WO2016133160A1 - Dérivé de sulfamide ou sel d'addition d'acide pharmaceutiquement acceptable correspondant - Google Patents

Dérivé de sulfamide ou sel d'addition d'acide pharmaceutiquement acceptable correspondant 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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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/ja
Publication of WO2016133160A1 publication Critical patent/WO2016133160A1/fr

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    • A61K31/18—Sulfonamides
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    • 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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    • 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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    • C07D209/18—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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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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

L'objet de la présente invention concerne un nouveau composé de bas poids moléculaire qui présente une activité agoniste du récepteur des orexines et dont on s'attend à ce qu'il soit utile en tant qu'excellent agent thérapeutique ou de prévention de la narcolepsie. La présente invention concerne un dérivé de sulfonamide représenté par la formule générale (I), qui présente une excellente activité agoniste du récepteur des orexines (dans laquelle chaque symbole a la même définition que celle décrite dans la description) et un sel d'addition d'acide pharmaceutiquement acceptable correspondant, ainsi qu'un agoniste du récepteur des orexines comprenant le dérivé ou le sel d'addition d'acide pharmaceutiquement acceptable correspondant.
PCT/JP2016/054700 2015-02-19 2016-02-18 Dérivé de sulfamide ou sel d'addition d'acide pharmaceutiquement acceptable correspondant WO2016133160A1 (fr)

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WO2018164192A1 (fr) 2017-03-08 2018-09-13 武田薬品工業株式会社 Composé de pyrrolidine substituée et son utilisation
WO2019027058A1 (fr) 2017-08-03 2019-02-07 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son utilisation
WO2019027003A1 (fr) 2017-08-03 2019-02-07 武田薬品工業株式会社 Composé hétérocyclique et son application
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WO2019117148A1 (fr) * 2017-12-12 2019-06-20 国立大学法人 筑波大学 Dérivé de sulfonamide ou sel d'addition d'acide pharmaceutiquement acceptable
WO2020004537A1 (fr) 2018-06-29 2020-01-02 武田薬品工業株式会社 Composé hétérocyclique et son utilisation
WO2020004536A1 (fr) 2018-06-29 2020-01-02 武田薬品工業株式会社 Composé hétérocyclique et son application
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US11542276B2 (en) 2019-11-25 2023-01-03 Alkermes, Inc. Substituted macrocyclic compounds and related methods of treatment
US11760747B2 (en) 2020-12-21 2023-09-19 Alkermes, Inc. Substituted piperidino compounds and related methods of treatment
US12006330B2 (en) 2020-12-21 2024-06-11 Alkermes, Inc. Substituted macrocyclic compounds and related methods of treatment

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