Alternatively, R 1 and R 2 together represent —NR a R b (where R a represents a hydrogen atom or C 1-4 alkyl, and R b represents a hydrogen atom or C 1-4 alkyl). Further, an optionally substituted benzene ring is formed.
　Ｒ２としては、－ＯＨであるか、あるいは
Ｒ１とＲ２が一緒になって－ＮＲａＲｂ（ここで、Ｒａは水素原子またはＣ１－４アルキル（例、メチル）を表し、Ｒｂは水素原子またはＣ１－４アルキル（例、メチル）を表す。）でさらに置換されていてもよいベンゼン環を形成するのが好ましい。 R 2 is —OH, or R 1 and R 2 together represent —NR a R b (where R a represents a hydrogen atom or C 1-4 alkyl (eg, methyl); R b preferably represents a hydrogen atom or a C 1-4 alkyl (eg, methyl), which may be further substituted to form a benzene ring.
　別の態様として、Ｒ２としては、Ｃ１－４アルコキシ（例、メトキシ）が好ましく、メトキシが特に好ましい。 In another embodiment, R 2 is preferably C 1-4 alkoxy (eg, methoxy), particularly preferably methoxy.
　Ｒ３はＣ１－６アルキル、
Ｃ２－６アルケニル、
Ｃ３－１０シクロアルキル、
Ｃ６－１０アリールまたは
５～１０員ヘテロアリール
（ここで、Ｃ１－６アルキル、Ｃ２－６アルケニル、Ｃ３－１０シクロアルキル、Ｃ６－１０アリールまたは５～１０員ヘテロアリールは任意に選択される１から４個のＲ４で置換されていてもよく、
Ｒ４は水素原子、
Ｃ１－４アルキル、
Ｃ１－４アルコキシ、
フェニル（ここで、フェニルはＣ１－４アルキル、Ｃ１－４アルコキシまたは－Ｃ（Ｏ）ＮＲ４ｘＲ４ｙ（ここで、Ｒ４ｘはＣ１－４アルキルを表し、Ｒ４ｙはＣ１－４アルキルを表す。）で置換されていてもよい。）、
５～１０員ヘテロアリール、
ハロゲン、
－ＯＨ、
－ＮＲ４ａＲ４ｂ（ここで、Ｒ４ａは水素原子、Ｃ１－４アルキルまたはＣ１－４アルコキシ－カルボニルを表し、Ｒ４ｂは水素原子またはＣ１－４アルキルを表す。）、
－Ｃ（Ｏ）ＯＲ４ｃ（ここで、Ｒ４ｃはＣ１－４アルキルを表す。）または
－Ｃ（Ｏ）ＮＲ４ｄＲ４ｅ（ここで、Ｒ４ｄは水素原子またはＣ１－４アルキルを表し、Ｒ４ｅは水素原子またはＣ１－４アルキルを表す。）を表す。
あるいは２個のＲ４は一緒になってメチレンジオキシを形成する。）を表す。 R 3 is C 1-6 alkyl,
C 2-6 alkenyl,
C 3-10 cycloalkyl,
C 6-10 aryl or 5-10 membered heteroaryl (where C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl is optionally Optionally substituted with 1 to 4 R 4 selected,
R 4 is a hydrogen atom,
C 1-4 alkyl,
C 1-4 alkoxy,
Phenyl (wherein phenyl is C 1-4 alkyl, C 1-4 alkoxy or —C (O) NR 4x R 4y (where R 4x represents C 1-4 alkyl, R 4y represents C 1-4 Represents alkyl.) And may be substituted with
5-10 membered heteroaryl,
halogen,
-OH,
—NR 4a R 4b (wherein R 4a represents a hydrogen atom, C 1-4 alkyl or C 1-4 alkoxy-carbonyl, and R 4b represents a hydrogen atom or C 1-4 alkyl),
—C (O) OR 4c (wherein R 4c represents C 1-4 alkyl) or —C (O) NR 4d R 4e (where R 4d represents a hydrogen atom or C 1-4 alkyl). , R 4e represents a hydrogen atom or C 1-4 alkyl.
Alternatively, two R 4 together form methylenedioxy. ).
　Ｒ３としては、Ｃ１－６アルキル（例、メチル、エチル、プロピル、イソブチル、ネオペンチル）、
Ｃ２－６アルケニル（例、エテニル）または
Ｃ３－１０シクロアルキル（例、アダマンチル）
（ここで、Ｃ１－６アルキル、Ｃ２－６アルケニルまたはＣ３－１０シクロアルキルは任意に選択される１から４個のＲ４で置換されていてもよく、
Ｒ４は水素原子、
Ｃ１－４アルキル（例、メチル）、
Ｃ１－４アルコキシ（例、メトキシ）、
フェニル（ここで、フェニルはＣ１－４アルキル（例、メチル）、Ｃ１－４アルコキシ（例、メトキシ）または－Ｃ（Ｏ）ＮＲ４ｘＲ４ｙ（ここで、Ｒ４ｘはＣ１－４アルキル（例、メチル）を表し、Ｒ４ｙはＣ１－４アルキル（例、メチル）を表す。）で置換されていてもよい。）、
５～１０員ヘテロアリール（例、フリル、ピリジル、インドリル）、
ハロゲン（フッ素原子、臭素原子）、
－ＯＨ、
－ＮＲ４ａＲ４ｂ（ここで、Ｒ４ａは水素原子、Ｃ１－４アルキル（例、メチル）またはＣ１－４アルコキシ－カルボニル（例、ｔｅｒｔ－ブトキシカルボニル）を表し、Ｒ４ｂは水素原子またはＣ１－４アルキル（例、メチル）を表す。）、
－Ｃ（Ｏ）ＯＲ４ｃ（ここで、Ｒ４ｃはＣ１－４アルキル（例、メチル）を表す。）または
－Ｃ（Ｏ）ＮＲ４ｄＲ４ｅ（ここで、Ｒ４ｄは水素原子またはＣ１－４アルキル（例、メチル）を表し、Ｒ４ｅは水素原子またはＣ１－４アルキル（例、メチル）を表す。）を表す。
あるいは２個のＲ４は一緒になってメチレンジオキシを形成する。）
が好ましい。 R 3 includes C 1-6 alkyl (eg, methyl, ethyl, propyl, isobutyl, neopentyl),
C 2-6 alkenyl (eg, ethenyl) or C 3-10 cycloalkyl (eg, adamantyl)
(Wherein C 1-6 alkyl, C 2-6 alkenyl or C 3-10 cycloalkyl may be optionally substituted with 1 to 4 R 4 ,
R 4 is a hydrogen atom,
C 1-4 alkyl (eg methyl),
C 1-4 alkoxy (eg, methoxy),
Phenyl (wherein phenyl is C 1-4 alkyl (eg, methyl), C 1-4 alkoxy (eg, methoxy) or —C (O) NR 4x R 4y (where R 4x is C 1-4 alkyl) (Eg, methyl), R 4y may be substituted with C 1-4 alkyl (eg, methyl)).
5-10 membered heteroaryl (eg, furyl, pyridyl, indolyl),
Halogen (fluorine atom, bromine atom),
-OH,
—NR 4a R 4b (where R 4a represents a hydrogen atom, C 1-4 alkyl (eg, methyl) or C 1-4 alkoxy-carbonyl (eg, tert-butoxycarbonyl), and R 4b represents a hydrogen atom or Represents C 1-4 alkyl (eg, methyl)),
—C (O) OR 4c (where R 4c represents C 1-4 alkyl (eg, methyl)) or —C (O) NR 4d R 4e (where R 4d is a hydrogen atom or C 1 -4 alkyl (eg, methyl), R 4e represents a hydrogen atom or C 1-4 alkyl (eg, methyl).
Alternatively, two R 4 together form methylenedioxy. )
Is preferred.
　別の態様として、Ｒ３としては、Ｃ６－１０アリール（例、フェニル、ナフチル）または
５～１０員ヘテロアリール（例、チアゾリル、キノリル、イソキノリル、キノキサリニル）（ここで、Ｃ６－１０アリールまたは５～１０員ヘテロアリールは任意に選択される１から４個のＲ４で置換されていてもよく、
Ｒ４は
フェニル（ここで、フェニルはＣ１－４アルキル（例、メチル）、Ｃ１－４アルコキシ（例、メトキシ）または－Ｃ（Ｏ）ＮＲ４ｘＲ４ｙ（ここで、Ｒ４ｘはＣ１－４アルキル（例、メチル）を表し、Ｒ４ｙはＣ１－４アルキル（例、メチル）を表す。）で置換されていてもよい。）、
５～１０員ヘテロアリール（例、フリル、ピリジル、インドリル）、
－Ｃ（Ｏ）ＯＲ４ｃ（ここで、Ｒ４ｃはＣ１－４アルキル（例、メチル）を表す。）または
－Ｃ（Ｏ）ＮＲ４ｄＲ４ｅ（ここで、Ｒ４ｄは水素原子またはＣ１－４アルキル（例、メチル）を表し、Ｒ４ｅは水素原子またはＣ１－４アルキル（例、メチル）を表す。）を表す。
あるいは２個のＲ４は一緒になってメチレンジオキシを形成する。）
が好ましい。 In another embodiment, R 3 includes C 6-10 aryl (eg, phenyl, naphthyl) or 5- to 10-membered heteroaryl (eg, thiazolyl, quinolyl, isoquinolyl, quinoxalinyl) (wherein C 6-10 aryl or The 5- to 10-membered heteroaryl may be optionally substituted with 1 to 4 R 4 ,
R 4 is phenyl (wherein phenyl is C 1-4 alkyl (eg, methyl), C 1-4 alkoxy (eg, methoxy) or —C (O) NR 4x R 4y (where R 4x is C 1 -4 alkyl (eg, methyl), R 4y may be substituted with C 1-4 alkyl (eg, methyl)).
5-10 membered heteroaryl (eg, furyl, pyridyl, indolyl),
—C (O) OR 4c (where R 4c represents C 1-4 alkyl (eg, methyl)) or —C (O) NR 4d R 4e (where R 4d is a hydrogen atom or C 1 -4 alkyl (eg, methyl), R 4e represents a hydrogen atom or C 1-4 alkyl (eg, methyl).
Alternatively, two R 4 together form methylenedioxy. )
Is preferred.
　さらに別の態様として、Ｒ３としては、－ＮＲ４ａＲ４ｂ（ここで、Ｒ４ａはＣ１－４アルキル（例、メチル）を表し、Ｒ４ｂはＣ１－４アルキル（例、メチル）を表す。）で置換されたフェニルが好ましい。 In yet another embodiment, R 3 represents —NR 4a R 4b (where R 4a represents C 1-4 alkyl (eg, methyl), and R 4b represents C 1-4 alkyl (eg, methyl). Represents a substituted phenyl.
　Ｗは－（ＣＨ２）ｎ－Ｃ（Ｏ）ＮＲＷａＲＷｂ（ここで、ｎは０から２の整数を表し、
ＲＷａは水素原子、Ｃ１－４アルキル（ここで、Ｃ１－４アルキルはＣ１－４アルキルもしくはＣ１－４アルコキシで置換されていてもよいフェニル、ピリジルまたはＣ１－４アルコキシ－カルボニルアミノで置換されていてもよい。）またはフェニル（ここで、フェニルはＣ１－４アルコキシ、－ＮＯ２またはＣ１－４アルコキシ－カルボニルアミノで置換されていてもよい。）を表し、ＲＷｂは水素原子またはＣ１－４アルキルを表す。）または
一般式（ＩＩ）： W represents — (CH 2 ) n —C (O) NR Wa R Wb (where n represents an integer of 0 to 2;
R Wa is a hydrogen atom, C 1-4 alkyl (where C 1-4 alkyl is phenyl, pyridyl or C 1-4 alkoxy-carbonyl optionally substituted with C 1-4 alkyl or C 1-4 alkoxy) Or phenyl (wherein the phenyl may be substituted with C 1-4 alkoxy, —NO 2 or C 1-4 alkoxy-carbonylamino), and R Wb Represents a hydrogen atom or C 1-4 alkyl. ) Or general formula (II):
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
（ここで、
Ｒ５は水素原子、Ｃ１－４アルコキシ、－ＮＲ５ａＲ５ｂ（ここで、Ｒ５ａは水素原子またはＣ１－４アルキルを表し、Ｒ５ｂは水素原子またはＣ１－４アルキルを表す。）または－Ｃ（Ｏ）ＮＲ５ｃＲ５ｄ（ここで、Ｒ５ｃは水素原子またはＣ１－４アルキルを表し、Ｒ５ｄは水素原子またはＣ１－４アルキルを表す。）を表し、
Ｒ６は水素原子、Ｃ１－４アルコキシ、－ＯＣＦ３、－ＮＲ６ａＲ６ｂ（ここで、Ｒ６ａは水素原子またはＣ１－４アルキルを表し、Ｒ６ｂは水素原子またはＣ１－４アルキルを表す。）または－Ｃ（Ｏ）ＮＲ６ｃＲ６ｄ（ここで、Ｒ６ｃは水素原子またはＣ１－４アルキルを表し、Ｒ６ｄは水素原子またはＣ１－４アルキルを表す。）を表し、
Ｒ７は水素原子、Ｃ１－４アルコキシまたは－ＯＣＦ３を表し、かつ
Ｘは－Ｎ＝または－ＣＨ＝を表す。
あるいはＲ５およびＲ６は一緒になってメチレンジオキシを形成する。）を表す。 (here,
R 5 is a hydrogen atom, C 1-4 alkoxy, —NR 5a R 5b (where R 5a represents a hydrogen atom or C 1-4 alkyl, and R 5b represents a hydrogen atom or C 1-4 alkyl) Or —C (O) NR 5c R 5d (where R 5c represents a hydrogen atom or C 1-4 alkyl, and R 5d represents a hydrogen atom or C 1-4 alkyl);
R 6 is a hydrogen atom, C 1-4 alkoxy, —OCF 3 , —NR 6a R 6b (where R 6a represents a hydrogen atom or C 1-4 alkyl, and R 6b represents a hydrogen atom or C 1-4 alkyl) Or —C (O) NR 6c R 6d (where R 6c represents a hydrogen atom or C 1-4 alkyl, and R 6d represents a hydrogen atom or C 1-4 alkyl),
R 7 represents a hydrogen atom, C 1-4 alkoxy or —OCF 3 , and X represents —N═ or —CH═.
Alternatively, R 5 and R 6 together form methylenedioxy. ).
　Ｗとしては、－（ＣＨ２）ｎ－Ｃ（Ｏ）ＮＲＷａＲＷｂ（ここで、ｎは０から２の整数を表し、ＲＷａは水素原子、Ｃ１－４アルキル（例、メチル）（ここで、Ｃ１－４アルキルはＣ１－４アルキル（例、メチル）もしくはＣ１－４アルコキシ（例、メトキシ）で置換されていてもよいフェニル、ピリジルまたはＣ１－４アルコキシ－カルボニルアミノ（例、ｔｅｒｔ－ブトキシカルボニルアミノ）で置換されていてもよい。）またはフェニル（ここで、フェニルはＣ１－４アルコキシ（例、メトキシ）、－ＮＯ２またはＣ１－４アルコキシ－カルボニルアミノ（例、ｔｅｒｔ－ブトキシカルボニルアミノ）で置換されていてもよい）を表し、ＲＷｂは水素原子またはＣ１－４アルキル（例、エチル）を表す。）または
一般式（ＩＩ）： W represents — (CH 2 ) n —C (O) NR Wa R Wb (where n represents an integer of 0 to 2, R Wa represents a hydrogen atom, C 1-4 alkyl (eg, methyl) ( Where C 1-4 alkyl is phenyl, pyridyl or C 1-4 alkoxy-carbonylamino (eg, methyl) or C 1-4 alkoxy (eg, methoxy) optionally substituted with C 1-4 alkyl (eg, methyl). Eg, tert-butoxycarbonylamino) or phenyl (where phenyl is C 1-4 alkoxy (eg, methoxy), —NO 2 or C 1-4 alkoxy-carbonylamino (eg, , Tert-butoxycarbonylamino) and R Wb represents a hydrogen atom or C 1-4 alkyl (eg, ethyl)) or a general formula ( II):
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
（ここで、
Ｒ５はＣ１－４アルコキシ（例、メトキシ）、－ＮＲ５ａＲ５ｂ（ここで、Ｒ５ａは水素原子またはＣ１－４アルキル（例、メチル）を表し、Ｒ５ｂは水素原子またはＣ１－４アルキル（例、メチル）を表す。）または－Ｃ（Ｏ）ＮＲ５ｃＲ５ｄ（ここで、Ｒ５ｃは水素原子またはＣ１－４アルキル（例、メチル）を表し、Ｒ５ｄは水素原子またはＣ１－４アルキル（例、メチル）を表す。）を表し、
Ｒ６は水素原子、Ｃ１－４アルコキシ（例、メトキシ）、－ＯＣＦ３、－ＮＲ６ａＲ６ｂ（ここで、Ｒ６ａは水素原子またはＣ１－４アルキル（例、メチル）を表し、Ｒ６ｂは水素原子またはＣ１－４アルキル（例、メチル）を表す。）または－Ｃ（Ｏ）ＮＲ６ｃＲ６ｄ（ここで、Ｒ６ｃは水素原子またはＣ１－４アルキル（例、メチル）を表し、Ｒ６ｄは水素原子またはＣ１－４アルキル（例、メチル）を表す。）を表し、
Ｒ７は水素原子、Ｃ１－４アルコキシ（例、メトキシ）または－ＯＣＦ３を表し、かつ
Ｘは－ＣＨ＝を表す。
あるいはＲ５およびＲ６は一緒になってメチレンジオキシを形成する。）を表す。）
が好ましい。 (here,
R 5 represents C 1-4 alkoxy (eg, methoxy), —NR 5a R 5b (where R 5a represents a hydrogen atom or C 1-4 alkyl (eg, methyl), and R 5b represents a hydrogen atom or C 1 -4 alkyl (eg, methyl)) or -C (O) NR 5c R 5d (where R 5c represents a hydrogen atom or C 1-4 alkyl (eg, methyl), and R 5d represents a hydrogen atom) Or C 1-4 alkyl (eg, methyl))
R 6 represents a hydrogen atom, C 1-4 alkoxy (eg, methoxy), —OCF 3 , —NR 6a R 6b (where R 6a represents a hydrogen atom or C 1-4 alkyl (eg, methyl), R 6b represents a hydrogen atom or C 1-4 alkyl (eg, methyl)) or —C (O) NR 6c R 6d (where R 6c represents a hydrogen atom or C 1-4 alkyl (eg, methyl)). R 6d represents a hydrogen atom or C 1-4 alkyl (eg, methyl)),
R 7 represents a hydrogen atom, C 1-4 alkoxy (eg, methoxy) or —OCF 3 , and X represents —CH═.
Alternatively, R 5 and R 6 together form methylenedioxy. ). )
Is preferred.
　Ｗの上記一般式（ＩＩ）に示される構造のうち、ｎとしては、０または２が好ましく、０が特に好ましい。 In the structure represented by the above general formula (II) of W, n is preferably 0 or 2, and 0 is particularly preferable.
　別の態様として、Ｗとしては、一般式（ＩＩ）： As another aspect, as W, general formula (II):
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
（ここで、
Ｒ５は水素原子を表し、
Ｒ６は－Ｃ（Ｏ）ＮＲ６ｃＲ６ｄ（ここで、Ｒ６ｃはＣ１－４アルキル（例、メチル）を表し、Ｒ６ｄはＣ１－４アルキル（例、メチル）を表す。）を表し、
Ｒ７は水素原子を表し、かつ
Ｘは－ＣＨ＝を表す。）
が好ましい。 (here,
R 5 represents a hydrogen atom,
R 6 represents —C (O) NR 6c R 6d (where R 6c represents C 1-4 alkyl (eg, methyl), and R 6d represents C 1-4 alkyl (eg, methyl)). Represent,
R 7 represents a hydrogen atom, and X represents —CH═. )
Is preferred.
　本発明の上記一般式（Ｉ）で示される化合物の好適な例としては、以下の一般式（Ｉ’） Preferred examples of the compound represented by the above general formula (I) of the present invention include the following general formula (I ′)
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
［式中、
Ｒ２’は－ＮＲ３ａ’Ｒ３ｂ’（ここで、Ｒ３ａ’はＣ１－４アルキル（例、メチル）を表し、Ｒ３ｂ’はＣ１－４アルキル（例、メチル）を表す。）で置換されたフェニルを表す。］
で示される化合物またはその薬学的に許容される酸付加塩が挙げられる。 [Where:
R 2 ′ represents —NR 3a ′ R 3b ′ (where R 3a ′ represents C 1-4 alkyl (eg, methyl) and R 3b ′ represents C 1-4 alkyl (eg, methyl)). Represents phenyl substituted with ]
Or a pharmaceutically acceptable acid addition salt thereof.
　一般式（Ｉ’）で表される化合物の具体例としては、
３’－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド、
　３’－（Ｎ－（３－（（２－（３－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド、および
　３’－（Ｎ－（３－（（２－（４－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド
またはその薬学的に許容される酸付加塩が好ましく、
３’－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド
またはその薬学的に許容される酸付加塩が特に好ましい。 Specific examples of the compound represented by the general formula (I ′) include
3 ′-(N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4′-methoxy-N, N-dimethyl- [1,1′-biphenyl] -3-carboxamide,
3 ′-(N- (3-((2- (3- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4′-methoxy-N, N-dimethyl- [1,1′-biphenyl] -3-carboxamide, and 3 '-(N- (3-((2- (4- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4'-methoxy-N, N-dimethyl- [1 , 1′-biphenyl] -3-carboxamide or a pharmaceutically acceptable acid addition salt thereof,
3 ′-(N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4′-methoxy-N, N-dimethyl- [1,1′-biphenyl] -3-Carboxamide or a pharmaceutically acceptable acid addition salt thereof is particularly preferred.
　本発明の一般式（Ｉ）の化合物の薬学的に許容される酸付加塩としては、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、ヨウ化水素酸塩、リン酸塩等の無機酸塩、酢酸塩、乳酸塩、クエン酸塩、シュウ酸塩、グルタル酸塩、リンゴ酸塩、酒石酸塩、フマル酸塩、マンデル酸塩、マレイン酸塩、安息香酸塩、フタル酸塩等の有機カルボン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、カンファースルホン酸塩等の有機スルホン酸塩等が挙げられ、これらは限定的なものではない。中でも、塩酸塩、臭化水素酸塩、リン酸塩、酒石酸塩、メタンスルホン酸塩、カンファースルホン酸塩が好ましく、塩酸塩、酒石酸塩またはメタンスルホン酸塩がさらに好ましく、塩酸塩が特に好ましく用いられるが、これらもまた限定的なものではない。 Examples of the pharmaceutically acceptable acid addition salt of the compound of the general formula (I) of the present invention include inorganic acids such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate. Organic carboxyl such as salt, acetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, phthalate Examples thereof include, but are not limited to, organic sulfonates such as acid salts, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, camphorsulfonates, and the like. Among them, hydrochloride, hydrobromide, phosphate, tartrate, methanesulfonate, camphorsulfonate are preferable, hydrochloride, tartrate or methanesulfonate is more preferable, and hydrochloride is particularly preferably used. These are also not limiting.
　上記一般式（Ｉ）で示される本発明の化合物は、その基本骨格や置換基に由来する特徴に基づいた適切な方法で製造することができる。なお、これらの化合物の製造に使用する出発物質と試薬は一般に入手することができるか、またはＯｒｇａｎｉｃ　Ｒｅａｃｔｉｏｎｓ（Ｗｉｌｅｙ＆Ｓｏｎｓ）、Ｆｉｅｓｅｒ　ａｎｄ　Ｆｉｅｓｅｒ’ｓ　Ｒｅａｇｅｎｔ　ｆｏｒ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ（Ｗｉｌｅｙ＆Ｓｏｎｓ）などの参考文献に記載の手順に従った、当業者に既知の方法によって合成できる。
　上記一般式（Ｉ）で示される本発明の化合物の具体的な製造方法として、例えばスキーム１から５に示す方法を挙げることができる。 The compound of the present invention represented by the general formula (I) can be produced by an appropriate method based on the characteristics derived from the basic skeleton and the substituent. The starting materials and reagents used in the production of these compounds are generally available or described in references such as Organic Reactions (Wiley & Sons), Fieser and Fieser's Reagent for Organic Synthesis (Wiley & Sons), etc. And can be synthesized by methods known to those skilled in the art.
Specific examples of the method for producing the compound of the present invention represented by the general formula (I) include the methods shown in Schemes 1 to 5.
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　［式中、Ｒ１、Ｒ２、Ｒ３およびＷは前記定義に同じである。］。
　具体的には、一般式（Ｉ）で表される化合物は、例えば、一般式（ＩＩＩ）で表されるアミン誘導体を、一般式（ＩＶ）で表されるカルボン酸でアミド化することにより得ることができる。
　溶媒としては、ジクロロメタン、クロロホルム、１，２－ジクロロエタンなどのハロゲン系溶媒、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，２－ジメトキシエタン（ＤＭＥ）、ジオキサンなどのエーテル系溶媒、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（ＤＭＳＯ）、酢酸エチルなどの非プロトン性極性溶媒、メタノール、エタノール、プロパノールなどのアルコール系溶媒あるいはそれらの混合溶媒を用いることができる。通常は、ジクロロメタンまたはＴＨＦが好ましく用いられる。カルボン酸（ＩＶ）は、アミン誘導体（ＩＩＩ）に対し０．５～２０当量、好ましくは０．５～１０当量用いられる。
　縮合剤としては、ジシクロヘキシルカルボジイミド、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド　塩酸塩（ＥＤＣＩ）、ベンゾトリアゾール－１－イルオキシトリス（ジメチルアミノ）ホスホニウム　ヘキサフルオロリン酸塩（ＢＯＰ）、Ｎ，Ｎ’－カルボニルジイミダゾール（ＣＤＩ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウムクロリド（ＤＭＴ－ＭＭ）、｛｛［（１－シアノ－２－エトキシ－２－オキソエチリデン）アミノ］オキシ｝－４－モルホリノメチレン｝ジメチルアンモニウム　ヘキサフルオロリン酸塩（ＣＯＭＵ）、Ｏ－（７－アザベンゾトリアゾール－１－イル）-Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム　ヘキサフルオロリン酸塩（ＨＡＴＵ）試薬等を用いることができ、特にＨＡＴＵ試薬が好ましく用いられる。縮合剤は、アミン誘導体（ＩＩＩ）に対し１．０～１００当量、好ましくは１．０～１０当量用いられる。
　塩基を用いる場合は、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、Ｎ－メチルモルホリン等を用いることができ、トリエチルアミンまたはジイソプロピルエチルアミンが好ましく用いられる。塩基は、アミン誘導体（ＩＩＩ）に対し３．０～１００当量、好ましくは３．０～１０当量用いられる。
　反応温度は、通常－４０～１５０℃、好ましくは０～６０℃である。反応時間は、反応温度等の条件に応じて適宜選択されるが、通常、２０分～４８時間程度である。また、反応系中の基質（ＩＩＩ）の濃度は、特に限定されるものではないが、通常、０．００１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 Wherein R 1 , R 2 , R 3 and W are the same as defined above. ].
Specifically, the compound represented by the general formula (I) is obtained, for example, by amidating an amine derivative represented by the general formula (III) with a carboxylic acid represented by the general formula (IV). be able to.
Solvents include halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane, ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane (DME) and dioxane, N, N-dimethylformamide An aprotic polar solvent such as (DMF), dimethyl sulfoxide (DMSO) or ethyl acetate, an alcohol solvent such as methanol, ethanol or propanol or a mixed solvent thereof can be used. Usually, dichloromethane or THF is preferably used. The carboxylic acid (IV) is used in an amount of 0.5 to 20 equivalents, preferably 0.5 to 10 equivalents, relative to the amine derivative (III).
Examples of the condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), N, N′-carbonyldiimidazole (CDI), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM), {{[ (1-Cyano-2-ethoxy-2-oxoethylidene) amino] oxy} -4-morpholinomethylene} dimethylammonium hexafluorophosphate (COMU), O- (7-azabenzotriazol-1-yl) -N , N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) test Or the like can be used, particularly preferably used HATU reagent. The condensing agent is used in an amount of 1.0 to 100 equivalents, preferably 1.0 to 10 equivalents, relative to the amine derivative (III).
When a base is used, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine and the like can be used, and triethylamine or diisopropylethylamine is preferably used. The base is used in an amount of 3.0 to 100 equivalents, preferably 3.0 to 10 equivalents, relative to the amine derivative (III).
The reaction temperature is usually −40 to 150 ° C., preferably 0 to 60 ° C. The reaction time is appropriately selected depending on the reaction temperature and other conditions, but is usually about 20 minutes to 48 hours. Further, the concentration of the substrate (III) in the reaction system is not particularly limited, but usually 0.001 mmol / L to 1 mol / L is preferable.
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　［式中、Ｘは水素原子またはベンジル基であり、Ｒ１、Ｒ２、Ｒ３およびＷは前記定義に同じである。］。
　一般式（Ｉ）または一般式（ＶＩＩ）で表される化合物は、例えば、一般式（Ｖ）で表される誘導体を、一般式（ＶＩ）で表されるボロン酸誘導体で鈴木カップリングすることにより得ることができる。
　鈴木カップリング反応は、パラジウム触媒および塩基の存在下、ホスフィンリガンドの存在下または非存在下に、適当な溶媒中で行われる。
　溶媒としては、ＴＨＦ、ＤＭＥ、ジオキサンなどのエーテル系溶媒、ＤＭＦ、ＤＭＳＯなどの非プロトン性極性溶媒、メタノール、エタノール、プロパノールなどのアルコール系溶媒、ベンゼン、トルエン、キシレンなどの芳香族系溶媒、水あるいはそれらの混合溶媒を用いることができる。通常は、ジオキサン、ＤＭＥ、ジオキサンおよび水の混合溶媒またはＤＭＥおよび水の混合溶媒が好ましく用いられる。
　ボロン酸誘導体（ＶＩ）としては、ボロン酸だけではなく、ボロン酸ピナコールエステル、ボロン酸Ｎ－メチルイミノ二酢酸（ＭＩＤＡ）エステルなどのボロン酸エステル、またはトリフルオロボレートカリウム塩も用いることができる。特に、ボロン酸またはボロン酸ピナコールエステルが好ましく用いられる。ボロン酸誘導体（ＶＩ）は、式（Ｖ）の誘導体に対し１．０～２０当量、好ましくは１．０～１０当量用いられる。
　パラジウム触媒としては、例えば、テトラキス（トリフェニルホスフィン）パラジウム、パラジウムアセテート、ビス（トリフェニルホスフィン）パラジウムジクロリド、ビス（ジベンジリデンアセトン）パラジウム、ビス（ジフェニルホスフィノ）フェロセンパラジウムジクロリドなどが挙げられ、テトラキス（トリフェニルホスフィン）パラジウムまたはビス（ジフェニルホスフィノ）フェロセンパラジウムジクロリドが好ましく用いられる。パラジウム触媒は、式（Ｖ）の誘導体に対し０．００１～１当量、好ましくは０．００５～０．５当量用いられる。
　塩基としては、例えば、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、リン酸カリウム、水酸化ナトリウム、水酸化カリウム、水酸化バリウム、トリエチルアミン、ジイソプロピルエチルアミンなどが挙げられ、炭酸ナトリウムまたは炭酸カリウムが好ましく用いられる。
　反応温度は、通常－４０～１５０℃、好ましくは２０～１１０℃である。反応時間は、反応温度等の条件に応じて適宜選択されるが、通常、２０分～４８時間程度である。また、反応系中の基質（Ｖ）の濃度は、特に限定されるものではないが、通常、０．００１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 [Wherein, X is a hydrogen atom or a benzyl group, and R 1 , R 2 , R 3 and W are as defined above. ].
For the compound represented by the general formula (I) or the general formula (VII), for example, the derivative represented by the general formula (V) is Suzuki-coupled with the boronic acid derivative represented by the general formula (VI). Can be obtained.
The Suzuki coupling reaction is performed in a suitable solvent in the presence of a palladium catalyst and a base, and in the presence or absence of a phosphine ligand.
Solvents include ether solvents such as THF, DME and dioxane, aprotic polar solvents such as DMF and DMSO, alcohol solvents such as methanol, ethanol and propanol, aromatic solvents such as benzene, toluene and xylene, water Alternatively, a mixed solvent thereof can be used. Usually, a mixed solvent of dioxane, DME, dioxane and water or a mixed solvent of DME and water is preferably used.
As the boronic acid derivative (VI), not only boronic acid but also boronic acid esters such as boronic acid pinacol ester, boronic acid N-methyliminodiacetic acid (MIDA) ester, or potassium trifluoroborate can be used. In particular, boronic acid or boronic acid pinacol ester is preferably used. The boronic acid derivative (VI) is used in an amount of 1.0 to 20 equivalents, preferably 1.0 to 10 equivalents, relative to the derivative of formula (V).
Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride, bis (dibenzylideneacetone) palladium, bis (diphenylphosphino) ferrocenepalladium dichloride, and the like. (Triphenylphosphine) palladium or bis (diphenylphosphino) ferrocenepalladium dichloride is preferably used. The palladium catalyst is used in an amount of 0.001 to 1 equivalent, preferably 0.005 to 0.5 equivalent, relative to the derivative of formula (V).
Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, barium hydroxide, triethylamine, diisopropylethylamine, and sodium carbonate or potassium carbonate is preferably used.
The reaction temperature is usually −40 to 150 ° C., preferably 20 to 110 ° C. The reaction time is appropriately selected depending on the reaction temperature and other conditions, but is usually about 20 minutes to 48 hours. Further, the concentration of the substrate (V) in the reaction system is not particularly limited, but usually 0.001 mmol / L to 1 mol / L is preferable.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　［式中、Ｒ１、Ｒ２、Ｒ３およびＷは前記定義に同じである。］。
　一般式（Ｉ）で表される化合物は、例えば、一般式（ＶＩＩ）で表される化合物のベンジル基を、加水素分解反応などにより脱保護することにより得ることができる。
　加水素分解反応は、パラジウム触媒の存在下および水素の雰囲気下に、適当な溶媒中で行われる。
　溶媒としては、ＴＨＦ、ＤＭＥ、ジオキサンなどのエーテル系溶媒、ＤＭＦ、ＤＭＳＯ、酢酸エチルなどの非プロトン性極性溶媒、メタノール、エタノール、プロパノールなどのアルコール系溶媒、ベンゼン、トルエン、キシレンなどの芳香族系溶媒、酢酸、水あるいはそれらの混合溶媒を用いることができる。通常は、トルエンやＴＨＦ、メタノールが好ましく用いられる。
　パラジウム触媒としては、例えば、パラジウム（Ｐｄ）、パラジウム炭素（Ｐｄ／Ｃ）、水酸化パラジウム（Ｐｄ（ＯＨ）２）、水酸化パラジウム炭素（Ｐｄ（ＯＨ）２／Ｃ）などが挙げられるが、パラジウム炭素（Ｐｄ／Ｃ）が好ましく用いられる。パラジウム触媒は、式（ＶＩＩ）の誘導体に対し０．００１～１当量、好ましくは０．００５～０．５当量用いられる。
　反応温度は、通常－４０～１５０℃、好ましくは２０～１１０℃である。反応時間は、反応温度等の条件に応じて適宜選択されるが、通常、２０分～４８時間程度である。また、反応系中の基質（ＶＩＩ）の濃度は、特に限定されるものではないが、通常、０．００１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 Wherein R 1 , R 2 , R 3 and W are the same as defined above. ].
The compound represented by the general formula (I) can be obtained, for example, by deprotecting the benzyl group of the compound represented by the general formula (VII) by a hydrogenolysis reaction or the like.
The hydrogenolysis reaction is carried out in a suitable solvent in the presence of a palladium catalyst and in an atmosphere of hydrogen.
Solvents include ether solvents such as THF, DME and dioxane, aprotic polar solvents such as DMF, DMSO and ethyl acetate, alcohol solvents such as methanol, ethanol and propanol, and aromatic solvents such as benzene, toluene and xylene. A solvent, acetic acid, water, or a mixed solvent thereof can be used. Usually, toluene, THF, and methanol are preferably used.
Examples of the palladium catalyst include palladium (Pd), palladium carbon (Pd / C), palladium hydroxide (Pd (OH) 2 ), palladium hydroxide carbon (Pd (OH) 2 / C), and the like. Palladium carbon (Pd / C) is preferably used. The palladium catalyst is used in an amount of 0.001 to 1 equivalent, preferably 0.005 to 0.5 equivalent, relative to the derivative of formula (VII).
The reaction temperature is usually −40 to 150 ° C., preferably 20 to 110 ° C. The reaction time is appropriately selected depending on the reaction temperature and other conditions, but is usually about 20 minutes to 48 hours. Further, the concentration of the substrate (VII) in the reaction system is not particularly limited, but is usually preferably 0.001 mmol / L to 1 mol / L.
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　一般式（Ｉ）で表される化合物は、例えば、一般式（ＶＩＩＩ）のスルホン酸クロリド誘導体を、一般式（ＩＸ）のアミン誘導体でアミド化することにより得ることができる。
　溶媒としては、ジクロロメタン、クロロホルム、１，２－ジクロロエタンなどのハロゲン系溶媒、ジエチルエーテル、ＴＨＦ、ＤＭＥ、ジオキサンなどのエーテル系溶媒、ＤＭＦ、ＤＭＳＯなどの非プロトン性極性溶媒あるいはそれらの混合溶媒を用いることができる。通常は、ジクロロメタンまたはＴＨＦが好ましく用いられる。スルホン酸クロリド誘導体（ＶＩＩＩ）はアミン誘導体（ＩＸ）に対し０．５～２０当量、好ましくは１．０～１０当量用いられる。
　塩基としては、例えば、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、リン酸カリウム、水酸化ナトリウム、水酸化カリウム、水酸化バリウム、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、４－ジメチルアミノピリジンなどが挙げられ、トリエチルアミンまたはピリジンが好ましく用いられる。
　反応温度は、通常－４０～１５０℃、好ましくは０～８０℃である。反応時間は、反応温度等の条件に応じて適宜選択されるが、通常、１０分～４８時間程度である。また、反応系中の基質（ＶＩＩＩ）の濃度は、特に限定されるものではないが、通常、０．００１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The compound represented by the general formula (I) can be obtained, for example, by amidating a sulfonic acid chloride derivative of the general formula (VIII) with an amine derivative of the general formula (IX).
As the solvent, halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, ether solvents such as diethyl ether, THF, DME, dioxane, aprotic polar solvents such as DMF, DMSO, or a mixed solvent thereof are used. be able to. Usually, dichloromethane or THF is preferably used. The sulfonic acid chloride derivative (VIII) is used in an amount of 0.5 to 20 equivalents, preferably 1.0 to 10 equivalents, relative to the amine derivative (IX).
Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, barium hydroxide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and the like. Pyridine is preferably used.
The reaction temperature is usually −40 to 150 ° C., preferably 0 to 80 ° C. The reaction time is appropriately selected depending on the reaction temperature and other conditions, but is usually about 10 minutes to 48 hours. Further, the concentration of the substrate (VIII) in the reaction system is not particularly limited, but usually 0.001 mmol / L to 1 mol / L is preferable.
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　［式中、Ｒ１、Ｒ２、Ｒ３、ＲＷａおよびＲＷｂは前記定義に同じである。］。
　一般式（Ｉ）で表される化合物のうち、Ｗが－Ｃ（Ｏ）ＮＲＷａＲＷｂである化合物（ＸＩＩ）は、例えば、一般式（Ｘ）で表されるカルボン酸誘導体を、一般式（ＸＩ）で表されるアミンでアミド化することにより得ることができる。
　溶媒としては、ジクロロメタン、クロロホルム、１，２－ジクロロエタンなどのハロゲン系溶媒、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，２－ジメトキシエタン（ＤＭＥ）、ジオキサンなどのエーテル系溶媒、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（ＤＭＳＯ）、酢酸エチルなどの非プロトン性極性溶媒、メタノール、エタノール、プロパノールなどのアルコール系溶媒あるいはそれらの混合溶媒を用いることができる。通常は、ジクロロメタンまたはＴＨＦが好ましく用いられる。アミン（ＸＩ）は、カルボン酸誘導体（Ｘ）に対し０．５～２０当量、好ましくは０．５～１０当量用いられる。
　縮合剤としては、ジシクロヘキシルカルボジイミド、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド　塩酸塩（ＥＤＣＩ）、ベンゾトリアゾール－１－イルオキシトリス（ジメチルアミノ）ホスホニウム　ヘキサフルオロリン酸塩（ＢＯＰ）、Ｎ，Ｎ’－カルボニルジイミダゾール（ＣＤＩ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウムクロリド（ＤＭＴ－ＭＭ）、｛｛［（１－シアノ－２－エトキシ－２－オキソエチリデン）アミノ］オキシ｝－４－モルホリノメチレン｝ジメチルアンモニウム　ヘキサフルオロリン酸塩（ＣＯＭＵ）、Ｏ－（７－アザベンゾトリアゾール－１－イル）-Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム　ヘキサフルオロリン酸塩（ＨＡＴＵ）試薬等を用いることができ、特にＨＡＴＵ試薬が好ましく用いられる。縮合剤は、カルボン酸誘導体（Ｘ）に対し１．０～１００当量、好ましくは１．０～１０当量用いられる。
　塩基を用いる場合は、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、Ｎ－メチルモルホリン等を用いることができ、トリエチルアミンまたはジイソプロピルエチルアミンが好ましく用いられる。塩基は、カルボン酸誘導体（Ｘ）に対し３．０～１００当量、好ましくは３．０～１０当量用いられる。
　反応温度は、通常－４０～１５０℃、好ましくは０～６０℃である。反応時間は、反応温度等の条件に応じて適宜選択されるが、通常、２０分～４８時間程度である。また、反応系中の基質（Ｘ）の濃度は、特に限定されるものではないが、通常、０．００１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 [Wherein, R 1 , R 2 , R 3 , R Wa and R Wb are the same as defined above. ].
Of the compounds represented by the general formula (I), the compound (XII) in which W is —C (O) NR Wa R Wb represents, for example, a carboxylic acid derivative represented by the general formula (X) It can be obtained by amidation with an amine represented by (XI).
Solvents include halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane, ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane (DME) and dioxane, N, N-dimethylformamide An aprotic polar solvent such as (DMF), dimethyl sulfoxide (DMSO) or ethyl acetate, an alcohol solvent such as methanol, ethanol or propanol or a mixed solvent thereof can be used. Usually, dichloromethane or THF is preferably used. The amine (XI) is used in an amount of 0.5 to 20 equivalents, preferably 0.5 to 10 equivalents, relative to the carboxylic acid derivative (X).
Examples of the condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), N, N′-carbonyldiimidazole (CDI), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM), {{[ (1-Cyano-2-ethoxy-2-oxoethylidene) amino] oxy} -4-morpholinomethylene} dimethylammonium hexafluorophosphate (COMU), O- (7-azabenzotriazol-1-yl) -N , N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) test Or the like can be used, particularly preferably used HATU reagent. The condensing agent is used in an amount of 1.0 to 100 equivalents, preferably 1.0 to 10 equivalents, relative to the carboxylic acid derivative (X).
When a base is used, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine and the like can be used, and triethylamine or diisopropylethylamine is preferably used. The base is used in an amount of 3.0 to 100 equivalents, preferably 3.0 to 10 equivalents, relative to the carboxylic acid derivative (X).
The reaction temperature is usually −40 to 150 ° C., preferably 0 to 60 ° C. The reaction time is appropriately selected depending on the reaction temperature and other conditions, but is usually about 20 minutes to 48 hours. Further, the concentration of the substrate (X) in the reaction system is not particularly limited, but is usually preferably 0.001 mmol / L to 1 mol / L.
　本発明の化合物を含有するオレキシン受容体作動薬（特にＯＸ２Ｒ作動薬）は、ヒトに対して有効であるだけではなく、ヒト以外の哺乳類、例えばマウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サルなどに対しても有効である。
　また本発明の化合物は、上記の通りナルコレプシーの予防剤または治療剤として用いられるだけではなく、ナルコレプシーの予防または治療方法、あるいはナルコレプシーを予防または治療するための医薬の製造に使用することができる。
　さらに本発明の化合物は、眠気改善剤、摂食抑制剤、体重増加抑制剤あるいは肥満症、糖尿病、うつ病、敗血症、重症敗血症または敗血症性ショックなどの予防剤または治療剤としても使用することができる。
　本発明の化合物をナルコレプシーの予防剤または治療剤、眠気改善剤、摂食抑制剤、体重増加抑制剤あるいは肥満症、糖尿病、うつ病、敗血症、重症敗血症または敗血症性ショックなどの予防剤または治療剤として臨床で使用する際には、薬剤は本発明化合物のフリー体またはその酸付加塩自体でもよく、また、賦形剤、安定化剤、保存剤、緩衝剤、溶解補助剤、乳化剤、希釈剤、等張化剤などの添加剤が適宜混合されてもよい。投与形態としては、錠剤、カプセル剤、顆粒剤、散剤、シロップ剤などによる経口剤、注射剤、坐剤、液剤などによる非経口剤、あるいは軟膏剤、クリーム剤、貼付剤などによる局所投与等を挙げることができる。
　本発明のナルコレプシーの予防剤または治療剤、眠気改善剤、摂食抑制剤、体重増加抑制剤あるいは肥満症、糖尿病、うつ病、敗血症、重症敗血症または敗血症性ショックなどの予防剤または治療剤は、上記有効成分を０．００１～９０重量％、好ましくは０．０１～７０重量％含有することが望ましい。その使用量は、症状、年齢、体重、投与方法に応じて適宜選択されるが、成人に対して、注射剤の場合、有効成分量として１日０．１μｇ～１ｇ、経口剤の場合１μｇ～１ｇ、貼付剤の場合１μｇ～１０ｇであり、それぞれ１回または数回に分けて投与することができる。
　また、本発明のナルコレプシーの予防剤または治療剤、あるいは眠気改善剤は、日中の強い眠気と居眠りの予防剤または治療剤、熟眠障害の予防剤または治療剤、カタプレキシーの予防剤または治療剤と組み合わせて用いることもできる。
　日中の強い眠気と居眠りの予防剤または治療剤としては、メチルフェニデート、ペモリン、モダフィニルなどの中枢神経賦活薬などを挙げることができる。
　熟眠障害の予防剤または治療剤としては、トリアゾラム、ベゲタミンＢなどの睡眠薬、および抗不安薬などを挙げることができる。
　カタプレキシーの予防剤または治療剤としては、塩酸クロミプラミン、ブロチゾラム、イミプラミン塩酸塩などの三環性抗うつ薬、フルボキサミン　マレイン酸塩、パロキセチン　塩酸塩などの選択的セロトニン再取り込み阻害薬（ＳＳＲＩ）、塩酸ミルナシプラン、デュロキセチン塩酸塩などのセロトニン・ノルアドレナリン再取り込み阻害薬（ＳＮＲＩ）などを挙げることができる。 Orexin receptor agonists (especially OX2R agonists) containing the compounds of the present invention are not only effective against humans but also non-human mammals such as mice, rats, hamsters, rabbits, cats, dogs, cows , Effective against sheep, monkeys, etc.
In addition, the compound of the present invention is not only used as a preventive or therapeutic agent for narcolepsy as described above, but also can be used for the prevention or treatment of narcolepsy or the manufacture of a medicament for preventing or treating narcolepsy.
Furthermore, the compound of the present invention can be used as a prophylactic or therapeutic agent for sleepiness improving agent, antifeedant, weight gain inhibitor or obesity, diabetes, depression, sepsis, severe sepsis or septic shock. it can.
The preventive or therapeutic agent for narcolepsy, the sleepiness improving agent, the antifeedant, the weight gain inhibitor or the preventive or therapeutic agent for obesity, diabetes, depression, sepsis, severe sepsis or septic shock In clinical use, the drug may be a free form of the compound of the present invention or its acid addition salt itself, and also excipients, stabilizers, preservatives, buffers, solubilizers, emulsifiers, diluents. Additives such as tonicity agents may be mixed as appropriate. Administration forms include oral preparations such as tablets, capsules, granules, powders, syrups, parenteral preparations such as injections, suppositories, and liquids, or topical administration such as ointments, creams, patches, etc. Can be mentioned.
The preventive or therapeutic agent for narcolepsy of the present invention, sleepiness improving agent, antifeedant, weight gain inhibitor or obesity, diabetes, depression, sepsis, severe sepsis or septic shock or the like, It is desirable to contain 0.001 to 90% by weight, preferably 0.01 to 70% by weight of the above active ingredient. The amount to be used is appropriately selected according to symptoms, age, body weight, and administration method. For adults, the amount of active ingredient is 0.1 μg to 1 g per day for an injection, and 1 μg to In the case of a patch, the dose is 1 μg to 10 g, and can be administered once or divided into several times.
The narcolepsy preventive or therapeutic agent or sleepiness improving agent of the present invention includes a prophylactic or therapeutic agent for strong daytime sleepiness and dozing, a prophylactic or therapeutic agent for deep sleep disorder, a prophylactic or therapeutic agent for cataplexy, and It can also be used in combination.
Examples of the preventive or therapeutic agent for strong daytime sleepiness and doze include central nervous system stimulants such as methylphenidate, pemoline, and modafinil.
Examples of the prophylactic or therapeutic agent for deep sleep disorder include sleeping drugs such as triazolam and begetamine B, and anxiolytic drugs.
Examples of prophylactic or therapeutic agents for cataplexy include tricyclic antidepressants such as clomipramine hydrochloride, brotizolam, imipramine hydrochloride, selective serotonin reuptake inhibitors (SSRI) such as fluvoxamine maleate, paroxetine hydrochloride, mil hydrochloride Examples include serotonin and noradrenaline reuptake inhibitors (SNRI) such as Nasiplan and duloxetine hydrochloride.
　以下、実施例を挙げて本発明を具体的に説明する。なお、以下の実施例においては下記の略号を使用する。
Ｂｏｃ：ｔｅｒｔ－ブトキシカルボニル
Ｂｎ：ベンジル
ＣＯＭＵ：{{[（１－シアノ－２－エトキシ－２－オキソエチリデン）アミノ]オキシ}－４－モルホリノメチレン}ジメチルアンモニウム　ヘキサフルオロリン酸塩
ＤＭＥ：１，２－ジメトキシエタン
ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
ＤＩＰＥＡ：Ｎ，Ｎ－ジイソプロピルエチルアミン
ＨＡＴＵ：Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム　ヘキサフルオロリン酸塩
Ｍｅ：メチル
ＴＦＡ：２，２，２－トリフルオロ酢酸
　化合物名はＣａｍｂｒｉｄｇｅ社のＣｈｅｍＢｉｏＤｒａｗ　Ｕｌｔｒａ　ｖｅｒ．１２．０．３を用い命名した。
　以下の製造例中の「室温」は通常約１０℃から約３５℃を示す。％は特記しない限り重量パーセントを示す。 Hereinafter, the present invention will be specifically described with reference to examples. In the following examples, the following abbreviations are used.
Boc: tert-butoxycarbonyl Bn: benzyl COMU: {{[(1-cyano-2-ethoxy-2-oxoethylidene) amino] oxy} -4-morpholinomethylene} dimethylammonium hexafluorophosphate DME: 1,2 -Dimethoxyethane DMF: N, N-dimethylformamide DIPEA: N, N-diisopropylethylamine HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexa Fluorophosphate Me: Methyl TFA: 2,2,2-trifluoroacetic acid The compound name is ChemBioDraw Ultra ver. Manufactured by Cambridge. Named using 12.0.3.
“Room temperature” in the following production examples usually indicates about 10 ° C. to about 35 ° C. % Indicates weight percent unless otherwise specified.
製造例（１） Production example (1)
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
（１）ｔｅｒｔ－ブチル　（２－（（３－ニトロフェニル）アミノ）エチル）カーバメイト (1) tert-butyl (2-((3-nitrophenyl) amino) ethyl) carbamate
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
　アルゴン雰囲気下、３－フルオロニトロベンゼン（３．２１ｍＬ）にエチレンジアミン（２５．０ｍＬ）を加え、１００℃で２４時間撹拌した。この反応液に、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣のジクロロメタン（５０ｍＬ）溶液にトリエチルアミン（４．６０ｍＬ）および二炭酸ジ－ｔｅｒｔ－ブチル（６．５５ｇ）を加え、室温で２時間撹拌した。この反応液に、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝１／４→１／３）で精製し、ｔｅｒｔ－ブチル　（２－（（３－ニトロフェニル）アミノ）エチル）カーバメイト（５．３１ｇ）を得た。 In an argon atmosphere, ethylenediamine (25.0 mL) was added to 3-fluoronitrobenzene (3.21 mL), and the mixture was stirred at 100 ° C. for 24 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. Triethylamine (4.60 mL) and di-tert-butyl dicarbonate (6.55 g) were added to a solution of the obtained residue in dichloromethane (50 mL), and the mixture was stirred at room temperature for 2 hr. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/4 → 1/3), and tert-butyl (2-((3-nitrophenyl) amino) ethyl) carbamate (5 .31 g) was obtained.
（２）ｔｅｒｔ－ブチル　（２－（（３－アミノフェニル）（ベンジル）アミノ）エチル）カーバメイト (2) tert-butyl (2-((3-aminophenyl) (benzyl) amino) ethyl) carbamate
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
（ｉ）アルゴン雰囲気下、ｔｅｒｔ－ブチル　（２－（（３－ニトロフェニル）アミノ）エチル）カーバメイト（４．４６ｇ）のジクロロメタン（３０．０ｍＬ）溶液に５０ｗｔ％水酸化ナトリウム水溶液（１０．０ｍＬ）、ベンジルブロミド（２．８４ｍＬ）およびテトラブチルアンモニウムヨージド（５８７．０ｍｇ）を加え、室温で４８時間撹拌した。この反応液に、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝１／６→１／４）で精製し、ｔｅｒｔ－ブチル　（２－（ベンジル（３－ニトロフェニル）アミノ）エチル）カーバメイト（４．６２ｇ）を得た。
（ｉｉ）アルゴン雰囲気下、ｔｅｒｔ－ブチル　（２－（ベンジル（３－ニトロフェニル）アミノ）エチル）カーバメイトのエタノール（５０．０ｍＬ）および水（２０．０ｍＬ）混合懸濁液に塩化アンモニウム（６．６９ｇ）および鉄粉（４．８６ｇ）を加え、２時間加熱還流した。この反応液をセライト濾過し、濾液を濃縮した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をアミンシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／酢酸エチル＝２／１）で精製し、ｔｅｒｔ－ブチル　（２－（（３－アミノフェニル）（ベンジル）アミノ）エチル）カーバメイト（４．５８ｇ）を得た。 (I) A solution of tert-butyl (2-((3-nitrophenyl) amino) ethyl) carbamate (4.46 g) in dichloromethane (30.0 mL) in a 50 wt% aqueous sodium hydroxide solution (10.0 mL) under an argon atmosphere , Benzyl bromide (2.84 mL) and tetrabutylammonium iodide (587.0 mg) were added, and the mixture was stirred at room temperature for 48 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/6 → 1/4), and tert-butyl (2- (benzyl (3-nitrophenyl) amino) ethyl) carbamate ( 4.62 g) was obtained.
(Ii) Ammonium chloride (6. 6) in a mixed suspension of tert-butyl (2- (benzyl (3-nitrophenyl) amino) ethyl) carbamate in ethanol (50.0 mL) and water (20.0 mL) under an argon atmosphere. 69 g) and iron powder (4.86 g) were added and heated to reflux for 2 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by amine silica gel column chromatography (eluent: chloroform / ethyl acetate = 2/1) to give tert-butyl (2-((3-aminophenyl) (benzyl) amino) ethyl) carbamate (4 .58 g) was obtained.
（３）ｔｅｒｔ－ブチル　（２－（（ベンジル）（３－（５－ブロモ－２－メトキシフェニルスルホンアミド）フェニル）アミノ）エチル）カーバメイト (3) tert-butyl (2-((benzyl) (3- (5-bromo-2-methoxyphenylsulfonamido) phenyl) amino) ethyl) carbamate
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
　アルゴン雰囲気下、ｔｅｒｔ－ブチル　（２－（（３－アミノフェニル）（ベンジル）アミノ）エチル）カーバメイト（１．５９ｇ）のジクロロメタン（２０．０ｍＬ）溶液にピリジン（４１３μＬ）および５－ブロモ－２－メトキシベンゼンスルホニルクロリド（１．３３ｇ）を加え、室温で終夜撹拌した。この反応液に、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝１／２）で精製し、ｔｅｒｔ－ブチル　（２－（（ベンジル）（３－（５－ブロモ－２－メトキシフェニルスルホンアミド）フェニル）アミノ）エチル）カーバメイト（２．５３ｇ）を得た。 Under an argon atmosphere, tert-butyl (2-((3-aminophenyl) (benzyl) amino) ethyl) carbamate (1.59 g) in dichloromethane (20.0 mL) was added to pyridine (413 μL) and 5-bromo-2- Methoxybenzenesulfonyl chloride (1.33 g) was added and stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/2) and tert-butyl (2-((benzyl) (3- (5-bromo-2-methoxyphenylsulfonamide)). ) Phenyl) amino) ethyl) carbamate (2.53 g) was obtained.
（４）３’－（Ｎ－（３－（（２－アミノエチル）アミノ）フェニル）スルファモイル）－４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド　二塩酸塩 (4) 3 ′-(N- (3-((2-aminoethyl) amino) phenyl) sulfamoyl) -4′-methoxy-N, N-dimethyl- [1,1′-biphenyl] -3-carboxamide Hydrochloride
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
（ｉ）アルゴン雰囲気下、ｔｅｒｔ－ブチル　（２－（（ベンジル）（３－（５－ブロモ－２－メトキシフェニルスルホンアミド）フェニル）アミノ）エチル）カーバメイト（４．６６ｇ）のＤＭＥ（８０．０ｍＬ）溶液に３－（Ｎ，Ｎ－ジメチルアミノカルボニル）フェニルボロン酸（３．５６ｇ）、炭酸ナトリウム（１．８０ｇ）、水（８．０ｍＬ）およびテトラキス（トリフェニルホスフィン）パラジウム（４６３．２ｍｇ）を加え、終夜加熱還流した。この反応液をセライト濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝７／５→１／１）で精製し、ｔｅｒｔ－ブチル　（２－（（ベンジル）（３－（３’－Ｎ，Ｎ－ジメチルアミノカルボニル－４－メトキシ－［１，１’－ビフェニル］－３－イルスルホンアミド）フェニル）アミノ）エチル）カーバメイト（４．８５ｇ）を得た。
（ｉｉ）ｔｅｒｔ－ブチル　（２－（ベンジル（３－（３’－Ｎ，Ｎ－ジメチルアミノカルボニル－４－メトキシ－［１，１’－ビフェニル］－３－イルスルホンアミド）フェニル）アミノ）エチル）カーバメイト（１．５０ｇ）のメタノール（３０．０ｍＬ）溶液に水酸化パラジウム（２２１．０ｍｇ）を加え、水素雰囲気下、室温で３時間撹拌した。この反応液をセライト濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル）で精製し、ｔｅｒｔ－ブチル　（２－（（３－（３’－（ジメチルアミノカルバモイル）－４－メトキシ［１，１’－ビフェニル］－３－イルスルホンアミド）フェニル）アミノ）エチル）カーバメイト（９５０．０ｍｇ）を得た。
（ｉｉｉ）ｔｅｒｔ－ブチル　（２－（（３－（３’－（ジメチルアミノカルバモイル）－４－メトキシ［１，１’－ビフェニル］－３－イルスルホンアミド）フェニル）アミノ）エチル）カーバメイト（２０３．０ｍｇ）に１０％塩化水素－メタノール溶液（４．０ｍＬ）を加え、５０℃で２時間撹拌した。この反応液を濃縮、乾燥することにより、３’－（Ｎ－（３－（（２－アミノエチル）アミノ）フェニル）スルファモイル）－４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド　二塩酸塩（１８７．０ｍｇ）を得た。 (I) DME (80.0 mL) of tert-butyl (2-((benzyl) (3- (5-bromo-2-methoxyphenylsulfonamido) phenyl) amino) ethyl) carbamate (4.66 g) under argon atmosphere ) 3- (N, N-dimethylaminocarbonyl) phenylboronic acid (3.56 g), sodium carbonate (1.80 g), water (8.0 mL) and tetrakis (triphenylphosphine) palladium (463.2 mg) And heated to reflux overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 7/5 → 1/1), and tert-butyl (2-((benzyl) (3- (3′-N, N -Dimethylaminocarbonyl-4-methoxy- [1,1'-biphenyl] -3-ylsulfonamido) phenyl) amino) ethyl) carbamate (4.85 g) was obtained.
(Ii) tert-butyl (2- (benzyl (3- (3′-N, N-dimethylaminocarbonyl-4-methoxy- [1,1′-biphenyl] -3-ylsulfonamido) phenyl) amino) ethyl) Palladium hydroxide (221.0 mg) was added to a solution of carbamate (1.50 g) in methanol (30.0 mL), and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) and tert-butyl (2-((3- (3 ′-(dimethylaminocarbamoyl) -4-methoxy [1,1′-biphenyl] ] -3-ylsulfonamido) phenyl) amino) ethyl) carbamate (950.0 mg) was obtained.
(Iii) tert-butyl (2-((3- (3 ′-(dimethylaminocarbamoyl) -4-methoxy [1,1′-biphenyl] -3-ylsulfonamido) phenyl) amino) ethyl) carbamate (203 0.0 mg) was added 10% hydrogen chloride-methanol solution (4.0 mL), and the mixture was stirred at 50 ° C. for 2 hours. The reaction solution is concentrated and dried to give 3 ′-(N- (3-((2-aminoethyl) amino) phenyl) sulfamoyl) -4′-methoxy-N, N-dimethyl- [1,1 ′. -Biphenyl] -3-carboxamide dihydrochloride (187.0 mg) was obtained.
（５）４’－メトキシ－Ｎ，Ｎ－ジメチル－３’－（Ｎ－（３－（（２－（４－メチルベンズアミド）エチル）アミノ）フェニル）スルファモイル）－［１，１’－ビフェニル］－３－カルボキサミド (5) 4′-methoxy-N, N-dimethyl-3 ′-(N- (3-((2- (4-methylbenzamido) ethyl) amino) phenyl) sulfamoyl)-[1,1′-biphenyl] -3-carboxamide
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
　アルゴン雰囲気下、３’－（Ｎ－（３－（（２－アミノエチル）アミノ）フェニル）スルファモイル）－４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド　二塩酸塩（４１．２ｍｇ）のピリジン（１．５０ｍＬ）溶液に４－トルオイルクロリド（４５．７μＬ）を加え、室温で終夜撹拌した。この反応液に、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を１規定塩酸および飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝２／１→１／０）で精製し、４’－メトキシ－Ｎ，Ｎ－ジメチル－３’－（Ｎ－（３－（（２－（４－メチルベンズアミド）エチル）アミノ）フェニル）スルファモイル）－［１，１’－ビフェニル］－３－カルボキサミド（１９．５ｍｇ）を得た。 3 '-(N- (3-((2-aminoethyl) amino) phenyl) sulfamoyl) -4'-methoxy-N, N-dimethyl- [1,1'-biphenyl] -3-carboxamide under argon atmosphere 4-Toluoyl chloride (45.7 μL) was added to a solution of dihydrochloride (41.2 mg) in pyridine (1.50 mL), and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with 1N hydrochloric acid and saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 2/1 → 1/0), and 4′-methoxy-N, N-dimethyl-3 ′-(N- (3- ((2- (4-Methylbenzamido) ethyl) amino) phenyl) sulfamoyl)-[1,1′-biphenyl] -3-carboxamide (19.5 mg) was obtained.
　以下の表１～４の化合物についても、同様に対応するＲ基を有するカルボン酸から合成を行った。 The compounds shown in Tables 1 to 4 below were also synthesized from carboxylic acids having a corresponding R group.
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
製造例（２） Production example (2)
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
（１）Ｎ－（３－（（２－アミノエチル）（ベンジル）アミノ）フェニル）－５－ブロモ－２－メトキシベンゼンスルホンアミド (1) N- (3-((2-aminoethyl) (benzyl) amino) phenyl) -5-bromo-2-methoxybenzenesulfonamide
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
　アルゴン雰囲気下、ｔｅｒｔ－ブチル　（２－（（ベンジル）（３－（５－ブロモ－２－メトキシフェニルスルホンアミド）フェニル）アミノ）エチル）カーバメイト（３．０４ｇ）のジクロロメタン（５１．０ｍＬ）溶液にＴＦＡ（７．８９ｍＬ）を氷冷下加え、室温に昇温し終夜撹拌した。この反応液を濃縮し、残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を濃縮し、乾燥することでＮ－（３－（（２－アミノエチル）（ベンジル）アミノ）フェニル）－５－ブロモ－２－メトキシベンゼンスルホンアミド（２．７８ｇ）を得た。 To a solution of tert-butyl (2-((benzyl) (3- (5-bromo-2-methoxyphenylsulfonamido) phenyl) amino) ethyl) carbamate (3.04 g) in dichloromethane (51.0 mL) under an argon atmosphere TFA (7.89 mL) was added under ice cooling, and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was concentrated and dried to obtain N- (3-((2-aminoethyl) (benzyl) amino) phenyl) -5-bromo-2-methoxybenzenesulfonamide (2.78 g).
（２）Ｎ－（２－（ベンジル（３－（５－ブロモ－２－メトキシフェニルスルホンアミド）フェニル）アミノ）エチル）－３－メチルベンズアミド (2) N- (2- (benzyl (3- (5-bromo-2-methoxyphenylsulfonamido) phenyl) amino) ethyl) -3-methylbenzamide
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
　アルゴン雰囲気下、３－トルイル酸（８８０．０ｍｇ）のＤＭＦ（２７．０ｍＬ）溶液に、ＤＩＰＥＡ（１．８８ｍＬ）、ＣＯＭＵ（２．７７ｇ）、Ｎ－（３－（（２－アミノエチル）（ベンジル）アミノ）フェニル）－５－ブロモ－２－メトキシベンゼンスルホンアミド（２．６４ｇ）を氷冷下加え、室温に昇温し終夜撹拌した。この反応液に、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝１／９→３／７）で精製し、Ｎ－（２－（ベンジル（３－（５－ブロモ－２－メトキシフェニルスルホンアミド）フェニル）アミノ）エチル）－３－メチルベンズアミド（３．２２ｇ）を得た。 Under an argon atmosphere, a solution of 3-toluic acid (880.0 mg) in DMF (27.0 mL) was added to DIPEA (1.88 mL), COMU (2.77 g), N- (3-((2-aminoethyl) ( Benzyl) amino) phenyl) -5-bromo-2-methoxybenzenesulfonamide (2.64 g) was added under ice cooling, and the mixture was warmed to room temperature and stirred overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/9 → 3/7), and N- [2- (benzyl (3- (5-bromo-2-methoxyphenylsulfone) was obtained. Amide) phenyl) amino) ethyl) -3-methylbenzamide (3.22 g) was obtained.
（３）Ｎ－（２－（（３－（４－メトキシ－［１，１’－ビフェニル］－３－イルスルホンアミド）フェニル）アミノ）エチル）－３－メチルベンズアミド (3) N- (2-((3- (4-Methoxy- [1,1'-biphenyl] -3-ylsulfonamido) phenyl) amino) ethyl) -3-methylbenzamide
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
（ｉ）アルゴン雰囲気下、Ｎ－（２－（ベンジル（３－（５－ブロモ－２－メトキシフェニルスルホンアミド）フェニル）アミノ）エチル）－３－メチルベンズアミド（５０．０ｍｇ）のＤＭＥ（３．３ｍＬ）溶液にフェニルボロン酸（１２．０ｍｇ）、炭酸ナトリウム（１４．７ｍｇ）、水（６６０μＬ）およびテトラキス（トリフェニルホスフィン）パラジウム（４．７ｍｇ）を加え、終夜加熱還流した。この反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝３／７→４／６）で精製し、Ｎ－（２－（ベンジル（３－（４－メトキシ－［１，１’－ビフェニル］－３－イルスルホンアミド）フェニル）アミノ）エチル）－３－メチルベンズアミド（４８．０ｍｇ）を得た。
（ｉｉ）Ｎ－（２－（ベンジル（３－（４－メトキシ－［１，１’－ビフェニル］－３－イルスルホンアミド）フェニル）アミノ）エチル）－３－メチルベンズアミド（３４．０ｍｇ）のＴＨＦ（２．０ｍＬ）溶液に水酸化パラジウム（８．０ｍｇ）を加え、水素雰囲気下、室温で終夜撹拌した。この反応液をセライト濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝４／１→１／０）で精製し、Ｎ－（２－（（３－（４－メトキシ－［１，１’－ビフェニル］－３－イルスルホンアミド）フェニル）アミノ）エチル）－３－メチルベンズアミド（２４．０ｍｇ）を得た。 (I) DME of N- (2- (benzyl (3- (5-bromo-2-methoxyphenylsulfonamido) phenyl) amino) ethyl) -3-methylbenzamide (50.0 mg) under argon atmosphere (3. To the 3 mL solution, phenylboronic acid (12.0 mg), sodium carbonate (14.7 mg), water (660 μL) and tetrakis (triphenylphosphine) palladium (4.7 mg) were added and heated to reflux overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 3/7 → 4/6), and N- (2- (benzyl (3- (4-methoxy- [1,1 ′ -Biphenyl] -3-ylsulfonamido) phenyl) amino) ethyl) -3-methylbenzamide (48.0 mg) was obtained.
(Ii) N- (2- (benzyl (3- (4-methoxy- [1,1′-biphenyl] -3-ylsulfonamido) phenyl) amino) ethyl) -3-methylbenzamide (34.0 mg) Palladium hydroxide (8.0 mg) was added to a THF (2.0 mL) solution, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 4/1 → 1/0), and N- (2-((3- (4-methoxy- [1,1′- Biphenyl] -3-ylsulfonamido) phenyl) amino) ethyl) -3-methylbenzamide (24.0 mg) was obtained.
　以下の表５の化合物についても、同様に対応するＲ基を有するボロン酸から合成を行った。 The following compounds in Table 5 were similarly synthesized from boronic acid having a corresponding R group.
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
製造例（３） Production example (3)
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
（１）３－（４－メトキシフェニル）－Ｎ，Ｎ－ジメチルプロパンアミド (1) 3- (4-Methoxyphenyl) -N, N-dimethylpropanamide
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
　アルゴン雰囲気下、３－（４－メトキシフェニル）プロピオン酸（９００．０ｍｇ）のジクロロメタン（２０．０ｍＬ）溶液に、ジメチルアミン塩酸塩（３．８０ｇ）、ジイソプロピルエチルアミン（１．７ｍＬ）およびＨＡＴＵ（４．０５ｇ）を加え、室温で終夜攪拌した。この反応液に、純水を加え、クロロホルム抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝１／１）で精製し、３－（４－メトキシフェニル）－Ｎ，Ｎ－ジメチルプロパンアミド（１．００ｇ）を得た。 Under an argon atmosphere, a solution of 3- (4-methoxyphenyl) propionic acid (900.0 mg) in dichloromethane (20.0 mL) was added dimethylamine hydrochloride (3.80 g), diisopropylethylamine (1.7 mL) and HATU (4 0.05 g) and stirred at room temperature overnight. To this reaction solution, pure water was added and extracted with chloroform. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/1) to obtain 3- (4-methoxyphenyl) -N, N-dimethylpropanamide (1.00 g). .
（２）５－（３－（ジメチルアミノ）－３－オキソプロピル）－２－メトキシベンゼン－１－スルホニルクロリド (2) 5- (3- (Dimethylamino) -3-oxopropyl) -2-methoxybenzene-1-sulfonyl chloride
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
　アルゴン雰囲気下、塩化スルホン酸（３３２μＬ）に３－（４－メトキシフェニル）－Ｎ，Ｎ－ジメチルプロパンアミド（２０７．０ｍｇ）のジクロロメタン（１．０ｍＬ）溶液をゆっくりと滴下し、氷冷下で３０分間攪拌した。その後反応液を室温まで昇温し、終夜攪拌した。この反応液を氷に流し込み、１時間攪拌した。生じた白色固体を濾取し、冷水で洗浄した。得られた固体を真空下で乾燥し、５－（３－（ジメチルアミノ）－３－オキソプロピル）－２－メトキシベンゼン－１－スルホニルクロリド（２４５．０ｍｇ）を得た。 Under an argon atmosphere, a solution of 3- (4-methoxyphenyl) -N, N-dimethylpropanamide (207.0 mg) in dichloromethane (1.0 mL) was slowly added dropwise to chlorosulfonic acid (332 μL), and the mixture was ice-cooled. Stir for 30 minutes. The reaction mixture was then warmed to room temperature and stirred overnight. The reaction solution was poured into ice and stirred for 1 hour. The resulting white solid was collected by filtration and washed with cold water. The resulting solid was dried under vacuum to give 5- (3- (dimethylamino) -3-oxopropyl) -2-methoxybenzene-1-sulfonyl chloride (245.0 mg).
（３）Ｎ－（２－（（３－アミノフェニル）アミノ）エチル）－２－（ジメチルアミノ）ベンズアミド (3) N- (2-((3-aminophenyl) amino) ethyl) -2- (dimethylamino) benzamide
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
（ｉ）アルゴン雰囲気下、３－フルオロニトロベンゼン（２．２０ｍＬ）にエチレンジアミン（１５．０ｍＬ）を加え、１００℃で２４時間撹拌した。この反応液に、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮することでＮ－（３－ニトロフェニル）－１，２－エチレンジアミン（３．４４ｇ）を得た。
（ｉｉ）アルゴン雰囲気下、２－ジメチルアミノ安息香酸（９００．０ｍｇ）のジクロロメタン（２０．０ｍＬ）溶液に、Ｎ－（３－ニトロフェニル）－１，２－エチレンジアミン（９８７．２ｍｇ）、トリエチルアミン（１．４９ｍＬ）およびＨＡＴＵ（２．４９ｇ）を加え、室温で終夜攪拌した。この反応液に、純水を加え、クロロホルム抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝１／１→３／１）で精製し、２－（ジメチルアミノ）－Ｎ－（２－（（３－ニトロフェニル）アミノ）エチル）ベンズアミド（１．４０ｇ）を得た。
（ｉｉｉ）２－（ジメチルアミノ）－Ｎ－（２－（（３－ニトロフェニル）アミノ）エチル）ベンズアミド（１．４０ｇ）のメタノール（２０．０ｍＬ）溶液に１０％パラジウム／炭素（３２０．０ｍｇ）を加え、水素雰囲気下、室温で２４時間攪拌した。この反応液をセライト濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル）で精製し、Ｎ－（２－（（３－アミノフェニル）アミノ）エチル）－２－（ジメチルアミノ）ベンズアミド（１．２０ｇ）を得た。 (I) Under an argon atmosphere, ethylenediamine (15.0 mL) was added to 3-fluoronitrobenzene (2.20 mL), and the mixture was stirred at 100 ° C. for 24 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated to give N- (3-nitrophenyl) -1,2-ethylenediamine (3.44 g).
(Ii) Under a argon atmosphere, a solution of 2-dimethylaminobenzoic acid (900.0 mg) in dichloromethane (20.0 mL) was mixed with N- (3-nitrophenyl) -1,2-ethylenediamine (987.2 mg), triethylamine ( 1.49 mL) and HATU (2.49 g) were added and stirred at room temperature overnight. To this reaction solution, pure water was added and extracted with chloroform. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/1 → 3/1) to give 2- (dimethylamino) -N- (2-((3-nitrophenyl) amino. ) Ethyl) benzamide (1.40 g) was obtained.
(Iii) 2- (dimethylamino) -N- (2-((3-nitrophenyl) amino) ethyl) benzamide (1.40 g) in methanol (20.0 mL) in 10% palladium / carbon (320.0 mg) ) And stirred at room temperature for 24 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give N- (2-((3-aminophenyl) amino) ethyl) -2- (dimethylamino) benzamide (1.20 g). Obtained.
（４）２－（ジメチルアミノ）－Ｎ－（２－（（３－（５－（３－（ジメチルアミノ）－３－オキソプロピル）－２－メトキシフェニルスルホンアミド）フェニル）アミノ）エチル）ベンズアミド (4) 2- (Dimethylamino) -N- (2-((3- (5- (3- (dimethylamino) -3-oxopropyl) -2-methoxyphenylsulfonamido) phenyl) amino) ethyl) benzamide
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
　アルゴン雰囲気下、Ｎ－（２－（（３－アミノフェニル）アミノ）エチル）－２－（ジメチルアミノ）ベンズアミド（１０．０ｍｇ）のピリジン（１．０ｍＬ）溶液に５－（３－（ジメチルアミノ）－３－オキソプロピル）－２－メトキシベンゼン－１－スルホニルクロリド（９．７０ｍｇ）を加え、室温で終夜撹拌した。反応液を濃縮後、残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル）で精製し、２－（ジメチルアミノ）－Ｎ－（２－（（３－（５－（３－（ジメチルアミノ）－３－オキソプロピル）－２－メトキシフェニルスルホンアミド）フェニル）アミノ）エチル）ベンズアミド（１５．０ｍｇ）を得た。 To a solution of N- (2-((3-aminophenyl) amino) ethyl) -2- (dimethylamino) benzamide (10.0 mg) in pyridine (1.0 mL) under an argon atmosphere, 5- (3- (dimethylamino ) -3-Oxopropyl) -2-methoxybenzene-1-sulfonyl chloride (9.70 mg) was added and stirred at room temperature overnight. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 2- (dimethylamino) -N- (2-((3- (5- (3- (dimethylamino) -3-oxo. Propyl) -2-methoxyphenylsulfonamido) phenyl) amino) ethyl) benzamide (15.0 mg) was obtained.
製造例（４） Production example (4)
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
（１）Ｎ－（２－（（３－アミノフェニル）アミノ）エチル）－２－メトキシベンズアミド (1) N- (2-((3-aminophenyl) amino) ethyl) -2-methoxybenzamide
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
（ｉ）アルゴン雰囲気下、２－メトキシ安息香酸（５０１．０ｍｇ）のジクロロメタン（５．０ｍＬ）溶液に、Ｎ－（３－ニトロフェニル）－１，２－エチレンジアミン（５００．０ｍｇ）、トリエチルアミン（１．４３ｍＬ）およびＨＡＴＵ（３．１０ｇ）を加え、室温で終夜攪拌した。この反応液に、純水を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝１／１→３／１）で精製し、２－メトキシ－Ｎ－（２－（（３－ニトロフェニル）アミノ）エチル）ベンズアミド（５５０．０ｍｇ）を得た。
（ｉｉ）２－メトキシ－Ｎ－（２－（（３－ニトロフェニル）アミノ）エチル）ベンズアミド（５５０．０ｍｇ）のメタノール（１１０．０ｍＬ）溶液に１０％パラジウム／炭素（３０．０ｍｇ）を加え、水素雰囲気下、室温で２４時間攪拌した。この反応液をセライト濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル）で精製し、Ｎ－（２－（（３－アミノフェニル）アミノ）エチル）－２－メトキシベンズアミド（４９２．４ｍｇ）を得た。 (I) Under a argon atmosphere, a solution of 2-methoxybenzoic acid (501.0 mg) in dichloromethane (5.0 mL) was mixed with N- (3-nitrophenyl) -1,2-ethylenediamine (500.0 mg), triethylamine (1 .43 mL) and HATU (3.10 g) were added and stirred at room temperature overnight. To this reaction solution, pure water was added and extracted with chloroform. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/1 → 3/1) and 2-methoxy-N- (2-((3-nitrophenyl) amino) ethyl) Benzamide (550.0 mg) was obtained.
(Ii) 10% palladium / carbon (30.0 mg) was added to a solution of 2-methoxy-N- (2-((3-nitrophenyl) amino) ethyl) benzamide (550.0 mg) in methanol (110.0 mL). The mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain N- (2-((3-aminophenyl) amino) ethyl) -2-methoxybenzamide (492.4 mg).
（２）Ｎ－（２－（（３－（５－ブロモ－２－メトキシフェニルスルホンアミド）フェニル）アミノ）エチル）－２－メトキシベンズアミド (2) N- (2-((3- (5-Bromo-2-methoxyphenylsulfonamido) phenyl) amino) ethyl) -2-methoxybenzamide
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
　アルゴン雰囲気下、Ｎ－（２－（（３－アミノフェニル）アミノ）エチル）－２－メトキシベンズアミド（１９２．２ｍｇ）のピリジン（２．０ｍＬ）溶液に５－ブロモ－２－メトキシベンゼンスルホニルクロリド（２３０．３ｍｇ）を加え、室温で終夜撹拌した。反応液を濃縮後、残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝１／２）で精製し、Ｎ－（２－（（３－（５－ブロモ－２－メトキシフェニルスルホンアミド）フェニル）アミノ）エチル）－２－メトキシベンズアミド（３０４．０ｍｇ）を得た。 Under an argon atmosphere, a solution of N- (2-((3-aminophenyl) amino) ethyl) -2-methoxybenzamide (192.2 mg) in pyridine (2.0 mL) was added to 5-bromo-2-methoxybenzenesulfonyl chloride ( 230.3 mg) was added and stirred at room temperature overnight. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/2) to give N- (2-((3- (5-bromo-2-methoxyphenylsulfonamido) phenyl) amino. ) Ethyl) -2-methoxybenzamide (304.0 mg) was obtained.
（３）４’－メトキシ－３’－（Ｎ－（３－（（２－（２－メトキシベンズアミド）エチル）アミノ）フェニル）スルファモイル）－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－４－カルボキサミド (3) 4′-methoxy-3 ′-(N- (3-((2- (2-methoxybenzamido) ethyl) amino) phenyl) sulfamoyl) -N, N-dimethyl- [1,1′-biphenyl] -4-carboxamide
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　アルゴン雰囲気下、Ｎ－（２－（（３－（５－ブロモ－２－メトキシフェニルスルホンアミド）フェニル）アミノ）エチル）－２－メトキシベンズアミド（５３．０ｍｇ）のＤＭＥ（３．０ｍＬ）溶液に４－（Ｎ，Ｎ－ジメチルアミノカルボニル）フェニルボロン酸（２９．０ｍｇ）、炭酸ナトリウム（２９．０ｍｇ）、水（１５０．０μＬ）およびテトラキス（トリフェニルホスフィン）パラジウム（６．０ｍｇ）を加え、終夜加熱還流した。この反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル）で精製し、４’－メトキシ－３’－（Ｎ－（３－（（２－（２－メトキシベンズアミド）エチル）アミノ）フェニル）スルファモイル）－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－４－カルボキサミド（５８．０ｍｇ）を得た。 In a DME (3.0 mL) solution of N- (2-((3- (5-bromo-2-methoxyphenylsulfonamido) phenyl) amino) ethyl) -2-methoxybenzamide (53.0 mg) under an argon atmosphere. 4- (N, N-dimethylaminocarbonyl) phenylboronic acid (29.0 mg), sodium carbonate (29.0 mg), water (150.0 μL) and tetrakis (triphenylphosphine) palladium (6.0 mg) were added, Heated to reflux overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate), and 4′-methoxy-3 ′-(N- (3-((2- (2-methoxybenzamido) ethyl) amino) phenyl). Sulfamoyl) -N, N-dimethyl- [1,1′-biphenyl] -4-carboxamide (58.0 mg) was obtained.
製造例（５） Production example (5)
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
（１）３’－（ジメチルカルバモイル）－４－メトキシ－［１，１’－ビフェニル］－３－スルホニルクロリド (1) 3 '-(dimethylcarbamoyl) -4-methoxy- [1,1'-biphenyl] -3-sulfonyl chloride
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
（ｉ）アルゴン雰囲気下、４－ブロモアニソール（１．０ｍＬ）のＤＭＥ（２０．０ｍＬ）溶液に３－（Ｎ，Ｎ－ジメチルアミノカルボニル）フェニルボロン酸（１．６０ｇ）、炭酸ナトリウム（１．８０ｇ）、水（２．０ｍＬ）およびテトラキス（トリフェニルホスフィン）パラジウム（２５０．０ｍｇ）を加え、終夜加熱還流した。この反応液をセライト濾過し、濾液を濃縮した。得られた残渣に純水を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝１／２→１／１）で精製し、４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド（１．７２ｇ）を得た。
（ｉｉ）アルゴン雰囲気下、塩化スルホン酸（８７０μＬ）に４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド（１．１０ｇ）のジクロロメタン（４．０ｍＬ）溶液をゆっくりと滴下し、氷冷下で１０分間攪拌した。反応液を室温まで昇温し、２時間攪拌した後、塩化チオニル（９５０μＬ）、ＤＭＦ（１．７０ｍＬ）を加え、室温で終夜撹拌した。反応液を氷に流し込み、１時間攪拌した後、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝１／１→１／０）で精製し、３’－（ジメチルカルバモイル）－４－メトキシ－［１，１’－ビフェニル］－３－スルホニルクロリド（１．４０ｇ）を得た。 (I) Under a argon atmosphere, a solution of 4-bromoanisole (1.0 mL) in DME (20.0 mL) was added 3- (N, N-dimethylaminocarbonyl) phenylboronic acid (1.60 g) and sodium carbonate (1. 80 g), water (2.0 mL) and tetrakis (triphenylphosphine) palladium (250.0 mg) were added, and the mixture was heated to reflux overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated. Pure water was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/2 → 1/1), and 4′-methoxy-N, N-dimethyl- [1,1′-biphenyl]- 3-Carboxamide (1.72 g) was obtained.
(Ii) A solution of 4′-methoxy-N, N-dimethyl- [1,1′-biphenyl] -3-carboxamide (1.10 g) in dichloromethane (4.0 mL) in chlorosulfonic acid (870 μL) under an argon atmosphere. Was slowly added dropwise and stirred for 10 minutes under ice cooling. The reaction solution was warmed to room temperature and stirred for 2 hours, and then thionyl chloride (950 μL) and DMF (1.70 mL) were added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice and stirred for 1 hour, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/1 → 1/0), and 3 ′-(dimethylcarbamoyl) -4-methoxy- [1,1′-biphenyl]. -3-Sulphonyl chloride (1.40 g) was obtained.
（２）３’－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド (2) 3 ′-(N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4′-methoxy-N, N-dimethyl- [1,1 ′ -Biphenyl] -3-carboxamide
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
　アルゴン雰囲気下、３’－（ジメチルカルバモイル）－４－メトキシ－［１，１’－ビフェニル］－３－スルホニルクロリド（２３６．０ｍｇ）のジクロロメタン（４．０ｍＬ）溶液にＮ－（２－（（３－アミノフェニル）アミノ）エチル）－２－（ジメチルアミノ）ベンズアミド（２１０．０ｍｇ）、ＤＩＰＥＡ（３５０μＬ）を加え、室温で終夜撹拌した。この反応液に、純水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル）で精製し、３’－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド（１１３．０ｍｇ）を得た。 In an argon atmosphere, N- (2-(((3 ′-(dimethylcarbamoyl) -4-methoxy- [1,1′-biphenyl] -3-sulfonyl chloride (236.0 mg) in dichloromethane (4.0 mL)) was added. 3-Aminophenyl) amino) ethyl) -2- (dimethylamino) benzamide (210.0 mg) and DIPEA (350 μL) were added, and the mixture was stirred at room temperature overnight. To this reaction solution, pure water was added and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate), and 3 ′-(N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl). -4′-methoxy-N, N-dimethyl- [1,1′-biphenyl] -3-carboxamide (113.0 mg) was obtained.
（３）３’－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４’－ヒドロキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド (3) 3 ′-(N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4′-hydroxy-N, N-dimethyl- [1,1 ′ -Biphenyl] -3-carboxamide
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
　アルゴン雰囲気下、３’－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド（５３．０ｍｇ）のジクロロメタン（２．０ｍＬ）溶液に１．０Ｍ三臭化ホウ素ジクロロメタン溶液（１．６ｍＬ）を氷冷下で加え、３時間撹拌した。この反応液に、氷冷下で飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル）で精製し、３’－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４’－ヒドロキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド（６３．０ｍｇ）を得た。 Under an argon atmosphere, 3 ′-(N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4′-methoxy-N, N-dimethyl- [1,1 To a solution of '-biphenyl] -3-carboxamide (53.0 mg) in dichloromethane (2.0 mL) was added 1.0 M boron tribromide dichloromethane solution (1.6 mL) under ice-cooling, and the mixture was stirred for 3 hours. To this reaction solution, a saturated aqueous sodium hydrogen carbonate solution was added under ice cooling, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate), and 3 ′-(N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl). -4′-Hydroxy-N, N-dimethyl- [1,1′-biphenyl] -3-carboxamide (63.0 mg) was obtained.
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000046
製造例（６） Production example (6)
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
（１）３－（クロロスルホニル）－４－メトキシ安息香酸 (1) 3- (Chlorosulfonyl) -4-methoxybenzoic acid
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
　アルゴン雰囲気下、塩化スルホン酸（２．２０ｍＬ）に４－メトキシ安息香酸（１．００ｇ）をゆっくりと氷冷下加え、１０分間攪拌した。その後反応液を６５℃まで昇温し、２時間攪拌した。放冷後、この反応液を氷に流し込み、１時間攪拌した。生じた白色固体を濾取し、冷水で洗浄した。得られた固体を真空下で乾燥し、３－（クロロスルホニル）－４－メトキシ安息香酸（９６６．０ｍｇ）を得た。 In an argon atmosphere, 4-methoxybenzoic acid (1.00 g) was slowly added to chlorosulfonic acid (2.20 mL) under ice-cooling and stirred for 10 minutes. Thereafter, the reaction solution was heated to 65 ° C. and stirred for 2 hours. After allowing to cool, the reaction solution was poured into ice and stirred for 1 hour. The resulting white solid was collected by filtration and washed with cold water. The resulting solid was dried under vacuum to give 3- (chlorosulfonyl) -4-methoxybenzoic acid (966.0 mg).
（２）３－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４－メトキシ安息香酸 (2) 3- (N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4-methoxybenzoic acid
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
　アルゴン雰囲気下、Ｎ－（２－（（３－アミノフェニル）アミノ）エチル）－２－（ジメチルアミノ）ベンズアミド（３０７．０ｍｇ）のジクロロメタン（１０．０ｍＬ）溶液にピリジン（３．０ｍＬ）および３－（クロロスルホニル）－４－メトキシ安息香酸（３５０．０ｍｇ）を加え、室温で終夜撹拌した。この反応液に１．０Ｍ塩酸を加え、クロロホルムで抽出した。有機層に飽和炭酸水素ナトリウム水溶液を加え、生成物を水層に抽出した。水層に１．０Ｍ塩酸を加え中和し、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮することで３－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４－メトキシ安息香酸（４７０．０ｍｇ）を得た。 Under an argon atmosphere, N- (2-((3-aminophenyl) amino) ethyl) -2- (dimethylamino) benzamide (307.0 mg) in dichloromethane (10.0 mL) was added to pyridine (3.0 mL) and 3 -(Chlorosulfonyl) -4-methoxybenzoic acid (350.0 mg) was added, and the mixture was stirred overnight at room temperature. 1.0 M hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. A saturated aqueous sodium hydrogen carbonate solution was added to the organic layer, and the product was extracted into the aqueous layer. The aqueous layer was neutralized with 1.0M hydrochloric acid, and extracted with chloroform. The organic layer is dried over sodium sulfate, filtered, and the filtrate is concentrated to give 3- (N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4 -Methoxybenzoic acid (470.0 mg) was obtained.
（３）３－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４－メトキシ－Ｎ－（２－メトキシ－５－ニトロフェニル）ベンズアミド (3) 3- (N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4-methoxy-N- (2-methoxy-5-nitrophenyl) benzamide
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
　アルゴン雰囲気下、３－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４－メトキシ安息香酸（１５．６ｍｇ）のジクロロメタン（３．０ｍＬ）溶液に、２－メトキシ－５－ニトロアニリン（６．１ｍｇ）、トリエチルアミン（１０．０μＬ）およびＨＡＴＵ（３２．２ｍｇ）を加え、室温で終夜攪拌した。この反応液に、純水を加え、クロロホルム抽出した。有機層を硫酸ナトリウムで乾燥した後、濾過し、濾液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル／ヘキサン＝１／１→３／１）で精製し、３－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４－メトキシ－Ｎ－（２－メトキシ－５－ニトロフェニル）ベンズアミド（１０．４ｍｇ）を得た。 3- (N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4-methoxybenzoic acid (15.6 mg) in dichloromethane (3.0 mL) under argon atmosphere ) 2-methoxy-5-nitroaniline (6.1 mg), triethylamine (10.0 μL) and HATU (32.2 mg) were added to the solution, and the mixture was stirred at room temperature overnight. To this reaction solution, pure water was added and extracted with chloroform. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/1 → 3/1) to give 3- (N- (3-((2- (2- (dimethylamino) benzamide). ) Ethyl) amino) phenyl) sulfamoyl) -4-methoxy-N- (2-methoxy-5-nitrophenyl) benzamide (10.4 mg) was obtained.
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000051
製造例（７） Production example (7)
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
（１）３’－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド　二塩酸塩 (1) 3 ′-(N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4′-methoxy-N, N-dimethyl- [1,1 ′ -Biphenyl] -3-carboxamide dihydrochloride
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
　３’－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド（８６．３ｍｇ）のメタノール（３．０ｍＬ）溶液に１０％塩酸含有メタノール（３００μＬ）を加え、室温で撹拌した。この反応液を濃縮し、残渣に酢酸エチルを加えることで白色懸濁液を得た。得られた懸濁液を濾過後、残渣を酢酸エチルで洗浄し、室温で乾燥させることで３’－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミド　二塩酸塩（６７．９ｍｇ）を得た。
融点：１３２．０～１３３．０℃（ｄｅｃ．）
元素分析：Ａｎａｌ．Ｃａｌｃｄ　ｆｏｒ　Ｃ３３Ｈ３７Ｎ５Ｏ５Ｓ１・２ＨＣｌ・２．５Ｈ２Ｏ：Ｃ，５４．０２；Ｈ，６．０４；Ｎ，９．５５，　ｆｏｕｎｄ：Ｃ，５３．８８；Ｈ，６．１０；Ｎ，９．４２． 3 ′-(N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4′-methoxy-N, N-dimethyl- [1,1′-biphenyl] To a solution of -3-carboxamide (86.3 mg) in methanol (3.0 mL) was added 10% hydrochloric acid-containing methanol (300 μL), and the mixture was stirred at room temperature. The reaction solution was concentrated, and ethyl acetate was added to the residue to obtain a white suspension. The resulting suspension was filtered, and the residue was washed with ethyl acetate and dried at room temperature to give 3 ′-(N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) Phenyl) sulfamoyl) -4′-methoxy-N, N-dimethyl- [1,1′-biphenyl] -3-carboxamide dihydrochloride (67.9 mg) was obtained.
Melting point: 132.0-133.0 ° C. (dec.)
Elemental analysis: Anal. Calcd for C 33 H 37 N 5 O 5 S 1 · 2HCl · 2.5H 2 O: C, 54.02; H, 6.04; N, 9.55, found: C, 53.88; H, 6 .10; N, 9.42.
試験例１
ＯＸ２Ｒに対する作動活性評価
　チャイニーズハムスター卵巣由来細胞株であるＣＨＯ細胞にＮＡＦＴ－ルシフェラーゼ遺伝子およびヒトＯＸ２Ｒ遺伝子を恒常的に発現させた細胞株（ＣＨＯＯＸ２Ｒ）を樹立した。それらの細胞を９６ウェルマルチプレート中に１０，０００個／ウェルで播種し、５％　ＦＢＳ（サーモサイエンティフィック）添加ＤＭＥＭ培地（シグマアルドリッチ）で４８時間培養した。培地を除去後、５μＭ　Ｆｕｒａ－２ＡＭ（ケイマンケミカル）を含むアッセイ用緩衝液（２０ｍＭ ＨＥＰＥＳ（シグマアルドリッチ）、Ｈａｎｋｓ’　ｂａｌａｎｃｅｄ　ｓａｌｔ　ｓｏｌｕｔｉｏｎ（ギブコ）、０．１％　ＢＳＡ（シグマアルドリッチ）、２．５ｍＭ　プロベネシド酸（和光純薬工業））を１００μＬ添加し、６０分間インキュベートした。Ｆｕｒａ－２ＡＭを含む緩衝液を除去した後、アッセイ用緩衝液７５μＬを添加した。そこに被験化合物を含むアッセイ用緩衝液２５μＬを添加し、反応を開始した。反応による細胞内カルシウムイオン濃度の変化は、ＦＤＳＳ７０００（浜松ホトニクス）を用いて、３４０、３８０ｎｍの二波長励起による蛍光強度比を測定することにより測定した。なお、被験化合物は１０ｍＭとなるようにＤＭＳＯに溶解し、最終濃度が１０－７Ｍから１０－５Ｍとなるようにアッセイ用緩衝液で希釈した（ＤＭＳＯの最終濃度は１％）。表８および表９に各化合物の作動活性値を示した。 Test example 1
Evaluation of agonistic activity against OX2R A cell line (CHOOX2R) was established in which NAFT-luciferase gene and human OX2R gene were constantly expressed in CHO cells, a Chinese hamster ovary-derived cell line. These cells were seeded in a 96-well multiplate at 10,000 cells / well and cultured in DMEM medium (Sigma Aldrich) supplemented with 5% FBS (Thermo Scientific) for 48 hours. After removing the medium, assay buffer containing 20 μM Fura-2AM (Cayman Chemical) (20 mM HEPES (Sigma Aldrich), Hanks' balanced salt solution (Gibco), 0.1% BSA (Sigma Aldrich), 2.5 mM probenecid 100 μL of acid (Wako Pure Chemical Industries) was added and incubated for 60 minutes. After removing the buffer containing Fura-2AM, 75 μL of assay buffer was added. Thereto was added 25 μL of assay buffer containing the test compound, and the reaction was started. The change in intracellular calcium ion concentration due to the reaction was measured by measuring the fluorescence intensity ratio by excitation at two wavelengths of 340 and 380 nm using FDSS7000 (Hamamatsu Photonics). The test compound was dissolved in DMSO so that the concentration was 10 mM, and diluted with an assay buffer so that the final concentration was 10 −7 M to 10 −5 M (the final concentration of DMSO was 1%). Tables 8 and 9 show the activity values of each compound.
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000055
（ここで、表８および表９のＲｅｓｐｏｎｓｅとは、オレキシン－Ａをフルアゴニスト（作動活性の最大値：１００％）として、それぞれ０．１μＭ、１．０μＭ、１０μＭで被験化合物を評価した際の作動活性値をオレキシン－Ａの作動活性値で割った値を示す。） (Here, the responses in Tables 8 and 9 are the results when the test compound was evaluated at 0.1 μM, 1.0 μM, and 10 μM, respectively, using orexin-A as a full agonist (maximum value of agonist activity: 100%). (The value obtained by dividing the activity value by the activity value of orexin-A is shown.)
試験例２
本発明化合物の野生型マウスへの明期脳室内投与による覚醒効果
　実験動物は、Ｃ５７ＢＬ/６系統のＷＴマウス、ｎｅｇａｔｉｖｅ ｃｏｎｔｒｏｌとしてオレキシン受容体欠損マウス（ＤＫＯマウス）（いずれも雄）を用いた。９週齢前後(±１週間)で、イソフルラン麻酔下で、脳波用電極の頭蓋骨への埋め込み（Ｂｒｅｇｍａ：Ｘ＝１.５；Ｙ＝０.６，Ｌａｍｂｄａ：Ｘ＝１.５；Ｙ＝０）、筋電図用電極の僧帽筋への挿入手術を行った。脳室内投与を行うマウスには側脳室へのカニューラ埋め込みも行った（Ｂｒｅｇｍａ：Ｘ＝－０.９;Ｙ＝－０.３）。その２週間後から投与、脳波測定を開始した。実験は、明期の始まりを９時（ＺＴ０）、暗期の始まりを２１時（ＺＴ１２）とする明暗サイクル環境下で行った。
　ＷＴマウスに対して、ＺＴ６に、イソフルラン麻酔下で、マイクロシリンジポンプを用い被験化合物（実施例７の化合物（二塩酸塩））（３２ｎｍｏｌ，１３０ｎｍｏｌ，２６０ｎｍｏｌ；生理食塩水に溶解）６μＬを０.６μＬ/ｍｉｎの流速でカニューラを通して側脳室に注入し、その後の脳波筋電図を測定した。投与はコントロールの生理食塩水から始め、次に低濃度の被験化合物から投与を行った。それぞれ、投与後一日を回復期間とした。ＤＫＯマウスでも同様の手順で６μＬの生理食塩水、被験化合物（２６０ｎｍｏｌ）の脳室内投与を行い、その後の脳波筋電図を測定した。
　結果を図１に示す。
　マウスにとって睡眠期である明期（ＺＴ６）に被験化合物の脳室内投与を行ったところ、ＷＴマウスでは、コントロールの生理食塩水投与と比べて、覚醒時間が有意に増加した。また、被験化合物は用量依存的に覚醒時間を延長することが確認された。ＤＫＯマウスにおいては、生理食塩水投与後と被験化合物投与後の覚醒時間に有意な差は見られなかった。
　統計処理は、コントロールおよび被験化合物（３２ｎｍｏｌ，１３０ｎｍｏｌ，２６０ｎｍｏｌ）投与後２時間の累積覚醒時間をＡＮＯＶＡ-Ｂｏｎｆｆｅｒｏｎｉ法によって評価した。 Test example 2
Awakening effect of the compound of the present invention by intracerebroventricular administration to wild-type mice As experimental animals, C57BL / 6 strain WT mice and oregrin control orexin receptor-deficient mice (DKO mice) (both male) were used. Around 9 weeks of age (± 1 week) under isoflurane anesthesia, an electroencephalogram electrode was implanted into the skull (Bregma: X = 1.5; Y = 0.6, Lambda: X = 1.5; Y = 0) ), An operation of inserting an electromyographic electrode into the trapezius muscle was performed. Mice that received intraventricular administration were also cannula implanted in the lateral ventricle (Bregma: X = −0.9; Y = −0.3). Administration and electroencephalogram measurement were started 2 weeks later. The experiment was performed in a light-dark cycle environment in which the beginning of the light period was 9 o'clock (ZT0) and the beginning of the dark period was 21 o'clock (ZT12).
To a WT mouse, 6 μL of a test compound (the compound of Example 7 (dihydrochloride)) (32 nmol, 130 nmol, 260 nmol; dissolved in physiological saline) was added to ZT6 under isoflurane anesthesia using a microsyringe pump. Injection into the lateral ventricle through the cannula at a flow rate of 6 μL / min, and subsequent electroencephalogram electromyogram was measured. Administration began with control saline, followed by administration at low concentrations of the test compound. In each case, the recovery period was defined as one day after administration. In DKO mice, 6 μL of physiological saline and test compound (260 nmol) were administered into the ventricle in the same procedure, and the electroencephalogram after that was measured.
The results are shown in FIG.
When intraventricular administration of the test compound was performed in the light period (ZT6), which is a sleeping period for mice, the wakefulness time was significantly increased in WT mice compared to physiological saline administration. Moreover, it was confirmed that the test compound prolongs the awakening time in a dose-dependent manner. In DKO mice, there was no significant difference in the arousal time after administration of physiological saline and after administration of the test compound.
In statistical processing, the cumulative wake-up time of 2 hours after administration of the control and test compounds (32 nmol, 130 nmol, 260 nmol) was evaluated by the ANOVA-Bonferoni method.
試験例３
本発明化合物の野生型マウスへの明期腹腔内投与による覚醒効果
　実験動物は、Ｃ５７ＢＬ/６系統のＷＴマウス、ｎｅｇａｔｉｖｅ ｃｏｎｔｒｏｌ としてオレキシン受容体欠損マウス（ＤＫＯマウス）（いずれも雄）を用いた。９週齢前後（±１週間）で、イソフルラン麻酔下で、脳波用電極の頭蓋骨への埋め込み（Ｂｒｅｇｍａ：Ｘ＝１.５；Ｙ＝０.６，Ｌａｍｂｄａ：Ｘ＝１.５；Ｙ＝０）、筋電図用電極の僧帽筋への挿入手術を行った。その２週間後から投与、脳波測定を開始した。実験は、明期の始まりを９時（ＺＴ０）、暗期の始まりを２１時（ＺＴ１２）とする明暗サイクル環境下で行った。ＷＴマウス、ＤＫＯマウスに対して、ＺＴ６に、注射針付シリンジ（２９ゲージ）を用い腹腔内に１００μＬのコントロール（ｐＨ、ｏｓｍｏｌａｌｉｔｙ調整生理食塩水）、または被験化合物（実施例７の化合物（二塩酸塩））（４０ｍｇ/ｋｇ；生理食塩水に溶解）を注入し、その後の脳波筋電図を測定した。投与はコントロール、被験化合物の順に行い、投与後一日は回復期間とした。
　結果を図２に示す。
　ＺＴ６に被験化合物の腹腔内投与を行ったところ、ＷＴマウスでは、コントロールである生理食塩水投与と比べて、被験化合物投与後の覚醒時間が有意に増加した。ＤＫＯマウスにおいては、生理食塩水の投与後と被験化合物投与後の覚醒時間に有意な差は見られず、明期脳室内投与と同様の結果が確認された。
　統計処理は、コントロールおよび被験化合物（４０ｍｇ/ｋｇ）投与後２時間の累積覚醒時間を対応のあるｔ検定で評価した。 Test example 3
Awakening effect by intraperitoneal administration of the compound of the present invention to wild-type mice As experimental animals, C57BL / 6 strain WT mice and negative control orexin receptor-deficient mice (DKO mice) (both male) were used. Around 9 weeks of age (± 1 week) under isoflurane anesthesia, an electroencephalogram electrode was implanted into the skull (Bregma: X = 1.5; Y = 0.6, Lambda: X = 1.5; Y = 0) ), An operation of inserting an electromyographic electrode into the trapezius muscle was performed. Administration and electroencephalogram measurement were started 2 weeks later. The experiment was performed in a light-dark cycle environment in which the beginning of the light period was 9 o'clock (ZT0) and the beginning of the dark period was 21 o'clock (ZT12). For WT mice and DKO mice, 100 μL of control (pH, osmolality adjusted saline) or test compound (compound of Example 7 (dihydrochloric acid) in ZIP6 using a syringe with a needle (29 gauge) Salt)) (40 mg / kg; dissolved in physiological saline) was injected, and the electroencephalogram after that was measured. Administration was performed in the order of the control and the test compound, and one day after administration was the recovery period.
The results are shown in FIG.
When intraperitoneal administration of the test compound to ZT6 was performed, the wakefulness time after administration of the test compound was significantly increased in the WT mice as compared with the physiological saline administration as a control. In DKO mice, no significant difference was observed in the arousal time after administration of physiological saline and after administration of the test compound, and the same results as in the photoperiodic intraventricular administration were confirmed.
For statistical treatment, the cumulative arousal time of 2 hours after administration of the control and test compounds (40 mg / kg) was evaluated by the corresponding t-test.
試験例４
本発明化合物のオレキシン欠損マウス（ＯＸＫＯマウス）への暗期脳室内投与によるカタプレキシー抑制効果
　ＯＸＫＯマウスに対して、ＺＴ１０付近で、イソフルラン麻酔下で、マイクロシリンジポンプとマウスの頭蓋に埋め込んであるカニューラを連結させ、ＺＴ１５に０.６μＬ/ｍｉｎの流速で６μＬ注入するようにプログラムを組み、その後マウスの脳波筋電図測定を再開し、ＺＴ１５に６μＬのコントロール（ｐＨ、ｏｓｍｏｌａｌｉｔｙ調整生理食塩水）、または被験化合物（実施例７の化合物（二塩酸塩））（２６０ｎｍｏｌ; 生理食塩水に溶解）を、脳波筋電図測定下で自動的に投与した。投与はコントロール、被験化合物の順に行い、投与後一日は回復期間とした。また、ナルコレプシーの症状のひとつであるカタプレキシーは、ナルコレプシーモデルマウスにおいて、活動期(暗期)に多く、チョコレートを与えると増加することが知られている。そのため、今回の実験では、カタプレキシーを誘発するためにマウスにチョコレート（Ｈｅｒｓｈｅｙ’ｓ）を与えて脳波筋電図の測定を行った。
　マウスにとって活動期であり、ナルコレプシーモデルマウスにおいてカタプレキシーが見られる暗期（ＺＴ１５）に、ＯＸＫＯマウスに対して被験化合物の脳室内投与を行ったところ、コントロールとして行った生理食塩水の投与後ではカタプレキシーが確認されたのに対して、被験化合物の投与後はカタプレキシーが抑制された（図３）。ＤＫＯマウスもナルコレプシーモデルマウスで、カタプレキシーが観察されるが、被験化合物投与後のカタプレキシーは抑制されなかった（図４）。
　統計処理は、コントロールおよび被験化合物（２６０ｎｍｏｌ）投与後６時間までのカタプレキシーの累積発生回数を対応のあるｔ検定で評価した。覚醒状態からＲＥＭ睡眠への遷移をカタプレキシーとしてカウントした（図５）。 Test example 4
Inhibitory effect of cataplexy by intraventricular administration of the compound of the present invention to orexin-deficient mice (OXKO mice) In the vicinity of ZT10, under an isoflurane anesthesia, a cannula embedded in the skull of a mouse and a microsyringe pump Connected and programmed to inject 6 μL into ZT15 at a flow rate of 0.6 μL / min, and then resumed electroencephalogram electromyogram measurement in mice, and 6 μL control (pH, osmolality adjusted saline) in ZT15, or A test compound (the compound of Example 7 (dihydrochloride)) (260 nmol; dissolved in physiological saline) was automatically administered under electroencephalogram electromyogram measurement. Administration was performed in the order of the control and the test compound, and one day after administration was the recovery period. Cataplex, which is one of the symptoms of narcolepsy, is known to increase in the active period (dark period) in narcolepsy model mice and increase when chocolate is given. Therefore, in this experiment, in order to induce cataplexy, chocolate (Hershey's) was given to the mouse and electroencephalogram was measured.
Intraventricular administration of the test compound to OXKO mice was performed in the dark period (ZT15) in which cataplexy was observed in narcolepsy model mice, and the cataplexy was observed after administration of physiological saline as a control. Was confirmed, but cataplexy was suppressed after administration of the test compound (FIG. 3). DKO mice were also narcolepsy model mice, and cataplexy was observed, but cataplexy after test compound administration was not suppressed (FIG. 4).
In statistical processing, the cumulative number of cataplexy occurrences up to 6 hours after administration of the control and test compounds (260 nmol) was evaluated by a corresponding t-test. Transition from wakefulness to REM sleep was counted as cataplexy (FIG. 5).
試験例５
本発明化合物のオレキシン欠損マウス（ＯＸＫＯマウス）への暗期腹腔内投与によるカタプレキシー抑制効果
　実験動物は、オレキシン欠損マウス（ＯＸＫＯマウス）、ｎｅｇａｔｉｖｅ　ｃｏｎｔｒｏｌとしてオレキシン受容体欠損マウス（ＤＫＯマウス）（いずれも雄）を用いた。９週齢前後（±１週間）で、イソフルラン麻酔下で、脳波用電極の頭蓋骨への埋め込み（Ｂｒｅｇｍａ：Ｘ＝１．５；Ｙ＝０．６，Ｌａｍｂｄａ：Ｘ＝１．５；Ｙ＝０）、筋電図用電極の僧帽筋への挿入手術を行った。その２週間後から投与、脳波測定を開始した。実験は、明期の始まりを９時（ＺＴ０）、暗期の始まりを２１時（ＺＴ１２）とする明暗サイクル環境下で行った。ＯＸＫＯマウス、ＤＫＯマウスに対して、暗期ＺＴ１５に腹腔内にｐＨ、ｏｓｍｏｌａｌｉｔｙ調整生理食塩水、または被験化合物（実施例７の化合物（二塩酸塩），１ｍｇ；生理食塩水に溶解）１００μＬ（２０ｍｇ／ｋｇ，４０ｍｇ／ｋｇ，６０ｍｇ／ｋｇ）を投与し、その後の脳波筋電図を測定した。ナルコレプシーモデルマウスにおいて、ナルコレプシー症状のひとつであるカタプレキシーは活動期（暗期）に多く、チョコレートを与えると増加することが知られている。そのため、今回の実験では、カタプレキシーを誘発するために、マウスにチョコレート（Ｈｅｒｓｈｅｙ’ｓ）を与えた。
　結果を図６，７に示す。
　マウスにとって活動期であり、カタプレキシーが見られる暗期（ＺＴ１５）に、ＯＸＫＯマウスに対して被験化合物の腹腔内投与を行ったところ、コントロールとして行った生理食塩水の投与後ではカタプレキシー（↓）が観察されたのに対して、被験化合物４０ｍｇ／ｋｇ、６０ｍｇ／ｋｇの腹腔内投与後はカタプレキシーが有意に抑制された（図６，７）。ＤＫＯマウスもナルコレプシーモデルでカタプレキシーが観察されるが、被験化合物投与後のカタプレキシーは抑制されなかった（図７）。
　統計処理は、生理食塩水および被験化合物（４０ｍｇ／ｋｇ）投与後、３時間までのカタプレキシーの累積発生回数を対応のあるｔ検定で評価した。覚醒状態からＲＥＭ睡眠への遷移をカタプレキシー（↓）としてカウントした。 Test Example 5
Inhibitory effect of cataplexy by intraperitoneal administration of the compound of the present invention to orexin-deficient mice (OXKO mice) The experimental animals are orexin-deficient mice (OXKO mice) and orexin receptor-deficient mice (DKO mice) as negative controls (both male) ) Was used. Around 9 weeks of age (± 1 week) under isoflurane anesthesia, an electroencephalogram electrode was implanted into the skull (Bregma: X = 1.5; Y = 0.6, Lambda: X = 1.5; Y = 0) ), An operation of inserting an electromyographic electrode into the trapezius muscle was performed. Administration and electroencephalogram measurement were started 2 weeks later. The experiment was performed in a light-dark cycle environment in which the beginning of the light period was 9 o'clock (ZT0) and the beginning of the dark period was 21 o'clock (ZT12). For OXKO and DKO mice, 100 μL (20 mg) dissolved in pH, osmolality adjusted physiological saline or test compound (Example 7 compound (dihydrochloride), 1 mg; dissolved in physiological saline) in dark phase ZT15 / Kg, 40 mg / kg, 60 mg / kg), and the subsequent electroencephalogram electromyogram was measured. In narcolepsy model mice, it is known that cataplexy, which is one of the symptoms of narcolepsy, is high in the active period (dark period) and increases when chocolate is given. Therefore, in this experiment, in order to induce cataplexy, mice were given chocolate (Hershey's).
The results are shown in FIGS.
When the test compound was administered intraperitoneally to OXKO mice in the dark period (ZT15) where cataplexy was observed, which was active for mice, cataplexy (↓) was observed after administration of physiological saline as a control. In contrast to the observation, cataplexy was significantly suppressed after intraperitoneal administration of 40 mg / kg and 60 mg / kg of the test compound (FIGS. 6 and 7). In DKO mice, cataplexy was observed in the narcolepsy model, but cataplexy after administration of the test compound was not suppressed (FIG. 7).
In statistical processing, the cumulative number of cataplexy occurrences up to 3 hours after the administration of physiological saline and test compound (40 mg / kg) was evaluated by the corresponding t-test. Transition from wakefulness to REM sleep was counted as cataplexy (↓).
試験例６
本発明化合物の野生型マウスへの明期経口投与による覚醒効果
　実験動物は、Ｃ５７ＢＬ／６系統野生型（ＷＴ）マウス、ｎｅｇａｔｉｖｅ　ｃｏｎｔｒｏｌとしてオレキシン受容体欠損マウス（ＤＫＯマウス）（いずれも雄）を用いた。９週齢前後（±１週間）で、イソフルラン麻酔下で、脳波用電極の頭蓋骨への埋め込み（Ｂｒｅｇｍａ：Ｘ＝１．５；Ｙ＝０．６，Ｌａｍｂｄａ：Ｘ＝１．５；Ｙ＝０）、筋電図用電極の僧帽筋への挿入手術を行った。その２週間後から投与、脳波測定を開始した。実験は、明期の始まりを９時（ＺＴ０）、暗期の始まりを２１時（ＺＴ１２）とする明暗サイクル環境下で行った。ＷＴマウス、ＤＫＯマウスに対して、明期のＺＴ６に、経口投与用ガベージを用い、１００μＬのｐＨ、ｏｓｍｏｌａｌｉｔｙ調整生理食塩水、または被験化合物（実施例７の化合物（二塩酸塩），１００ｍｇ；生理食塩水に溶解）１００μＬ（１００ｍｇ／ｂｏｄｙ）を経口投与し、その後の脳波筋電図を測定した。
　結果を図８に示す。
　マウスにとって睡眠期である明期（ＺＴ６）に被験化合物の経口投与を行ったところ、ＷＴマウスでは、生理食塩水投与と比べて、覚醒時間が有意に増加した。
　統計処理は、生理食塩水および被験化合物投与後２時間の累積覚醒時間を対応のあるｔ検定で評価した。 Test Example 6
Awakening effect by oral administration of the compound of the present invention to wild-type mice Experimental animals are C57BL / 6 strain wild-type (WT) mice, negative control orexin receptor-deficient mice (DKO mice) (both male) It was. Around 9 weeks of age (± 1 week) under isoflurane anesthesia, an electroencephalogram electrode was implanted into the skull (Bregma: X = 1.5; Y = 0.6, Lambda: X = 1.5; Y = 0) ), An operation of inserting an electromyographic electrode into the trapezius muscle was performed. Administration and electroencephalogram measurement were started 2 weeks later. The experiment was performed in a light-dark cycle environment in which the beginning of the light period was 9 o'clock (ZT0) and the beginning of the dark period was 21 o'clock (ZT12). For WT mice and DKO mice, using a garbage for oral administration in ZT6 in the light period, pH of 100 μL, osmolality adjusted saline, or test compound (compound of Example 7 (dihydrochloride), 100 mg; physiological 100 μL (100 mg / body) was orally administered, and the subsequent electroencephalogram electromyogram was measured.
The results are shown in FIG.
When the test compound was orally administered during the light period (ZT6), which is a sleep period for mice, the wakefulness time was significantly increased in WT mice compared to physiological saline administration.
In statistical processing, the cumulative wake-up time 2 hours after administration of physiological saline and test compound was evaluated by a corresponding t test.
試験例７
本発明化合物のオレキシン神経変性マウス（オレキシン／アタキシン３マウス）への暗期腹腔内投与によるカタプレキシー抑制効果
　実験動物は、オレキシン／アタキシン３マウス（Ｈａｒａ　ｅｔ　ａｌ．，Ｎｅｕｒｏｎ，３０，３４５－５４，２００１）、ｎｅｇａｔｉｖｅ　ｃｏｎｔｒｏｌとしてオレキシン受容体欠損マウス（ＤＫＯマウス）（いずれも雄）を用いた。１５週齢前後（±１週間）で、イソフルラン麻酔下で、脳波用電極の頭蓋骨への埋め込み（Ｂｒｅｇｍａ：Ｘ＝１．５；Ｙ＝０．６，Ｌａｍｂｄａ：Ｘ＝１．５；Ｙ＝０）、筋電図用電極の僧帽筋への挿入手術を行った。その２週間後から投与、脳波測定を開始した。実験は、明期の始まりを９時（ＺＴ０）、暗期の始まりを２１時（ＺＴ１２）とする明暗サイクル環境下で行った。オレキシン／アタキシン３マウス、ＤＫＯマウスに対して、暗期ＺＴ１５に腹腔内にｐＨ、ｏｓｍｏｌａｌｉｔｙ調整生理食塩水、または被験化合物（実施例７の化合物（二塩酸塩），１ｍｇ；生理食塩水に溶解）１００μＬ（４０ｍｇ／ｋｇ）を投与し、その後の脳波筋電図を測定した。今回の実験でも、カタプレキシーを誘発するために、マウスにチョコレート（Ｈｅｒｓｈｅｙ’ｓ）を与えた。
　結果を図９，１０に示す。
　マウスにとって活動期であり、カタプレキシーが見られる暗期（ＺＴ１５）に、オレキシン／アタキシン３マウスに対して被験化合物の腹腔内投与を行ったところ、コントロールとして行った生理食塩水の投与後ではカタプレキシー（↓）が観察されたのに対して、被験化合物４０ｍｇ／ｋｇの腹腔内投与後は、カタプレキシーが有意に抑制された（図９，１０）。
　統計処理は、生理食塩水および被験化合物（４０ｍｇ／ｋｇ）投与後、３時間までのカタプレキシーの累積発生回数を対応のあるｔ検定で評価した。覚醒状態からＲＥＭ睡眠への遷移をカタプレキシー（↓）としてカウントした。 Test Example 7
Inhibitory effect of cataplexy by intraperitoneal administration of the compound of the present invention to orexin neurodegenerative mice (orexin / ataxin 3 mice) in the dark period The experimental animals are orexin / ataxin 3 mice (Hara et al., Neuron, 30, 345-54, 2001). ), Orexin receptor-deficient mice (DKO mice) (both males) were used as negative controls. Around 15 weeks of age (± 1 week) under isoflurane anesthesia, an electroencephalogram electrode was implanted into the skull (Bregma: X = 1.5; Y = 0.6, Lambda: X = 1.5; Y = 0) ), An operation of inserting an electromyographic electrode into the trapezius muscle was performed. Administration and electroencephalogram measurement were started 2 weeks later. The experiment was performed in a light-dark cycle environment in which the beginning of the light period was 9 o'clock (ZT0) and the beginning of the dark period was 21 o'clock (ZT12). Orexin / Ataxin 3 mice, DKO mice, dark phase ZT15 intraperitoneal pH, osmolality adjusted saline, or test compound (Compound of Example 7 (dihydrochloride), 1 mg; dissolved in saline) 100 μL (40 mg / kg) was administered, and the subsequent electroencephalogram electromyogram was measured. In this experiment, too, mice were given chocolate (Hershey's) to induce cataplexy.
The results are shown in FIGS.
When the test compound was administered intraperitoneally to Orexin / Ataxin 3 mice in the dark period (ZT15), in which cataplexy was observed, which was active for the mice, cataplexy ( ↓) was observed, whereas cataplexy was significantly suppressed after intraperitoneal administration of 40 mg / kg of the test compound (FIGS. 9 and 10).
In statistical processing, the cumulative number of cataplexy occurrences up to 3 hours after the administration of physiological saline and test compound (40 mg / kg) was evaluated by the corresponding t-test. Transition from wakefulness to REM sleep was counted as cataplexy (↓).
試験例８
オレキシン欠損マウス（ＯＸＫＯマウス）への本発明化合物の連続投与による体重増加抑制効果
　実験動物は、オレキシン欠損マウス（ＯＸＫＯマウス）、ｎｅｇａｔｉｖｅ　ｃｏｎｔｒｏｌとしてオレキシン受容体欠損マウス（ＤＫＯマウス）（いずれも雄、それぞれＮ＝６）を用いた。２４週齢前後（±１週間）のマウスを、明期の始まりを９時（ＺＴ０）、暗期の始まりを２１時（ＺＴ１２）とする明暗サイクル環境下で１週間の慣らし飼育を行い、注射によるストレスを軽減させるため一日一回針刺しの慣らしを行った。
　えさは通常の飼料（オリエンタル酵母社製、脂質５．１％）で飼育した。ＯＸＫＯマウス、ＤＫＯマウスに対して、暗期ＺＴ１５に腹腔内にｐＨ、ｏｓｍｏｌａｌｉｔｙ調整生理食塩水、または被験化合物（実施例７の化合物（二塩酸塩），１ｍｇ；生理食塩水に溶解）１００μＬ（４０ｍｇ／ｋｇ）を１４日間投与した。３日ごとに体重、摂餌量を測定した。
　結果を図１１－ａ～図１１－ｈに示す。
　ＯＸＫＯマウス、ＤＫＯマウスともに、試験前の体重は有意な変化はなかった（図１１－ａ，図１１－ｅ）。ＯＸＫＯマウスに、実施例７の化合物４０ｍｇ／ｋｇを１４日間連続投与することにより、体重増加が有意に抑制された（図１１－ｂ、*<0.05 vs生理食塩水群 by 2 Way-ANOVA）。この効果は生理食塩水投与群では観察されなかった。さらにＯＸＫＯマウスでは一日の摂餌量（体重あたり）が有意に減少していた（図１１－ｃ、*** <0.001 vs 生理食塩水群 by unpaired t-test）。また、実施例７の化合物４０ｍｇ／ｋｇの投与を中止すると、体重の増加が観察された（図１１－ｄ）。以上の効果はＤＫＯマウスでは観察されなかった（図１１－ｅ～図１１－ｈ）。 Test Example 8
Effect of inhibiting body weight gain by continuous administration of the compound of the present invention to orexin-deficient mice (OXKO mice) Experimental animals include orexin-deficient mice (OXKO mice) and negative control orexin receptor-deficient mice (DKO mice) (both male, respectively) N = 6) was used. Mice around 24 weeks old (± 1 week) were bred for 1 week in a light-dark cycle environment where the beginning of the light period was 9 o'clock (ZT0) and the beginning of the dark period was 21 o'clock (ZT12). In order to relieve the stress caused by this, I practiced needle stick once a day.
The food was bred with normal feed (Oriental Yeast Co., Ltd., lipid 5.1%). For OXKO and DKO mice, 100 μL (40 mg) dissolved in pH, osmolality adjusted physiological saline or test compound (Example 7 compound (dihydrochloride), 1 mg; dissolved in physiological saline) in dark phase ZT15 / Kg) was administered for 14 days. Body weight and food intake were measured every 3 days.
The results are shown in FIGS. 11-a to 11-h.
In both OXKO and DKO mice, there was no significant change in body weight before the test (FIGS. 11-a and 11-e). By continuously administering 40 mg / kg of the compound of Example 7 to OXKO mice for 14 days, weight gain was significantly suppressed (FIG. 11-b, * <0.05 vs saline group by 2 Way-ANOVA). This effect was not observed in the saline administration group. Furthermore, the daily food intake (per body weight) was significantly decreased in OXKO mice (FIG. 11-c, *** <0.001 vs physiological saline group by unpaired t-test). When the administration of the compound of Example 7 at 40 mg / kg was discontinued, an increase in body weight was observed (FIG. 11-d). The above effects were not observed in DKO mice (FIGS. 11-e to 11-h).
　本発明化合物は、オレキシン受容体作動活性を示し、ナルコレプシー等の予防剤または治療剤として有用である。
　本出願は、日本国で２０１５年２月１９日に出願された特願２０１５－３１０４１を基礎としており、その内容は本明細書にすべて包含されるものである。 The compound of the present invention exhibits orexin receptor agonist activity and is useful as a prophylactic or therapeutic agent such as narcolepsy.
This application is based on a patent application No. 2015-31041 filed on Feb. 19, 2015 in Japan, the contents of which are incorporated in full herein.

Claims (24)

  1. 　一般式（Ｉ）
    Figure JPOXMLDOC01-appb-C000001
     ［式中、
    Ｒ１は水素原子を表し、
    Ｒ２は－ＯＨまたは
    Ｃ１－４アルコキシを表し、
    あるいはＲ１とＲ２は一緒になって－ＮＲａＲｂ（ここで、Ｒａは水素原子またはＣ１－４アルキルを表し、Ｒｂは水素原子またはＣ１－４アルキルを表す。）でさらに置換されていてもよいベンゼン環を形成し、
    Ｒ３はＣ１－６アルキル、
    Ｃ２－６アルケニル、
    Ｃ３－１０シクロアルキル、
    Ｃ６－１０アリールまたは
    ５～１０員ヘテロアリール
    （ここで、Ｃ１－６アルキル、Ｃ２－６アルケニル、Ｃ３－１０シクロアルキル、Ｃ６－１０アリールまたは５～１０員ヘテロアリールは任意に選択される１から４個のＲ４で置換されていてもよく、
    Ｒ４は水素原子、
    Ｃ１－４アルキル、
    Ｃ１－４アルコキシ、
    フェニル（ここで、フェニルはＣ１－４アルキル、Ｃ１－４アルコキシまたは－Ｃ（Ｏ）ＮＲ４ｘＲ４ｙ（ここで、Ｒ４ｘはＣ１－４アルキルを表し、Ｒ４ｙはＣ１－４アルキルを表す。）で置換されていてもよい。）、
    ５～１０員ヘテロアリール、
    ハロゲン、
    －ＯＨ、
    －ＮＲ４ａＲ４ｂ（ここで、Ｒ４ａは水素原子、Ｃ１－４アルキルまたはＣ１－４アルコキシ－カルボニルを表し、Ｒ４ｂは水素原子またはＣ１－４アルキルを表す。）、
    －Ｃ（Ｏ）ＯＲ４ｃ（ここで、Ｒ４ｃはＣ１－４アルキルを表す。）または
    －Ｃ（Ｏ）ＮＲ４ｄＲ４ｅ（ここで、Ｒ４ｄは水素原子またはＣ１－４アルキルを表し、Ｒ４ｅは水素原子またはＣ１－４アルキルを表す。）を表す。
    あるいは２個のＲ４は一緒になってメチレンジオキシを形成する。）を表し、
    Ｗは－（ＣＨ２）ｎ－Ｃ（Ｏ）ＮＲＷａＲＷｂ（ここで、ｎは０から２の整数を表し、ＲＷａは水素原子、Ｃ１－４アルキル（ここで、Ｃ１－４アルキルはＣ１－４アルキルもしくはＣ１－４アルコキシで置換されていてもよいフェニル、ピリジルまたはＣ１－４アルコキシ－カルボニルアミノで置換されていてもよい。）またはフェニル（ここで、フェニルはＣ１－４アルコキシ、－ＮＯ２またはＣ１－４アルコキシ－カルボニルアミノで置換されていてもよい。）を表し、ＲＷｂは水素原子またはＣ１－４アルキルを表す。）または
    一般式（ＩＩ）：
    Figure JPOXMLDOC01-appb-C000002
     （ここで、
    Ｒ５は水素原子、Ｃ１－４アルコキシ、－ＮＲ５ａＲ５ｂ（ここで、Ｒ５ａは水素原子またはＣ１－４アルキルを表し、Ｒ５ｂは水素原子またはＣ１－４アルキルを表す。）または－Ｃ（Ｏ）ＮＲ５ｃＲ５ｄ（ここで、Ｒ５ｃは水素原子またはＣ１－４アルキルを表し、Ｒ５ｄは水素原子またはＣ１－４アルキルを表す。）を表し、
    Ｒ６は水素原子、Ｃ１－４アルコキシ、－ＯＣＦ３、－ＮＲ６ａＲ６ｂ（ここで、Ｒ６ａは水素原子またはＣ１－４アルキルを表し、Ｒ６ｂは水素原子またはＣ１－４アルキルを表す。）または－Ｃ（Ｏ）ＮＲ６ｃＲ６ｄ（ここで、Ｒ６ｃは水素原子またはＣ１－４アルキルを表し、Ｒ６ｄは水素原子またはＣ１－４アルキルを表す。）を表し、
    Ｒ７は水素原子、Ｃ１－４アルコキシまたは－ＯＣＦ３を表し、かつ
    Ｘは－Ｎ＝または－ＣＨ＝を表す。
    あるいはＲ５およびＲ６は一緒になってメチレンジオキシを形成する。）を表す。］
    で示される化合物またはその薬学的に許容される酸付加塩。     Formula (I)
    Figure JPOXMLDOC01-appb-C000001
     [Where:
    R 1 represents a hydrogen atom,
    R 2 represents —OH or C 1-4 alkoxy;
    Alternatively, R 1 and R 2 together represent —NR a R b (wherein R a represents a hydrogen atom or C 1-4 alkyl, and R b represents a hydrogen atom or C 1-4 alkyl). Furthermore, an optionally substituted benzene ring is formed,
    R 3 is C 1-6 alkyl,
    C 2-6 alkenyl,
    C 3-10 cycloalkyl,
    C 6-10 aryl or 5-10 membered heteroaryl (where C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl is optionally Optionally substituted with 1 to 4 R 4 selected,
    R 4 is a hydrogen atom,
    C 1-4 alkyl,
    C 1-4 alkoxy,
    Phenyl (wherein phenyl is C 1-4 alkyl, C 1-4 alkoxy or —C (O) NR 4x R 4y (where R 4x represents C 1-4 alkyl, R 4y represents C 1-4 Represents alkyl.) And may be substituted with
    5-10 membered heteroaryl,
    halogen,
    -OH,
    —NR 4a R 4b (wherein R 4a represents a hydrogen atom, C 1-4 alkyl or C 1-4 alkoxy-carbonyl, and R 4b represents a hydrogen atom or C 1-4 alkyl),
    —C (O) OR 4c (wherein R 4c represents C 1-4 alkyl) or —C (O) NR 4d R 4e (where R 4d represents a hydrogen atom or C 1-4 alkyl). , R 4e represents a hydrogen atom or C 1-4 alkyl.
    Alternatively, two R 4 together form methylenedioxy. )
    W represents — (CH 2 ) n —C (O) NR Wa R Wb (where n represents an integer of 0 to 2, R Wa represents a hydrogen atom, C 1-4 alkyl (where C 1-4 Alkyl may be substituted with phenyl, pyridyl or C 1-4 alkoxy-carbonylamino optionally substituted with C 1-4 alkyl or C 1-4 alkoxy, or phenyl (where phenyl is C And optionally substituted with 1-4 alkoxy, —NO 2 or C 1-4 alkoxy-carbonylamino.), R Wb represents a hydrogen atom or C 1-4 alkyl)) or the general formula (II) :
    Figure JPOXMLDOC01-appb-C000002
     (here,
    R 5 is a hydrogen atom, C 1-4 alkoxy, —NR 5a R 5b (where R 5a represents a hydrogen atom or C 1-4 alkyl, and R 5b represents a hydrogen atom or C 1-4 alkyl) Or —C (O) NR 5c R 5d (where R 5c represents a hydrogen atom or C 1-4 alkyl, and R 5d represents a hydrogen atom or C 1-4 alkyl);
    R 6 is a hydrogen atom, C 1-4 alkoxy, —OCF 3 , —NR 6a R 6b (where R 6a represents a hydrogen atom or C 1-4 alkyl, and R 6b represents a hydrogen atom or C 1-4 alkyl) Or —C (O) NR 6c R 6d (where R 6c represents a hydrogen atom or C 1-4 alkyl, and R 6d represents a hydrogen atom or C 1-4 alkyl),
    R 7 represents a hydrogen atom, C 1-4 alkoxy or —OCF 3 , and X represents —N═ or —CH═.
    Alternatively, R 5 and R 6 together form methylenedioxy. ). ]
    Or a pharmaceutically acceptable acid addition salt thereof.
  2. 　一般式（Ｉ’）
    Figure JPOXMLDOC01-appb-C000003
     ［式中、
    Ｒ２’は－ＮＲ３ａ’Ｒ３ｂ’（ここで、Ｒ３ａ’はＣ１－４アルキルを表し、Ｒ３ｂ’はＣ１－４アルキルを表す。）で置換されたフェニルを表す。］
    で示される化合物またはその薬学的に許容される酸付加塩。     Formula (I ')
    Figure JPOXMLDOC01-appb-C000003
     [Where:
    R 2 ′ represents phenyl substituted with —NR 3a ′ R 3b ′ (where R 3a ′ represents C 1-4 alkyl and R 3b ′ represents C 1-4 alkyl). ]
    Or a pharmaceutically acceptable acid addition salt thereof.
  3. 　３’－（Ｎ－（３－（（２－（２－（ジメチルアミノ）ベンズアミド）エチル）アミノ）フェニル）スルファモイル）－４’－メトキシ－Ｎ，Ｎ－ジメチル－［１，１’－ビフェニル］－３－カルボキサミドまたはその薬学的に許容される酸付加塩。 3 ′-(N- (3-((2- (2- (dimethylamino) benzamido) ethyl) amino) phenyl) sulfamoyl) -4′-methoxy-N, N-dimethyl- [1,1′-biphenyl] -3-carboxamide or a pharmaceutically acceptable acid addition salt thereof.
  4. 　Ｗが－（ＣＨ２）ｎ－Ｃ（Ｏ）ＮＲＷａＲＷｂ（ここで、ｎは０から２の整数を表し、
    ＲＷａは水素原子、Ｃ１－４アルキル（ここで、Ｃ１－４アルキルはＣ１－４アルキルもしくはＣ１－４アルコキシで置換されていてもよいフェニル、ピリジルまたはＣ１－４アルコキシ－カルボニルアミノで置換されていてもよい。）またはフェニル（ここで、フェニルはＣ１－４アルコキシ、－ＮＯ２またはＣ１－４アルコキシ－カルボニルアミノで置換されていてもよい。）を表し、ＲＷｂは水素原子またはＣ１－４アルキルを表す。）または
    一般式（ＩＩ）：
    Figure JPOXMLDOC01-appb-C000004
     （ここで、
    Ｒ５はＣ１－４アルコキシ、－ＮＲ５ａＲ５ｂ（ここで、Ｒ５ａは水素原子またはＣ１－４アルキルを表し、Ｒ５ｂは水素原子またはＣ１－４アルキルを表す。）または－Ｃ（Ｏ）ＮＲ５ｃＲ５ｄ（ここで、Ｒ５ｃは水素原子またはＣ１－４アルキルを表し、Ｒ５ｄは水素原子またはＣ１－４アルキルを表す。）を表し、
    Ｒ６は水素原子、Ｃ１－４アルコキシ、－ＯＣＦ３、－ＮＲ６ａＲ６ｂ（ここで、Ｒ６ａは水素原子またはＣ１－４アルキルを表し、Ｒ６ｂは水素原子またはＣ１－４アルキルを表す。）または－Ｃ（Ｏ）ＮＲ６ｃＲ６ｄ（ここで、Ｒ６ｃは水素原子またはＣ１－４アルキルを表し、Ｒ６ｄは水素原子またはＣ１－４アルキルを表す。）を表し、
    Ｒ７は水素原子、Ｃ１－４アルコキシまたは－ＯＣＦ３を表し、かつ
    Ｘは－ＣＨ＝を表す。
    あるいはＲ５およびＲ６は一緒になってメチレンジオキシを形成する。）である、請求項１記載の化合物またはその薬学的に許容される酸付加塩。     W is — (CH 2 ) n —C (O) NR Wa R Wb (where n represents an integer of 0 to 2;
    R Wa is a hydrogen atom, C 1-4 alkyl (where C 1-4 alkyl is phenyl, pyridyl or C 1-4 alkoxy-carbonyl optionally substituted with C 1-4 alkyl or C 1-4 alkoxy) Or phenyl (wherein the phenyl may be substituted with C 1-4 alkoxy, —NO 2 or C 1-4 alkoxy-carbonylamino), and R Wb Represents a hydrogen atom or C 1-4 alkyl. ) Or general formula (II):
    Figure JPOXMLDOC01-appb-C000004
     (here,
    R 5 is C 1-4 alkoxy, —NR 5a R 5b (where R 5a represents a hydrogen atom or C 1-4 alkyl, and R 5b represents a hydrogen atom or C 1-4 alkyl) or —C (O) NR 5c R 5d (wherein R 5c represents a hydrogen atom or C 1-4 alkyl, and R 5d represents a hydrogen atom or C 1-4 alkyl),
    R 6 is a hydrogen atom, C 1-4 alkoxy, —OCF 3 , —NR 6a R 6b (where R 6a represents a hydrogen atom or C 1-4 alkyl, and R 6b represents a hydrogen atom or C 1-4 alkyl) Or —C (O) NR 6c R 6d (where R 6c represents a hydrogen atom or C 1-4 alkyl, and R 6d represents a hydrogen atom or C 1-4 alkyl),
    R 7 represents a hydrogen atom, C 1-4 alkoxy or —OCF 3 , and X represents —CH═.
    Alternatively, R 5 and R 6 together form methylenedioxy. Or a pharmaceutically acceptable acid addition salt thereof.
  5. 　Ｒ３がＣ１－６アルキル、
    Ｃ２－６アルケニルまたは
    Ｃ３－１０シクロアルキル
    （ここで、Ｃ１－６アルキル、Ｃ２－６アルケニルまたはＣ３－１０シクロアルキルは任意に選択される１から４個のＲ４で置換されていてもよく、
    Ｒ４は水素原子、
    Ｃ１－４アルキル、
    Ｃ１－４アルコキシ、
    フェニル（ここで、フェニルはＣ１－４アルキル、Ｃ１－４アルコキシ、メチレンジオキシまたは－Ｃ（Ｏ）ＮＲ４ｘＲ４ｙ（ここで、Ｒ４ｘはＣ１－４アルキルを表し、Ｒ４ｙはＣ１－４アルキルを表す。）で置換されていてもよい。）、
    ５～１０員ヘテロアリール、
    ハロゲン、
    －ＯＨ、
    －ＮＲ４ａＲ４ｂ（ここで、Ｒ４ａは水素原子、Ｃ１－４アルキルまたはＣ１－４アルコキシ－カルボニルを表し、Ｒ４ｂは水素原子またはＣ１－４アルキルを表す。）、
    －Ｃ（Ｏ）ＯＲ４ｃ（ここで、Ｒ４ｃはＣ１－４アルキルを表す。）または
    －Ｃ（Ｏ）ＮＲ４ｄＲ４ｅ（ここで、Ｒ４ｄはＣ１－４アルキルを表し、Ｒ４ｅはＣ１－４アルキルを表す。）
    を表す。
    あるいは２個のＲ４は一緒になってメチレンジオキシを形成する。）である、請求項１記載の化合物またはその薬学的に許容される酸付加塩。     R 3 is C 1-6 alkyl,
    C 2-6 alkenyl or C 3-10 cycloalkyl, wherein C 1-6 alkyl, C 2-6 alkenyl or C 3-10 cycloalkyl is optionally substituted with 1 to 4 R 4 You may,
    R 4 is a hydrogen atom,
    C 1-4 alkyl,
    C 1-4 alkoxy,
    Phenyl (wherein phenyl is C 1-4 alkyl, C 1-4 alkoxy, methylenedioxy or —C (O) NR 4x R 4y (where R 4x represents C 1-4 alkyl and R 4y represents Represents C 1-4 alkyl.) And may be substituted.
    5-10 membered heteroaryl,
    halogen,
    -OH,
    —NR 4a R 4b (wherein R 4a represents a hydrogen atom, C 1-4 alkyl or C 1-4 alkoxy-carbonyl, and R 4b represents a hydrogen atom or C 1-4 alkyl),
    —C (O) OR 4c (where R 4c represents C 1-4 alkyl) or —C (O) NR 4d R 4e (where R 4d represents C 1-4 alkyl and R 4e Represents C 1-4 alkyl.)
    Represents.
    Alternatively, two R 4 together form methylenedioxy. Or a pharmaceutically acceptable acid addition salt thereof.
  6. 　Ｒ３がＣ６－１０アリールまたは
    ５～１０員ヘテロアリール
    （ここで、Ｃ６－１０アリールまたは５～１０員ヘテロアリールは任意に選択される１から４個のＲ４で置換されていてもよく、
    Ｒ４はフェニル（ここで、フェニルはＣ１－４アルキル、Ｃ１－４アルコキシまたは－Ｃ（Ｏ）ＮＲ４ｘＲ４ｙ（ここで、Ｒ４ｘはＣ１－４アルキルを表し、Ｒ４ｙはＣ１－４アルキルを表す。）で置換されていてもよい。）、
    ５～１０員ヘテロアリール、
    －Ｃ（Ｏ）ＯＲ４ｃ（ここで、Ｒ４ｃはＣ１－４アルキルを表す。）または
    －Ｃ（Ｏ）ＮＲ４ｄＲ４ｅ（ここで、Ｒ４ｄはＣ１－４アルキルを表し、Ｒ４ｅはＣ１－４アルキルを表す。
    あるいは２個のＲ４は一緒になってメチレンジオキシを形成する。）である、請求項１記載の化合物またはその薬学的に許容される酸付加塩。     R 3 is C 6-10 aryl or 5- to 10-membered heteroaryl (where C 6-10 aryl or 5- to 10-membered heteroaryl may be optionally substituted with 1 to 4 R 4) Often,
    R 4 is phenyl (wherein phenyl is C 1-4 alkyl, C 1-4 alkoxy or —C (O) NR 4x R 4y (where R 4x represents C 1-4 alkyl and R 4y represents C 4 1-4 represents an alkyl group, which may be substituted with
    5-10 membered heteroaryl,
    —C (O) OR 4c (where R 4c represents C 1-4 alkyl) or —C (O) NR 4d R 4e (where R 4d represents C 1-4 alkyl and R 4e Represents C 1-4 alkyl.
    Alternatively, two R 4 together form methylenedioxy. Or a pharmaceutically acceptable acid addition salt thereof.
  7. 　Ｒ２が－ＯＨであるか、あるいは
    Ｒ１とＲ２が一緒になって－ＮＲａＲｂ（ここで、Ｒａは水素原子またはＣ１－４アルキルを表し、Ｒｂは水素原子またはＣ１－４アルキルを表す。）でさらに置換されていてもよいベンゼン環を形成する、請求項１記載の化合物またはその薬学的に許容される酸付加塩。     R 2 is —OH, or R 1 and R 2 are taken together to form —NR a R b (where R a represents a hydrogen atom or C 1-4 alkyl, and R b represents a hydrogen atom or C 1 The compound according to claim 1, or a pharmaceutically acceptable acid addition salt thereof, which forms a benzene ring which may be further substituted with 1-4 alkyl.
  8. 　請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩を含有する医薬。 A medicament comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable acid addition salt thereof.
  9. 　請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩を含有するオレキシン受容体作動薬。 An orexin receptor agonist containing the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable acid addition salt thereof.
  10. 　請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩を含有する抗ナルコレプシー剤。 An anti-narcolepsy containing the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable acid addition salt thereof.
  11. 　請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩を含有する眠気改善剤。 A sleepiness improving agent comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable acid addition salt thereof.
  12. 　請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩を含有する、肥満症、糖尿病またはうつ病の予防剤または治療剤。 A preventive or therapeutic agent for obesity, diabetes or depression, comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable acid addition salt thereof.
  13. 　請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩を含有する、敗血症、重症敗血症または敗血症性ショックの予防剤または治療剤。 A prophylactic or therapeutic agent for sepsis, severe sepsis or septic shock, comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable acid addition salt thereof.
  14. 　請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩を含有する、摂食抑制剤または体重増加抑制剤。 An antifeedant or a weight gain inhibitor comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable acid addition salt thereof.
  15. 　請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩の有効量を投与することを含むナルコレプシーの治療または予防方法。 A method for treating or preventing narcolepsy, which comprises administering an effective amount of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable acid addition salt thereof.
  16. 　請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩の有効量を投与することを含む眠気の改善方法。 A method for improving drowsiness, comprising administering an effective amount of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable acid addition salt thereof.
  17. 　請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩の有効量を投与することを含む、肥満症、糖尿病またはうつ病の治療または予防方法。 A method for treating or preventing obesity, diabetes or depression, comprising administering an effective amount of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable acid addition salt thereof.
  18. 　請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩の有効量を投与することを含む、敗血症、重症敗血症または敗血症性ショックの治療または予防方法。 A method for treating or preventing sepsis, severe sepsis or septic shock, comprising administering an effective amount of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable acid addition salt thereof.
  19. 　請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩の有効量を投与することを含む、摂食または体重増加を抑制する方法。 A method for inhibiting feeding or weight gain, comprising administering an effective amount of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable acid addition salt thereof.
  20. 　ナルコレプシーを治療または予防するための、請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩。 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable acid addition salt thereof, for treating or preventing narcolepsy.
  21. 　眠気を改善するための、請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩。 The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable acid addition salt thereof for improving drowsiness.
  22. 　肥満症、糖尿病またはうつ病を治療または予防するための、請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩。 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable acid addition salt thereof, for treating or preventing obesity, diabetes or depression.
  23. 　敗血症、重症敗血症または敗血症性ショックを治療または予防するための、請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩。 The compound or a pharmaceutically acceptable acid addition salt thereof according to any one of claims 1 to 7, for treating or preventing sepsis, severe sepsis or septic shock.
  24. 　摂食または体重増加を抑制するための、請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される酸付加塩。 The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable acid addition salt thereof for suppressing feeding or weight gain.
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