WO2012105635A1 - Dérivé de 8-oxodihydropurine 2-oxy-substitué - Google Patents

Dérivé de 8-oxodihydropurine 2-oxy-substitué Download PDF

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WO2012105635A1
WO2012105635A1 PCT/JP2012/052336 JP2012052336W WO2012105635A1 WO 2012105635 A1 WO2012105635 A1 WO 2012105635A1 JP 2012052336 W JP2012052336 W JP 2012052336W WO 2012105635 A1 WO2012105635 A1 WO 2012105635A1
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group
optionally substituted
substituted
alkyl
membered
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圭司 足立
中井　陽子
智行 古田
佑樹 藤井
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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • 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

Definitions

  • the present invention relates to a novel 2-oxy-substituted 8-oxodihydropurine derivative having an inhibitory action on fatty acid amide hydrolase (Fatty Acid Amide Hydrolase; hereinafter also referred to as "FAAH”) and pharmaceutically acceptable derivatives thereof. And a therapeutic or prophylactic agent for depression, anxiety or pain comprising the compound as an active ingredient.
  • Fatty Acid Amide Hydrolase hereinafter also referred to as "FAAH”
  • FAAH fatty Acid Amide Hydrolase
  • a therapeutic or prophylactic agent for depression, anxiety or pain comprising the compound as an active ingredient.
  • Cannabis is known since ancient times to show various psychiatric effects or analgesic such, their action on the 1960s delta 9 - series of compounds around the -tetrahydrocannabinol ( ⁇ 9 -THC) (cannabinoids ).
  • ⁇ 9 -THC cannabinoid receptors
  • CB1 and CB2 cannabinoid receptors
  • Anandamide (AEA) was found in the pig brain.
  • Anandamide is known to be metabolized mainly by FAAH.
  • FAAH inhibitors show an effect in animal models of pain (neuropathic pain, inflammatory pain, nociceptive pain), anxiety and depression (for example, see Non-Patent Document 2). ).
  • FAAH and its fatty acid amide are known to be associated with various diseases.
  • FAAH is increased in the brain of Alzheimer's patients
  • OEA is related to regulation of feeding
  • oleamide is related to induction of sleep (eg, non-patent literature). 3)
  • FAAH inhibitors have been reported to show a brain / neuroprotective effect, as well as frequent urinary / urinary incontinence treatment effect and overactive bladder treatment effect.
  • Examples of low molecular weight compounds having FAAH inhibitory activity include 4,5-diphenylimidazole derivatives (see Patent Document 1), dioxane-2-alkylcarbamic acid derivatives (see Patent Document 2), and O-aryl-N-alkylcarbamines. Acid aryl ester derivatives (see Patent Document 3), ⁇ -keto heterocyclic derivatives (see Patent Document 4), biaryl ether urea derivatives (see Patent Document 5), triazolopyridine (or pyrimidine) carboxamide derivatives (Patent Documents 6 and 7) For example, a benzimidazolone carboxamide derivative (see Patent Document 8) has been reported as a low molecular weight compound having CB1 receptor binding activity.
  • these prior art documents do not describe any compounds of the present invention having a 2-oxy-substituted 8-oxodihydropurine structure represented by the following formula (1), and there are descriptions suggesting the compounds of the present invention. Absent.
  • the problem to be solved by the present invention is a novel 2-oxy-substituted 8-oxodihydropurine derivative and a pharmaceutically acceptable salt thereof, and fatty acid amide hydrolase (FAAH) containing the compound as an active ingredient It is to provide an inhibitor and a medicament, a pharmaceutical composition and use thereof, which are useful for the treatment or prevention of depression, anxiety or pain, and a preventive or therapeutic method using the compound.
  • FAAH fatty acid amide hydrolase
  • a 2-oxy-substituted 8-oxodihydropurine derivative having a urea structure at the 7-position or 9-position that is, a compound represented by the following formula (1) is a strong FAAH. It has been found that it has an inhibitory action and is useful as a therapeutic or prophylactic agent for depression, anxiety or pain, and the present invention has been completed. That is, the present invention is as follows.
  • W represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may be substituted with a halogen atom or a C 1-6 alkyloxy group which may be substituted with a halogen atom
  • A represents a C 1-6 alkyl group [the C 1-6 alkyl group is a halogen atom, a hydroxy group, an optionally substituted C 3-8 cycloalkyl group, or an optionally substituted C 4-10 cyclo group.
  • An optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 4-10 cycloalkenyl group, an optionally substituted C 6-10 aryl group, an optionally substituted 5 Represents a 10-membered heteroaryl group, an optionally substituted 3- to 10-membered heterocycloalkyl group
  • X and Y are either a group represented by the formula [Q]: —CONR 1 R 2 , and the other is a hydrogen atom, a C 1-6 alkyl group (the C 1-6 alkyl group is a halogen atom)
  • R 1 represents a C 1-6 alkyl group (the C 1-6 alkyl group is a halogen atom, an optionally substituted C 3-8 cycloalkyl group.
  • R 3 and R 4 together form a methylene group, an ethylene group, a propylene group, a butylene group, and the cyclic group represented by the above formula (2) may form a bridged ring
  • R 5 represents a C 1-6 alkyl group (the C 1-6 alkyl group is a halogen atom, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 6-10 aryl group, and 1 or 2 or more substituents selected from the group consisting of optionally substituted 5- to 10-membered heteroaryl groups, which may be substituted at any substitutable position.
  • R 6 represents an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 6-10 aryl group, or an optionally substituted 5--10 membered heteroaryl group.
  • the cyclic group represented by this is represented. Or a pharmaceutically acceptable salt thereof.
  • Either X or Y is a C 1-6 alkyl group (the C 1-6 alkyl group is substituted by one or more halogen atoms at any substitutable position). Or a pharmaceutically acceptable salt thereof.
  • A is a C 1-6 alkyl group (the C 1-6 alkyl group is a halogen atom, a hydroxy group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 4 A -10 cycloalkenyl group, an optionally substituted 3-10 membered heterocycloalkyl group, an optionally substituted C 6-10 aryl group, an optionally substituted 5-10 membered heteroaryl group, Any position that can be substituted by one or more substituents selected from the group consisting of an optionally substituted C 1-6 alkyloxy group and an optionally substituted C 6-10 aryloxy group An optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 6-10 aryl group, an optionally substituted 5- to 10-membered hetero
  • the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [3], which is an aryl group or an optionally substituted 3- to 10-membered heterocycloalkyl
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 6-10 aryl group, a substituted Optionally substituted 5-10 membered heteroaryl group, optionally substituted C 6-10 aryloxy group, optionally substituted 5-10 membered heteroaryloxy group, substituted C 6-10 Aryl (C 1-6 alkyl) oxy group, C 1-6 alkyl group [wherein the C 1-6 alkyl group is a halogen atom, an optionally substituted C 3-8 cycloalkyl group, which may be substituted; C 1-6 alkyloxy group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 6-10 aryl group, an optionally substituted 5-10 membered heteroaryl Group, optionally substituted C 6-10 aryloxy group, a substituted-5 may be 10-membered heteroaryloxy group,
  • R 3 and R 4 are the same or different and each is a hydrogen atom, an optionally substituted C 6-10 aryl group or an optionally substituted C 6-10 aryloxy group The described compound or a pharmaceutically acceptable salt thereof.
  • a medicament comprising as an active ingredient the compound according to any one of [1] to [14] or a pharmaceutically acceptable salt thereof.
  • a fatty acid amide hydrolase (FAAH) inhibitor comprising the compound according to any one of [1] to [14] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition comprising the compound according to any one of [1] to [14] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • [23] Depression characterized by administering a therapeutically effective amount of the compound according to any one of [1] to [14] or a pharmaceutically acceptable salt thereof to a patient in need of treatment Treatment or prevention of disease, anxiety or pain.
  • the present invention provides a fatty acid amide hydrolase (FAAH) inhibitor containing a 2-oxy-substituted 8-oxodihydropurine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the FAAH inhibitor of the present invention is useful as a therapeutic or prophylactic agent for depression, anxiety or pain.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Alkyl group means a linear or branched saturated aliphatic hydrocarbon group, and specifically includes methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group. Group, tert-butyl group, pentyl group, hexyl group and the like.
  • the alkyl group includes an alkyl group having 1 to 6 carbon atoms, and preferably an alkyl group having 1 to 4 carbon atoms. In the present specification, for example, C 1-6 has 1 to 6 carbon atoms, C 1-4 has 1 to 4 carbon atoms, and C 6 represents 6 carbon atoms. . The same applies to other numbers.
  • alkenyl group means a linear or branched unsaturated aliphatic hydrocarbon group having one or more double bonds, and specifically includes a vinyl group, 1-propenyl group, 2- Propenyl group, 1-methylvinyl group, 1-butenyl group, 1-ethylvinyl group, 1-methyl-2-propenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2-methyl Examples include -2-propenyl group, 1-pentenyl group, 1-hexenyl group and the like.
  • the alkenyl group includes an alkenyl group having 2 to 6 carbon atoms, preferably an alkenyl group having 2 to 4 carbon atoms.
  • Alkynyl group means a linear or branched unsaturated aliphatic hydrocarbon group having one or more triple bonds, and specifically includes an ethynyl group, a 1-propynyl group, and 2-propynyl group. Group, 1-butynyl group, 1-methyl-2-propynyl group, 3-butynyl group, 1-pentynyl group, 1-hexynyl group and the like.
  • the alkynyl group includes an alkynyl group having 2 to 6 carbon atoms, and preferably an alkynyl group having 2 to 4 carbon atoms.
  • alkyloxy group means an oxy group substituted with the above alkyl group, specifically, a methoxy group, an ethoxy group, a propoxy group, a 1-methylethoxy group, a butoxy group, a 1-methylpropoxy group, Examples include 2-methylpropoxy group, 1,1-dimethylethoxy group, pentyloxy group, hexyloxy group and the like.
  • the alkyl moiety of the alkyloxy group usually includes an alkyl group having 1 to 6 carbon atoms, and preferably an alkyl group having 1 to 4 carbon atoms.
  • alkyloxy group optionally substituted with a halogen atom means a linear or branched haloalkyloxy group substituted with 1 to 5 identical or different halogen atoms in addition to the above alkyloxy group.
  • haloalkyloxy groups such as a pentafluoroethoxy group and a 3,3,3-trifluoropropoxy group.
  • the haloalkyl part of the haloalkyloxy group usually includes a haloalkyl group having 1 to 6 carbon atoms, preferably a haloalkyl group having 1 to 4 carbon atoms.
  • cycloalkyl group refers to a monocyclic saturated aliphatic carbocyclic group, or a monocyclic saturated aliphatic carbocyclic group, a monocyclic saturated aliphatic carbocyclic group, a monocyclic unsaturated aliphatic carbocyclic group, A cyclic saturated aliphatic heterocyclic ring, a monocyclic unsaturated aliphatic heterocyclic ring, a monocyclic aromatic ring or a bicyclic cyclic group to which a monocyclic aromatic heterocyclic ring is fused.
  • Examples thereof include a propyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and a bicyclo [3.2.0] heptyl group.
  • the cycloalkyl group usually includes a C 3-8 cycloalkyl group, preferably a C 3-6 cycloalkyl group.
  • Cycloalkyloxy group means an oxy group substituted with the above cycloalkyl group, specifically, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group. And cyclooctyloxy group.
  • the cycloalkyloxy group usually includes a C 3-8 cycloalkyloxy group, preferably a C 3-6 cycloalkyloxy group.
  • cycloalkyl (alkyl) oxy group means an alkyloxy group substituted with the “cycloalkyl group”, specifically, a cyclohexylmethyloxy group, a cyclopentylmethyloxy group, a cyclobutylmethyloxy group, Examples include a cyclohexylethyloxy group, a cyclohexylpropyloxy group, a cyclopentylethyloxy group, and a cyclopentylpropyloxy group.
  • the cycloalkyl (alkyl) oxy group usually includes a C 1-6 alkyloxy group substituted with a C 3-8 cycloalkyl group, preferably a C 3-6 cycloalkyl group substituted with a C 3-6 cycloalkyl group.
  • a 1-6 alkyloxy group is mentioned.
  • the substituted cycloalkyl (alkyl) oxy group is one or two or more substituents in which the cycloalkyl part of the cycloalkyl (alkyl) oxy group is selected from the group of substituents ( ⁇ ) described later Means a cycloalkyl (alkyl) oxy group substituted by.
  • “Cycloalkenyl group” means a monocyclic unsaturated aliphatic carbocyclic group having one or more double bonds on the ring, or a monocyclic saturated aliphatic carbocyclic group.
  • Aliphatic carbocycle, monocyclic unsaturated aliphatic carbocycle, monocyclic saturated aliphatic heterocycle, monocyclic unsaturated aliphatic heterocycle, monocyclic aromatic ring or monocyclic aromatic heterocycle (However, the position of the double bond is not particularly limited as long as it is chemically stable.) Specifically, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, A cyclooctenyl group is mentioned.
  • heterocycloalkyl group is a monocyclic saturated aliphatic heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or the monocyclic saturated aliphatic heterocyclic group Monocyclic saturated aliphatic carbocyclic ring, monocyclic unsaturated aliphatic carbocyclic ring, monocyclic saturated aliphatic heterocyclic ring, monocyclic unsaturated aliphatic heterocyclic ring, monocyclic aromatic ring or monocyclic This means a bicyclic group to which an aromatic heterocycle is fused (the position of the heteroatom on the ring is not particularly limited as long as it is chemically stable).
  • the heterocycloalkyl group usually includes a 3- to 10-membered heterocycloalkyl group, preferably a 4- to 8-membered heterocycloalkyl group (for example, azetidinyl group, pyrrolidinyl group, piperidyl group, piperidino group, piperazinyl group).
  • azetidinyl group for example, azetidinyl group, pyrrolidinyl group, piperidyl group, piperidino group, piperazinyl group.
  • More preferably 4 to 6-membered heterocycloalkyl group for example, azetidinyl group, pyrrolidinyl group, piperidyl group, piperidino group, piperazinyl group, tetrahydrofuryl group, tetrahydrothienyl group, tetrahydropyranyl group, morpholinyl group, morpholino group, thiolino group, Morpholinyl group, 1,4-dioxanyl group, an oxetanyl group).
  • azetidinyl group for example, azetidinyl group, pyrrolidinyl group, piperidyl group, piperidino group, piperazinyl group, tetrahydrofuryl group, tetrahydrothienyl group, tetrahydropyranyl group, morpholinyl group, morpholino group, thiolino group, Morpholinyl group, 1,4-d
  • Heterocycloalkyloxy group means an oxy group substituted with the above “heterocycloalkyl group”, and specific examples include a 3-pyrrolidinyloxy group and a 3- or 4-piperidyloxy group. It is done.
  • the heterocycloalkyloxy group usually includes an oxy group substituted with a 3 to 10-membered heterocycloalkyl group, preferably an oxy group substituted with a 4 to 8 membered heterocycloalkyl group.
  • Heterocycloalkyl (alkyl) oxy group means an alkyloxy group substituted with the above “heterocycloalkyl group”, specifically, 3-pyrrolidinylmethyloxy group, 3- or 4- Piperidylmethyloxy group, piperidinomethyloxy group, N-piperazinylethyloxy group, 1-, 2- or 3-pyrrolidinylethyloxy group, 1-, 2- or 3-pyrrolidinylpropyloxy group Is mentioned.
  • the heterocycloalkyl (alkyl) oxy group includes a C 1-6 alkyloxy group usually substituted with a 3 to 10-membered heterocycloalkyl group, preferably a 4- to 8-membered heterocycloalkyl group.
  • the substituted heterocycloalkyl (alkyl) oxy group is one heterocycloalkyl part of the heterocycloalkyl (alkyl) oxy group selected from the group of substituents ( ⁇ ) described later, or two or more same or different Means a heterocycloalkyl (alkyl) oxy group substituted by the above substituent.
  • a heterocyclic ring, a monocyclic aromatic ring, or a bicyclic cyclic group to which a monocyclic aromatic heterocyclic ring is fused (especially if the position of the heteroatom and the double bond on the ring is chemically stable)
  • Specific examples include pyrrolinyl group, tetrahydropyridyl group, imidazolinyl group, tetrahydroisoquinolyl group, etc., preferably 3-pyrrolinyl group, 3-tetrahydropyridyl group, 2-imidazolinyl group.
  • the heterocycloalkenyl group usually includes a 4- to 10-membered heterocycloalkenyl group, preferably a 5- to 8-membered heterocycloalkenyl group, and more preferably a 5- to 6-membered heterocycloalkenyl group. Can be mentioned.
  • An ⁇ aryl group '' is a monocyclic aromatic cyclic group, or a monocyclic saturated aliphatic carbocyclic ring, a monocyclic unsaturated aliphatic carbocyclic ring, a monocyclic saturated aliphatic heterocyclic group A ring, a monocyclic unsaturated aliphatic heterocyclic ring or a bicyclic cyclic group in which a monocyclic aromatic ring is condensed, specifically, a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an indanyl group Etc.
  • the aryl group usually includes a C 6-10 aryl group, preferably a C 6 or C 10 aryl group.
  • Heteroaryl group means a monocyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a monocyclic aromatic heterocyclic group Saturated aliphatic carbocycles, monocyclic unsaturated aliphatic carbocycles, monocyclic saturated aliphatic heterocycles, monocyclic unsaturated aliphatic heterocycles, monocyclic aromatic rings or monocyclic aromatic heterocycles Means a bicyclic cyclic group in which a monocyclic aromatic heterocyclic group is fused to a monocyclic aromatic cyclic group (the position of the heteroatom on the ring is chemically stable) In particular, furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, furazanyl group, oxadiazoly
  • the heteroaryl group usually includes a 5- to 10-membered monocyclic or bicyclic heteroaryl group, preferably a 5- or 6-membered monocyclic heteroaryl group or a 9- or 10-membered bicyclic heteroaryl group Groups.
  • alkylcarbonyl group means a carbonyl group substituted with the “alkyl group”, and specific examples include an acetyl group, a propionyl group, a butyryl group, and the like.
  • the alkylcarbonyl group usually includes a carbonyl group substituted with an alkyl group having 1 to 6 carbon atoms, and preferably includes a carbonyl group substituted with an alkyl group having 1 to 4 carbon atoms.
  • a C 1-6 alkylcarbonyl group and a C 1-4 alkylcarbonyl group are a carbonyl group substituted by an alkyl group having 1 to 6 carbon atoms and an alkyl group having 1 to 4 carbon atoms, respectively. It means a substituted carbonyl group.
  • Alkylcarbonyloxy group means an oxy group substituted with the above “alkylcarbonyl group”, and specific examples include an acetoxy group, a propionyloxy group, a butyryloxy group, and the like.
  • the alkylcarbonyloxy group usually includes an oxy group substituted with an alkylcarbonyl group having 1 to 6 carbon atoms, and preferably an oxy group substituted with an alkylcarbonyl group having 1 to 4 carbon atoms.
  • a C 1-6 alkyloxycarbonyl group and a C 1-4 alkyloxycarbonyl group are a carbonyl group substituted with an alkyloxy group having 1 to 6 carbon atoms, respectively, and a C 1-4 alkyl group. This means a carbonyl group substituted with an alkyloxy group.
  • the “arylcarbonyl group” means a carbonyl group substituted with the above “aryl group”, and specific examples include a benzoyl group, a 1-naphthoyl group, and a 2-naphthoyl group.
  • the arylcarbonyl group usually includes a C 6-10 arylcarbonyl group, preferably a C 6 or C 10 arylcarbonyl group.
  • a C 6-10 arylcarbonyl group means a carbonyl group substituted with an aryl group having 6 to 10 carbon atoms.
  • heteroaryl (alkyl) oxy group means an alkyloxy group substituted with the above “heteroaryl group”, and specifically includes a 2-, 3- or 4-pyridylmethyloxy group.
  • examples of the heteroaryl (alkyl) oxy group include C 1-6 alkyloxy groups substituted with a 5- to 10-membered monocyclic or bicyclic heteroaryl group, and preferably a 5- or 6-membered monocyclic group.
  • the substituted heteroaryl (alkyl) oxy group is one or two or more substituents in which the heteroaryl part of the heteroaryl (alkyl) oxy group is selected from the group of substituents ( ⁇ ) described later Means a heteroaryl (alkyl) oxy group substituted by
  • Alkylthio group means a thio group substituted with the above “alkyl group”, specifically, methylthio group, ethylthio group, propylthio group, 1-methylethylthio group, butylthio group, 1-methylpropyl group. Examples thereof include a thio group, a 2-methylpropylthio group, a 1,1-dimethylethylthio group, a pentylthio group, and a hexylthio group.
  • alkylthio group usually include an alkylthio group having 1 to 6 carbon atoms, preferably an alkylthio group having 1 to 4 carbon atoms.
  • Alkylsulfonyl group means a sulfonyl group substituted with the above “alkyl group”, specifically, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, 1-methylethylsulfonyl group, butylsulfonyl group 1-methylpropylsulfonyl group, 2-methylpropylsulfonyl group, 1,1-dimethylethylsulfonyl group, pentylsulfonyl group, hexylsulfonyl group and the like.
  • the alkylsulfonyl group usually includes an alkylsulfonyl group having 1 to 6 carbon atoms, preferably an alkylsulfonyl group having 1 to 4 carbon atoms.
  • arylsulfonyl group means a sulfonyl group substituted with the above “aryl group”, and specific examples include a phenylsulfonyl group, a 1-naphthylsulfonyl group, and a 2-naphthylsulfonyl group.
  • the arylsulfonyl group usually includes a C 6-10 arylsulfonyl group, preferably a C 6 or C 10 arylsulfonyl group.
  • one or two or more substituents selected from the group of the following substituents ( ⁇ ′) are the same or different:
  • Cycloalkyl “Cycloalkyl”, “cycloalkenyl”, “heterocycloalkyl”, “heterocycloalkenyl” group or moiety, “saturated aliphatic carbocycle”, “unsaturated aliphatic carbocycle”, “saturated aliphatic heterocycle” And the substituent in the case where the “unsaturated aliphatic heterocycle” is substituted, unless otherwise specified, one selected from the group of the following substituents ( ⁇ ), or two or more same or different substitutions Groups, and these substituents are substituted at any substitutable position:
  • Substituent ( ⁇ ) A C 1-6 alkyl group optionally substituted with one or more halogen atoms, a halogen atom, a C 3-8 cycloalkyl group, a C 4-10 cycloalkenyl group, or a trifluoromethoxy group.
  • “Saturated aliphatic carbocycle” means a monocyclic or bicyclic saturated aliphatic carbocycle, specifically, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, bicyclo [3 .2.0] heptane and the like.
  • saturated aliphatic carbocycle usually a 3- to 8-membered saturated aliphatic carbocycle is mentioned, and preferably a 3- to 6-membered saturated aliphatic carbocycle is mentioned.
  • “Unsaturated aliphatic carbocycle” means a monocyclic or bicyclic unsaturated aliphatic carbocycle having one or more double bonds on the ring (the position of the double bond is chemical).
  • cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene can be used.
  • the unsaturated aliphatic carbocycle include a 4- to 10-membered unsaturated aliphatic carbocycle, preferably a 4- to 6-membered unsaturated aliphatic carbocycle, and more preferably 5- or 6-membered. Of the unsaturated aliphatic carbocycle.
  • “Saturated aliphatic heterocyclic ring” means a monocyclic or bicyclic saturated aliphatic heterocyclic ring containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (on the ring).
  • the position of the hetero atom is not particularly limited as long as it is chemically stable.
  • azetidine, pyrrolidine, piperidine, piperazine, perhydroazepine, perhydroazocine, perhydroazonin, perhydroazesin, Tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, morpholine, thiomorpholine, 1,4-dioxane, oxetane and the like can be mentioned.
  • the saturated aliphatic heterocyclic ring usually includes a 3 to 10-membered saturated aliphatic heterocyclic ring, and preferably a 4 to 8-membered saturated aliphatic heterocyclic ring (for example, azetidine, pyrrolidine, piperidine, piperazine, perhydroazepine).
  • Perhydroazocine tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, morpholine, thiomorpholine, 1,4-dioxane, oxetane), more preferably a 4-6 membered saturated aliphatic heterocycle (for example, azetidine, pyrrolidine) , Piperidine, piperazine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, morpholine, thiomorpholine, 1,4-dioxane, oxetane).
  • a 4-6 membered saturated aliphatic heterocycle for example, azetidine, pyrrolidine
  • Piperidine piperazine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, morpholine, thiomorpholine, 1,4-dioxane,
  • “Unsaturated aliphatic heterocycle” refers to a monocyclic or bicyclic ring containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and 1 to 3 double bonds. It means a saturated aliphatic heterocycle (the positions of heteroatoms and double bonds on the ring are not particularly limited as long as they are chemically stable.) Specifically, pyrroline, tetrahydropyridine, imidazoline, tetrahydroisoquinoline, etc. Preferably, 3-pyrroline, 3-tetrahydropyridine and 2-imidazoline are used.
  • “Aromatic ring” means a monocyclic or bicyclic aromatic carbocycle, and specific examples include benzene, naphthalene and the like.
  • the aromatic ring usually includes a C 6-10 aromatic ring, preferably a C 6 or C 10 aromatic ring.
  • the “aromatic heterocycle” means a monocyclic or bicyclic aromatic heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (a heteroatom on the ring).
  • the position of is not particularly limited as long as it is chemically stable.
  • the aromatic heterocycle include a 5- to 10-membered aromatic heterocycle, and preferably a 5- or 6-membered monocyclic aromatic heterocycle or a 9- or 10-membere
  • W is preferably a hydrogen atom or a halogen atom, More preferably, it is a hydrogen atom.
  • W include hydrogen atom, fluorine atom, chlorine atom, methyl group, ethyl group, propyl group, difluoromethyl group, trifluoromethyl group, methoxy group, ethoxy group, difluoromethoxy group, and trifluoromethoxy group. It is done.
  • A is preferably a C 1-6 alkyl group (the C 1-6 alkyl group is a halogen atom, a hydroxy group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 4).
  • optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 6-10 aryl group, a substituted 5 may be 1-10 membered f Roariru group or substituted heterocycloalkyl group which may 3-10 membered, More preferably, a C 1-6 alkyl group (
  • a C 6-10 aryl group or an optionally substituted 3- to 10-membered heterocycloalkyl group More preferably, a C 1-6 alkyl group (the C 1-6 alkyl group is an optionally substituted C 6-10 aryl group, an optionally substituted C 1-6 alkyloxy group, and a substituted C 1-6 alkyl group) And may be substituted at any substitutable position with one or more substituents selected from the group consisting of C 6-10 aryloxy groups.
  • One of X and Y is a group represented by the formula [Q]: —CONR 1 R 2 , and the following formula (1-1a) or (1-1b): (In the formula, A, W, R 1 and R 2 have the same meanings as defined in [1] above, and X a and Y a are, among X and Y, respectively, the formula [Q]: —CONR 1 R And a pharmaceutically acceptable salt thereof is included in the present invention. It means a group other than the group represented by 2 and has the same definition as in [8] above.
  • X a and Y a are preferably a C 1-6 alkyl group (the C 1-6 alkyl group may be substituted at any substitutable position with one or two or more halogen atoms. Or an optionally substituted C 3-8 cycloalkyl group, More preferably, an unsubstituted C 1-6 alkyl group or an optionally substituted C 3-8 cycloalkyl group, More preferably, it is an unsubstituted C 1-6 alkyl group.
  • X a and Y a include a hydrogen atom, a methyl group, an ethyl group, a propyl group, and a cyclopropyl group.
  • R 1 is preferably a C 1-6 alkyl group (the C 1-6 alkyl group is a halogen atom, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 6-10 An aryl group, an optionally substituted 5- to 10-membered heteroaryl group, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 3-8 cycloalkyloxy group, a substituted At any substitutable position by one or more substituents selected from the group consisting of an optionally substituted C 6-10 aryloxy group and an optionally substituted 5- to 10-membered heteroaryloxy group Or a C 6-10 aryl group which may be substituted, More preferably, it is a C 1-6 alkyl group (the C 1-6 alkyl group is a halogen atom, an optionally substituted C 6-10 aryl group, an optionally substituted 5-10 membered heteroaryl group) Substitutable by one or more
  • the C 1-6 alkyl group includes a halogen atom, an optionally substituted C 6-10 aryl group and an optionally substituted C 6-10 aryloxy group. And may be substituted at any substitutable position by one or more substituents selected from the group consisting of:
  • R 1 examples include methyl group, ethyl group, propyl group, phenyl group, benzyl group, phenylethyl group, pyridyl group, furyl group, thienyl group, pyrimidinyl group, pyrazinyl group, cyclohexyl group, methoxyethyl group, 2 -, 3- or 4-fluorophenylmethyl group, 2-, 3- or 4-fluorophenylethyl group, 2-, 3- or 4-chlorophenylmethyl group, 2-, 3- or 4-trifluoromethylphenylmethyl Group, cyclohexylethyl group, and cyclohexenylethyl group.
  • R 2 is preferably a C 1-6 alkyl group which may be substituted with a halogen atom, and more preferably a C 1-4 alkyl group. Specific examples of R 2 include a methyl group, an ethyl group, a propyl group, a cyclopropyl group, and a methoxyethyl group.
  • R 1 and R 2 together with the nitrogen atom to be bonded together have the following formula (2): (Wherein, n, m, G, R 3 and R 4 have the same meanings as defined in [1] above).
  • G is preferably —CH 2 — or —NR 5 —, and more preferably —CH 2 —.
  • R 3 and R 4 are bonded to a carbon atom on the cyclic group represented by the above formula (2) (provided that when G is —CH 2 — or —CH ⁇ CH—, R 3 and R 4 are , G can be bonded to any carbon atom of —CH 2 — or —CH ⁇ CH— in place of a hydrogen atom.
  • R 3 and R 4 are bonded to the same carbon atom on the cyclic group represented by the above formula (2), and together with the bonded carbon atom, C 3-8 saturated Aliphatic carbocycle, optionally substituted C 4-10 unsaturated aliphatic carbocycle, optionally substituted 3 to 10 membered saturated aliphatic heterocycle or optionally substituted 4 to 10 membered
  • An unsaturated aliphatic heterocyclic ring may be formed, and the cyclic group represented by the above formula (2) may have a spiro ring structure.
  • Specific examples of the spiro ring include 6-azaspiro [3.3] heptane, 2-oxa-6-azaspiro [3.3] heptane, and 7-azaspiro [3.5] nonane.
  • R 3 and R 4 are each bonded to adjacent carbon atoms on the cyclic group represented by the above formula (2), and together with the bonded carbon atoms, C 3-8 may be substituted.
  • Saturated aliphatic carbocyclic ring, optionally substituted C 4-10 unsaturated aliphatic carbocyclic ring, optionally substituted 3 to 10 membered saturated aliphatic heterocyclic ring, optionally substituted 4 to 10 member An unsaturated aliphatic heterocyclic ring, an optionally substituted C 6-10 aromatic ring or an optionally substituted 5- to 10-membered aromatic heterocyclic ring, and represented by the above formula (2)
  • the cyclic group may have a condensed ring structure. Specific examples of the condensed ring include 1-indoline, 2-indoline, 1,2,3,4-tetrahydro-1-quinoline, and 1,2,3,4-tetrahydro-2-quinoline.
  • R 3 and R 4 are each bonded to non-adjacent different carbon atoms on the cyclic group represented by the above formula (2), and R 3 and R 4 together are a methylene group, an ethylene group, a propylene group,
  • the cyclic group which forms a butylene group and is represented by the above formula (2) may have a crosslinked ring structure.
  • Specific examples of the bridged ring include 2-azabicyclo [2.2.2] octane and 9-azabicyclo [3.3.1] nonane.
  • R 3 and R 4 are preferably the same or different and are each a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 6-10 aryl group, a substituted Optionally substituted 5-10 membered heteroaryl group, optionally substituted C 6-10 aryloxy group, optionally substituted 5-10 membered heteroaryloxy group, substituted C 6-10 An aryl (C 1-6 alkyl) oxy group or a C 1-6 alkyl group [the C 1-6 alkyl group is a halogen atom, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted A C 1-6 alkyloxy group, an optionally substituted C 3-8 cycloalkyloxy group, an optionally substituted C 6-10 aryl group, an optionally substituted 5-10 membered Teloaryl group, optionally substituted C 6-10 aryloxy group, optionally substituted 5- to 10-membered heteroaryloxy
  • ком ⁇ онентs are the same or different and are a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 6-10 aryl group, an optionally substituted 5 to A 10-membered heteroaryl group, an optionally substituted C 6-10 aryloxy group, an optionally substituted 5- to 10-membered heteroaryloxy group, a substituted C 6-10 aryl (C 1-6 alkyl) group or a C 1-6 alkyl group (said C 1-6 alkyl group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, optionally substituted C 6-10 aryl group, a heteroaryl group, an optionally substituted C 6-10 aryloxy group and is substituted substituted 1-5 may be 10-membered By one or more substituents selected from the group consisting heteroaryloxy group which may 5-10 membered optionally, it may be substituted at any
  • R 3 and R 4 include hydrogen atom, fluorine atom, chlorine atom, benzyl group, methyl group, ethyl group, propyl group, pyridyl group, furyl group, thienyl group, pyrimidinyl group, pyrazinyl group, phenyl group, Phenoxy group, methoxymethyl group, phenylethyl group, 2-, 3- or 4-fluorophenylethyl group, 2-, 3- or 4-chlorophenylethyl group, 2-, 3- or 4-methoxyphenylethyl group, 2 -, 3- or 4-fluorophenoxy group, 2-, 3- or 4-methoxyphenoxy group, 2-, 3- or 4-fluorophenyl group, benzyloxy group, 2-, 3- or 4-fluorobenzyloxy Group, cyclopropylmethoxy group, cyclopropylmethoxymethyl group, benzyloxymethyl group, 2-, 3- or 4-eth Cyphenyl group
  • R 5 is preferably an optionally substituted C 6-10 aryl group or an optionally substituted 5-10 membered heteroaryl group; More preferably, it is an optionally substituted C 6-10 aryl group.
  • R 6 is preferably an optionally substituted C 6-10 aryl group.
  • R 6 include a phenyl group, 2-, 3- or 4-fluorophenyl group, 2-, 3- or 4-chlorophenyl group, and cyclopropyl group.
  • cyclic group represented by the formula (2) examples include azetidinyl group, pyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, difluoroazetidinyl group, 2- or 3-methylpyrrolidinyl group, 3 -Phenylpyrrolidinyl group, 4-methylpiperidyl group, 4-phenylpiperidyl group, 3-phenylazetidinyl group, 3-phenoxyazetidinyl group, 3-phenoxypyrrolidinyl group.
  • Specific examples of the above formula [Q] include dimethylaminocarbonyl group, diethylaminocarbonyl group, dipropylaminocarbonyl group, ethylmethylaminocarbonyl group, benzylmethylaminocarbonyl group, methyl (2-phenylethyl) aminocarbonyl group, azeti Examples thereof include a dinocarbonyl group, a pyrrolidinocarbonyl group, a piperidinocarbonyl group, a 3-phenylazetidinocarbonyl group, and a 3-phenoxyazetidinocarbonyl group.
  • suitable compounds include the following compounds or pharmaceutically acceptable salts thereof.
  • A represents a C 1-6 alkyl group (the C 1-6 alkyl group is a halogen atom, a hydroxy group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 4-10 cyclo group).
  • A is a C 1-6 alkyl group (wherein the C 1-6 alkyl group is an optionally substituted C 6-10 aryl group, an optionally substituted C 1-6 alkyloxy group, and a substituted group). And may be substituted at any substitutable position by one or more substituents selected from the group consisting of C 6-10 aryloxy groups which may be substituted).
  • X and Y are either a group represented by the formula [Q]: —CONR 1 R 2 , and the other is an unsubstituted C 1-6 alkyl group, W is a hydrogen atom, R 1 represents a C 1-6 alkyl group (the C 1-6 alkyl group includes a halogen atom, an optionally substituted C 6-10 aryl group and an optionally substituted C 6-10 aryloxy group).
  • preferred cyclic groups include the following cyclic groups.
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 6-10 aryl group, or an optionally substituted 5-10 membered heteroaryl group, optionally substituted C 6-10 aryloxy group, optionally substituted 5-10 membered heteroaryloxy group, substituted C 6-10 aryl (C 1-6 alkyl) group or a C 1-6 alkyl group (said C 1-6 alkyl group, an optionally substituted C 1-6 alkyl group, optionally C 3-8 cycloalkyl which may be substituted An oxy group, an optionally substituted C 6-10 aryl group, an optionally substituted 5- to 10-membered heteroaryl group, an optionally substituted C 6-10 aryloxy group and a substituent Which may be substituted at any substitutable position with
  • R 3 and R 4 are the same or different and are a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 6-10 aryl group, a substituted Optionally substituted 5-10 membered heteroaryl group, optionally substituted C 6-10 aryloxy group, optionally substituted 5-10 membered heteroaryloxy group, substituted C 6-10 aryl (C 1-6 alkyl) group or a C 1-6 alkyl group (said C 1-6 alkyl group may optionally be substituted C 1-6 alkyl group, optionally substituted C 3- 8 an cycloalkyloxy group, an optionally substituted C 6-10 aryl group, an optionally substituted 5- to 10-membered heteroaryl group, an optionally substituted C 6-10 aryloxy And may be substituted at any substitutable position by one or more substituents selected from the group consisting of a group and an optionally substituted 5- to 10-membered heteroaryloxy
  • an acid addition salt or alkali addition salt with a pharmaceutically acceptable inorganic acid or organic acid can do.
  • pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, and formate, acetate, fumarate, Maleate, oxalate, citrate, malate, tartrate, aspartate, glutamate and other organic carboxylic acids, methanesulfonate, benzenesulfonate, p-toluenesulfonate And salts with sulfonic acids such as hydroxybenzene sulfonate and dihydroxybenzene sulfonate.
  • the present invention also includes solvates such as a hydrate of the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof, and an ethanol solvate.
  • the present invention includes all tautomers, stereoisomers such as optical isomers or racemates of the compound represented by the general formula (1), and crystal forms of all forms. These can be appropriately isolated using methods such as silica gel column chromatography, HPLC, ion exchange chromatography, and recrystallization well known to those skilled in the art.
  • an optical resolution method known to those skilled in the art may be used.
  • an optically active acid for example, monocarboxylic acid such as mandelic acid, N-benzyloxyalanine, lactic acid, etc.
  • an optically active acid for example, monocarboxylic acid such as mandelic acid, N-benzyloxyalanine, lactic acid, etc.
  • camphorsulfonic acid and bromocamphorsulfonic acid can be formed and separated by recrystallization or the like.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may be used for other diseases involving FAAH or the endogenous cannabinoid system, such as Alzheimer's disease, cognitive impairment, schizophrenia, Parkinson's disease, attention deficit hyperactivity disorder. (ADHD), sleep disorder, glaucoma, multiple sclerosis, fibromyalgia, inflammation, colon cancer, rectal cancer, prostate cancer, cancer-related anorexia, nausea, vomiting can also be used as a therapeutic or prophylactic agent.
  • ADHD attention deficit hyperactivity disorder
  • sleep disorder glaucoma
  • multiple sclerosis multiple sclerosis
  • fibromyalgia inflammation
  • colon cancer rectal cancer
  • prostate cancer cancer-related anorexia
  • nausea, vomiting can also be used as a therapeutic or prophylactic agent.
  • the therapeutic agent or prophylactic agent for depression, anxiety or pain of the present invention is a pharmaceutically acceptable conventional carrier, binder, stabilizer, excipient, diluent, pH buffer, disintegrant, Various preparation compounding components such as a solubilizer, a solubilizer, and an isotonic agent can be added.
  • These therapeutic or prophylactic agents can be administered orally or parenterally. That is, orally, it can be administered orally in a dosage form such as tablets, pills, powders, powders, granules, capsules, solutions, syrups, emulsions, suspensions and the like that are usually used. it can.
  • the compound used in the following production method may form a salt similar to the salt formed by the compound represented by formula (1) as long as the reaction is not hindered.
  • a functional group that may participate in the reaction when included in the structure of the starting material, for example, an amino group, a carboxyl group, a hydroxy group, or a carbonyl group, You may protect by introduce
  • amino-protecting group examples include an alkylcarbonyl group (for example, acetyl group, propionyl group), formyl group, phenylcarbonyl group, alkyloxycarbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group). ), Phenyloxycarbonyl group, arylalkyloxycarbonyl group (for example, benzyloxycarbonyl group), trityl group, phthaloyl group, tosyl group, and benzyl group.
  • alkylcarbonyl group for example, acetyl group, propionyl group
  • formyl group formyl group
  • phenylcarbonyl group alkyloxycarbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group).
  • Phenyloxycarbonyl group arylalkyloxycarbony
  • Examples of the protective group for hydroxy group include methyl group, tert-butyl group, allyl group, substituted methyl group (for example, methoxymethyl group, methoxyethoxymethyl group), ethoxyethyl group, tetrahydropyranyl group, tetrahydrofuranyl group, Trityl group, arylalkyl group (for example, benzyl group), alkylcarbonyl group (for example, acetyl group, propionyl group), formyl group, benzoyl group, arylalkyloxycarbonyl group (for example, benzyloxycarbonyl group), silyl group (for example, , Trimethylsilyl group, tert-butyldimethylsilyl group).
  • the carbonyl group can be protected by converting the carbonyl group into an acyclic ketal (such as dimethyl ketal or diethyl ketal) or a cyclic ketal (such as 1,3-dioxolane or 1,3-dioxane).
  • acyclic ketal such as dimethyl ketal or diethyl ketal
  • a cyclic ketal such as 1,3-dioxolane or 1,3-dioxane
  • the solvent to be used should be selected according to the type of raw material compound, etc., and for example, toluene, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, ethyl acetate, acetone, acetonitrile, N, N-dimethylformamide, 1- And methylpyrrolidin-2-one. These solvents are used alone or as a mixed solvent of two or more.
  • the base include sodium hydride, triethylamine, 1,4-diazabicyclo [2.2.2] octane, potassium carbonate, and sodium carbonate. While the reaction temperature varies depending on the type of raw material compound used, it is generally about ⁇ 30 ° C. to 150 ° C., preferably about ⁇ 10 ° C. to about 70 ° C.
  • the compound of formula (B) may be a commercially available one, or a known method such as J. Am. Chem. Soc., 72 , 1888 (1950); Tetrahedron Lett., 30 , 3229 (1989). What was manufactured according to the method of description can be used.
  • a known compound can be used, or a compound produced according to a known compound production method can be used.
  • the typical manufacturing method is illustrated below.
  • Step 1 The reaction of the compound of the substitution reaction formula (a) and the compound of the formula (b) is carried out in the absence of a solvent or in a suitable solvent under normal pressure or pressure.
  • the solvent to be used should be appropriately selected according to the kind of the raw material compound.
  • aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, 1,4-dioxane.
  • Ethers such as methylene chloride, halogenated hydrocarbons such as chloroform, alcohols such as ethanol, isopropanol and ethylene glycol, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethyl
  • ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethyl
  • formamide 1-methylpyrrolidin-2-one, and dimethyl sulfoxide.
  • This reaction is performed in the presence of a base as necessary.
  • the base include inorganic substances such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, alkali carbonate, sodium bicarbonate, and potassium bicarbonate.
  • examples include bases or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, but an excess of the compound of formula (b) may be used.
  • the compound of the formula (b) may be used in the form of an acid addition salt such as hydrochloride and the free base may be generated in the reaction system. While the reaction temperature varies depending on the kind of starting compound used, etc., it is generally about ⁇ 10 ° C. to about 100 ° C., preferably about 0 ° C. to about 70 ° C.
  • Step 3 Cyclization This cyclization involves reacting the compound of formula (d) with urea, carbonyldiimidazole, diethyl carbonate, or phosgene or its equivalent (diphosgene, triphosgene, 4-nitrophenyl chloroformate, etc.). Is done.
  • This reaction is carried out in the absence of solvent or in a suitable solvent at normal pressure or under pressure.
  • suitable solvent include tetrahydrofuran, 1,4-dioxane, toluene, N, N-dimethylformamide, and 1-methylpyrrolidin-2-one.
  • reaction temperature varies depending on the kind of raw material compound used, it is generally about 20 ° C. to about 250 ° C., preferably about 50 ° C. to about 220 ° C.
  • Step 4 Substitution or coupling This substitution or coupling is carried out by reacting the compound of formula (e) with the compound of formula (f).
  • the substitution reaction is carried out in the absence of a solvent or in a suitable solvent under normal pressure or pressure.
  • the solvent to be used should be appropriately selected according to the kind of the raw material compound and the like, and for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, 1,4-dioxane, etc.
  • Ethers such as methylene chloride, halogenated hydrocarbons such as chloroform, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, 1-methylpyrrolidin-2-one, dimethyl sulfoxide Is mentioned. These solvents are used alone or as a mixed solvent of two or more.
  • This substitution reaction is usually performed in the presence of a base, and specific examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, potassium carbonate, and cesium carbonate. . While the reaction temperature varies depending on the kind of starting compound used, etc., it is generally about 20 ° C. to about 250 ° C., preferably about 50 ° C. to about 200 ° C.
  • the coupling reaction is, for example, Ber Dtsch Chem Ges, 36, 2389 (1903);........ Angew Chem Int Ed, can be carried out according to the method described in 42 5400 (2003)..
  • the reaction is performed by reacting the compound of the formula (e) with the compound of the formula (f) in the presence of a suitable catalyst (for example, a copper catalyst, a palladium catalyst, a nickel catalyst, or an iron catalyst).
  • a suitable catalyst for example, a copper catalyst, a palladium catalyst, a nickel catalyst, or an iron catalyst.
  • This reaction is performed in the presence of a base as necessary.
  • the base include sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, tributylamine, and diisopropylethylamine.
  • the reaction temperature varies depending on the kind of raw material compound used, it is generally about 0 ° C. to about 250 ° C., preferably about 20 ° C. to about 200 ° C.
  • Z is a halogen atom such as chlorine, bromine and iodine, a lower alkylsulfonyloxy group such as methanesulfonyloxy, a trihalogenomethanesulfonyloxy group such as trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyl A leaving group such as an arylsulfonyloxy group such as oxy means A and W have the same definitions as in [1] above, and Y a has the same definition as in [8] above. )
  • Step 1 Substitution or coupling This reaction is the same as the method described in the above-mentioned "Production method 1 of the compound of formula (A) 1 (step 4)" using the compound of formula (c) and the compound of formula (f). It can be done by a method.
  • Step 2 Reduction This reaction can be carried out in the same manner as described in the above-mentioned “Production Method 1 (Step 2) of the compound of the formula (A)” using the compound of the formula (g).
  • Step 3 Cyclization This reaction can be carried out by the same method as described in the above-mentioned “Production Method 1 (Step 3) of the compound of the formula (A)” using the compound of the formula (h).
  • the compound of the formula (3) is produced by reacting the compound of the following formula (A) with phosgene or an equivalent thereof (diphosgene, triphosgene, 4-nitrophenyl chloroformate, etc.) and the compound of the following formula (C). can do.
  • phosgene or an equivalent thereof diphosgene, triphosgene, 4-nitrophenyl chloroformate, etc.
  • C the compound of the following formula (C).
  • This reaction is usually carried out in the presence of a base, in the absence of a solvent, or in a suitable solvent under normal pressure or pressure.
  • the compound of Formula (C) may be used in the form of an acid addition salt such as hydrochloride, and a free base may be generated in the reaction system.
  • the solvent to be used should be selected according to the type of raw material compound and the like.
  • examples include formamide and 1-methylpyrrolidin-2-one.
  • These solvents are used alone or as a mixed solvent of two or more.
  • the base include sodium hydride, triethylamine, diisopropylethylamine, 1,4-diazabicyclo [2.2.2] octane, potassium carbonate, and sodium carbonate.
  • the reaction temperature varies depending on the type of raw material compound used, it is generally about ⁇ 30 ° C. to 150 ° C., preferably about ⁇ 10 ° C. to about 70 ° C.
  • the compound of formula (C) may be a commercially available one, or a known method such as Arch. Pharm., 318 , 727 (1985); Eur. J. Org. Chem., 12 , 2582 (2004). What was manufactured according to the method as described in (1) can be used.
  • the compound of the formula (3) can be produced by reacting the compound of the following formula (A) with the compound of the following formula (D).
  • R a represents a C 1-6 alkyl group
  • M represents a halogen atom such as chlorine, bromine or iodine, a lower alkylsulfonyloxy such as methanesulfonyloxy, a trihalogeno group such as trifluoromethanesulfonyloxy.
  • methanesulfonyloxy, benzenesulfonyloxy, means an aryl sulfonyloxy such as p- toluenesulfonyloxy
  • a, W, R 1 and R 2 have the same meanings as defined according to the above [1]
  • Y a is the (It is synonymous with the definition of [8].)
  • This reaction is usually performed in the presence of a base, in the absence of a solvent, or in a suitable solvent under normal pressure or pressure.
  • the solvent to be used should be selected according to the type of raw material compound and the like. For example, toluene, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methylene chloride, ethyl acetate, acetone, acetonitrile, N, N-dimethyl Examples include formamide, 1-methylpyrrolidin-2-one, and dimethyl sulfoxide. These solvents are used alone or as a mixed solvent of two or more.
  • the base examples include sodium hydride, triethylamine, diisopropylethylamine, 1,4-diazabicyclo [2.2.2] octane, potassium carbonate, sodium carbonate, and cesium carbonate.
  • the reaction temperature varies depending on the kind of raw material compound used, it is generally about 0 ° C. to 150 ° C., preferably about 30 ° C. to about 100 ° C.
  • the compound of formula (D) may be a commercially available one, or a known method such as the method described in Chem. Ber., 95 , 1298 (1962); Chem. Ber., 98 , 1134 (1965) Can be used.
  • the compound of the following formula (4) in which Y is a group represented by the formula [Q] is obtained by reacting the compound of the following formula (E) with the compound of the formula (B), The compound of the following formula (E) is reacted with the compound of the above formula (C) and phosgene or an equivalent thereof (diphosgene, triphosgene, 4-nitrophenyl chloroformate, etc.), or the compound of the following formula (E) And the compound of the formula (D).
  • Step 1 Acylation This reaction can be carried out by a method similar to the method described in the above production method A using a compound of formula (i) and an alkyl chloroformate (for example, methyl chloroformate and ethyl chloroformate).
  • a compound of formula (i) and an alkyl chloroformate for example, methyl chloroformate and ethyl chloroformate.
  • Step 2 Alkylation or cycloalkylation
  • the reaction of the compound of formula (j) and the compound of formula (k) is carried out in the presence of a base, in the absence of a solvent or in a suitable solvent under normal pressure or pressure.
  • the solvent to be used should be appropriately selected according to the kind of the raw material compound, etc., for example, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, 1,4-dioxane, N, N-dimethylformamide, 1-methylpyrrolidin-2-one is mentioned. These solvents are used alone or as a mixed solvent of two or more.
  • the base include sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide.
  • the reaction temperature varies depending on the type of raw material compound used, it is generally about ⁇ 10 ° C. to about 100 ° C., preferably about 0 ° C. to about 70 ° C.
  • Step 3 Cyclization This cyclization can be carried out using the compound of the formula (m) in the presence of a base, in the absence of a solvent, or in a suitable solvent under normal pressure or pressure.
  • the solvent to be used should be appropriately selected according to the type of raw material compound, etc., for example, benzene, toluene, xylene, methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide. 1-methylpyrrolidin-2-one. These solvents are used alone or as a mixed solvent of two or more.
  • Specific examples of the base include sodium methoxide and sodium ethoxide. While the reaction temperature varies depending on the type of raw material compound used, it is generally about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C.
  • Step 4 Substitution or coupling This reaction is the same as the method described in the above-mentioned “Production method 1 of the compound of formula (A) 1 (step 4)” using the compound of formula (n) and the compound of formula (f). It can be done by a method.
  • the compound represented by the formula (1) can be produced by reacting the compound of the formula (F) with the compound of the formula (G).
  • This reaction is usually carried out in the presence of a base, in the absence of a solvent, or in a suitable solvent under normal pressure or pressure.
  • the solvent to be used should be selected according to the type of raw material compound and the like.
  • solvents are used alone or as a mixed solvent of two or more.
  • the base include sodium hydride and potassium hydride. While the reaction temperature varies depending on the kind of raw material compound used, it is generally about ⁇ 30 ° C. to about 150 ° C., preferably about ⁇ 10 ° C. to about 70 ° C.
  • the compound of formula (F) is obtained by catalytic hydrogenation of a compound in which A is a benzyl group such as benzyl group, methoxybenzyl group, dimethoxybenzyl group in formula (3) or formula (4) in the presence of a suitable catalyst.
  • A is a benzyl group such as benzyl group, methoxybenzyl group, dimethoxybenzyl group in formula (3) or formula (4) in the presence of a suitable catalyst.
  • the compound of the formula (G) may be a commercially available one, or a known method such as J. Am. Chem. Soc., 55 , 2468 (1933); J. Am. Chem. Soc., 61 , 2693 (1939); Chem. Ber., 25 , 2261 (1892) can be used.
  • the present invention will be described more specifically with reference to the following reference examples and examples. However, the technical scope of the present invention is not limited to these examples.
  • the compound was identified by proton nuclear magnetic resonance spectrum ( 1 H-NMR), high performance liquid chromatography mass spectrometer (LC-MS) and the like.
  • the proton nuclear magnetic resonance spectrum was measured using a FT-NMR measuring apparatus (300 MHz or 400 MHz) manufactured by Bruker, Varian, or JEOL.
  • the chemical shift value was described as a ⁇ value (ppm) using tetramethylsilane as a standard substance.
  • the high performance liquid chromatography mass spectrometer was measured using an LC-MS measuring apparatus manufactured by Waters or Shimadzu. Mass spectrometry was performed by electrospray ionization (ESI).
  • Reference Examples 3 to 84 The compounds shown in Tables 1 and 2 were produced in the same manner as in Reference Example 1 or 2.
  • Reference examples 86-95 The compounds shown in Table 3 were produced in the same manner as in Reference Example 85.
  • Example 1 7- ⁇ [3- (4-Fluorophenyl) azetidin-1-yl] carbonyl ⁇ -2- (2-methoxyethoxy) -9-methyl-7,9-dihydro-8H-purine-8- Manufacturing on To a solution of triphosgene (374 mg) in dichloromethane (20 ml) was added dropwise a solution of 4-fluorophenylazetidine trifluoroacetate (500 mg) and diisopropylethylamine (835 ⁇ l) in dichloromethane (5 ml), and the mixture was stirred for 5 minutes.
  • Example 2 Preparation of 2 -[(4-chlorobenzyl) oxy] -N, N, 7-trimethyl-8-oxo-7,8-dihydro-9H-purine-9-carboxamide 2-[(4-Chlorobenzyl) oxy] -7-methyl-7,9-dihydro-8H-purin-8one ⁇ compound of Reference Example 2> (40.0 g), potassium carbonate (47.5 g) and 1 A solution of-(dimethylaminocarbamoyl) -3-methyl-1H-imidazol-3-ium iodide (46.4 g) in acetonitrile (1.0 L) was heated to reflux for 1 hour.
  • Example 3 Preparation of 7-ethyl-2- [2- (4-fluorophenoxy) ethoxy] -N, N-dimethyl-8-oxo-7,8-dihydro-9H-purine-9-carboxamide 7-Ethyl-2- [2- (4-fluorophenoxy) ethoxy] -7,9-dihydro-8H-purin-8one ⁇ Compound of Reference Example 68> (100 mg) and 1,4-diazabicyclo [2.2 .2] Dimethylcarbamoyl chloride (50 mg) was added to a solution of octane (50 mg) in dichloromethane (2 ml) at room temperature and stirred for 10 hours.
  • Examples 4 to 305 The compounds shown in Tables 4 to 7 were produced in the same manner as in Examples 1 to 3.
  • Example 306 Preparation of 2- [2- (2-chlorophenyl) ethoxy] -N, N, 7-trimethyl-8-oxo-7,8-dihydro-9H-purine-9-carboxamide
  • octane 9.1 g
  • methylene chloride 100 ml
  • dimethylcarbamoyl chloride 8.7 g
  • Example 330 7- ⁇ [3- (3-fluorophenyl) azetidin-1-yl] carbonyl ⁇ -2- (2-hydroxyethoxy) -9-methyl-7,9-dihydro-8H-purine-8- Manufacturing on (1)
  • 2-benzyloxyethanol 4.52 ml
  • 2-Chloro-4-methylamino-5-nitropyrimidine was added little by little at the same temperature, followed by stirring at room temperature for 15 minutes.
  • Example 331 Preparation of 7- ⁇ [3- (4-Fluorophenyl) azetidin-1-yl] carbonyl ⁇ -2- (2-methoxyethoxy) -7,9-dihydro-8H-purin-8-one
  • 2-Chloro-5-nitropyrimidin-4-amine ⁇ Compound of Reference Example 2 (1)> Potassium carbonate (3.2 g) was added to a solution of 2-methoxyethanol (60 ml) in 30 ml at room temperature. Stir for minutes. The reaction solution was poured into water (200 ml) and stirred, and the precipitated solid was collected by filtration.
  • Example 333 Preparation of 2-[(4-chlorobenzyl) oxy] -N, N-dimethyl-8-oxo-7,8-dihydro-9H-purine-9-carboxamide (1)
  • a mixed solution of 4-chlorobenzyl alcohol (18 g) and 2-chloro-5-nitropyrimidin-4-amine ⁇ the compound of Reference Example 2 (1)> (2 g) was dissolved by heating at 80 ° C. Potassium (3.2 g) was added and stirred for 1 hour. The reaction solution was poured into water (100 ml) and stirred, and the precipitated solid was collected by filtration.
  • Test example Measurement of rat FAAH inhibitory activity Preparation of rat brain membrane preparation and measurement of FAAH inhibitory activity were performed according to the method of Jonsson et al. [Br. J. Pharmacol., 133 , 1263 (2001)].
  • This re-suspension is incubated at 37 ° C for 15 minutes, centrifuged (36,000 ⁇ g, 20 minutes), and then the enzyme solution buffer (50 mM Tris-HCl buffer pH 7.4, 1 mM EDTA, 3 mM MgCl 2 ) And suspended.
  • the protein concentration of the obtained membrane preparation was measured by a colorimetric method (BCA Protein Assay: PIERCE) and stored frozen at ⁇ 80 ° C. until the assay was used.
  • DMSO was added instead of the test substance DMSO solution as a control.
  • DMSO was added instead of the test substance DMSO solution, and an enzyme solution preparation buffer was added instead of the membrane preparation.
  • 400 ⁇ L of ice-cooled chloroform and methanol 1: 1 (volume ratio) solution was added and stirred. Centrifugation (1,000 ⁇ g, 10 minutes) separates ethanolamine (ethanolamine-1- [ 3 H]), a decomposition product, in the upper layer (water / methanol layer).

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Abstract

L'invention concerne un agent destiné à traiter ou à prévenir des troubles dans lesquels intervient la FAAH, et spécifiquement la dépression, l'anxiété, la douleur ou d'autres troubles. Cet agent comprend un composé représenté par la formule (1) ou un sel pharmaceutiquement acceptable de celui-ci (dans la formule, W représente un atme d'hydrogène, un atome d'halogène ou analogue; A représente un groupe aryle, un groupe alkyle éventuellement substitué par un groupe aryle ou analogue; soit X, soit Y représente un groupe alkylaminocarbonyle disubstitué ou analogue, l'autre (X ou Y) représentant un atome d'hydrogène, un groupe alkyle ou analogue).
PCT/JP2012/052336 2011-02-03 2012-02-02 Dérivé de 8-oxodihydropurine 2-oxy-substitué Ceased WO2012105635A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07258257A (ja) * 1994-03-25 1995-10-09 Nippon Zoki Pharmaceut Co Ltd 新規プリン誘導体及びその薬学的に許容される塩
WO1998001448A1 (fr) * 1996-07-03 1998-01-15 Japan Energy Corporation Nouveaux derives de purine
WO1999028320A1 (fr) * 1997-12-03 1999-06-10 Dainippon Pharmaceutical Co., Ltd. Derives de 2-aryl-8-oxodihydropurine, procede de production de ces derives, compositions medicales contenant ces derives, et intermediaires de ces derives
JP2001048882A (ja) * 1999-06-02 2001-02-20 Dainippon Pharmaceut Co Ltd ２−アリール−８−オキソジヒドロプリン誘導体からなる医薬
WO2008032164A2 (fr) * 2006-09-12 2008-03-20 Pfizer Products Inc. Dérivés de benzimidazolone
WO2008145843A1 (fr) * 2007-04-18 2008-12-04 Sanofi-Aventis Dérivés de triazolopyridine-carboxamides et triazolopyrimidine-carboxamides, leur préparation et leur application en thérapeutique
WO2008145839A1 (fr) * 2007-04-18 2008-12-04 Sanofi-Aventis Dérivés de triazolopyridine-carboxamides et triazolopyrimidine-carboxamides, leur préparation et leur application en thérapeutique

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07258257A (ja) * 1994-03-25 1995-10-09 Nippon Zoki Pharmaceut Co Ltd 新規プリン誘導体及びその薬学的に許容される塩
WO1998001448A1 (fr) * 1996-07-03 1998-01-15 Japan Energy Corporation Nouveaux derives de purine
WO1999028320A1 (fr) * 1997-12-03 1999-06-10 Dainippon Pharmaceutical Co., Ltd. Derives de 2-aryl-8-oxodihydropurine, procede de production de ces derives, compositions medicales contenant ces derives, et intermediaires de ces derives
JP2001048882A (ja) * 1999-06-02 2001-02-20 Dainippon Pharmaceut Co Ltd ２−アリール−８−オキソジヒドロプリン誘導体からなる医薬
WO2008032164A2 (fr) * 2006-09-12 2008-03-20 Pfizer Products Inc. Dérivés de benzimidazolone
WO2008145843A1 (fr) * 2007-04-18 2008-12-04 Sanofi-Aventis Dérivés de triazolopyridine-carboxamides et triazolopyrimidine-carboxamides, leur préparation et leur application en thérapeutique
WO2008145839A1 (fr) * 2007-04-18 2008-12-04 Sanofi-Aventis Dérivés de triazolopyridine-carboxamides et triazolopyrimidine-carboxamides, leur préparation et leur application en thérapeutique

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