WO2006129609A1 - Derive 2-naphtylimino-5,5-disubstitue-1,3-thiazine - Google Patents

Derive 2-naphtylimino-5,5-disubstitue-1,3-thiazine Download PDF

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Publication number
WO2006129609A1
WO2006129609A1 PCT/JP2006/310679 JP2006310679W WO2006129609A1 WO 2006129609 A1 WO2006129609 A1 WO 2006129609A1 JP 2006310679 W JP2006310679 W JP 2006310679W WO 2006129609 A1 WO2006129609 A1 WO 2006129609A1
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alkyl
substituted
solvate
pharmaceutically acceptable
acceptable salt
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PCT/JP2006/310679
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English (en)
Japanese (ja)
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Hiroyuki Kai
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Shionogi & Co., Ltd.
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Publication of WO2006129609A1 publication Critical patent/WO2006129609A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a 2-naphthylimino 5,5-disubstituted-1,3-thiazine derivative having a cannapinoid receptor agonistic action and a pharmaceutical use thereof.
  • Cannapinoids were discovered in 1960 as the main active substance of marijuana, and their effects include central nervous system effects (such as hallucinations, euphoria, and spatiotemporal sensations) and peripheral cell system effects (immunosuppression) , Anti-inflammatory, analgesic action, etc.).
  • Non-Patent Document 1 reports the effects of anandamide on the cardiovascular system.
  • a cannapinoid receptor a cannapinoid type 1 receptor was discovered in 1990 and found to be distributed in the central nervous system such as the brain, and its agonist suppresses the release of neurotransmitters and is central to hallucinations. It was very powerful to show the action.
  • Non-patent Document 2 discloses that the cannapinoid receptor agonist ⁇ 9 -tetrahydrocannabinol and the like have a bronchodilator action.
  • Sarako and Patent Document 1 disclose that a cannapinoid receptor agonist has an anti-epileptic action.
  • Patent Document 2 discloses that cannapinoid receptor agonists have an anti-asthma effect.
  • cannapinoid receptor agonists examples include isoindolinone derivatives (Patent Document 3), pyrazole derivatives (Patent Document 4), quinolone derivatives (Patent Documents 5 and 6), pyridone derivatives (Patent Document 7), etc.
  • Thiazine derivatives Patent Document 8, Patent Document 9 and Patent Document 10 having a structure similar to the inventive compound are known.
  • Patent Document 1 International Publication No. 03Z035109 Pamphlet
  • Patent Document 2 Pamphlet of International Publication No. 2005Z016351
  • Patent Document 3 International Publication No. 97Z29079 Pamphlet
  • Patent Document 4 International Publication No.98Z41519 Pamphlet
  • Patent Document 5 Pamphlet of International Publication No. 99Z02499
  • Patent Document 6 Pamphlet of International Publication No. 00Z40562
  • Patent Document 7 Pamphlet of International Publication No. 02Z053543
  • Patent Document 8 International Publication No.01Z19807 Pamphlet
  • Patent Document 9 Pamphlet of International Publication No. 02Z072562
  • Patent Document 10 International Publication 2005Z026138 Pamphlet
  • Non-Patent Document 1 Hypertension 1997, 29th, p. 1204—12 10
  • Non-Patent Document 2 Nature 1993, 365, p. 61-65
  • Non-Patent Document 3 Journal of Cannabi s Therapeutics 2002, No. 2-1, p. 59—71
  • a compound having a cannapinoid receptor agonist action and a pharmaceutical composition containing the compound as an active ingredient are created to provide an analgesic agent, a pain therapeutic agent, an antidepressant, or a bronchodilator.
  • the present inventors show that the following 2 naphthylimino 5,5 disubstituted 1,3 thiazine derivatives have a strong cannapinoid receptor agonist action, and analgesics and pains containing them as an active ingredient It was found to be effective as a therapeutic agent, an antidepressant, or a bronchodilator.
  • R 2 and R 3 are different and are C 1 C 6 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl; or
  • R 2 and R 3 together are 5 to 8 membered cycloalkanes containing adjacent carbon atoms and substituted with C1 C4 alkyl or adjacent carbon atoms and substituted with C1—C4 alkyl and 5 8 membered May form an oxygen-containing heterocycle ⁇ ;
  • R 4 is CI—C4 alkyl, C2—C4 alkyl, C2—C4 alkyl, or CI—C4 alkyl C 1—C4 alkyl;
  • X is an oxygen atom or a sulfur atom
  • n is an integer of 0 7
  • an optically active isomer a pharmaceutically acceptable salt thereof, or a solvate thereof
  • R 2 and R 3 together form a 5- to 7-membered cycloalkane containing an adjacent carbon atom and substituted with C1 C4 alkyl, the compound according to 1), an optically active form thereof, a product thereof A pharmaceutically acceptable salt, or a solvate thereof,
  • R 4 is methyl, ethyl, or aryl, the compound according to any one of 1) to 3), an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof,
  • R 1 is the same or different and is alkyl, alkoxy, an optionally substituted amino-substituted halogen atom, hydroxy, haloalkyl, haloalkoxy, silane-containing or alkoxy force norboninoleanoloxy;
  • R 2 and R 3 are different and are C 1 C 6 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl; or
  • R 2 and R 3 together may form a 5-8 membered cycloalkane containing an adjacent carbon atom and substituted with C1 C4 alkyl! / ⁇ ;
  • R 4 is C 1 C4 alkyl or C2-C4 alkenyl
  • X is an oxygen atom or a sulfur atom
  • n is an integer of 0 to 4
  • an optically active form thereof a pharmaceutically acceptable salt thereof, or a solvate thereof
  • R 2 and R 3 together form a 5- to 7-membered cycloalkane containing an adjacent carbon atom and substituted with C1 C4 alkyl, the compound according to 5), an optically active substance thereof, a product thereof A pharmaceutically acceptable salt, or a solvate thereof, 8) The compound according to any one of 5) to 7), wherein R 4 is methyl, ethyl, or allyl, an optically active isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof,
  • R 1 is the same or different and is alkyl, alkoxy, an optionally substituted amino-substituted halogen atom, hydroxy, haloalkyl, haloalkoxy, silane-containing or alkoxy force norboninoleanoloxy;
  • R 2 and R 3 are different and are C 1 C 6 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl; or
  • R 2 and R 3 together may form a 5-8 membered cycloalkane containing an adjacent carbon atom and substituted with C1 C4 alkyl! / ⁇ ;
  • R 4 is C 1 C4 alkyl or C2-C4 alkenyl
  • X is an oxygen atom or a sulfur atom
  • n is an integer of 0 to 3
  • R 2 and R 3 together form a 5- to 7-membered cycloalkane containing an adjacent carbon atom and substituted with C1 C4 alkyl. 9)
  • R 4 force methyl, ethyl, or aryl, the compound according to any one of 9) to 11), an optically active form thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,
  • a pharmaceutical composition comprising the compound according to any one of 1) to 13), an optically active isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient,
  • a method for treating pain comprising administering the compound according to any one of 1) to 13), a pharmaceutically acceptable salt thereof, or a solvate thereof,
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • Alkyl includes straight-chain or branched alkyl having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butylene, n-pentinoles, isopentinoles, neo-pentinoles, n-hexynole, n-heptyl, n-octyl, n-noel, n-decyl and the like.
  • alkyl having 1 to 6 carbon atoms is preferred.
  • Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n- Pentyl, isopentyl, neo-pentyl and n-hexyl are preferred.
  • a carbon number when specified, it means “alkyl” having a carbon number within the range of the number.
  • Alkoxyalkyl includes the above “alkyl” substituted with one or more of the following “alkoxy” and includes, for example, methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl and the like.
  • a carbon number when a carbon number is specified, it means “alkoxy” having the number of carbons in the number range and “alkyl” having the number of carbons in the number range.
  • Alkylthioalkyl includes the above “alkyl” substituted with one or more of the following “alkylthio”, for example, methylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 3-methylthiopropyl, etc. It is done.
  • Substituted, optionally, aminoamino includes the above “alkyl” substituted by one or more of the following “substituted, optionally, amino”, for example, methylaminomethyl, 2-dimethyl And ruaminoethyl, 2-jetylaminoethyl, 3-dimethylaminopropyl and the like.
  • Alkoxyiminoalkyl includes the above “alkyl” substituted with one or more imino groups substituted with the following “alkoxy” and includes, for example, methoxyiminomethyl, 2-methoxyiminoethyl, 2-ethoxyimino. Examples thereof include ethyl and 2-methoxyiminopropyl.
  • Alkenyl includes linear or branched alkenyl having 2 to 8 carbon atoms having one or more double bonds to the above “alkyl”, and includes, for example, vinyl, 1-probe. -L, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1,3-butagel, 3-methyl-2-butul and the like.
  • straight chain or branched alkaryl having 2 to 4 carbon atoms is preferred, and allyl, iso-probe, and 3_butul are preferred.
  • a carbon number when a carbon number is specified, it means “alkell” having a carbon number within that range.
  • Alkynyl includes linear or branched alkynyl having 2 to 8 carbon atoms having one or more triple bonds in the above “alkyl”, and examples thereof include ethynyl, propargyl and the like. It is done. In particular, a linear or branched alkyl having 2 to 4 carbon atoms is preferable, and specifically, propargyl is preferable.
  • Haloalkyl means a group in which one or more halogens are substituted on the above “alkyl”. For example, chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, chloroethyl (for example, 2-chloroethyl) , Dichloroethyl (for example, 1,2-dichloroethyl, 2,2-dichloroethinole, etc.), black-mouthed propinole (f-row separation, 2-black-headed propinole, 3-black-headed propylene, etc.) and the like. C1-C3 haloalkyl is preferred.
  • “Cycloalkane” includes a cycloalkane having 3 to 10 carbon atoms. Pan, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like. Preferably, it is a C5-C8 cycloalkane, for example, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. In particular, when the number of carbons is specified, it means “cycloalkane” having members within the range of the number.
  • Cycloalkyl includes cycloalkyl having 3 to 10 carbon atoms, and examples thereof include cyclopropinole, cyclobutinole, cyclopentinole, cyclohexinole, cycloheptinole, cyclooctyl and the like. Preferred is cycloalkyl having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In particular, when the number of carbons is specified, it means “cycloalkyl” having the number of carbons within the range.
  • the “aryl” includes aryl having 6 to 14 carbon atoms, and examples thereof include phenol, naphthyl, anthryl, phenanthryl and the like. In particular, phenol and naphthyl are preferable.
  • “Aralkyl” includes a group in which the above “alkyl” is substituted with the above “aryl”, and examples thereof include benzyl, ferroethyl (for example, 1-phenyl, 2-phenyl), propyl ( For example, 1-propylpropyl, 2-phenylpropyl, 3-phenylpropyl, etc.), naphthylmethyl (eg, 1-naphthylmethyl, 2-naphthylmethyl, etc.) and the like can be mentioned. In particular, benzyl and naphthylmethyl are preferable.
  • Heteroaryl includes a nitrogen atom, an oxygen atom, and a heteroaryl having 1 to 9 carbon atoms containing 1 to 4 Z or sulfur atoms, such as furyl (eg, 2-furyl, 3-furyl). ), Chael (eg, 2-chael, 3-chael), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (eg 1, 2, 4-triazol-1-yl, 1, 2, 4-triazolyl-3- 1,2,4-triazol-4-yl), tetrazolyl (eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (eg 2-oxazolyl, 4-
  • oxygen-containing heterocycle includes a 3- to 8-membered heterocycle in which one or two oxygen atoms may be present, and includes oxolan, oxetane, oxolan, dioxolan, oxane, dioxane, oxepane, oxocan Etc. In particular, oxolan, oxane and oxepane are preferred.
  • Non-aromatic heterocyclic group means a nitrogen atom, an oxygen atom, and 1 to
  • non-aromatic cyclic groups containing 1 to 9 carbon atoms such as 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidino, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl, 3- Examples include piperidyl, 4-piperidyl, piperazino, 2-piperazinyl, 2-morpholinyl, 3-morpholinyl, morpholinated tetrahydrobiral and the like.
  • morpholy-containing pyrrolidi-containing piperidino-containing piperazino is preferred.
  • alkyl part of “alkoxy” has the same meaning as the above “alkyl”.
  • alkoxy examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy and the like. Can be mentioned.
  • methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and t-butoxy are preferred, where C 1-4 alkoxy is preferred.
  • a carbon number when a carbon number is specified, it means “alkoxy” having a carbon number within the range of the number.
  • Haloalkoxy means a group in which one or more halogens are substituted on the above “alkoxy”. For example, dichloromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy (2, 2, 2 —Trifluoroethoxy) and the like. In particular, difluoromethoxy and trifluoromethoxy are preferred.
  • Aryloxy includes a group in which one of the above “aryl” is substituted on an oxygen atom.
  • aryl e.g., 1-naphthoxy, 2-naphthoxy, etc.
  • anthrinoloxy e.g, 1— Anthryloxy, 2-anthryloxy, etc.
  • phenanthrylloxy for example, 1-phenanthroxy, 2-phenanthroxy
  • phenoxy and naphthoxy are preferable.
  • Alkyloxy includes a group in which one above-mentioned “aralkyl” is substituted on an oxygen atom, and examples thereof include benzyloxy and phenethyloxy. In particular, benzyloxy is preferred.
  • Alkoxyalkoxy includes the above “alkoxy” substituted with the above “alkoxy”, for example, methoxymethoxy, ethoxymethoxy, n-propoxymethoxy, isopropoxymethoxy, 1-methoxyethoxy, 2-methoxyethoxy and the like. Is mentioned. In particular, 1-methoxyethoxy and 2-methoxyethoxy are preferable.
  • Alkylthioalkoxy includes the above “alkoxy” substituted with the following “alkylthio” and includes, for example, methylthiomethoxy, ethylthiomethoxy, n-propylthiomethoxy, isopropylthiomethoxy, 1-methylthioethoxy, Examples include 2-methylthioethoxy. In particular, 1-methylthioethoxy and 2-methylthioethoxy are preferable.
  • Carboxyalkoxy includes the above “alkoxy” substituted with one or more of “carboxy” and includes, for example, carboxymethoxy, 2-carboxyethoxy and the like.
  • Alkoxycarbonalkoxy means a group in which the above “alkoxy” is substituted by the following “alkoxycarbol”, and includes, for example, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, n-propoxycarbonylaminoremethoxy, Topropoxy carbonyl methoxy, n-butoxy carbonyl methoxy, i-butoxy carbonyl methoxy, sec-butoxy carbonyl methoxy, tert-butoxy carbonyl methoxy, 2- (tert-butoxy carbonyl) ethoxy, 2— ( n-pentyloxycarbol) ethoxy, 2- (n-hexyloxycarboro) ethoxy, n-heptyloxycarboromethoxy, n-octyloxycarboromethoxy and the like.
  • tert-butoxycarboromethoxy and 2- (tert-butoxycarboro) ethoxy are preferable.
  • cyanalkoxy includes the above “alkoxy” substituted with one or more “ciano” and includes, for example, cyanomethoxy, 2-cyanethoxy and the like.
  • alkyl part of “alkylthio” has the same meaning as the above “alkyl”.
  • alkylthio include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec butylthio, t-butylthio, n pentylthio, n-hexylthio and the like.
  • straight chain or branched alkylthio having 1 to 4 carbon atoms is preferred, and methylthio, ethylthio, n propylthio, isopropylthio, n-butinoreio, isobutinoreio, sec butinoreio, and tbutinoreio are preferred.
  • optionally substituted amino examples include unsubstituted C1 C4 alkylamino, (C 1 C4 alkyl) carborylaminocarbonylcarbonylamino, N— (C1—C4 alkyl) carbol CI— C4 alkylamine-containing alkylalkylamino, CI—C4 alkylsulfo Nylamino, C2—C4 alkenylcarboxylamine (CI—C4 alkoxy) carboninoreamino, C2—C4 anorekeninoreamino, arenorecanenoboninoreamino, heteroarino carbo-lamino.
  • Especially preferred are unsubstituted amino-containing C1 C4 alkylamino, (C1-C4 alkyl) carbolumino, and (C1-C4 alkoxy) carbolumino! /.
  • Examples of CI-C4 alkylamino include methylamino, ethylamino, n-propylamino, i-propylamino-containing dimethylamino-containing ketylamino-containing ethylmethylamino, and propylmethylamino.
  • Examples of (C1-C4 alkyl) carboamino include acetylamino, formylamino, and propio-lumino.
  • Examples of aryl carbonates include benzoylamino.
  • Examples of N— (CI—C4 alkyl) carboalkylamino include N-acetylmethylamino.
  • Aralkylamino includes, for example, benzylamino-containing 1-phenylamino-containing 2-phenylethyl-containing 1-phenylpropylamino-containing 2-phenylpropylamino-containing 3-phenylpropylamino-containing 1-naphthylmethylamino-containing dibenzylamino.
  • Examples of the C1-C4 alkyl sulforamino include methanesulfo-amid ethane sulforamino.
  • Examples of the C2-C4 alkenylcarbolumino include bicarboxylamine-containing carboxycarboxylamino.
  • Examples of (C1-C4alkoxy) carbolamino include methoxycarbolamylated ethoxycarbolamino and tert-butoxycarbolamino.
  • Examples of the C2—C4 alkamino include buramino and allylamino.
  • An example of aryl carbonamino is benzoylamino.
  • Examples of the heteroaryl carbolumino include pyridine carbolumino.
  • “Acyl” means a carbo group substituted with a group other than hydrogen, such as an alkyl carboyl (eg, acetyl, propiol, butyryl, isobutyryl, valeryl, isovaleryl, bivaloyl, hexanoyl, Otatanyl, lauroyl, etc.), alkaryl carbo yl (eg, atalyloyl, meta atalyloyl), cycloalkyl carbo yl (eg, cyclopropane carbonyl, cyclobutane carbonyl, cyclopentane carbonyl, cyclohexane carbonyl, etc.), aryl carbo -Lole (benzoyl, naphthoyl, etc.), heteroaryl carbole (pyridyl carbole, etc.).
  • an alkyl carboyl eg, acetyl, propiol, butyryl,
  • arylalkyl substituted with alkyl includes a toluoyl group
  • alkylcarbonyl substituted with halogen includes a trifluoroacetyl group.
  • Alkoxycarbon means a group in which the above “alkoxy” is substituted on the carbocycle, and includes, for example, methoxycarbonyl, ethoxycarbonyl, n_propoxy carbonylbonole, i-poxoxy carbonylbonole, n -Butoxycarbonyl, i-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, n-hexynoleoxy carbo yl, n-heptyloxy carbo yl, n-octyloxy carbo -Le.
  • methoxycarbol, ethoxycarbol and the like are preferable.
  • substituent of “optionally substituted rubamoyl” examples include alkyl (for example, methyl, ethyl, n-propyl, i-propyl, etc.), isyl (for example, formyl, acetyl, propionyl, benzoyl, etc.) and the like. Can be mentioned. Nitrogen nuclear power of the rubermoyl group may be mono- or di-substituted with these substituents. As the “substituted but optionally rubamoyl”, rubamoyl, N-methylcarbamoyl, N-ethylcarbamoyl and the like are preferable.
  • alkyl part of “alkylsulfiel” has the same meaning as the above “alkyl”, and examples of “alkylsulfiel” include methanesulfiel, ethanesulfiel and the like.
  • alkyl part of the “alkylsulfol” has the same meaning as the above “alkyl”, and examples of the “alkylsulfol” include methanesulfol, ethanesulfol and the like.
  • alkyl sulfol moiety of the “alkyl sulfo-oxy” has the same meaning as the above “alkyl sulfo”, and examples of the “alkyl sulfo-oxy” include methane sulfo-oxy, ethane sulfo-oxy and the like.
  • aryl may be non-aromatic heterocyclic group”, “substituted, may be aryloxy”
  • any one to four substituents may be substituted at any position.
  • substituents include hydroxy, carboxy, halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), haloalkyl (for example, CF, CHCF, CHCC1, etc.),
  • alkyl eg, methyl, ethyl, isopropyl, tert-butyl, etc.
  • alkyl eg, butyl
  • formyl isyl (eg, acetyl, propiol, butyryl, pivalol, benzoyl)
  • alkyl eg, etul
  • cycloalkyl eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • alkoxy eg, methoxy, Ethoxy, propoxy, butoxy, etc.
  • alkoxy carbs eg, methoxy carbol, ethoxy carbol, tert-butoxy carbol etc.
  • nitro, -toroso, oxo optionally substituted amino
  • the “optically active substance” includes a specific optical isomer when the compound of the present invention has an asymmetric carbon.
  • Racemic means a compound having equal amounts of enantiomers.
  • R 2 and R 3 taken together include the following groups as 5- to 8-membered cycloalkanes containing adjacent carbon atoms and substituted with C 1 C 4 alkyl.
  • a cycloalkane in which 1 to 4 C 1 C4 alkyl is substituted at the substitutable position of the cycloalkane is preferred.
  • C1-C4 alkyl methyl and ethyl are preferred.
  • the 5- to 7-membered cycloalkane shown below is preferable.
  • C 1 -C 4 alkyl methyl is particularly preferred.
  • (R 1 ) is preferably (la) a hydrogen atom, a halogen atom, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, an optionally substituted amino or alkoxycarboalkoxy, and (lb) hydrogen. Atom, halogen atom, alkyl, alkoxy, optionally substituted amino or alkoxy carboalkoxy are preferred, although (Ic
  • a hydrogen atom, a halogen atom, an optionally substituted amino or alkoxycarboalkoxy is preferred.
  • R 2 and R 3 are different, (Id) —preferably C2—C4 alkyl or C2—C3 alkenyl and the other is C1—C4 alkyl or C2—C3 alkenyl. — Is preferably C2—C4 alkyl and the other is CI—C4 alkyl.
  • R 4 is preferably (1 £) 1 to 4 alkyl or 2 to 4 alkyl, and (ig) Cl C4 alkyl is preferred! /.
  • X is (Ih) an oxygen atom or a sulfur atom.
  • R 2 and R 3 taken together are preferably 5-8 membered cycloalkanes containing adjacent carbon atoms and substituted with (Ik) C1 C4 alkyl, and (I1) C1—C4 alkyl substituted.
  • the converted 5- to 7-membered cycloalkane is preferred!
  • n is preferably an integer of (Im) 0 to 2, and more preferably an integer of (In) 0 to 1.
  • the compound of the present invention has an excellent cannapinoid receptor agonist action and high safety, and is therefore useful as a pharmaceutical, particularly as a therapeutic agent for pain.
  • the compound according to the present invention can be produced by the following steps.
  • the structural formulas of the formulas (I) to (V) indicate a racemate or an optically active substance.
  • R 2 and R 3 are different and are C 1 C 6 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl; or
  • R 2 and R 3 taken together include an adjacent carbon atom and may be substituted with C1 C4 alkyl, or include an 8-membered cycloalkane or an adjacent carbon atom and substituted with C1-C4 alkyl; However, it may form a 58-membered oxygenated heterocycle.
  • R 4 is CI—C4 alkyl, C2—C4 alkyl, C2—C4 alkyl, or CI—C4 alkyl C 1—C4 alkyl;
  • R 5 s are the same or different and are alkyl, alkoxy, alkylthio, optionally substituted amide-substituted aryl, substituted with an optionally substituted amide-substituted protecting group.
  • X is an oxygen atom or a sulfur atom
  • n is an integer of 0 7) 1st process
  • the conversion method from an amino group to an isothiocyanate includes (i)
  • a base 1.0 to 1.5 equivalents
  • carbon dioxide 1.0 to 1.5 equivalents
  • an aprotic solvent for example, Jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, black mouth form, etc.
  • ketyl carbonate 1.0 to 1.5 equivalents
  • triethylamine 1.0 to 1.5 equivalents
  • an aprotic solvent eg, jetyl ether, tetrahydrofuran, dimethylformamide
  • Benzene, toluene, dichloromethane, chloroform, etc. for 0.5 to 10 hours.
  • the reaction temperature is preferably 0 ° C to 100 ° C, particularly preferably 0 ° C to room temperature.
  • thiophosgene (1.0 to 1.5 equivalents) is added to the compound (IV) and an aprotic solvent (for example, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, Stir in dichloromethane, chloroform, etc.) for 0.5-10 hours.
  • the reaction temperature is preferably 0 ° C to 100 ° C, particularly preferably 0 ° C to room temperature.
  • thiocarbodiimidazole 1.0 to 1.5 equivalents is added to compound (IV), and an aprotic solvent (eg, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, Stir in dichloromethane, chloroform, etc.) for 0.5-10 hours.
  • the reaction temperature is preferably 0 ° C to 100 ° C, particularly preferably o ° c to room temperature.
  • Compounds represented by the formula (IV) include 1-aminonaphthalene, 1-amino-2-fluoronaphtalene, 1-amino-3-funole-old ronaphthalene, 1-amino-4-funole-aged naphthaphthalene, 1-amino-1-fluoronaphthalene, 1-- Amino 1 Fluoronaphthalene, 1—Amino 1— Funole-old Lonaphthalene, 1 Amino-8 Funole-old Lonaphthalene, 1 Amino-2 Chloronaphthalene, 1 Amino-3 Chloronaphthalene, 1 Amino-4 Chloronaphthalene, 1 Amino-5 Chloronaphthalene, 1 Amino-6 Chloronaphthalene, 1 Amino-7 Chloronaphthalene 1 amino-8 chloronaphthalene, 1 amino-2 bromonaphthalene, 1 amino-3-bromonaphthalene, 1 amino-4-bromon
  • This step can be carried out in an aprotic solvent (for example, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, black mouth form, etc.). wear.
  • an aprotic solvent for example, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, black mouth form, etc.
  • the reaction temperature is preferably 0 ° C to 100 ° C, and the reaction time is particularly preferably o ° c to room temperature, and is preferably 0.5 hours to 10 hours.
  • NH 2 —CH 2 C 3 (R 2 R 3 ) CH—OH includes 3-amino-2-isopropyl-2-methyl
  • Ring closure methods include: (1) after treatment with tetrasalt carbon and triphenylphosphine (Ph P),
  • Examples include a method of treating with a base such as potassium carbonate, and a method of treating with (2) hydrochloric acid.
  • an aprotic solvent for example, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, black mouthform, etc.
  • aprotic solvent for example, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, black mouthform, etc.
  • Tetrasalt carbon and triphenylphosphine (Ph P) should be used in an amount of 1.0 to 1.5 equivalents to the compound (VI), respectively. Yes.
  • the mixture may be heated to reflux in concentrated hydrochloric acid for 0.5 to 10 hours.
  • a base eg, triethylamine, pyridine, N, N-dimethylaminopyridine, etc.
  • Hal represents a halogen atom
  • an aprotic solvent for example, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, black mouth form, etc.
  • the reaction may be performed at 0 ° C to 100 ° C for 0.5 hour to 10 hours.
  • an alkyl halide for example, odomethane, odoethane, etc.
  • an alkoxyalkyl halide for example, chloromethyl methyl ether
  • an aprotic solvent for example, jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform, etc.
  • the reaction proceeds from o ° c to room temperature.
  • R 5 has a group protected by a protecting group
  • a) deprotection or b) deprotection followed by alkylation to produce a compound represented by formula (I).
  • Alkylation is carried out in the presence of a base (for example, sodium hydride) in the presence of an alkylno, a ride (for example, odomethane, odoethane, or the like) or an (alkoxycarbon) alkyl halide (for example, t-butoxycarbonylmethyl bromide).
  • a base for example, sodium hydride
  • an alkylno for example, a ride
  • an (alkoxycarbon) alkyl halide for example, t-butoxycarbonylmethyl bromide.
  • the solvent may be an aprotic solvent (e.g., jetyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, Etc.), and the reaction proceeds from o ° c to room temperature.
  • each step it can be purified by a usual method such as recrystallization, distillation, column chromatography (when a chiral column is used, an optically active substance can be obtained) and used in the next step.
  • the compounds of the present invention can be converted into prodrugs.
  • a prodrug is a compound that becomes a pharmaceutically active compound of the present invention in vivo under physiological conditions. Methods for selecting and producing suitable prodrug derivatives can be found, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985.
  • the prodrug of the compound according to the present invention can be produced by introducing a leaving group into a substituent on the A ring that can introduce a leaving group (for example, amino-containing hydroxy).
  • a leaving group for example, amino-containing hydroxy.
  • prodrugs of amino groups include force rubamates (eg, methyl carbamate, cyclopropylmethyl carbamate, t-butyl carbamate, benzyl carbamate, etc.), amides (eg, formamide, acetamide, etc.), N-alkyls (eg, , N-arylamine, N-methoxymethylamine, etc.).
  • the hydroxy group prodrug include an ether form (methoxymethyl ether, methoxyethoxymethyl ether, etc.), an ester form (eg, acetate, pivaloate, benzoate, etc.) and the like.
  • Examples of the pharmaceutically acceptable salt include basic salts such as alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt. , Aliphatic amine salts such as triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, brocaine salt; aralkylamine salts such as ⁇ , ⁇ -dibenzylethylenediamine; pyridine salt, picoline Heterocyclic aromatic amine salts such as salts, quinoline salts and isoquinoline salts; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributyl Ammonium salt, methyl trioctyl ammonium salt, tetraptyl ammonium Quaternary ammonia salt
  • acidic salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate , Fumarate, tartrate, malate, kenate Organic salts such as ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, and P-toluenesulfonate; acidic amino acids such as aspartate and glutamate Can be mentioned.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate
  • acetate, propionate, lactate, maleate Fumarate, tartrate, malate, kenate
  • Organic salts such as ascorbate
  • sulfonates such as methanesulfonate, isethionate, benz
  • Solvate means a solvate of a compound represented by formula (I) or formula ( ⁇ ), a prodrug thereof, or a pharmaceutically acceptable salt thereof, for example, a monosolvate, a disolvate Japanese hydrate, monohydrate, dihydrate and the like can be mentioned.
  • the compound of the present invention can be used for the purpose of treatment or prevention for diseases involving cannapinoid receptor agonists.
  • Cannapinoid receptor agonists have anti-inflammatory and analgesic effects
  • the journal of Cannabis Thetas Journal of Cannabis The (rapeutics) 2002, 2-1, p. 59-71 states that the cannapinoid receptor agonist has bronchodilator activity and that WO 03Z035109 has an anti-epileptic activity. Has been.
  • the compound of the present invention is an anti-inflammatory agent, antiallergic agent, analgesic agent, pain treatment agent (invasive pain treatment agent, neuropathic pain treatment agent, psychogenic pain treatment agent, acute pain treatment agent, chronicity Pain treatment, etc.), immunodeficiency treatment, immunosuppressant, immunomodulator, autoimmune disease treatment, rheumatoid arthritis treatment, multiple sclerosis treatment, airway inflammatory cell infiltration inhibitor, airway hypersensitivity It can be used as an hyperinhibitory agent, bronchodilator, mucus secretion inhibitor, antidepressant, and the like.
  • the pharmaceutical composition containing the compound of the present invention can take a dosage form for oral and parenteral administration. That is, orally administered preparations such as tablets, capsules, granules, powders, syrups, or injection solutions or suspensions such as intravenous injections, intramuscular injections, subcutaneous injections, inhalants, eye drops, nasal drops, suppositories Or a parenteral preparation such as a preparation for transdermal administration such as an ointment or an ointment.
  • preparations can be produced using appropriate carriers, excipients, solvents, bases and the like known to those skilled in the art.
  • the active ingredient and auxiliary ingredients are compressed or molded together.
  • Auxiliary ingredients include pharmaceutically acceptable excipients such as binders (e.g. Rocco starch etc.), fillers (eg latatose, microcrystalline cellulose etc.), disintegrants (eg sodium starch glycolate etc.) or lubricants (eg magnesium stearate etc.) etc. are used.
  • the tablet may be appropriately coated.
  • suspending agents for example, methylcellulose
  • emulsifiers for example, lecithin
  • preservatives etc.
  • injectable preparations they may be in the form of solutions, suspensions or oily or aqueous emulsions, which may contain suspension stabilizers or dispersants.
  • an inhaler it is used as a solution that can be applied to an inhaler, and when used as an eye drop, it is also used as a solution or suspending agent.
  • the dose of the compound of the present invention varies depending on the administration form, patient symptom, age, body weight, sex, or concomitant drug (if any), and is ultimately left to the judgment of the doctor.
  • oral administration per day per kg body weight: 0.01 to: LOOmg, preferably 0.01 to 10 mg, more preferably 0.1 to: LOmg
  • parenteral administration per kg body weight, 0.001 to 10 Omg per day, preferably 0.001 to 1 mg, more preferably 0.01 to 1 mg is administered. This should be divided into 1 to 4 doses.
  • OAV 60962 ⁇ pu 0 inch is ⁇ s
  • a membrane fraction of CHO cells stably expressing CB1 or CB2 receptor was used as the human cannapinoid receptor.
  • test compound was added to CHO cells expressing human CB1 or CB2 receptor and incubated for 15 minutes, followed by incubation with forskolin (final concentration 4 M, SIGMA) for 20 minutes. After IN HC1 was added to stop the reaction, the amount of cAMP in the supernatant was measured using a Cynch AMP kit (CIS bio international). The concentration of cAMP (IC value) showing a 50% inhibitory effect was determined by setting cAMP production by stimulation with forskolin as 100% against no stimulation with forskolin.
  • mice ddy male mice (5 weeks old) were used, and the inhibitory effect of the compound of the present invention on formalin noxious stimulation was examined.
  • the test compound was dissolved in sesame oil and orally administered to mice 2 hours before formalin administration, and then formalin (2%, 20 L) was subcutaneously administered to the right hind limb.
  • formalin 2%, 20 L
  • measurement was performed for 30 minutes after formalin administration, and was divided into 5 minutes (first) immediately after formalin administration and 20 minutes (second phase) from 10 to 30 minutes.
  • the inhibitory effect of the test compound was measured using the total time of licking and biting actions on the right hind limb as an index, and the ED value was calculated.
  • Test Example 4 Inhibitory effect on Compound 48 / 80-induced itch in ddy mice An experiment was carried out by partially modifying the method of Inagaki et al. (Eur J Pharmacol 1999; 367: 361-371). Specifically, compound 48/80 (3 ⁇ g / 50 ⁇ 1 / site) was injected intradermally into a pre-shaved back of a female ddy mouse to induce a reaction, and the hind limbs to the injection site observed immediately thereafter I counted the number of whirlings in I for 30 minutes. After the test compound was dissolved in sesame oil and orally administered to mice, itching was induced by inoculation with compound 48/80 at the time when the maximum blood concentration set in advance was obtained. The evaluation of itch control is performed by comparing the number of pulls in the compound administration group with the number of pulls in the vehicle administration group, and the ED value is calculated. It was.
  • active ingredient means a compound of the present invention, a tautomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • Hard gelatin capsules are manufactured using the following ingredients:
  • Tablets are manufactured using the following ingredients:
  • the ingredients are mixed and compressed into tablets each weighing 665 mg.
  • An aerosol solution is prepared containing the following ingredients:
  • Propellant 22 (Chlorodifluoromethane) 74. 00
  • a tablet containing 60 mg of active ingredient is prepared as follows:
  • the active ingredient, starch, and cellulose are sifted through a No. 45 mesh US sieve and mixed thoroughly.
  • the aqueous solution containing polybulurpyrrolidone is mixed with the resulting powder, and the mixture is then passed through a No. 14 mesh U.S. sieve.
  • the granules so obtained are dried at 50 ° C and passed through a No. 18 mesh U.S. sieve.
  • Sodium carboxymethyl starch, magnesium stearate, and talc passed through a No. 60 mesh U.S. sieve in advance are added to the granules, mixed, and compressed by a tableting machine to obtain tablets each weighing 150 mg.
  • Capsules containing 80 mg of active ingredient are prepared as follows:
  • a suppository containing 225 mg of active ingredient is prepared as follows:
  • a suspension containing 50 mg of active ingredient is prepared as follows:
  • Intravenous preparations are manufactured as follows:
  • Saturated fatty acid glyceride 1000ml Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.
  • 2-naphthylimino 5,5 disubstituted 1,3 thiazine derivatives having cannapinoid receptor agonist activity show an analgesic effect, a pain treatment effect, an antidepressant effect, or a bronchodilator effect.

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Abstract

La présente invention concerne la préparation d’un dérivé 2-naphtylimino-5,5-disubstitué-1,3-thiazine et d’une composition pharmaceutique comprenant le composé en tant que substance active et la fourniture d’un agent analgésique, d’un agent thérapeutique contre la douleur, d’un agent antiprurigineux ou d’un bronchodilatateur. L’invention concerne un composé représenté par la formule générale (I) ou une forme optiquement active ou un sel pharmaceutiquement acceptable du composé ou un produit de solvatation du composé, de la forme optiquement active ou du sel : (I) où R1 représente indépendamment un groupe alkyle ou analogues ; R2 et R3 sont différents l'un de l'autre et représentent un groupe alkyle en C1 à C6 ou analogues, ou R2 et R3 peuvent former conjointement un cycloalcane ayant de 5 à 8 chaînons qui a un atome de carbone adjacent et est substitué par un groupe alkyle en C1 à C4 ou analogues ; R4 représente un groupe alkyle en C1 à C4 ou analogues ; X représente un atome d'oxygène ou de soufre ; W représente -CH=CH-CH=CH- ou analogues ; et n est un nombre entier de 0 à 7.
PCT/JP2006/310679 2005-05-30 2006-05-29 Derive 2-naphtylimino-5,5-disubstitue-1,3-thiazine WO2006129609A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012020742A1 (fr) 2010-08-10 2012-02-16 塩野義製薬株式会社 Nouveaux dérivés hétérocycliques, et composition pharmaceutique comprenant ceux-ci
US10689371B2 (en) 2018-04-18 2020-06-23 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US11919912B2 (en) 2018-05-21 2024-03-05 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003070277A1 (fr) * 2002-02-19 2003-08-28 Shionogi & Co., Ltd. Antiprurigineux
WO2004029027A1 (fr) * 2002-09-27 2004-04-08 Glaxo Group Limited Derives de pyridine en tant que modulateurs du recepteur cb2
WO2004060882A1 (fr) * 2003-01-07 2004-07-22 Astrazeneca Ab Ligands des recepteurs cb 1/cb 2 et utilisation associee dans le traitement de la douleur
WO2005026138A1 (fr) * 2003-08-26 2005-03-24 Shionogi & Co., Ltd. Derive de 2-naphthylimino-1,3-thiazine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003070277A1 (fr) * 2002-02-19 2003-08-28 Shionogi & Co., Ltd. Antiprurigineux
WO2004029027A1 (fr) * 2002-09-27 2004-04-08 Glaxo Group Limited Derives de pyridine en tant que modulateurs du recepteur cb2
WO2004060882A1 (fr) * 2003-01-07 2004-07-22 Astrazeneca Ab Ligands des recepteurs cb 1/cb 2 et utilisation associee dans le traitement de la douleur
WO2005026138A1 (fr) * 2003-08-26 2005-03-24 Shionogi & Co., Ltd. Derive de 2-naphthylimino-1,3-thiazine

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012020742A1 (fr) 2010-08-10 2012-02-16 塩野義製薬株式会社 Nouveaux dérivés hétérocycliques, et composition pharmaceutique comprenant ceux-ci
US10689371B2 (en) 2018-04-18 2020-06-23 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US11274095B2 (en) 2018-04-18 2022-03-15 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US11919912B2 (en) 2018-05-21 2024-03-05 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof

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