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WO2009081892A1 - Novel catechol derivative, pharmaceutical composition containing the same, and use of those - Google Patents

Novel catechol derivative, pharmaceutical composition containing the same, and use of those Download PDF

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Publication number
WO2009081892A1
WO2009081892A1 PCT/JP2008/073270 JP2008073270W WO2009081892A1 WO 2009081892 A1 WO2009081892 A1 WO 2009081892A1 JP 2008073270 W JP2008073270 W JP 2008073270W WO 2009081892 A1 WO2009081892 A1 WO 2009081892A1
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WO
WIPO (PCT)
Prior art keywords
group
alkyl group
lower alkyl
nmr
ppm
Prior art date
Application number
PCT/JP2008/073270
Other languages
French (fr)
Japanese (ja)
Inventor
Hiroaki Shiohara
Takehiro Ishikawa
Satoko Kobayashi
Hitoshi Inoue
Masako Yoshida
Yasunori Ueno
Nobuyuki Tanaka
Original Assignee
Kissei Pharmaceutical Co., Ltd.
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Publication date
Application filed by Kissei Pharmaceutical Co., Ltd. filed Critical Kissei Pharmaceutical Co., Ltd.
Priority to JP2009547093A priority Critical patent/JP5369000B2/en
Publication of WO2009081892A1 publication Critical patent/WO2009081892A1/en

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/46—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylureas
    • C07C275/48—Y being a hydrogen or a carbon atom
    • C07C275/54—Y being a carbon atom of a six-membered aromatic ring, e.g. benzoylureas
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to a novel catechol derivative having a catechol-O-methyltransferase inhibitory action, a pharmaceutical composition containing it, and uses thereof.
  • Parkinson's disease is a progressive neurodegenerative disease that frequently occurs in middle-aged and elderly people, and the number of patients is increasing with the progress of an aging society. Parkinson's disease is a disease whose main symptoms are coordinated motor dysfunction such as resting tremor, rigidity, ataxia, and postural reflex disorder, and its etiology is striae due to degeneration of midbrain dopaminergic neurons. It is believed to be due to a lack of body dopamine. For these reasons, L-dopa and dopamine receptor stimulants are used as therapeutic agents for Parkinson's disease.
  • L-dopa is a precursor of dopamine and is a drug that is metabolized to dopamine in the brain and has an effect, but has a drawback that its blood half-life is very short. Therefore, L-DOPA is commonly used with peripheral aromatic L-amino acid decarboxylase inhibitors and / or catechol-O-methyltransferase inhibitors, which are L-DOPA metabolic enzyme inhibitors.
  • COMT Catechol-O-methyltransferase
  • a COMT inhibitor is also expected to be useful as a therapeutic agent for hypertension because it has an action of promoting urinary sodium excretion (see, for example, Non-Patent Document 2).
  • COMT inhibitors are also expected to be useful as therapeutic agents for depression (see, for example, Non-Patent Document 3).
  • entacapone has a problem that its effect is weaker than that of tolcapone and has a short action duration (for example, see Non-Patent Document 5). Therefore, a novel COMT inhibitor having high safety and a strong COMT inhibitory action is desired.
  • Patent Document 3 discloses a compound represented by the general formula (III), which is useful as a nitric oxide synthase inhibitor, and Table 2 describes Compound Ia-12 as one exemplified compound ( (See Patent Document 3). However, nothing is described about the COMT inhibitory action of these compounds. Nutt JG et al., “Lancet”, 1998, 351, 9111, p.1221-1222 Eklof AC et al., "Kidney Int.”, 1997, 52, 3, p.742-747 Moreau JL et al., “Behav. Pharmacol.”, 1994, 5 (3), p.344-350 Benabou R. et al., "Expert Opin. Drug Saf.”, 2003, Vol. 2, No.
  • An object of the present invention is to provide a novel compound having a strong COMT inhibitory action and preferably having high safety.
  • the catechol derivative represented by the general formula (I) has an excellent COMT inhibitory action and further has high safety.
  • the headline and the present invention were completed.
  • R 1 and R 2 each independently represents a hydrogen atom, a lower acyl group, a lower alkoxycarbonyl group, or —C (O) NR 7 R 8 , or R 1 and R 2 taken together— Forming C (O)-;
  • R 3 is a halogen atom, a halo lower alkyl group, a lower alkoxycarbonyl group, or a cyano group;
  • R 4 is a hydrogen atom, a lower alkyl group, a lower alkoxy lower alkyl group or an aralkyl group;
  • R 5 and R 6 are each independently the following a) to l): a) a hydrogen atom, b) an alkyl group, c) a cycloalkyl group, d) a cycloalkyl lower alkyl group, e) a bridged cyclic hydrocarbon group, f) a heterocycloalkyl group,
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof.
  • the present invention also relates to a catechol-O-methyltransferase inhibitor comprising as an active ingredient the compound described in general formula (I) or a pharmacologically acceptable salt thereof.
  • the present invention also includes a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and at least one selected from L-dopa and aromatic L-amino acid decarboxylase inhibitors.
  • the present invention relates to a combined medicine.
  • the present invention also relates to a therapeutic or prophylactic agent for Parkinson's disease, depression, or hypertension containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention also relates to the use of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof for producing a therapeutic or prophylactic agent for Parkinson's disease, depression or hypertension.
  • the present invention also relates to a method for treating or preventing Parkinson's disease, depression or hypertension, which comprises administering an effective amount of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof. Process.
  • halogen atom represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • R 3 a chlorine atom is preferable.
  • Alkyl group means a linear or branched C 1-10 alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert -Butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, heptyl, octyl, etc. Can be mentioned.
  • R 5 and R 6 a C 1-7 alkyl group is preferable, and a C 1-4 alkyl group is more preferable.
  • the “lower alkyl group” means a linear or branched C 1-6 alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, Examples thereof include tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group and the like.
  • C 1-4 alkyl is preferred.
  • halo lower alkyl group means a C 1-6 alkyl group substituted with 1 to 3 of the same or different halogen atoms, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, 2 2,2-trifluoroethyl group and the like. In R 3 , a trifluoromethyl group is preferable.
  • “Lower alkoxy group” means a linear or branched C 1-6 alkoxy group, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group Tert-butoxy group, pentyloxy group, hexyloxy group and the like.
  • the “cycloalkyl group” means a 3 to 7-membered saturated cyclic hydrocarbon, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
  • the cycloalkyl group may be optionally substituted with 1 to 2 lower alkyl groups.
  • the cycloalkyl group may form a bicyclic condensed hydrocarbon condensed with a phenyl ring if necessary. Examples of such a bicyclic condensed hydrocarbon include, for example, an indan-2-yl group. Etc.
  • cycloalkyl lower alkyl group means a cycloalkyl-C 1-6 alkyl group, and examples thereof include a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and the like, and preferably a cyclopropylmethyl group It is.
  • Bridged cyclic hydrocarbon group means a bridged saturated cyclic hydrocarbon having 7 to 10 carbon atoms and having a 5- to 7-membered ring.
  • bicyclo [2.2.1] heptane- 2-yl group, adamantane-1-yl group and the like can be mentioned.
  • Heterocycloalkyl group means a 4 to 7-membered saturated heterocyclic group containing —NH—, —O— or —S— in the ring and bonded via a carbon atom. Examples include furyl group, tetrahydrothienyl group, tetrahydropyranyl group, pyrrolidin-2-yl group, pyrrolidin-3-yl group, piperidin-2-yl group, piperidin-3-yl group, and piperidin-4-yl group. .
  • the heterocycloalkyl group contains a nitrogen atom in the ring, the nitrogen atom may be optionally substituted with a lower alkoxycarbonyl group or a lower acyl group.
  • a substituted heterocycloalkyl group examples thereof include an N-ethoxycarbonylpiperidin-4-yl group.
  • the “aryl group” means a C 6-10 aromatic hydrocarbon, and includes a phenyl group, a 1-naphthyl group, and a 2-naphthyl group, and is preferably a phenyl group.
  • the “aralkyl group” means an aryl-C 1-6 alkyl group, and examples thereof include a benzyl group, a phenethyl group, a 1-phenylethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, and a naphthylmethyl group. .
  • a benzyl group is preferable.
  • a “heteroaryl group” is a 5-6 membered monocyclic containing 1 to 5 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of O, N and S atoms
  • An aromatic heterocycle or an 8-10 membered bicyclic aromatic containing 1 to 4 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of O, N and S atoms Means a heterocycle, provided that these rings do not contain adjacent oxygen and / or sulfur atoms.
  • Examples of the monocyclic aromatic heterocycle include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, triazolyl, Examples include pyridyl, pyrazinyl, pyrimidyl and pyridazinyl.
  • bicyclic aromatic heterocycle examples include indolyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, quinolyl, isoquinolyl, phthalazinyl, benzimidazolyl, benzoxazolyl and the like. All positional isomers of these heterocycles are contemplated (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.).
  • “Lower alkoxy lower alkyl group” means a C 1-6 alkoxy-C 1-6 alkyl group, and includes, for example, a methoxymethyl group, a 2-methoxyethyl group, a 3-methoxypropyl group, an ethoxymethyl group, a 2- Examples thereof include an ethoxyethyl group, a 3-ethoxypropyl group, and a 3-isopropoxypropyl group.
  • “Lower acyl group” means a group represented by (C 1-6 alkyl) -C (O) —, for example, acetyl group, propionyl group, butyryl group, isobutyryl group, pivaloyl group, valeryl group, And isovaleryl group.
  • the “lower acylamino lower alkyl group” means a group represented by (C 1-6 alkyl) -C (O) NH—C 1-6 alkyl, such as acetylaminoethyl group, acetylaminopropyl group, etc. Is mentioned.
  • the “lower alkoxycarbonyl group” means a group represented by (C 1-6 alkoxy) -C (O) —, and includes, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, Examples include butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group and the like. In R 3 , a methoxycarbonyl group is preferred.
  • Cyclic amino group means a 5- to 7-membered saturated cyclic amine which may contain —NH—, —O— or —S— in the ring, for example, 1-pyrrolidyl group, piperidino group, piperazino Group, morpholino group, thiomorpholino group and the like.
  • the cyclic amino group may be optionally substituted with 1 to 2 lower alkyl groups or lower alkoxycarbonyl groups.
  • the present invention relates to a compound in which each asymmetric carbon atom is in the R configuration, a compound in the S configuration, Any of those combinations of compounds are included. Also included within the scope of the present invention are those racemates, racemic mixtures, single enantiomers and diastereomeric mixtures.
  • the present invention includes any of the geometric isomers.
  • the atropisomer is present in the compound represented by the general formula (I) of the present invention, the present invention includes any of the atropisomers.
  • the compound represented by the general formula (I) of the present invention includes solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.
  • the compound represented by the general formula (I) of the present invention can exist in the form of a salt.
  • Such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid Acids with organic acids such as p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid Examples thereof include salts with inorganic bases such as addition salts, lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts, and salts with organic bases such as triethylamine, piperidine, morpholine, and
  • R 1 and R 2 are preferably hydrogen atoms;
  • R 3 is preferably a halogen atom, a halo lower alkyl group, a methoxycarbonyl group or a cyano group, more preferably a halogen atom or a halo lower alkyl group, still more preferably a chlorine atom or a trifluoromethyl group.
  • R 4 is preferably a hydrogen atom, a lower alkyl group, or an aralkyl group, more preferably a hydrogen atom; or in one aspect, R 5 and R 6 are preferably each independently selected from the following a ) To l): a) a hydrogen atom, b) an alkyl group, c) a cycloalkyl group, d) a cycloalkyl lower alkyl group, e) a bridged cyclic hydrocarbon group, f) a heterocycloalkyl group, g) a halo lower alkyl group, h) unsubstituted or group consisting of: aryl having a ring substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Group, i) unsubstituted or a group consisting of the following:
  • R 1 and R 2 are hydrogen atoms.
  • R 1 and R 2 are hydrogen atoms;
  • R 5 is a hydrogen atom,
  • R 6 represents the following a) to k): a) an alkyl group, b) a cycloalkyl group, c) a cycloalkyl lower alkyl group, d) a bridged cyclic hydrocarbon group, e) a heterocycloalkyl group, f) a halo lower alkyl group, g) Unsubstituted or group consisting of: aryl having a ring substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Group, h) an unsubstituted or group consisting of the following: a heteroaryl group in which the ring is substituted with 1 to 3 groups independently selected from a halogen atom, a lower al
  • R 1 and R 2 are hydrogen atoms;
  • R 5 is a hydrogen atom,
  • R 6 represents the following a) to h): a) an alkyl group, b) a cycloalkyl group, c) a cycloalkyl lower alkyl group, d) a bridged cyclic hydrocarbon group, e) a heterocycloalkyl group, f) a halo lower alkyl group, g) Unsubstituted or group consisting of: aryl having a ring substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Or h) a lower alkoxy lower alkyl group.
  • R 1 and R 2 are hydrogen atoms;
  • R 4 is a hydrogen atom, a lower alkyl group or an aralkyl group,
  • R 5 is a hydrogen atom,
  • R 6 represents the following a) to h): a) an alkyl group, b) a cycloalkyl group, c) a cycloalkyl lower alkyl group, d) a bridged cyclic hydrocarbon group, e) a heterocycloalkyl group, f) a halo lower alkyl group, g) Unsubstituted or group consisting of: aryl having a ring substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Or h) a lower alkoxy lower alkyl group.
  • R 1 and R 2 are hydrogen atoms;
  • R 4 is a hydrogen atom, a lower alkyl group or an aralkyl group,
  • R 5 is a hydrogen atom,
  • R 6 represents the following a) to e): a) an alkyl group, b) a cycloalkyl group, c) a cycloalkyl lower alkyl group, d) Unsubstituted or the group consisting of: aryl in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Or e) a lower alkoxy lower alkyl group.
  • R 1 and R 2 are hydrogen atoms;
  • R 3 is a halogen atom or a halo lower alkyl group,
  • R 4 is a hydrogen atom,
  • R 5 is a hydrogen atom,
  • R 6 represents the following a) to e): a) an alkyl group, b) a cycloalkyl group, c) a cycloalkyl lower alkyl group, d) Unsubstituted or the group consisting of: aryl in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Or e) a lower alkoxy lower alkyl group.
  • Specific examples of preferred embodiments of the present invention are compounds selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • the compound represented by the general formula (I) of the present invention can be produced by the methods shown in Schemes 1 to 4.
  • R 3 , R 5 and R 6 are as defined above;
  • R 10 represents a lower acyl group, a lower alkoxycarbonyl group or —CONR 7 R 8 ;
  • Me represents a methyl group, and
  • Bn represents Represents a benzyl group.
  • Step 1-1 The acyl isocyanate derivative (XI) is obtained by reacting the amide derivative (X) with oxalyl chloride in an inert solvent.
  • the inert solvent used in this reaction include methylene chloride, chloroform, 1,2-dichloroethane and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • Step 1-2 The acyl urea derivative (XIII) is obtained by reacting the acyl isocyanate derivative (XI) with an amine (XII) or a salt thereof in an inert solvent in the presence or absence of a base.
  • the inert solvent used in this reaction include acetonitrile, N, N-dimethylformamide, tetrahydrofuran, methylene chloride, dimethyl sulfoxide, 1,4-dioxane, 1-methyl-2-pyrrolidone, and mixed solvents thereof.
  • Examples of the base include potassium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, N-methylmorpholine, N, N-dimethylaniline and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 15 minutes to 24 hours, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.
  • Step 1-3 The benzyl group of the acylurea derivative (XIII) is placed in an inert solvent (eg, ethanol, N, N-dimethylformamide, tetrahydrofuran, etc.) in a hydrogen atmosphere and in the presence of a metal catalyst (eg, palladium carbon, platinum oxide, etc.). Removal of the phenol derivative (XIV) is obtained.
  • an inert solvent eg, ethanol, N, N-dimethylformamide, tetrahydrofuran, etc.
  • a metal catalyst eg, palladium carbon, platinum oxide, etc.
  • This debenzylation is carried out by using acylurea derivative (XIII) with an acid or Lewis acid (eg, hydrogen bromide, aluminum chloride, titanium tetrachloride, etc.) in an inert solvent (eg, methylene chloride, toluene, etc.). It can also be done by processing.
  • the reaction temperature is usually from 0 ° C. to 80 ° C., and the reaction time is usually from 15 minutes to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature, and the like.
  • Step 1-4 Nitrophenol derivative (XV) is obtained by nitrating phenol derivative (XIV) in an inert solvent using a nitrating agent.
  • the inert solvent used in this reaction include methylene chloride, 1,2-dichloroethane, ethyl acetate, acetic acid, tetrahydrofuran and the like.
  • the nitrating agent include nitric acid, fuming nitric acid, nitronium tetrafluoroborate, and the like.
  • the reaction temperature is usually from ⁇ 20 ° C. to 80 ° C.
  • the reaction time is usually from 5 minutes to 12 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • the compound (Ia) can be obtained by demethylating the nitrophenol derivative (XV) in an inert solvent using a demethylating agent.
  • a demethylating agent examples include aluminum chloride-pyridine.
  • the reaction temperature is usually from 20 ° C. to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature, and the like.
  • Step 1-6 Compound (Ib) is obtained by acylating compound (Ia) with an acylating agent.
  • acylation is well known to those skilled in the art and can be performed, for example, according to the methods described in TWGreene and PGHWuts, “Protective Groups in Organic Synthesis”, 4th edition.
  • R 3 , R 5 , R 6 , R 10 , Me and Bn are as defined above; R 11 represents a lower alkyl group, a lower alkoxy lower alkyl group or an aralkyl group.
  • Step 2-1 Carboxylic acid (XVI) in an inert solvent in the presence of a condensing agent (eg, dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphoryl azide, etc.) Is condensed with amine (XVII) to give amide derivative (XVIII).
  • the amide derivative (XVIII) is a reactive derivative of the carboxylic acid (XVI) according to a conventional method (for example, acid halide, acid anhydride, mixed acid anhydride, benzotriazol-1-yl ester, 4-nitrophenyl ester).
  • reaction temperature is usually from ⁇ 20 ° C. to the reflux temperature, and the reaction time is usually from 15 minutes to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • Step 2-2 Chlorocarbonyl derivative (XIX) is obtained by chlorocarbonylating amide derivative (XVIII) with chlorotrimethylsilane and triphosgene in the presence of a base in an inert solvent.
  • a base inert solvent used in this reaction include methylene chloride, chloroform, 1,2-dichloroethane and the like.
  • the base include triethylamine, N, N-diisopropylethylamine and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • Step 2-3 The acyl urea derivative (XX) is obtained by condensing the chlorocarbonyl derivative (XIX) with an amine (XII) or a salt thereof in an inert solvent in the presence or absence of a base.
  • the inert solvent used in this reaction include acetonitrile, N, N-dimethylformamide, tetrahydrofuran, methylene chloride, dimethyl sulfoxide, 1,4-dioxane, 1-methyl-2-pyrrolidone, and mixed solvents thereof.
  • Examples of the base include potassium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, N-methylmorpholine, N, N-dimethylaniline and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 15 minutes to 24 hours, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.
  • compound (Ic) can be synthesized from acylurea derivative (XX) in the same manner as in steps 1-3 to 1-5 of Scheme 1, and compound from compound (Ic) in the same manner as in step 1-6.
  • (Id) can be synthesized.
  • R 5 , R 6 , R 11 , Bn and Me are as defined above; L represents a bromine atom or an iodine atom, and R 12 represents a lower alkoxycarbonyl group or a cyano group.
  • Step 3-1 The acyl urea derivative (XXII) is obtained by condensing the acyl urea derivative (XXI) with carbon monoxide / lower alcohol or cyanating agent in the presence of a palladium catalyst and a ligand in an inert solvent.
  • the inert solvent used in this reaction include 1,4-dioxane, N, N-dimethylformamide, 1,2-dimethoxyethane, 1-methyl-2-pyrrolidone and the like.
  • the base include cesium fluoride, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, triethylamine, N, N-diisopropylethylamine and the like.
  • Examples of the cyanating agent include cuprous cyanide and potassium cyanide.
  • Examples of the catalyst include tris (dibenzylideneacetone) dipalladium (0).
  • Examples of the ligand include 1,1′-bis (diphenylphosphino) ferrocene.
  • the reaction temperature is usually from 80 ° C. to 110 ° C., and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature, and the like. In addition, this reaction may be carried out by adding an additive such as tetraethylammonium cyanide and a base such as triethylamine or N, N-diisopropylethylamine as necessary.
  • compound (Ie) can be synthesized from acylurea derivative (XXII) in the same manner as in steps 1-3 to 1-5 of scheme 1.
  • R 3 , R 4 , R 5 , R 6 and Me are as defined above; R 13 represents a lower alkyl group.
  • Step 4-1 The benzyl ether derivative (XXIII) is debenzylated in the same manner as in Step 1-3 to give the phenol derivative (XXIV).
  • Step 4-2 Nitrophenol derivative (XXV) is obtained by nitration of phenol derivative (XXIV) in the same manner as in Step 1-4.
  • the ester derivative (XXVI) is obtained by methylating the nitrophenol derivative (XXV) in an inert solvent using a methylating agent in the presence of a base.
  • a methylating agent examples include N, N-dimethylformamide, acetone and the like.
  • the methylating agent examples include iodomethane, dimethyl sulfate, methyl trifluoromethanesulfonate, and the like.
  • the base include potassium carbonate, sodium hydrogen carbonate, cesium carbonate, N, N-diisopropylethylamine and the like.
  • the reaction temperature is usually from room temperature to 110 ° C.
  • the reaction time is usually from 1 hour to 72 hours, although it varies depending on the raw materials and solvents used, the reaction temperature, and the like.
  • Step 4-4 Carboxylic acid derivative (XXVII) is obtained by alkaline hydrolysis of ester derivative (XXVI) in a suitable solvent.
  • the solvent used in this reaction include methanol, ethanol, water, tetrahydrofuran, a mixed solvent thereof, and the like.
  • the base include sodium hydroxide and potassium hydroxide.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 10 minutes to 24 hours, although it varies depending on the raw material and solvent used, the reaction temperature and the like.
  • Step 4-5 The amide derivative (XXIX) is obtained by condensing the carboxylic acid derivative (XXVII) and the amine (XXVIII) in the same manner as in Step 2-1.
  • Step 4-6 The acylurea derivative (XXX) is obtained by urea-forming the amide derivative (XXIX) in the same manner as in Step 1-1 and Step 1-2 or Step 2-2 and Step 2-3.
  • Step 4-7 The nitrophenol derivative (XXXI) is obtained by demethylating the acylurea derivative (XXX) using a demethylating agent in an inert solvent.
  • a demethylating agent examples include N, N-dimethylformamide, 1,2-dimethoxyethane, dimethyl sulfoxide and the like.
  • the demethylating agent examples include lithium chloride, sodium cyanide, potassium cyanide and the like.
  • the reaction temperature is usually from 80 ° C. to 150 ° C.
  • the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • Step 4-8 The compound (If) can be obtained by demethylating the nitrophenol derivative (XXXI) in the same manner as in Step 1-5.
  • Step 4-9 The compound (If) is obtained by demethylating the acylurea derivative (XXX) in an inert solvent using a demethylating agent.
  • a demethylating agent examples include aluminum chloride and boron tribromide.
  • the reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 5 minutes to 24 hours, although it varies depending on the raw materials and solvents used, the reaction temperature, and the like.
  • the compound represented by the general formula (I) of the present invention and the intermediate used for producing the compound are isolation / purification means well known to those skilled in the art, if necessary. It can be isolated and purified by performing operations such as solvent extraction, crystallization, recrystallization, chromatography, high performance liquid chromatography and the like.
  • the compound of the present invention thus produced has an excellent COMT inhibitory action and thus is useful as a therapeutic or prophylactic agent for Parkinson's disease, and is preferably used in combination with L-dopa.
  • the compound of the present invention and L-dopa may be used in combination with an aromatic L-amino acid decarboxylase inhibitor.
  • the aromatic L-amino acid decarboxylase inhibitor that can be used in combination with the COMT inhibitor of the present invention include carbidopa and benserazide.
  • a parkinson therapeutic agent other than the COMT inhibitor and L-dopa may be used in combination.
  • Parkinson's disease therapeutic agents include droxidopa, melevodopa, throdops; dopamine D 2 receptor agonists (eg cabergoline, bromocriptine mesylate, terguride, talipexol hydrochloride, ropinirole mesilate, pergolide mesylate, pramipexole hydrochloride, rotigotine, etc.
  • dopamine D 2 receptor agonists eg cabergoline, bromocriptine mesylate, terguride, talipexol hydrochloride, ropinirole mesilate, pergolide mesylate, pramipexole hydrochloride, rotigotine, etc.
  • Anticholinergic agents eg, prophenamine, trihexyphenidyl hydrochloride, masaticol hydrochloride, piperidene, pyroheptin hydrochloride, methixene hydrochloride, etc.
  • adenosine A 2A antagonists eg, istradefylline
  • NMDA antagonists eg, Monodioxidase B inhibitors (for example, selegiline hydrochloride, rasagiline mesylate, safinamide mesylate, etc.); zonisamide; amantadine hydrochloride, etc.
  • the compound of the present invention is also useful as a therapeutic or prophylactic agent for depression.
  • the compound of the present invention is also useful as a therapeutic agent for hypertension because it has an action of promoting urinary sodium excretion.
  • the pharmaceutical composition containing the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is used in various dosage forms depending on the usage.
  • dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches and the like, orally or parenterally. Administered.
  • compositions are prepared according to pharmacologically known methods depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives. It can be prepared by mixing or diluting / dissolving appropriately with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents.
  • the dose of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is appropriately determined depending on the age, sex, weight, disease, degree of treatment, etc. of the patient.
  • parenteral administration in the range of about 10 mg to about 3000 mg per day for an adult, it can be appropriately administered once or divided into several times within the range of about 5 mg to about 1000 mg per day for an adult.
  • the resulting medicament can be administered as a formulation containing these active ingredients together or as a formulation in which each of these active ingredients is formulated separately.
  • the formulations can be administered separately or simultaneously.
  • those formulations can be mixed using a diluent etc. at the time of use, and can be administered simultaneously.
  • the compounding ratio of the drugs can be appropriately selected depending on the age, sex and weight of the patient, symptoms, administration time, dosage form, administration method, combination of drugs, and the like.
  • the compound of the present invention has a strong COMT inhibitory action.
  • the compound of the present invention has a slight effect on the liver and has high safety. Therefore, the compound of the present invention is useful as a therapeutic or prophylactic agent for Parkinson's disease, depression, and hypertension.
  • the compound of the present invention in combination with L-dopa, Since the bioavailability can be increased, it is suitable for the treatment or prevention of Parkinson's disease.
  • Reference Example 1-2 was synthesized in the same manner as Reference Example 1-1 using 3-benzyloxy-4-methoxybenzaldehyde instead of 3-benzyloxy-4-methoxybenzamide. These are shown in Table 1.
  • Reference Example 2-2 was synthesized in the same manner as Reference Example 2-1, using methyl 3-benzyloxy-4-methoxybenzoate instead of 3-benzyloxy-4-methoxybenzaldehyde.
  • the structural formula is shown in Table 2.
  • Reference Example 3-1 The same method as Reference Example 3-1, except that 5-benzyloxy-2-iodo-4-methoxybenzaldehyde (Reference Example 2-1) was used instead of methyl 5-benzyloxy-2-iodo-4-methoxybenzoate Thus, Reference Example 3-2 was synthesized.
  • the structural formula is shown in Table 3.
  • Reference Example 4-2 The same method as Reference Example 4-1, except that 5-benzyloxy-2-chloro-4-methoxybenzaldehyde (Reference Example 1-2) was used instead of 5-benzyloxy-4-methoxy-2-trifluoromethylbenzaldehyde. Thus, Reference Example 4-2 was synthesized. The structural formula is shown in Table 4.
  • Reference Example 6-1 5-benzyloxy-4-methoxy-2-trifluoromethylbenzamide 5-benzyloxy-4-methoxy-2-trifluoromethylbenzoic acid (Reference Example 4-1) (19.6 g) in N, N-dimethylformamide ( 80 mL) solution was added 1-hydroxybenzotriazole monohydrate (11.2 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (13.9 g) at 5 ° C. or less at room temperature. Stir for 1 hour. 28% aqueous ammonia (80 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr.
  • Reference Example 7-1 1- (5-benzyloxy-2-chloro-4-methoxybenzoyl) -3-cyclopropylmethylurea 5-benzyloxy-2-chloro-4-methoxybenzamide (Reference Example 1-1) (0.500 g) Oxalyl chloride (0.429 mL) was added to a solution of 2-dichloroethane (9 mL) at room temperature. After heating to reflux for 1 hour, oxalyl chloride (0.214 mL) was added to the reaction mixture and heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure to give 5-benzyloxy-2-chloro-4-methoxybenzoyl isocyanate.
  • Reference Example 8-1 5-Benzyloxy-4-methoxy-2-trifluoromethylbenzoyl) -3- (3-methoxypropyl) -1-methylurea 5-benzyloxy-4-methoxy-N-methyl-2-trifluoro Chlorotrimethylsilane (0.231 mL) and triethylamine (0.447 mL) were added to a solution of methylbenzamide (Reference Example 6-2) (0.518 g) in methylene chloride (10 mL) under ice cooling. After heating under reflux for 1 hour, triphosgene (0.453 g) was added little by little to the reaction mixture under ice cooling, and the mixture was heated under reflux for 30 minutes.
  • Reference Example 8-1 5-Benzyloxy-4-methoxy-2-trifluoromethylbenzoyl) -3- (3-methoxypropyl) -1-methylurea 5-benzyloxy-4-methoxy-N-methyl-2-trifluoro Chlorotrimethylsilane (0.231
  • Reference Example 9-1 4-Benzyloxy-2- (3-cyclopropyl-1-methylureidocarbonyl) -5-methoxybenzoic acid methyl tris (dibenzylideneacetone) dipalladium (0) (67 mg) and 1,1′-bis (diphenylphos A suspension of fino) ferrocene (162 mg) in N, N-dimethylformamide (5 mL) was stirred at room temperature under argon for 10 minutes.
  • Reference Example 10-1 (5-benzyloxy-2-cyano-4-methoxybenzoyl) -3-cyclopropyl-1-methylurea 1- (5-benzyloxy-2-iodo-4-methoxybenzoyl) -3-cyclopropyl- 1-methylurea (Reference Example 8-9) (0.600 g), cuprous cyanide (5 mL), tris (dibenzylideneacetone) dipalladium (0) (57 mg) and 1,1′-bis (diphenylphosphino) ) Tetraethylammonium cyanide (195 mg) was added to a suspension of ferrocene (139 mg) in 1,4-dioxane (10 mL) at room temperature under argon, and the mixture was stirred at 100 ° C.
  • Reference Example 11-1 5-Benzyloxy-4-methoxy-2-trifluoromethylbenzoyl) -3-methyltetrahydropyrimidin-2-one 5-benzyloxy-N- (3-dimethylaminopropyl) -4-methoxy-2-
  • To a solution of trifluoromethylbenzamide (Reference Example 6-7) (0.623 g) in methylene chloride (20 mL) were added chlorotrimethylsilane (0.232 mL) and triethylamine (0.423 mL) at room temperature. After heating to reflux for 0.5 hour, triphosgene (0.463 g) was added to the reaction mixture at room temperature, and the mixture was heated to reflux for 1.5 hours.
  • Reference Example 12-1 (2-Chloro-5-hydroxy-4-methoxybenzoyl) -3-cyclopropylmethylurea 1- (5-benzyloxy-2-chloro-4-methoxybenzoyl) -3-cyclopropylmethylurea (reference example) 7-1) Titanium tetrachloride (0.236 mL) was added to a methylene chloride (10 mL) solution of (0.334 g) under ice cooling, and the mixture was stirred at 0 ° C. for 15 minutes. Ice (15 g) and 2 mol / L hydrochloric acid (5 mL) were added to the reaction mixture, and the mixture was stirred until the ice melted. The separated organic layer was concentrated.
  • Reference Example 12-2 was prepared in the same manner as Reference Example 12-1, except that the corresponding benzyl derivative was used instead of 1- (5-benzyloxy-2-chloro-4-methoxybenzoyl) -3-cyclopropylmethylurea.
  • Reference Example 12-91 was synthesized. These are shown in Table 8.
  • Reference Example 13-1 (6-Chloro-3-hydroxy-4-methoxy-2-nitrobenzoyl) -3-cyclopropylmethylurea 1- (2-chloro-5-hydroxy-4-methoxybenzoyl) -3-cyclopropylmethylurea (Reference Example 12-1)
  • fuming nitric acid 0.039 mL
  • the reaction mixture was washed with water and the organic layer was concentrated to give the title compound (0.227 g).
  • the structural formula is shown in Table 9.
  • Reference Example 17-1 3- (3,4-Dimethoxy-2-nitro-6-trifluoromethylbenzoyl) -3-indan-2-ylurea 3,4-dimethoxy instead of 5-benzyloxy-2-chloro-4-methoxybenzamide
  • the title compound was synthesized in the same manner as in Reference Example 7-1 using -2-nitro-6-trifluoromethylbenzamide (Reference Example 16-1).
  • the structural formula is shown in Table 10.
  • Reference Example 18-1 3-hydroxy-4-methoxy-2-nitro-6-trifluoromethylbenzoyl) -3-indan-2-ylurea 1- (3,4-dimethoxy-2-nitro-6-trifluoromethylbenzoyl) ) 3-Indan-2-ylurea (Reference Example 17-1) (0.191 g) in N, N-dimethylformamide (7 mL) was added lithium chloride (179 mg) at room temperature under argon, and the reaction mixture was removed. The mixture was heated and stirred at a temperature of 130 ° C. for 1 hour and 20 minutes. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 1-1 (6-Chloro-3,4-dihydroxy-2-nitrobenzoyl) -3-cyclopropylmethylurea (Compound 1-1)
  • a mixture of 1- (6-chloro-3-hydroxy-4-methoxy-2-nitrobenzoyl) -3-cyclopropylmethylurea (Reference Example 13-1) (0.248 g) and ethyl acetate (10 mL) was stirred at room temperature.
  • Aluminum chloride (0.299 g) and pyridine (0.248 mL) were added, and the mixture was heated to reflux for 2 hours.
  • the reaction mixture was cooled to room temperature, and 5 mol / L hydrochloric acid (3 mL) was added.
  • the reaction mixture was stirred at room temperature for 30 minutes.
  • Test example 1 Human COMT Inhibitory Activity 1 Preparation of Recombinant Human COMT (1) Preparation of Recombinant Human Catechol-O-Methyltransferase NCBI (National Center for NC) encoding full-length human catechol-O-methyltransferase (hereinafter referred to as COMT) Based on the DNA sequence of Accession No. BC011935 registered on Biotechnology Information), two oligonucleotide primers were designed to amplify the DNA sequence encoding the recombinant human COMT described in SEQ ID NO: 1. The sequence of the 5 ′ primer is shown in SEQ ID NO: 3, and the sequence of the 3 ′ primer is shown in SEQ ID NO: 4.
  • primers contain a restriction enzyme site (BamH I on the 5 ′ side and EcoR I on the 3 ′ side) to facilitate insertion of the PCR product into the desired vector.
  • a restriction enzyme site BamH I on the 5 ′ side and EcoR I on the 3 ′ side
  • Each of the 5 ′ primer described in SEQ ID NO: 3 and the 3 ′ primer described in SEQ ID NO: 4 was diluted with TE buffer to obtain a 15 pmol / ⁇ L solution.
  • H 2 O for PCR, 34.8 ⁇ L
  • 25 mmol / L MgSO 4 2.0 ⁇ L
  • 2 mmol / L dNTPs 5.0 ⁇ L
  • 10-fold concentrated DNA polymerase KOD plus buffer 5.0 ⁇ L, Toyobo
  • human liver cDNA (5.0 ⁇ L, Clontech) and each primer pair (1 ⁇ L, 15 pmol) were added to the above mixture, and finally 1.0 ⁇ L of KOD plus (Toyobo) was added. Thereafter, a PCR reaction was performed. The PCR reaction was carried out at 94 ° C. for 2 minutes, followed by 40 cycles of 94 ° C. for 15 seconds, 59 ° C. for 30 seconds, and 68 ° C. for 1 minute. Subsequently, it was completed at 68 ° C. for 5 minutes and at 4 ° C. for 10 minutes. The PCR product was purified with QIAquick PCR Purification Kit (QIAGEN). The desired insert DNA was eluted with EB buffer (30 ⁇ L) of the same kit.
  • QIAquick PCR Purification Kit QIAquick PCR Purification Kit
  • a detected band having a migration position close to that of the pGEX-2T vector having no insert DNA was determined as a primary positive colony, and reconfirmation was performed by the following restriction enzyme double digestion.
  • the DNA solution derived from the primary positive colonies (7 ⁇ L each) was mixed with 10-fold concentrated EcoR I buffer (0.9 ⁇ L, New England Biolab), then BamHI (0.5 ⁇ L, 10 U / ⁇ L) and EcoR I ( 0.5 ⁇ L, 15 U / ⁇ L) was added. The solution was heated at 37 ° C. for 1 hour and then subjected to electrophoresis.
  • a colony from which a sample in which a band was detected at a position of about 670 bp was determined as a secondary positive colony.
  • This culture solution was diluted with 7 LB-ampicillin media (ampicillin concentration 100 ⁇ g / mL) in 500 mL portions, and cultured with shaking at 20 ° C. for 4.5 hours. After confirming that the absorbance at 600 nm of the culture solution was 0.44, 50 ⁇ L of isopropyl- ⁇ -D-thiogalactopyranoside (1 mol / L) was added and shake culture at 20 ° C. for 18 hours. Went. The culture broth was centrifuged at 9000 rpm for 20 minutes to recover the E. coli pellet, and divided into 4 pieces of 4 g and stored frozen at ⁇ 80 ° C. until use.
  • the obtained resin was washed 5 times with 30 mL of D-PBS, and 30 mL of thrombin treatment buffer (150 mmol / L NaCl, 50 mmol / L Tris-HCl, pH 8.0, 10% glycerol, 2.5 mmol / L CaCl 2). , 0.5% ⁇ -octyl-D-glucopyranoside).
  • thrombin treatment buffer was added to the resin to make 30 mL, and 30 units of thrombin (Amersham Biosciences) were added. After the resin mixture was gently stirred at 4 ° C. for 15 hours, the resin was filtered, and the resulting recombinant human COMT solution was stored at ⁇ 80 ° C. until use.
  • a control sample was prepared in a similar manner, but dimethyl sulfoxide (5 ⁇ L) was added instead of the test compound.
  • the reaction mixture (final volume 0.25 mL) was incubated at 37 ° C. for 30 minutes.
  • the reaction was stopped by adding ice-cooled 1 mol / L hydrochloric acid (0.25 mL) containing 0.1 g / L guaiacol.
  • Test example 2 Rat hepatotoxicity 3 ⁇ 10 ⁇ 6 cells / vial of rat frozen hepatocytes stored at ⁇ 150 ° C. were warmed to 37 ° C., added to a glucose-containing thawing medium (10 mL), mixed, and then centrifuged at 1000 rpm for 1 minute. After removing the supernatant, the cell pellet was suspended in Williams E. medium (15 mL). Drugs were prepared to 45, 15, 4.5, 1.5, and 0.45 mmol / L using dimethyl sulfoxide, and each drug solution and control (dimethyl sulfoxide) were dispensed in 2.0 ⁇ L aliquots into the test tube. The suspension (300 ⁇ L) was dispensed and mixed.
  • the compound of the present invention Since the compound of the present invention has an excellent COMT inhibitory action, it is useful as a therapeutic or prophylactic agent for Parkinson's disease, depression and hypertension.
  • the bioavailability of L-dopa can be increased and the action time can be extended, so that the treatment and prevention of Parkinson's disease can be achieved. It is suitable for.
  • SEQ ID NO: 1 is the sequence of recombinant human catechol-O-methyltransferase.
  • SEQ ID NO: 2> SEQ ID NO: 2 is a DNA sequence amplified using the primers of SEQ ID NOs: 3 and 4 to express the recombinant human catechol-O-methyltransferase of SEQ ID NO: 1.
  • SEQ ID NO: 3> SEQ ID NO: 3 is the sequence of the 5 ′ primer used to amplify the DNA of SEQ ID NO: 2.
  • SEQ ID NO: 4> SEQ ID NO: 4 is the sequence of the 3 ′ primer used to amplify the DNA of SEQ ID NO: 2.

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Abstract

Disclosed is a compound represented by the general formula (I) below which has a strong COMT inhibitory effect, or a pharmacologically acceptable salt thereof. Also disclosed are a pharmaceutical composition containing such a compound or a pharmacologically acceptable salt thereof, and a use of those. (In the formula, R1 and R2 independently represent a hydrogen, a lower acyl, a lower alkoxycarbonyl or the like; R3 represents a halogen, a halo-lower alkyl, a cyano or the like; R4 represents a hydrogen, a lower alkyl or the like; and R5 and R6 independently represent a hydrogen, an alkyl, a cycloalkyl, a heterocycloalkyl, a halo-lower alkyl, an optionally substituted aryl, an optionally substituted heteroaryl or the like.)

Description

新規なカテコール誘導体、それを含有する医薬組成物およびそれらの用途Novel catechol derivatives, pharmaceutical compositions containing them, and uses thereof
　本発明は、カテコール－Ｏ－メチルトランスフェラーゼ阻害作用を有する新規なカテコール誘導体、それを含有する医薬組成物およびそれらの用途に関する。 The present invention relates to a novel catechol derivative having a catechol-O-methyltransferase inhibitory action, a pharmaceutical composition containing it, and uses thereof.
　パーキンソン病は中高年齢者に好発する進行性の神経変性疾患であり、高齢化社会の進展とともにその患者数が増加している。パーキンソン病は、安静時振戦、固縮、無動、姿勢反射障害などの協調性運動機能障害を主症状とする疾患であり、その病因は中脳黒質ドパミン性神経細胞の変性による線条体ドパミンの欠乏に起因すると考えられている。このようなことから、パーキンソン病の治療薬として、Ｌ－ドパおよびドパミンレセプター刺激薬などが使用されている。 Parkinson's disease is a progressive neurodegenerative disease that frequently occurs in middle-aged and elderly people, and the number of patients is increasing with the progress of an aging society. Parkinson's disease is a disease whose main symptoms are coordinated motor dysfunction such as resting tremor, rigidity, ataxia, and postural reflex disorder, and its etiology is striae due to degeneration of midbrain dopaminergic neurons. It is believed to be due to a lack of body dopamine. For these reasons, L-dopa and dopamine receptor stimulants are used as therapeutic agents for Parkinson's disease.
　Ｌ－ドパは、ドパミンの前駆物質であり、脳内でドパミンに代謝されて効果を示す薬剤であるが、血中半減期が非常に短い欠点を有する。そのため、Ｌ－ドパは、通常Ｌ－ドパの代謝酵素阻害剤である、末梢性芳香族Ｌ－アミノ酸デカルボキシラーゼ阻害剤および／またはカテコール－Ｏ－メチルトランスフェラーゼ阻害剤とともに使用されている。カテコール－Ｏ－メチルトランスフェラーゼ（以下、ＣＯＭＴと称する）は、その補酵素であるＳ－アデノシル－Ｌ－メチオニンからカテコール基質へのメチル基の転送を触媒する酵素であり、この酵素を阻害することによりＬ－ドパから３－Ｏ－メチル－Ｌ－ドパへの代謝が阻害され、Ｌ－ドパの血中半減期が増加し、さらには血液脳関門を透過するＬ－ドパ量が増加することが知られている。このようにＣＯＭＴ阻害剤は、Ｌ－ドパと一緒に投与することにより、Ｌ－ドパの生体内利用率を増加させ、その作用時間を延長させることが知られている（例えば、非特許文献１参照）。 L-dopa is a precursor of dopamine and is a drug that is metabolized to dopamine in the brain and has an effect, but has a drawback that its blood half-life is very short. Therefore, L-DOPA is commonly used with peripheral aromatic L-amino acid decarboxylase inhibitors and / or catechol-O-methyltransferase inhibitors, which are L-DOPA metabolic enzyme inhibitors. Catechol-O-methyltransferase (hereinafter referred to as COMT) is an enzyme that catalyzes the transfer of a methyl group from its coenzyme S-adenosyl-L-methionine to a catechol substrate, and by inhibiting this enzyme Metabolism of L-dopa to 3-O-methyl-L-dopa is inhibited, the blood half-life of L-dopa increases, and the amount of L-dopa penetrating the blood brain barrier increases It is known to do. Thus, it is known that a COMT inhibitor increases the bioavailability of L-dopa and prolongs its action time when administered together with L-dopa (eg, non-patented). Reference 1).
　ＣＯＭＴ阻害剤は、また、尿中ナトリウム排泄促進作用を有するので高血圧症の治療薬として有用であると期待されている（例えば、非特許文献２参照）。ＣＯＭＴ阻害剤は、また、うつ病の治療薬として有用であると期待されている（例えば、非特許文献３参照）。 A COMT inhibitor is also expected to be useful as a therapeutic agent for hypertension because it has an action of promoting urinary sodium excretion (see, for example, Non-Patent Document 2). COMT inhibitors are also expected to be useful as therapeutic agents for depression (see, for example, Non-Patent Document 3).
　近年、種々のＣＯＭＴ阻害剤が報告されている。今日まで知られている最も強力なＣＯＭＴ阻害剤は、トルカポン（３，４－ジヒドロキシ－４’－メチル－５－ニトロベンゾフェノン，特許文献１参照）およびエンタカポン（（Ｅ）－２－シアノ－Ｎ，Ｎ－ジエチル－３－（３，４－ジヒドロキシ－５－ニトロフェニル）アクリルアミド，特許文献２参照）であり、これら２剤がパーキンソン病患者に使用されている。しかしながら、トルカポンは、重篤な肝機能障害が認められたことから、厳重な肝機能の監視下での投与が必要とされている（例えば、非特許文献４参照）。また、エンタカポンは、トルカポンに比べて効果が弱く、さらに作用持続時間が短い問題点を有している（例えば、非特許文献５参照）。このようなことから、安全性が高く、強力なＣＯＭＴ阻害作用を有する新規なＣＯＭＴ阻害剤が望まれている。 In recent years, various COMT inhibitors have been reported. The most potent COMT inhibitors known to date are tolcapone (3,4-dihydroxy-4′-methyl-5-nitrobenzophenone, see US Pat. No. 6,057,049) and entacapone ((E) -2-cyano-N, N-diethyl-3- (3,4-dihydroxy-5-nitrophenyl) acrylamide, see Patent Document 2), and these two agents are used in Parkinson's disease patients. However, since tolcapone has been observed to have severe liver dysfunction, it needs to be administered under strict monitoring of liver function (for example, see Non-Patent Document 4). In addition, entacapone has a problem that its effect is weaker than that of tolcapone and has a short action duration (for example, see Non-Patent Document 5). Therefore, a novel COMT inhibitor having high safety and a strong COMT inhibitory action is desired.
　Szilagyi G.らは、抗痙攣作用を有する、一般式（II）で表される化合物：
Figure JPOXMLDOC01-appb-C000002
  （式中、ＲＡは、メチル、n-ペンチル、n-ノニルまたはn-ドデシルを表す）を開示している（例えば、非特許文献６参照の表３参照）。しかしながら当該化合物（II）と本発明の一般式（Ｉ）で表される化合物とは、フェニル環上のウレイドカルボニル基の結合位置が異なる。さらに化合物（II）のＣＯＭＴ阻害作用については何ら記載されていない。 Szilagyi G. et al. Have an anticonvulsant action and are represented by the general formula (II):
Figure JPOXMLDOC01-appb-C000002
 (Wherein R A represents methyl, n-pentyl, n-nonyl or n-dodecyl) (for example, see Table 3 of Non-Patent Document 6). However, the compound (II) and the compound represented by the general formula (I) of the present invention differ in the bonding position of the ureidocarbonyl group on the phenyl ring. Furthermore, nothing is described about the COMT inhibitory action of compound (II).
　特許文献３には、一酸化窒素合成酵素阻害剤として有用な、一般式（III）で表される化合物が開示され、表２にはひとつの例示化合物として化合物Ia-12が記載されている（特許文献３参照）。しかしながらこれらの化合物のＣＯＭＴ阻害作用については何ら記載されていない。
Figure JPOXMLDOC01-appb-C000003
 Nutt J.G.ら，「Lancet」, 1998年, 351巻, 9111号, p.1221-1222 Eklof A.C.ら, 「Kidney Int.」, 1997年, 52巻, 3号, p.742-747 Moreau J.L.ら, 「Behav. Pharmacol.」, 1994年, 5巻, 3号, p.344-350 Benabou R.ら, 「Expert Opin. Drug Saf.」, 2003年, 2巻, 3号, p.263-267 Forsberg M.ら, 「J. Pharmacol. Exp. Ther.」, 2003年, 304巻, 2号, p.498-506 Szilagyi G.ら, 「Acta Pharmaceutica Hungarica」, 1975年, 45巻, p.145-154 欧州特許出願公開第２３７９２９号明細書 英国特許出願公開第２２００１０９号明細書 特開2004-217600号公報 Patent Document 3 discloses a compound represented by the general formula (III), which is useful as a nitric oxide synthase inhibitor, and Table 2 describes Compound Ia-12 as one exemplified compound ( (See Patent Document 3). However, nothing is described about the COMT inhibitory action of these compounds.
Figure JPOXMLDOC01-appb-C000003
 Nutt JG et al., "Lancet", 1998, 351, 9111, p.1221-1222 Eklof AC et al., "Kidney Int.", 1997, 52, 3, p.742-747 Moreau JL et al., "Behav. Pharmacol.", 1994, 5 (3), p.344-350 Benabou R. et al., "Expert Opin. Drug Saf.", 2003, Vol. 2, No. 3, p.263-267 Forsberg M. et al., "J. Pharmacol. Exp. Ther.", 2003, 304, 2, 498-506 Szilagyi G. et al., `` Acta Pharmaceutica Hungarica '', 1975, 45, p.145-154 European Patent Application No. 237929 British Patent Application No. 2200109 JP 2004-217600 A
　本発明の目的は、強力なＣＯＭＴ阻害作用を有し、好ましくは高い安全性を有する新規な化合物を提供することである。 An object of the present invention is to provide a novel compound having a strong COMT inhibitory action and preferably having high safety.
　本発明者らは、上記課題を解決すべく鋭意研究を重ねた結果、一般式（Ｉ）で表されるカテコール誘導体が、優れたＣＯＭＴ阻害作用を有し、さらには高い安全性を有することを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have found that the catechol derivative represented by the general formula (I) has an excellent COMT inhibitory action and further has high safety. The headline and the present invention were completed.
　すなわち、本発明は、一般式（Ｉ）：
Figure JPOXMLDOC01-appb-C000004
  〔式中、
　Ｒ１およびＲ２は、それぞれ独立して、水素原子、低級アシル基、低級アルコキシカルボニル基、または－Ｃ（Ｏ）ＮＲ７Ｒ８を表すか、あるいはＲ１およびＲ２が一緒になって－Ｃ（Ｏ）－を形成し；
　Ｒ３は、ハロゲン原子、ハロ低級アルキル基、低級アルコキシカルボニル基、またはシアノ基であり；
　Ｒ４は、水素原子、低級アルキル基、低級アルコキシ低級アルキル基またはアラルキル基であり；
　Ｒ５およびＲ６は、それぞれ独立して、以下のａ）～ｌ）：
　ａ）水素原子、
　ｂ）アルキル基、
　ｃ）シクロアルキル基、
　ｄ）シクロアルキル低級アルキル基、
　ｅ）橋かけ環状炭化水素基、
　ｆ）ヘテロシクロアルキル基、
　ｇ）ハロ低級アルキル基、
　ｈ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基および低級アルコキシカルボニル基から独立して選択される１～５個の基で環が置換されるアリール基、
　ｉ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、および低級アルコキシ基から独立して選択される１～３個の基で環が置換されるヘテロアリール基、
　ｊ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、シアノ基および低級アルコキシ基から独立して選択される１～５個の基で環が置換されるアラルキル基、
　ｋ）低級アシルアミノ低級アルキル基、または
　ｌ）低級アルコキシ低級アルキル基であるか、あるいは
　Ｒ５およびＲ６が、それらが結合している窒素原子と一緒になって、環状アミノ基を形成するか、あるいは
　Ｒ４およびＲ５が、－（ＣＨ２）ｍ－で表される基を形成する場合、Ｒ６は水素原子または低級アルキル基であり；
　Ｒ７およびＲ８は、それぞれ独立して、水素原子、低級アルキル基またはアラルキル基を表すか、あるいはＲ７およびＲ８が、それらが結合している窒素原子と一緒になって、環状アミノ基を形成し；
　ｍは、２～４である〕
で表される化合物またはその薬理学的に許容される塩に関する。 That is, the present invention relates to the general formula (I):
Figure JPOXMLDOC01-appb-C000004
 [Where,
R 1 and R 2 each independently represents a hydrogen atom, a lower acyl group, a lower alkoxycarbonyl group, or —C (O) NR 7 R 8 , or R 1 and R 2 taken together— Forming C (O)-;
R 3 is a halogen atom, a halo lower alkyl group, a lower alkoxycarbonyl group, or a cyano group;
R 4 is a hydrogen atom, a lower alkyl group, a lower alkoxy lower alkyl group or an aralkyl group;
R 5 and R 6 are each independently the following a) to l):
a) a hydrogen atom,
b) an alkyl group,
c) a cycloalkyl group,
d) a cycloalkyl lower alkyl group,
e) a bridged cyclic hydrocarbon group,
f) a heterocycloalkyl group,
g) a halo lower alkyl group,
h) unsubstituted or group consisting of: aryl having a ring substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Group,
i) unsubstituted or a group consisting of the following: a heteroaryl group in which the ring is substituted with 1 to 3 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group,
j) The group consisting of unsubstituted or the following: an aralkyl group in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a cyano group and a lower alkoxy group,
k) a lower acylamino lower alkyl group, or 1) a lower alkoxy lower alkyl group, or R 5 and R 6 together with the nitrogen atom to which they are attached form a cyclic amino group, Or when R 4 and R 5 form a group represented by — (CH 2 ) m —, R 6 is a hydrogen atom or a lower alkyl group;
R 7 and R 8 each independently represents a hydrogen atom, a lower alkyl group or an aralkyl group, or R 7 and R 8 together with the nitrogen atom to which they are bonded, a cyclic amino group Forming;
m is 2-4]
Or a pharmaceutically acceptable salt thereof.
　また、本発明は、一般式（Ｉ）で表される化合物またはその薬理学的に許容される塩を有効成分として含有する医薬組成物に関する。 The present invention also relates to a pharmaceutical composition comprising as an active ingredient a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof.
　また、本発明は、一般式（Ｉ）に記載の化合物またはその薬理学的に許容される塩を有効成分として含有する、カテコール－Ｏ－メチルトランスフェラーゼ阻害剤に関する。 The present invention also relates to a catechol-O-methyltransferase inhibitor comprising as an active ingredient the compound described in general formula (I) or a pharmacologically acceptable salt thereof.
　また、本発明は、一般式（Ｉ）に記載の化合物またはその薬理学的に許容される塩と、Ｌ－ドパおよび芳香族Ｌ－アミノ酸デカルボキシラーゼ阻害剤から選択される少なくとも１種とを組み合わせてなる医薬に関する。 The present invention also includes a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and at least one selected from L-dopa and aromatic L-amino acid decarboxylase inhibitors. The present invention relates to a combined medicine.
　また、本発明は、一般式（I）に記載の化合物またはその薬理学的に許容される塩を有効成分として含有する、パーキンソン病、うつ病または高血圧症の治療または予防剤に関する。 The present invention also relates to a therapeutic or prophylactic agent for Parkinson's disease, depression, or hypertension containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
　また、本発明は、パーキンソン病、うつ病または高血圧症の治療または予防剤を製造するための、一般式（I）に記載の化合物またはその薬理学的に許容される塩の使用に関する。 The present invention also relates to the use of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof for producing a therapeutic or prophylactic agent for Parkinson's disease, depression or hypertension.
　また、本発明は、パーキンソン病、うつ病または高血圧症の治療または予防方法に関し、該方法は、一般式（I）に記載の化合物またはその薬理学的に許容される塩の有効量を投与する工程を包含する。 The present invention also relates to a method for treating or preventing Parkinson's disease, depression or hypertension, which comprises administering an effective amount of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof. Process.
　一般式（Ｉ）で表される化合物において、下記の用語は、特に断らない限り、以下の意味を有する。 In the compound represented by the general formula (I), the following terms have the following meanings unless otherwise specified.
　本明細書において、「低級」との用語は、特に断らない限り、炭素数１～６個を有することを意味する。 In this specification, the term “lower” means having 1 to 6 carbon atoms unless otherwise specified.
　「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子を表す。Ｒ３においては、塩素原子が好適である。 The “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. In R 3 , a chlorine atom is preferable.
　「アルキル基」とは、直鎖または分岐鎖状のＣ１－１０アルキル基を意味し、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、sec－ブチル基、tert－ブチル基、ペンチル基、イソペンチル基、ネオペンチル基、tert－ペンチル基、１－メチルブチル基、２－メチルブチル基、１，２－ジメチルプロピル基、ヘキシル基、イソヘキシル基、へプチル基、オクチル基などが挙げられる。Ｒ５、Ｒ６においては、Ｃ１－７アルキル基が好適であり、Ｃ１－４アルキル基がさらに好適である。 “Alkyl group” means a linear or branched C 1-10 alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert -Butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, heptyl, octyl, etc. Can be mentioned. In R 5 and R 6 , a C 1-7 alkyl group is preferable, and a C 1-4 alkyl group is more preferable.
　「低級アルキル基」とは、直鎖または分岐鎖状のＣ１－６アルキル基を意味し、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、sec－ブチル基、tert－ブチル基、ペンチル基、イソペンチル基、ネオペンチル基、tert－ペンチル基、１－メチルブチル基、２－メチルブチル基、１，２－ジメチルプロピル基、ヘキシル基、イソヘキシル基などが挙げられる。Ｒ４においては、Ｃ１－４アルキルが好適である。 The “lower alkyl group” means a linear or branched C 1-6 alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, Examples thereof include tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group and the like. In R 4 , C 1-4 alkyl is preferred.
　「ハロ低級アルキル基」とは、１～３個の同種または異種のハロゲン原子で置換されたＣ１－６アルキル基を意味し、例えば、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、２，２，２－トリフルオロエチル基などが挙げられる。Ｒ３においては、トリフルオロメチル基が好適である。 The “halo lower alkyl group” means a C 1-6 alkyl group substituted with 1 to 3 of the same or different halogen atoms, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, 2 2,2-trifluoroethyl group and the like. In R 3 , a trifluoromethyl group is preferable.
　「低級アルコキシ基」とは、直鎖または分岐鎖状のＣ１－６アルコキシ基を意味し、例えば、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、sec－ブトキシ基、tert－ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基などが挙げられる。 “Lower alkoxy group” means a linear or branched C 1-6 alkoxy group, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group Tert-butoxy group, pentyloxy group, hexyloxy group and the like.
　「シクロアルキル基」とは、３～７員の飽和環状炭化水素を意味し、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基およびシクロヘプチル基が挙げられる。当該シクロアルキル基は、必要に応じて１～２個の低級アルキル基で置換されてもよい。また、当該シクロアルキル基は、必要に応じてフェニル環と縮合された２環性縮合炭化水素を形成してもよく、このような２環性縮合炭化水素として、例えば、インダン－２－イル基などが挙げられる。 The “cycloalkyl group” means a 3 to 7-membered saturated cyclic hydrocarbon, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. The cycloalkyl group may be optionally substituted with 1 to 2 lower alkyl groups. In addition, the cycloalkyl group may form a bicyclic condensed hydrocarbon condensed with a phenyl ring if necessary. Examples of such a bicyclic condensed hydrocarbon include, for example, an indan-2-yl group. Etc.
　「シクロアルキル低級アルキル基」とは、シクロアルキル－Ｃ１－６アルキル基を意味し、例えば、シクロプロピルメチル基、シクロペンチルメチル基、シクロへキシルメチル基などが挙げられ、好適にはシクロプロピルメチル基である。 The “cycloalkyl lower alkyl group” means a cycloalkyl-C 1-6 alkyl group, and examples thereof include a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and the like, and preferably a cyclopropylmethyl group It is.
　「橋かけ環状炭化水素基」とは、炭素数７～１０個を有し、５～７員環を有する橋かけ状の飽和環状炭化水素を意味し、例えば、ビシクロ[2.2.1]ヘプタン－２－イル基、アダマンタン－１－イル基などが挙げられる。 “Bridged cyclic hydrocarbon group” means a bridged saturated cyclic hydrocarbon having 7 to 10 carbon atoms and having a 5- to 7-membered ring. For example, bicyclo [2.2.1] heptane- 2-yl group, adamantane-1-yl group and the like can be mentioned.
　「ヘテロシクロアルキル基」とは、環内に－ＮＨ－、－Ｏ－または－Ｓ－を含有し、炭素原子を介して結合する４～７員の飽和複素環基を意味し、例えば、テトラヒドロフリル基、テトラヒドロチエニル基、テトラヒドロピラニル基、ピロリジン－２－イル基、ピロリジン－３－イル基、ピペリジン－２－イル基、ピペリジン－３－イル基、ピペリジン－４－イル基などが挙げられる。またヘテロシクロアルキル基が環内に窒素原子を含有する場合、当該窒素原子は、必要に応じて低級アルコキシカルボニル基または低級アシル基で置換されてもよく、このような置換ヘテロシクロアルキル基として、例えば、Ｎ－エトキシカルボニルピペリジン－４－イル基などが挙げられる。 “Heterocycloalkyl group” means a 4 to 7-membered saturated heterocyclic group containing —NH—, —O— or —S— in the ring and bonded via a carbon atom. Examples include furyl group, tetrahydrothienyl group, tetrahydropyranyl group, pyrrolidin-2-yl group, pyrrolidin-3-yl group, piperidin-2-yl group, piperidin-3-yl group, and piperidin-4-yl group. . When the heterocycloalkyl group contains a nitrogen atom in the ring, the nitrogen atom may be optionally substituted with a lower alkoxycarbonyl group or a lower acyl group. As such a substituted heterocycloalkyl group, Examples thereof include an N-ethoxycarbonylpiperidin-4-yl group.
　「アリール基」とは、Ｃ６－１０芳香族炭化水素を意味し、フェニル基、１－ナフチル基、２－ナフチル基が挙げられ、好適にはフェニル基である。 The “aryl group” means a C 6-10 aromatic hydrocarbon, and includes a phenyl group, a 1-naphthyl group, and a 2-naphthyl group, and is preferably a phenyl group.
　「アラルキル基」とは、アリール－Ｃ１－６アルキル基を意味し、ベンジル基、フェネチル基、１－フェニルエチル基、３－フェニルプロピル基、４－フェニルブチル基、ナフチルメチル基などが挙げられる。Ｒ５、Ｒ６においては、ベンジル基が好適である。 The “aralkyl group” means an aryl-C 1-6 alkyl group, and examples thereof include a benzyl group, a phenethyl group, a 1-phenylethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, and a naphthylmethyl group. . In R 5 and R 6 , a benzyl group is preferable.
　「ヘテロアリール基」とは、１～５個の炭素原子ならびにＯ、ＮおよびＳ原子からなる群から独立して選択される１～４個のヘテロ原子を含有する５～６員の単環式芳香族複素環、あるいは１～９個の炭素原子ならびにＯ、ＮおよびＳ原子からなる群から独立して選択される１～４個のヘテロ原子を含有する８～１０員の二環式芳香族複素環を意味し、但し、これらの環は、隣接する酸素原子および／または硫黄原子を含まない。単環式芳香族複素環としては、例えば、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、イソキサゾリル、１，２，４－オキサジアゾリル、テトラゾリル、チアゾリル、イソチアゾリル、１，２，３－チアジアゾリル、トリアゾリル、ピリジル、ピラジニル、ピリミジルおよびピリダジニルなどが挙げられる。二環式芳香族複素環としては、例えば、インドリル、インダゾリル、ベンゾフラニル、ベンゾチエニル、ベンゾチアゾリル、キノリル、イソキノリル、フタラジニル、ベンズイミダゾリル、ベンゾオキサゾリルなどが挙げられる。これらの複素環の全ての位置異性体が考えられる（例えば、２－ピリジル、３－ピリジル、４－ピリジルなど）。 A “heteroaryl group” is a 5-6 membered monocyclic containing 1 to 5 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of O, N and S atoms An aromatic heterocycle or an 8-10 membered bicyclic aromatic containing 1 to 4 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of O, N and S atoms Means a heterocycle, provided that these rings do not contain adjacent oxygen and / or sulfur atoms. Examples of the monocyclic aromatic heterocycle include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, triazolyl, Examples include pyridyl, pyrazinyl, pyrimidyl and pyridazinyl. Examples of the bicyclic aromatic heterocycle include indolyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, quinolyl, isoquinolyl, phthalazinyl, benzimidazolyl, benzoxazolyl and the like. All positional isomers of these heterocycles are contemplated (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.).
　「低級アルコキシ低級アルキル基」とは、Ｃ１－６アルコキシ－Ｃ１－６アルキル基を意味し、例えば、メトキシメチル基、２－メトキシエチル基、３－メトキシプロピル基、エトキシメチル基、２－エトキシエチル基、３－エトキシプロピル基、３－イソプロポキシプロピル基などが挙げられる。 “Lower alkoxy lower alkyl group” means a C 1-6 alkoxy-C 1-6 alkyl group, and includes, for example, a methoxymethyl group, a 2-methoxyethyl group, a 3-methoxypropyl group, an ethoxymethyl group, a 2- Examples thereof include an ethoxyethyl group, a 3-ethoxypropyl group, and a 3-isopropoxypropyl group.
　「低級アシル基」とは、（Ｃ１－６アルキル）－Ｃ（Ｏ）－で表される基を意味し、例えば、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、ピバロイル基、バレリル基、イソバレリル基などが挙げられる。 “Lower acyl group” means a group represented by (C 1-6 alkyl) -C (O) —, for example, acetyl group, propionyl group, butyryl group, isobutyryl group, pivaloyl group, valeryl group, And isovaleryl group.
　「低級アシルアミノ低級アルキル基」とは、（Ｃ１－６アルキル）－Ｃ（Ｏ）ＮＨ－Ｃ１－６アルキルで表される基を意味し、例えば、アセチルアミノエチル基、アセチルアミノプロピル基などが挙げられる。 The “lower acylamino lower alkyl group” means a group represented by (C 1-6 alkyl) -C (O) NH—C 1-6 alkyl, such as acetylaminoethyl group, acetylaminopropyl group, etc. Is mentioned.
　「低級アルコキシカルボニル基」とは、（Ｃ１－６アルコキシ）－Ｃ（Ｏ）－で表される基を意味し、例えば、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、イソプロポキシカルボニル基、ブトキシカルボニル基、イソブトキシカルボニル基、sec－ブトキシカルボニル基、tert－ブトキシカルボニル基、ペンチルオキシカルボニル基、ヘキシルオキシカルボニル基などが挙げられる。Ｒ３においては、メトキシカルボニル基が好適である。 The “lower alkoxycarbonyl group” means a group represented by (C 1-6 alkoxy) -C (O) —, and includes, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, Examples include butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group and the like. In R 3 , a methoxycarbonyl group is preferred.
　「環状アミノ基」とは、環内に－ＮＨ－、－Ｏ－または－Ｓ－を含んでもよい、５～７員の飽和環状アミンを意味し、例えば、１－ピロリジル基、ピペリジノ基、ピペラジノ基、モルホリノ基、チオモルホリノ基などが挙げられる。当該環状アミノ基は、必要に応じて１～２個の低級アルキル基または低級アルコキシカルボニル基で置換されてもよい。 “Cyclic amino group” means a 5- to 7-membered saturated cyclic amine which may contain —NH—, —O— or —S— in the ring, for example, 1-pyrrolidyl group, piperidino group, piperazino Group, morpholino group, thiomorpholino group and the like. The cyclic amino group may be optionally substituted with 1 to 2 lower alkyl groups or lower alkoxycarbonyl groups.
　本発明の一般式（Ｉ）で表される化合物において１つまたはそれ以上の不斉炭素原子が存在する場合、本発明は各々の不斉炭素原子がＲ配置の化合物、Ｓ配置の化合物、およびそれらの任意の組み合せの化合物のいずれも包含する。またそれらのラセミ化合物、ラセミ混合物、単一のエナンチオマー、ジアステレオマー混合物が本発明の範囲に含まれる。本発明の一般式（Ｉ）で表される化合物において幾何学異性が存在する場合、本発明はその幾何学異性体のいずれも包含する。本発明の一般式（Ｉ）で表される化合物においてアトロプ異性体が存在する場合、本発明はそのアトロプ異性体のいずれも包含する。さらに本発明の一般式（Ｉ）で表される化合物には、水和物やエタノール等の医薬品として許容される溶媒との溶媒和物も含まれる。 When one or more asymmetric carbon atoms are present in the compound represented by the general formula (I) of the present invention, the present invention relates to a compound in which each asymmetric carbon atom is in the R configuration, a compound in the S configuration, Any of those combinations of compounds are included. Also included within the scope of the present invention are those racemates, racemic mixtures, single enantiomers and diastereomeric mixtures. When geometric isomerism exists in the compound represented by the general formula (I) of the present invention, the present invention includes any of the geometric isomers. When the atropisomer is present in the compound represented by the general formula (I) of the present invention, the present invention includes any of the atropisomers. Furthermore, the compound represented by the general formula (I) of the present invention includes solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.
　本発明の一般式（Ｉ）で表される化合物は、塩の形態で存在することができる。このような塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸などの鉱酸との酸付加塩、ギ酸、酢酸、トリフルオロ酢酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、プロピオン酸、クエン酸、コハク酸、酒石酸、フマル酸、酪酸、シュウ酸、マロン酸、マレイン酸、乳酸、リンゴ酸、炭酸、グルタミン酸、アスパラギン酸等の有機酸との酸付加塩、リチウム塩、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩等の無機塩基との塩、トリエチルアミン、ピペリジン、モルホリン、リジン等の有機塩基との塩を挙げることができる。 The compound represented by the general formula (I) of the present invention can exist in the form of a salt. Such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid Acids with organic acids such as p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid Examples thereof include salts with inorganic bases such as addition salts, lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts, and salts with organic bases such as triethylamine, piperidine, morpholine, and lysine.
　本発明の一般式（Ｉ）で表される化合物のひとつの実施態様において、
　Ｒ１およびＲ２は、好ましくは、水素原子であり；
　Ｒ３は、好ましくは、ハロゲン原子、ハロ低級アルキル基、メトキシカルボニル基またはシアノ基であり、さらに好ましくは、ハロゲン原子またはハロ低級アルキル基であり、なおさらに好ましくは塩素原子またはトリフルオロメチル基であり；
　Ｒ４は、好ましくは水素原子、低級アルキル基、またはアラルキル基であり、さらに好ましくは水素原子であり；あるいは
　一つの局面では、Ｒ５およびＲ６は、好ましくはそれぞれ独立して、以下のａ）～ｌ）：
　ａ）水素原子、
　ｂ）アルキル基、
　ｃ）シクロアルキル基、
　ｄ）シクロアルキル低級アルキル基、
　ｅ）橋かけ環状炭化水素基、
　ｆ）ヘテロシクロアルキル基、
　ｇ）ハロ低級アルキル基、
　ｈ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基および低級アルコキシカルボニル基から独立して選択される１～５個の基で環が置換されるアリール基、
　ｉ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、および低級アルコキシ基から独立して選択される１～３個の基で環が置換されるヘテロアリール基、
　ｊ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、シアノ基および低級アルコキシ基から独立して選択される１～５個の基で環が置換されるアラルキル基、
　ｋ）低級アシルアミノ低級アルキル基、または
　ｌ）低級アルコキシ低級アルキル基であり、
　別の局面では、Ｒ５は、好ましくは水素原子であり、
　Ｒ６は、好ましくは以下のａ）～ｋ）：
　ａ）アルキル基、
　ｂ）シクロアルキル基、
　ｃ）シクロアルキル低級アルキル基、
　ｄ）橋かけ環状炭化水素基、
　ｅ）ヘテロシクロアルキル基、
　ｆ）ハロ低級アルキル基、
　ｇ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基および低級アルコキシカルボニル基から独立して選択される１～５個の基で環が置換されるアリール基、
　ｈ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、シアノ基および低級アルコキシ基から独立して選択される１～３個の基で環が置換されるヘテロアリール基、
　ｉ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、および低級アルコキシ基から独立して選択される１～５個の基で環が置換されるアラルキル基、
　ｊ）低級アシルアミノ低級アルキル基、または
　ｋ）低級アルコキシ低級アルキル基であり、
　さらに好ましくは、Ｒ６は、以下のａ）～ｈ）：
　ａ）アルキル基、
　ｂ）シクロアルキル基、
　ｃ）シクロアルキル低級アルキル基、
　ｄ）橋かけ環状炭化水素基、
　ｅ）ヘテロシクロアルキル基、
　ｆ）ハロ低級アルキル基、
　ｇ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基および低級アルコキシカルボニル基から独立して選択される１～５個の基で環が置換されるアリール基、または
　ｈ）低級アルコキシ低級アルキル基であり、
　なおさらに好ましくは、Ｒ６は、以下のａ）～ｅ）：
　ａ）アルキル基、
　ｂ）シクロアルキル基、
　ｃ）シクロアルキル低級アルキル基、
　ｄ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基および低級アルコキシカルボニル基から独立して選択される１～５個の基で環が置換されるアリール基、または
　ｅ）低級アルコキシ低級アルキル基である。 In one embodiment of the compound represented by the general formula (I) of the present invention,
R 1 and R 2 are preferably hydrogen atoms;
R 3 is preferably a halogen atom, a halo lower alkyl group, a methoxycarbonyl group or a cyano group, more preferably a halogen atom or a halo lower alkyl group, still more preferably a chlorine atom or a trifluoromethyl group. Yes;
R 4 is preferably a hydrogen atom, a lower alkyl group, or an aralkyl group, more preferably a hydrogen atom; or in one aspect, R 5 and R 6 are preferably each independently selected from the following a ) To l):
a) a hydrogen atom,
b) an alkyl group,
c) a cycloalkyl group,
d) a cycloalkyl lower alkyl group,
e) a bridged cyclic hydrocarbon group,
f) a heterocycloalkyl group,
g) a halo lower alkyl group,
h) unsubstituted or group consisting of: aryl having a ring substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Group,
i) unsubstituted or a group consisting of the following: a heteroaryl group in which the ring is substituted with 1 to 3 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group,
j) The group consisting of unsubstituted or the following: an aralkyl group in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a cyano group and a lower alkoxy group,
k) a lower acylamino lower alkyl group, or l) a lower alkoxy lower alkyl group,
In another aspect, R 5 is preferably a hydrogen atom,
R 6 is preferably the following a) to k):
a) an alkyl group,
b) a cycloalkyl group,
c) a cycloalkyl lower alkyl group,
d) a bridged cyclic hydrocarbon group,
e) a heterocycloalkyl group,
f) a halo lower alkyl group,
g) Unsubstituted or group consisting of: aryl having a ring substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Group,
h) Unsubstituted or a group consisting of the following: a heteroaryl group in which the ring is substituted with 1 to 3 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a cyano group and a lower alkoxy group ,
i) An unsubstituted or group consisting of the following: an aralkyl group in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group,
j) a lower acylamino lower alkyl group, or k) a lower alkoxy lower alkyl group,
More preferably, R 6 represents the following a) to h):
a) an alkyl group,
b) a cycloalkyl group,
c) a cycloalkyl lower alkyl group,
d) a bridged cyclic hydrocarbon group,
e) a heterocycloalkyl group,
f) a halo lower alkyl group,
g) Unsubstituted or group consisting of: aryl having a ring substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group A group, or h) a lower alkoxy lower alkyl group,
Even more preferably, R 6 is a) to e):
a) an alkyl group,
b) a cycloalkyl group,
c) a cycloalkyl lower alkyl group,
d) Unsubstituted or the group consisting of: aryl in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Or e) a lower alkoxy lower alkyl group.
　本発明の好ましい実施態様では、
Ｒ１およびＲ２は、水素原子である。 In a preferred embodiment of the invention,
R 1 and R 2 are hydrogen atoms.
　本発明のさらに好ましい実施態様では、
Ｒ１およびＲ２は、水素原子であり、
Ｒ５は、水素原子であり、
Ｒ６は、以下のａ）～ｋ）：
　ａ）アルキル基、
　ｂ）シクロアルキル基、
　ｃ）シクロアルキル低級アルキル基、
　ｄ）橋かけ環状炭化水素基、
　ｅ）ヘテロシクロアルキル基、
　ｆ）ハロ低級アルキル基、
　ｇ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基および低級アルコキシカルボニル基から独立して選択される１～５個の基で環が置換されるアリール基、
　ｈ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、および低級アルコキシ基から独立して選択される１～３個の基で環が置換されるヘテロアリール基、
　ｉ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、シアノ基および低級アルコキシ基から独立して選択される１～５個の基で環が置換されるアラルキル基、
　ｊ）低級アシルアミノ低級アルキル基、または
　ｋ）低級アルコキシ低級アルキル基である。 In a further preferred embodiment of the invention,
R 1 and R 2 are hydrogen atoms;
R 5 is a hydrogen atom,
R 6 represents the following a) to k):
a) an alkyl group,
b) a cycloalkyl group,
c) a cycloalkyl lower alkyl group,
d) a bridged cyclic hydrocarbon group,
e) a heterocycloalkyl group,
f) a halo lower alkyl group,
g) Unsubstituted or group consisting of: aryl having a ring substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Group,
h) an unsubstituted or group consisting of the following: a heteroaryl group in which the ring is substituted with 1 to 3 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group;
i) An unsubstituted or group consisting of: an aralkyl group in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a cyano group and a lower alkoxy group,
j) a lower acylamino lower alkyl group, or k) a lower alkoxy lower alkyl group.
　本発明のなおさらに好ましい実施態様では、
　Ｒ１およびＲ２は、水素原子であり、
　Ｒ５は、水素原子であり、
　Ｒ６は、以下のａ）～ｈ）：
　ａ）アルキル基、
　ｂ）シクロアルキル基、
　ｃ）シクロアルキル低級アルキル基、
　ｄ）橋かけ環状炭化水素基、
　ｅ）ヘテロシクロアルキル基、
　ｆ）ハロ低級アルキル基、
　ｇ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基および低級アルコキシカルボニル基から独立して選択される１～５個の基で環が置換されるアリール基、または
　ｈ）低級アルコキシ低級アルキル基である。 In a still further preferred embodiment of the invention,
R 1 and R 2 are hydrogen atoms;
R 5 is a hydrogen atom,
R 6 represents the following a) to h):
a) an alkyl group,
b) a cycloalkyl group,
c) a cycloalkyl lower alkyl group,
d) a bridged cyclic hydrocarbon group,
e) a heterocycloalkyl group,
f) a halo lower alkyl group,
g) Unsubstituted or group consisting of: aryl having a ring substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Or h) a lower alkoxy lower alkyl group.
　本発明の別のなおさらに好ましい実施態様では、
　Ｒ１およびＲ２は、水素原子であり、
　Ｒ４は、水素原子、低級アルキル基またはアラルキル基であり、
　Ｒ５は、水素原子であり、
　Ｒ６は、以下のａ）～ｈ）：
　ａ）アルキル基、
　ｂ）シクロアルキル基、
　ｃ）シクロアルキル低級アルキル基、
　ｄ）橋かけ環状炭化水素基、
　ｅ）ヘテロシクロアルキル基、
　ｆ）ハロ低級アルキル基、
　ｇ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基および低級アルコキシカルボニル基から独立して選択される１～５個の基で環が置換されるアリール基、または
　ｈ）低級アルコキシ低級アルキル基である。 In yet another more preferred embodiment of the present invention,
R 1 and R 2 are hydrogen atoms;
R 4 is a hydrogen atom, a lower alkyl group or an aralkyl group,
R 5 is a hydrogen atom,
R 6 represents the following a) to h):
a) an alkyl group,
b) a cycloalkyl group,
c) a cycloalkyl lower alkyl group,
d) a bridged cyclic hydrocarbon group,
e) a heterocycloalkyl group,
f) a halo lower alkyl group,
g) Unsubstituted or group consisting of: aryl having a ring substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Or h) a lower alkoxy lower alkyl group.
　本発明の別のなおさらに好ましい実施態様では、
　Ｒ１およびＲ２は、水素原子であり、
　Ｒ４は、水素原子、低級アルキル基またはアラルキル基であり、
　Ｒ５は、水素原子であり、
　Ｒ６は、以下のａ）～ｅ）：
　ａ）アルキル基、
　ｂ）シクロアルキル基、
　ｃ）シクロアルキル低級アルキル基、
　ｄ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基および低級アルコキシカルボニル基から独立して選択される１～５個の基で環が置換されるアリール基、または
　ｅ）低級アルコキシ低級アルキル基である。 In yet another more preferred embodiment of the present invention,
R 1 and R 2 are hydrogen atoms;
R 4 is a hydrogen atom, a lower alkyl group or an aralkyl group,
R 5 is a hydrogen atom,
R 6 represents the following a) to e):
a) an alkyl group,
b) a cycloalkyl group,
c) a cycloalkyl lower alkyl group,
d) Unsubstituted or the group consisting of: aryl in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Or e) a lower alkoxy lower alkyl group.
　本発明の特に好ましい実施態様では、
　Ｒ１およびＲ２は、水素原子であり、
　Ｒ３は、ハロゲン原子またはハロ低級アルキル基であり、
　Ｒ４は、水素原子であり、
　Ｒ５は、水素原子であり、
　Ｒ６は、以下のａ）～ｅ）：
　ａ）アルキル基、
　ｂ）シクロアルキル基、
　ｃ）シクロアルキル低級アルキル基、
　ｄ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基および低級アルコキシカルボニル基から独立して選択される１～５個の基で環が置換されるアリール基、または
　ｅ）低級アルコキシ低級アルキル基である。 In a particularly preferred embodiment of the invention,
R 1 and R 2 are hydrogen atoms;
R 3 is a halogen atom or a halo lower alkyl group,
R 4 is a hydrogen atom,
R 5 is a hydrogen atom,
R 6 represents the following a) to e):
a) an alkyl group,
b) a cycloalkyl group,
c) a cycloalkyl lower alkyl group,
d) Unsubstituted or the group consisting of: aryl in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Or e) a lower alkoxy lower alkyl group.
　本発明の好ましい実施態様の具体例は、以下からなる群から選択される化合物またはその薬理学的に許容される塩である：
　１－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）－３－シクロプロピルメチル尿素；
　１－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）－３－プロピル尿素；
　１－ブチル－３－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）尿素；
　１－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）－３－ペンチル尿素； 
　１－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）－３－イソプロピル尿素；
　１－ｔｅｒｔ－ブチル－３－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）尿素；
　１－ブチル－３－（３，４－ジヒドロキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）尿素；
　１－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）－３－シクロヘプチル尿素；
　１－シクロヘキシル－３－（３，４－ジヒドロキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）尿素；
　１－シクロヘプチル－３－（３，４－ジヒドロキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）尿素；
　１－（３，４－ジヒドロキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）－３－フェニル尿素；
　１－（３，４－ジヒドロキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）－３－（２，６－ジメチルフェニル）尿素；
　２－［３－（３，４－ジヒドロキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）ウレイド］安息香酸メチル；
　１－（３，４－ジヒドロキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）－３－（３－メトキシプロピル）－１－メチル尿素；
　２－（３－シクロプロピル－１－メチルウレイドカルボニル）－４，５－ジヒドロキシ－３－ニトロ安息香酸メチル；および
　１－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）－３－（３－エトキシプロピル）尿素。 Specific examples of preferred embodiments of the present invention are compounds selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
1- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) -3-cyclopropylmethylurea;
1- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) -3-propylurea;
1-butyl-3- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) urea;
1- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) -3-pentylurea;
1- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) -3-isopropylurea;
1-tert-butyl-3- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) urea;
1-butyl-3- (3,4-dihydroxy-2-nitro-6-trifluoromethylbenzoyl) urea;
1- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) -3-cycloheptylurea;
1-cyclohexyl-3- (3,4-dihydroxy-2-nitro-6-trifluoromethylbenzoyl) urea;
1-cycloheptyl-3- (3,4-dihydroxy-2-nitro-6-trifluoromethylbenzoyl) urea;
1- (3,4-dihydroxy-2-nitro-6-trifluoromethylbenzoyl) -3-phenylurea;
1- (3,4-dihydroxy-2-nitro-6-trifluoromethylbenzoyl) -3- (2,6-dimethylphenyl) urea;
2- [3- (3,4-dihydroxy-2-nitro-6-trifluoromethylbenzoyl) ureido] methyl benzoate;
1- (3,4-dihydroxy-2-nitro-6-trifluoromethylbenzoyl) -3- (3-methoxypropyl) -1-methylurea;
Methyl 2- (3-cyclopropyl-1-methylureidocarbonyl) -4,5-dihydroxy-3-nitrobenzoate; and 1- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) -3- (3-Ethoxypropyl) urea.
　本発明の一般式（Ｉ）で表される化合物は、スキーム１～４に示す方法により製造することができる。 The compound represented by the general formula (I) of the present invention can be produced by the methods shown in Schemes 1 to 4.
Figure JPOXMLDOC01-appb-C000005
  （式中、Ｒ３、Ｒ５およびＲ６は、前記と同義であり；Ｒ１０は、低級アシル基、低級アルコキシカルボニル基または－ＣＯＮＲ７Ｒ８を表し；Ｍｅはメチル基を表し、Ｂｎはベンジル基を表す。）
Figure JPOXMLDOC01-appb-C000005
 Wherein R 3 , R 5 and R 6 are as defined above; R 10 represents a lower acyl group, a lower alkoxycarbonyl group or —CONR 7 R 8 ; Me represents a methyl group, and Bn represents Represents a benzyl group.)
工程１－１
　アミド誘導体（X）を、不活性溶媒中、塩化オキサリルと反応させることによりアシルイソシアナート誘導体（XI）が得られる。本反応に用いられる不活性溶媒としては、例えば、塩化メチレン、クロロホルム、１，２－ジクロロエタンなどが挙げられる。その反応温度は、通常、０℃～還流温度であり、反応時間は、使用する原料物質や溶媒、反応温度などにより異なるが、通常、１時間～２４時間である。 Step 1-1
The acyl isocyanate derivative (XI) is obtained by reacting the amide derivative (X) with oxalyl chloride in an inert solvent. Examples of the inert solvent used in this reaction include methylene chloride, chloroform, 1,2-dichloroethane and the like. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
工程１－２
　アシルイソシアナート誘導体（XI）を、不活性溶媒中、塩基の存在下または非存在下にアミン（XII）またはその塩と反応させることにより、アシルウレア誘導体（XIII）が得られる。本反応に用いられる不活性溶媒としては、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、テトラヒドロフラン、塩化メチレン、ジメチルスルホキシド、１，４－ジオキサン、１－メチル－２－ピロリドンおよびそれらの混合溶媒等が挙げられる。塩基としては、例えば、炭酸カリウム、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、Ｎ－メチルモルホリン、Ｎ，Ｎ－ジメチルアニリンなどが挙げられる。その反応温度は通常０℃～還流温度であり、反応時間は使用する原料物質や溶媒、反応温度等により異なるが、通常、１５分～２４時間である。 Step 1-2
The acyl urea derivative (XIII) is obtained by reacting the acyl isocyanate derivative (XI) with an amine (XII) or a salt thereof in an inert solvent in the presence or absence of a base. Examples of the inert solvent used in this reaction include acetonitrile, N, N-dimethylformamide, tetrahydrofuran, methylene chloride, dimethyl sulfoxide, 1,4-dioxane, 1-methyl-2-pyrrolidone, and mixed solvents thereof. . Examples of the base include potassium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, N-methylmorpholine, N, N-dimethylaniline and the like. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 15 minutes to 24 hours, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.
工程１－３
　アシルウレア誘導体（XIII）のベンジル基を、不活性溶媒（例えば、エタノール、Ｎ，Ｎ－ジメチルホルムアミド、テトラヒドロフランなど）中、水素雰囲気下、金属触媒（例えば、パラジウム炭素、酸化白金など）の存在下に除去することにより、フェノール誘導体（XIV）が得られる。その反応温度は、通常、室温～８０℃であり、反応時間は使用する原料物質や溶媒、反応温度等により異なるが、通常、３０分～１２時間である。
　また、この脱ベンジル化は、アシルウレア誘導体（XIII）を、不活性溶媒（例えば、塩化メチレン、トルエンなど）中、酸またはルイス酸（例えば、臭化水素、塩化アルミニウム、四塩化チタンなど）を用いて処理することによっても行うこともできる。その反応温度は、通常、０℃～８０℃であり、反応時間は使用する原料物質や溶媒、反応温度等により異なるが、通常１５分～２４時間である。 Step 1-3
The benzyl group of the acylurea derivative (XIII) is placed in an inert solvent (eg, ethanol, N, N-dimethylformamide, tetrahydrofuran, etc.) in a hydrogen atmosphere and in the presence of a metal catalyst (eg, palladium carbon, platinum oxide, etc.). Removal of the phenol derivative (XIV) is obtained. The reaction temperature is usually from room temperature to 80 ° C., and the reaction time is usually from 30 minutes to 12 hours, although it varies depending on the raw material used, solvent, reaction temperature, and the like.
This debenzylation is carried out by using acylurea derivative (XIII) with an acid or Lewis acid (eg, hydrogen bromide, aluminum chloride, titanium tetrachloride, etc.) in an inert solvent (eg, methylene chloride, toluene, etc.). It can also be done by processing. The reaction temperature is usually from 0 ° C. to 80 ° C., and the reaction time is usually from 15 minutes to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature, and the like.
工程１－４
　フェノール誘導体（XIV）を、不活性溶媒中、ニトロ化剤を用いニトロ化することにより、ニトロフェノール誘導体（XV）が得られる。本反応に用いられる不活性溶媒としては、例えば、塩化メチレン、１，２－ジクロロエタン、酢酸エチル、酢酸、テトラヒドロフランなどが挙げられる。ニトロ化剤としては、例えば、硝酸、発煙硝酸、テトラフルオロホウ酸ニトロニウムなどが挙げられる。その反応温度は、通常、－２０℃～８０℃であり、反応時間は、使用する原料物質や溶媒、反応温度などにより異なるが、通常、５分～１２時間である。また、本反応は、必要に応じて、硫酸などの添加剤を加えて行ってもよい。 Step 1-4
Nitrophenol derivative (XV) is obtained by nitrating phenol derivative (XIV) in an inert solvent using a nitrating agent. Examples of the inert solvent used in this reaction include methylene chloride, 1,2-dichloroethane, ethyl acetate, acetic acid, tetrahydrofuran and the like. Examples of the nitrating agent include nitric acid, fuming nitric acid, nitronium tetrafluoroborate, and the like. The reaction temperature is usually from −20 ° C. to 80 ° C., and the reaction time is usually from 5 minutes to 12 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like. Moreover, you may perform this reaction by adding additives, such as a sulfuric acid, as needed.
工程１－５
　ニトロフェノール誘導体（XV）を、不活性溶媒中、脱メチル化剤を用いて脱メチル化することにより、化合物（Ia）が得られる。本反応に用いられる不活性溶媒としては、例えば、酢酸エチル、ピリジン、１，４－ジオキサンなどが挙げられる。脱メチル化剤としては、例えば、塩化アルミニウム－ピリジンなどが挙げられる。その反応温度は、通常、２０℃～還流温度であり、反応時間は、使用する原料物質や溶媒、反応温度などにより異なるが、通常、１時間～２４時間である。 Step 1-5
The compound (Ia) can be obtained by demethylating the nitrophenol derivative (XV) in an inert solvent using a demethylating agent. Examples of the inert solvent used in this reaction include ethyl acetate, pyridine, 1,4-dioxane and the like. Examples of the demethylating agent include aluminum chloride-pyridine. The reaction temperature is usually from 20 ° C. to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature, and the like.
工程１－６
　化合物（Ia）を、アシル化剤を用いてアシル化することにより、化合物（Ib）が得られる。このようなアシル化は、当業者には周知であり、例えば、T.W.GreeneおよびP.G.H.Wuts,「Protective Groups in Organic Synthesis」第４版に記載された方法に従って行うことができる。 Step 1-6
Compound (Ib) is obtained by acylating compound (Ia) with an acylating agent. Such acylation is well known to those skilled in the art and can be performed, for example, according to the methods described in TWGreene and PGHWuts, “Protective Groups in Organic Synthesis”, 4th edition.
Figure JPOXMLDOC01-appb-C000006
 （式中、Ｒ３、Ｒ５、Ｒ６、Ｒ１０、ＭｅおよびＢｎは、前記と同義であり；Ｒ１１は、低級アルキル基、低級アルコキシ低級アルキル基またはアラルキル基を表す。）
Figure JPOXMLDOC01-appb-C000006
 (In the formula, R 3 , R 5 , R 6 , R 10 , Me and Bn are as defined above; R 11 represents a lower alkyl group, a lower alkoxy lower alkyl group or an aralkyl group.)
工程２－１
　カルボン酸（XVI）を、不活性溶媒中、縮合剤（例えば、ジシクロヘキシルカルボジイミド、１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩、シアノリン酸ジエチル、アジ化ジフェニルホスホリルなど）の存在下にアミン（XVII）と縮合させることにより、アミド誘導体（XVIII）が得られる。
　また、アミド誘導体（XVIII）は、カルボン酸（XVI）を常法に従ってその反応性誘導体（例えば、酸ハライド、酸無水物、混合酸無水物、ベンゾトリアゾール－１－イルエステル、４－ニトロフェニルエステル、２，５－ジオキサピロリジンエステルなど）に変換後、塩基の存在下または非存在下にアミン（XVII）またはその塩と縮合させることによっても得ることができる。この縮合反応に用いられる溶媒としては、例えば、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、テトラヒドロフラン、塩化メチレン、およびそれらの混合溶媒などが挙げられる。塩基としては、例えば、炭酸カリウム、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、Ｎ－メチルモルホリン、Ｎ，Ｎ－ジメチルアニリンなどが挙げられる。その反応温度は通常－２０℃～還流温度であり、反応時間は使用する原料物質や溶媒、反応温度等により異なるが、通常、１５分～２４時間である。 Step 2-1
Carboxylic acid (XVI) in an inert solvent in the presence of a condensing agent (eg, dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphoryl azide, etc.) Is condensed with amine (XVII) to give amide derivative (XVIII).
The amide derivative (XVIII) is a reactive derivative of the carboxylic acid (XVI) according to a conventional method (for example, acid halide, acid anhydride, mixed acid anhydride, benzotriazol-1-yl ester, 4-nitrophenyl ester). , 2,5-dioxapyrrolidine ester, etc.) and then condensed with amine (XVII) or a salt thereof in the presence or absence of a base. Examples of the solvent used in this condensation reaction include acetonitrile, N, N-dimethylformamide, tetrahydrofuran, methylene chloride, and mixed solvents thereof. Examples of the base include potassium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, N-methylmorpholine, N, N-dimethylaniline and the like. The reaction temperature is usually from −20 ° C. to the reflux temperature, and the reaction time is usually from 15 minutes to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
工程２－２
　アミド誘導体（XVIII）を、不活性溶媒中、塩基存在下，クロロトリメチルシランとトリホスゲンを用いてクロロカルボニル化することにより、クロロカルボニル誘導体（XIX）が得られる。本反応に用いられる不活性溶媒としては、例えば、塩化メチレン、クロロホルム、１，２－ジクロロエタンなどが挙げられる。塩基としては、例えば、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミンなどが挙げられる。その反応温度は、通常、０℃～還流温度であり、反応時間は、使用する原料物質や溶媒、反応温度などにより異なるが、通常、１時間～２４時間である。 Step 2-2
Chlorocarbonyl derivative (XIX) is obtained by chlorocarbonylating amide derivative (XVIII) with chlorotrimethylsilane and triphosgene in the presence of a base in an inert solvent. Examples of the inert solvent used in this reaction include methylene chloride, chloroform, 1,2-dichloroethane and the like. Examples of the base include triethylamine, N, N-diisopropylethylamine and the like. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
工程２－３
　クロロカルボニル誘導体（XIX）を、不活性溶媒中、塩基の存在下または非存在下にアミン（XII）またはその塩と縮合させることにより、アシルウレア誘導体（XX）が得られる。本反応に用いられる不活性溶媒としては、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、テトラヒドロフラン、塩化メチレン、ジメチルスルホキシド、１，４－ジオキサン、１－メチル－２－ピロリドンおよびそれらの混合溶媒などが挙げられる。塩基としては、例えば、炭酸カリウム、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、Ｎ－メチルモルホリン、Ｎ，Ｎ－ジメチルアニリンなどが挙げられる。その反応温度は通常０℃～還流温度であり、反応時間は使用する原料物質や溶媒、反応温度等により異なるが、通常、１５分～２４時間である。 Step 2-3
The acyl urea derivative (XX) is obtained by condensing the chlorocarbonyl derivative (XIX) with an amine (XII) or a salt thereof in an inert solvent in the presence or absence of a base. Examples of the inert solvent used in this reaction include acetonitrile, N, N-dimethylformamide, tetrahydrofuran, methylene chloride, dimethyl sulfoxide, 1,4-dioxane, 1-methyl-2-pyrrolidone, and mixed solvents thereof. . Examples of the base include potassium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, N-methylmorpholine, N, N-dimethylaniline and the like. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 15 minutes to 24 hours, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.
　以下、スキーム１の工程１－３～工程１－５と同様にして、アシルウレア誘導体（XX）から化合物（Ic）を合成することができ、工程１－６と同様にして化合物（Ic）から化合物（Id）を合成することができる。 Thereafter, compound (Ic) can be synthesized from acylurea derivative (XX) in the same manner as in steps 1-3 to 1-5 of Scheme 1, and compound from compound (Ic) in the same manner as in step 1-6. (Id) can be synthesized.
Figure JPOXMLDOC01-appb-C000007
 （式中、Ｒ５、Ｒ６、Ｒ１１、ＢｎおよびＭｅは、前記と同義であり；Ｌは、臭素原子あるいはヨウ素原子を表し、Ｒ１２は、低級アルコキシカルボニル基、またはシアノ基を表す。）
Figure JPOXMLDOC01-appb-C000007
 (In the formula, R 5 , R 6 , R 11 , Bn and Me are as defined above; L represents a bromine atom or an iodine atom, and R 12 represents a lower alkoxycarbonyl group or a cyano group. )
工程３－１
　アシルウレア誘導体（XXI）と、一酸化炭素／低級アルコール、またはシアノ化剤とを、不活性溶媒中、パラジウム触媒、配位子の存在下に縮合させることにより、アシルウレア誘導体（XXII）が得られる。本反応に用いられる不活性溶媒としては、例えば、１，４－ジオキサン、Ｎ，Ｎ－ジメチルホルムアミド、１，２－ジメトキシエタン、１－メチル－２－ピロリドンなどが挙げられる。塩基としては、例えば、フッ化セシウム、ナトリウムｔｅｒｔ－ブトキシド、カリウムｔｅｒｔ－ブトキシド、炭酸カリウム、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミンなどが挙げられる。シアノ化剤としては、例えば、シアン化第一銅、シアン化カリウムなどが挙げられる。触媒としては、例えば、トリス（ジベンジリデンアセトン）ジパラジウム（０）などが挙げられる。配位子としては、例えば、１，１’－ビス（ジフェニルホスフィノ）フェロセンなどが挙げられる。その反応温度は、通常、８０℃～１１０℃であり、反応時間は、使用する原料物質や溶媒、反応温度等により異なるが、通常１時間～２４時間である。また、本反応は、必要に応じて、シアン化テトラエチルアンモニウムなどの添加剤やトリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミンなどの塩基を加えて行ってもよい。 Step 3-1
The acyl urea derivative (XXII) is obtained by condensing the acyl urea derivative (XXI) with carbon monoxide / lower alcohol or cyanating agent in the presence of a palladium catalyst and a ligand in an inert solvent. Examples of the inert solvent used in this reaction include 1,4-dioxane, N, N-dimethylformamide, 1,2-dimethoxyethane, 1-methyl-2-pyrrolidone and the like. Examples of the base include cesium fluoride, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, triethylamine, N, N-diisopropylethylamine and the like. Examples of the cyanating agent include cuprous cyanide and potassium cyanide. Examples of the catalyst include tris (dibenzylideneacetone) dipalladium (0). Examples of the ligand include 1,1′-bis (diphenylphosphino) ferrocene. The reaction temperature is usually from 80 ° C. to 110 ° C., and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature, and the like. In addition, this reaction may be carried out by adding an additive such as tetraethylammonium cyanide and a base such as triethylamine or N, N-diisopropylethylamine as necessary.
　以下、スキーム１の工程１－３～工程１－５と同様にして、アシルウレア誘導体（XXII）から化合物（Ie）を合成することができる。 Hereinafter, compound (Ie) can be synthesized from acylurea derivative (XXII) in the same manner as in steps 1-3 to 1-5 of scheme 1.
Figure JPOXMLDOC01-appb-C000008
  （式中、Ｒ３、Ｒ４、Ｒ５、Ｒ６およびＭｅは、前記と同義であり；Ｒ１３は、低級アルキル基を表す。）
Figure JPOXMLDOC01-appb-C000008
 (Wherein R 3 , R 4 , R 5 , R 6 and Me are as defined above; R 13 represents a lower alkyl group.)
工程４－１
　ベンジルエーテル誘導体（XXIII）を、工程１－３と同様にして脱ベンジル化することにより、フェノール誘導体（XXIV）が得られる。 Step 4-1
The benzyl ether derivative (XXIII) is debenzylated in the same manner as in Step 1-3 to give the phenol derivative (XXIV).
工程４－２
　フェノール誘導体（XXIV）を、工程１－４と同様にしてニトロ化することにより、ニトロフェノール誘導体（XXV）が得られる。 Step 4-2
Nitrophenol derivative (XXV) is obtained by nitration of phenol derivative (XXIV) in the same manner as in Step 1-4.
工程４－３
　ニトロフェノール誘導体（XXV）を、不活性溶媒中、塩基の存在下メチル化剤を用いてメチル化することにより、エステル誘導体（XXVI）が得られる。本反応に用いられる不活性溶媒としては、例えば、Ｎ，Ｎ－ジメチルホルムアミド、アセトンなどが挙げられる。メチル化剤としては、例えば、ヨードメタン、硫酸ジメチル、トリフルオロメタンスルホン酸メチルなどが挙げられる。塩基としては、例えば、炭酸カリウム、炭酸水素ナトリウム、炭酸セシウム、Ｎ，Ｎ－ジイソプロピルエチルアミンなどが挙げられる。その反応温度は、通常、室温～１１０℃であり、反応時間は、使用する原料物質や溶媒、反応温度等により異なるが、通常１時間～７２時間である。 Step 4-3
The ester derivative (XXVI) is obtained by methylating the nitrophenol derivative (XXV) in an inert solvent using a methylating agent in the presence of a base. Examples of the inert solvent used in this reaction include N, N-dimethylformamide, acetone and the like. Examples of the methylating agent include iodomethane, dimethyl sulfate, methyl trifluoromethanesulfonate, and the like. Examples of the base include potassium carbonate, sodium hydrogen carbonate, cesium carbonate, N, N-diisopropylethylamine and the like. The reaction temperature is usually from room temperature to 110 ° C., and the reaction time is usually from 1 hour to 72 hours, although it varies depending on the raw materials and solvents used, the reaction temperature, and the like.
工程４－４
　エステル誘導体（XXVI）を適切な溶媒中、アルカリ加水分解することにより、カルボン酸誘導体（XXVII）が得られる。本反応に用いられる溶媒としては、例えば、メタノール、エタノール、水、テトラヒドロフラン、それらの混合溶媒などが挙げられ、塩基としては、例えば、水酸化ナトリウム、水酸化カリウムなどが挙げられる。その反応温度は通常、室温～還流温度であり、反応時間は使用する原料物質や溶媒、反応温度等により異なるが、通常１０分～２４時間である。 Step 4-4
Carboxylic acid derivative (XXVII) is obtained by alkaline hydrolysis of ester derivative (XXVI) in a suitable solvent. Examples of the solvent used in this reaction include methanol, ethanol, water, tetrahydrofuran, a mixed solvent thereof, and the like. Examples of the base include sodium hydroxide and potassium hydroxide. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 10 minutes to 24 hours, although it varies depending on the raw material and solvent used, the reaction temperature and the like.
工程４－５
　カルボン酸誘導体（XXVII）とアミン（XXVIII）とを、工程２－１と同様にして縮合することにより、アミド誘導体（XXIX）が得られる。 Step 4-5
The amide derivative (XXIX) is obtained by condensing the carboxylic acid derivative (XXVII) and the amine (XXVIII) in the same manner as in Step 2-1.
工程４－６
　アミド誘導体（XXIX）を、工程１－１および工程１－２、あるいは工程２－２および工程２－３と同様にしてウレア化することにより、アシルウレア誘導体（XXX）が得られる。 Step 4-6
The acylurea derivative (XXX) is obtained by urea-forming the amide derivative (XXIX) in the same manner as in Step 1-1 and Step 1-2 or Step 2-2 and Step 2-3.
工程４－７　
　アシルウレア誘導体（XXX）を、不活性溶媒中、脱メチル化剤を用いて脱メチル化することにより、ニトロフェノール誘導体（XXXI）が得られる。本反応に用いられる不活性溶媒としては、例えば、Ｎ，Ｎ－ジメチルホルムアミド、１，２－ジメトキシエタン、ジメチルスルホキシドなどが挙げられる。脱メチル化剤としては、例えば、塩化リチウム、シアン化ナトリウム、シアン化カリウムなどが挙げられる。その反応温度は、通常、８０℃～１５０℃であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常、１時間～２４時間である。 Step 4-7
The nitrophenol derivative (XXXI) is obtained by demethylating the acylurea derivative (XXX) using a demethylating agent in an inert solvent. Examples of the inert solvent used in this reaction include N, N-dimethylformamide, 1,2-dimethoxyethane, dimethyl sulfoxide and the like. Examples of the demethylating agent include lithium chloride, sodium cyanide, potassium cyanide and the like. The reaction temperature is usually from 80 ° C. to 150 ° C., and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
工程４－８
　ニトロフェノール誘導体（XXXI）を、工程１－５と同様にして脱メチル化することにより、化合物（If）が得られる。 Step 4-8
The compound (If) can be obtained by demethylating the nitrophenol derivative (XXXI) in the same manner as in Step 1-5.
工程４－９　
　アシルウレア誘導体（XXX）を、不活性溶媒中、脱メチル化剤を用いて脱メチル化することにより、化合物（If）が得られる。本反応に用いられる不活性溶媒としては、例えば、塩化メチレン、１，２－ジクロロエタンなどが挙げられる。脱メチル化剤としては、例えば、塩化アルミニウム、三臭化ホウ素などが挙げられる。その反応温度は、通常、０℃～還流温度であり、反応時間は、使用する原料物質や溶媒、反応温度などにより異なるが、通常、５分～２４時間である。 Step 4-9
The compound (If) is obtained by demethylating the acylurea derivative (XXX) in an inert solvent using a demethylating agent. Examples of the inert solvent used in this reaction include methylene chloride and 1,2-dichloroethane. Examples of the demethylating agent include aluminum chloride and boron tribromide. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 5 minutes to 24 hours, although it varies depending on the raw materials and solvents used, the reaction temperature, and the like.
　上記に示したスキームは、本発明の化合物またはその製造中間体を製造するための方法のいくつかの例示であり、当業者には容易に理解され得るようにこれらのスキームの様々な改変が可能である。 The schemes shown above are several examples of methods for preparing the compounds of the present invention or their intermediates, and various modifications of these schemes are possible as will be readily understood by those skilled in the art. It is.
　本発明の一般式（Ｉ）で表される化合物、および当該化合物を製造するために使用される中間体は、必要に応じて、当該分野の当業者には周知の単離・精製手段である溶媒抽出、結晶化、再結晶、クロマトグラフィー、高速液体クロマトグラフィーなどの操作を行うことにより、単離・精製することができる。 The compound represented by the general formula (I) of the present invention and the intermediate used for producing the compound are isolation / purification means well known to those skilled in the art, if necessary. It can be isolated and purified by performing operations such as solvent extraction, crystallization, recrystallization, chromatography, high performance liquid chromatography and the like.
　このようにして製造される本発明の化合物は、優れたＣＯＭＴ阻害作用を有するのでパーキンソン病の治療または予防薬として有用であり、好適にはＬ－ドパと組み合わせて使用される。また、本発明の化合物およびＬ－ドパと、芳香族Ｌ－アミノ酸デカルボキシラーゼ阻害剤とを組み合わせて使用してもよい。本発明のＣＯＭＴ阻害剤と組み合わせて使用できる芳香族Ｌ－アミノ酸デカルボキシラーゼ阻害剤としては、例えば、カルビドパ、ベンセラジドなどが挙げられる。
　また、必要に応じて、ＣＯＭＴ阻害剤およびＬ－ドパ以外のパーキンソン治療剤をさらに組み合わせて使用してもよい。このようなパーキンソン病治療薬としては、例えば、ドロキシドパ、メレボドパ、スレオドプス；ドパミンＤ２受容体アゴニスト（例えば、カベルゴリン、メシル酸ブロモクリプチン、テルグリド、塩酸タリペキソール、塩酸ロピニロール、メシル酸ペルゴリド、塩酸プラミペキソール、ロチゴチンなど）；抗コリン剤（例えば、プロフェナミン、塩酸トリヘキシフェニジル、塩酸マザチコール、ピペリデン、塩酸ピロヘプチン、塩酸メチキセンなど）；アデノシンＡ２Ａ拮抗剤（例えば、イストラデフィリンなど）；ＮＭＤＡ拮抗剤（例えば、ブジピンなど）；モノアミンオキシダーゼＢ阻害剤（例えば、塩酸セレギリン、メシル酸ラサギリン、メシル酸サフィナミドなど）；ゾニサミド；塩酸アマンタジンなどが挙げられる。 The compound of the present invention thus produced has an excellent COMT inhibitory action and thus is useful as a therapeutic or prophylactic agent for Parkinson's disease, and is preferably used in combination with L-dopa. Further, the compound of the present invention and L-dopa may be used in combination with an aromatic L-amino acid decarboxylase inhibitor. Examples of the aromatic L-amino acid decarboxylase inhibitor that can be used in combination with the COMT inhibitor of the present invention include carbidopa and benserazide.
Further, if necessary, a parkinson therapeutic agent other than the COMT inhibitor and L-dopa may be used in combination. Examples of such Parkinson's disease therapeutic agents include droxidopa, melevodopa, throdops; dopamine D 2 receptor agonists (eg cabergoline, bromocriptine mesylate, terguride, talipexol hydrochloride, ropinirole mesilate, pergolide mesylate, pramipexole hydrochloride, rotigotine, etc. ); Anticholinergic agents (eg, prophenamine, trihexyphenidyl hydrochloride, masaticol hydrochloride, piperidene, pyroheptin hydrochloride, methixene hydrochloride, etc.); adenosine A 2A antagonists (eg, istradefylline); NMDA antagonists (eg, Monodioxidase B inhibitors (for example, selegiline hydrochloride, rasagiline mesylate, safinamide mesylate, etc.); zonisamide; amantadine hydrochloride, etc.
　本発明の化合物は、また、うつ病の治療または予防薬として有用である。本発明の化合物は、また、尿中ナトリウム排泄促進作用を有するので高血圧症の治療薬として有用である。 The compound of the present invention is also useful as a therapeutic or prophylactic agent for depression. The compound of the present invention is also useful as a therapeutic agent for hypertension because it has an action of promoting urinary sodium excretion.
　本発明の一般式（Ｉ）で表される化合物またはその薬理学的に許容される塩を有効成分として含有する医薬組成物は、用法に応じ種々の剤型のものが使用される。このような剤型としては例えば、散剤、顆粒剤、細粒剤、ドライシロップ剤、錠剤、カプセル剤、注射剤、液剤、軟膏剤、坐剤、貼付剤などを挙げることができ、経口または非経口的に投与される。 The pharmaceutical composition containing the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is used in various dosage forms depending on the usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches and the like, orally or parenterally. Administered.
　これらの医薬組成物は、その剤型に応じ製剤学的に公知の手法により、適切な賦形剤、崩壊剤、結合剤、滑沢剤、希釈剤、緩衝剤、等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、溶解補助剤などの医薬品添加物と適宜混合または希釈・溶解することにより調剤することができる。 These pharmaceutical compositions are prepared according to pharmacologically known methods depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives. It can be prepared by mixing or diluting / dissolving appropriately with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents.
　一般式（Ｉ）で表される化合物またはその薬理学的に許容される塩の投与量は、患者の年齢、性別、体重、疾患および治療の程度等により適宜決定されるが、経口投与の場合成人１日当たり約１０ｍｇ～約３０００ｍｇの範囲で、非経口投与の場合は、成人１日当たり約５ｍｇ～約１０００ｍｇの範囲で、一回または数回に分けて適宜投与することができる。 The dose of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is appropriately determined depending on the age, sex, weight, disease, degree of treatment, etc. of the patient. In the case of parenteral administration in the range of about 10 mg to about 3000 mg per day for an adult, it can be appropriately administered once or divided into several times within the range of about 5 mg to about 1000 mg per day for an adult.
　本発明の一般式（Ｉ）で表される化合物またはその薬理学的に許容される塩と、Ｌ－ドパおよび芳香族Ｌ－アミノ酸デカルボキシラーゼ阻害剤から選択される少なくとも１種とを組み合わせてなる医薬は、これらの有効成分を一緒に含有する製剤、またはこれらの有効成分の各々を別々に製剤化した製剤として投与することができる。別々に製剤化した場合、それらの製剤を別々にまたは同時に投与することができる。また、別々に製剤化した場合、それらの製剤を使用時に希釈剤などを用いて混合し、同時に投与することができる。 A combination of the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof and at least one selected from L-dopa and aromatic L-amino acid decarboxylase inhibitors. The resulting medicament can be administered as a formulation containing these active ingredients together or as a formulation in which each of these active ingredients is formulated separately. When formulated separately, the formulations can be administered separately or simultaneously. Moreover, when it formulates separately, those formulations can be mixed using a diluent etc. at the time of use, and can be administered simultaneously.
　本発明の一般式（Ｉ）で表される化合物またはその薬理学的に許容される塩と、Ｌ－ドパおよび芳香族Ｌ－アミノ酸デカルボキシラーゼ阻害剤から選択される少なくとも１種とを組み合わせてなる医薬において、薬剤の配合比は、患者の年齢、性別、および体重、症状、投与時間、剤形、投与方法、薬剤の組み合わせなどにより、適宜選択することができる。 A combination of the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof and at least one selected from L-dopa and aromatic L-amino acid decarboxylase inhibitors. In such a medicament, the compounding ratio of the drugs can be appropriately selected depending on the age, sex and weight of the patient, symptoms, administration time, dosage form, administration method, combination of drugs, and the like.
　本発明の化合物は、強力なＣＯＭＴ阻害作用を有する。また、本発明の化合物は、肝への影響が軽微であり、高い安全性を有する。従って本発明の化合物は、パーキンソン病、うつ病、高血圧症の治療または予防剤として有用であり、特に本発明の化合物と、Ｌ－ドパとを組み合わせて使用することにより、Ｌ－ドパの生体内利用率を増加させることができるので、パーキンソン病の治療または予防に好適である。 The compound of the present invention has a strong COMT inhibitory action. In addition, the compound of the present invention has a slight effect on the liver and has high safety. Therefore, the compound of the present invention is useful as a therapeutic or prophylactic agent for Parkinson's disease, depression, and hypertension. In particular, by using the compound of the present invention in combination with L-dopa, Since the bioavailability can be increased, it is suitable for the treatment or prevention of Parkinson's disease.
　本発明の内容を以下の参考例、実施例および試験例でさらに詳細に説明するが、本発明はこれらの内容に限定されるものではない。 The contents of the present invention will be described in more detail with reference to the following reference examples, examples and test examples, but the present invention is not limited to these contents.
参考例１－１
５－ベンジルオキシ－２－クロロ－４－メトキシベンズアミド
　３－ベンジルオキシ－４－メトキシベンズアミド(1.73g)とＮ，Ｎ－ジメチルホルムアミド(40mL)の混合物にＮ－クロロこはく酸イミド(1.08g)を室温にて加え、その混合物を70℃にて3時間撹拌した。反応混合物に水を加え、室温で30分撹拌した。析出物を濾取して、表題化合物(1.09g)を得た。構造式を表１に示した。
１H-NMR（CDCl3）δ ppm：3.91 (3H, s), 5.16 (2H, s), 5.94 (1H, br s), 6.69 (1H, br s), 6.87 (1H, s), 7.20-7.50 (5H, m), 7.59 (1H, s)　 Reference Example 1-1
5-Benzyloxy-2-chloro-4-methoxybenzamide N-chlorosuccinimide (1.08 g) was added to a mixture of 3-benzyloxy-4-methoxybenzamide (1.73 g) and N, N-dimethylformamide (40 mL). At room temperature, the mixture was stirred at 70 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration to give the title compound (1.09 g). The structural formula is shown in Table 1.
1 H-NMR (CDCl 3 ) δ ppm: 3.91 (3H, s), 5.16 (2H, s), 5.94 (1H, br s), 6.69 (1H, br s), 6.87 (1H, s), 7.20- 7.50 (5H, m), 7.59 (1H, s)
　３－ベンジルオキシ－４－メトキシベンズアミドの代わりに３－ベンジルオキシ－４－メトキシベンズアルデヒドを用い、参考例１－１と同様の方法により、参考例１－２を合成した。これらを表１に示した。 Reference Example 1-2 was synthesized in the same manner as Reference Example 1-1 using 3-benzyloxy-4-methoxybenzaldehyde instead of 3-benzyloxy-4-methoxybenzamide. These are shown in Table 1.
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
　参考例１－２の物性値を以下に示した。 The physical property values of Reference Example 1-2 are shown below.
参考例１－２ 
１H-NMR（CDCl3）δ ppm：3.99 (3H, s), 5.15 (2H, s), 6.89 (1H, s), 7.25-7.55 (6H, m), 10.29 (1H, s) Reference Example 1-2
1 H-NMR (CDCl 3 ) δ ppm: 3.99 (3H, s), 5.15 (2H, s), 6.89 (1H, s), 7.25-7.55 (6H, m), 10.29 (1H, s)
参考例２－１ 
５－ベンジルオキシ－２－ヨード－４－メトキシベンズアルデヒド
　３－ベンジルオキシ－４－メトキシベンズアルデヒド(30.3g)の塩化メチレン(250mL)溶液に室温にてトリフルオロ酢酸銀(35.9g)を加え、ヨウ素(37.3g)を4℃にて加えた。その反応混合物を室温にて3時間撹拌した。反応混合物に亜硫酸水素ナトリウム水溶液を加え、不溶物をセライト（登録商標）にて濾別した。濾液から分離した有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水にて洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣にメタノールを加え、析出物を濾取して表題化合物(37.9g)を得た。構造式を表２に示した。
１H-NMR（CDCl3）δ ppm：3.95 (3H, s), 5.16 (2H, s), 7.25-7.50 (7H, m), 9.84 (1H, s) Reference Example 2-1
5-Benzyloxy-2-iodo-4-methoxybenzaldehyde To a solution of 3-benzyloxy-4-methoxybenzaldehyde (30.3 g) in methylene chloride (250 mL) was added silver trifluoroacetate (35.9 g) at room temperature, and iodine ( 37.3 g) was added at 4 ° C. The reaction mixture was stirred at room temperature for 3 hours. An aqueous sodium hydrogen sulfite solution was added to the reaction mixture, and insoluble matters were filtered off through Celite (registered trademark). The organic layer separated from the filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Methanol was added to the residue, and the precipitate was collected by filtration to give the title compound (37.9 g). The structural formula is shown in Table 2.
1 H-NMR (CDCl 3 ) δ ppm: 3.95 (3H, s), 5.16 (2H, s), 7.25-7.50 (7H, m), 9.84 (1H, s)
　３－ベンジルオキシ－４－メトキシベンズアルデヒドの代わりに３－ベンジルオキシ－４－メトキシ安息香酸メチルを用い、参考例２－１と同様の方法により、参考例２－２を合成した。構造式を表２に示した。 Reference Example 2-2 was synthesized in the same manner as Reference Example 2-1, using methyl 3-benzyloxy-4-methoxybenzoate instead of 3-benzyloxy-4-methoxybenzaldehyde. The structural formula is shown in Table 2.
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
　参考例２－２の物性値を以下に示した。 The physical property values of Reference Example 2-2 are shown below.
参考例２－２ 
１H-NMR（CDCl3）δ ppm：3.88 (3H, s), 3.91 (3H, s), 5.13 (2H, s), 7.30-7.45 (6H, m), 7.51 (1H, s) Reference Example 2-2
1 H-NMR (CDCl 3 ) δ ppm: 3.88 (3H, s), 3.91 (3H, s), 5.13 (2H, s), 7.30-7.45 (6H, m), 7.51 (1H, s)
参考例３－１ 
５－ベンジルオキシ－４－メトキシ－２－トリフルオロメチル安息香酸メチル
　５－ベンジルオキシ－２－ヨード－４－メトキシ安息香酸メチル（参考例２－２）(19.1g)のＮ，Ｎ－ジメチルホルムアミド(90mL)溶液に、フルオロスルホニルジフルオロ酢酸メチル(18.5mL)、ヨウ化銅(I)(3.25g)を加え、アルゴン雰囲気下85℃にて1晩撹拌した。反応混合物に塩化メチレン(200mL)を加え、不溶物を濾別した。濾液を水(50mL)/28%アンモニア水(20mL)、飽和炭酸水素ナトリウム水溶液、および飽和食塩水にて順次洗浄した。有機層を無水硫酸マグネシウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン/塩化メチレン＝19/1～1/1）にて精製し、粗生成物を得た。これにメタノールを加え、不溶物を濾取して表題化合物(8.80g)を得た。構造式を表３に示した。
１H-NMR（CDCl3）δ ppm：3.90 (3H, s), 3.95 (3H, s), 5.20 (2H, s), 7.20 (1H, s), 7.30-7.50 (6H, m) Reference Example 3-1
Methyl 5-benzyloxy-4-methoxy-2-trifluoromethylbenzoate N, N-dimethylformamide of methyl 5-benzyloxy-2-iodo-4-methoxybenzoate (Reference Example 2-2) (19.1 g) To the (90 mL) solution were added methyl fluorosulfonyldifluoroacetate (18.5 mL) and copper (I) iodide (3.25 g), and the mixture was stirred overnight at 85 ° C. under an argon atmosphere. Methylene chloride (200 mL) was added to the reaction mixture, and the insoluble material was filtered off. The filtrate was washed successively with water (50 mL) / 28% aqueous ammonia (20 mL), saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / methylene chloride = 19/1 to 1/1) to obtain a crude product. Methanol was added thereto, and the insoluble material was collected by filtration to obtain the title compound (8.80 g). The structural formula is shown in Table 3.
1 H-NMR (CDCl 3 ) δ ppm: 3.90 (3H, s), 3.95 (3H, s), 5.20 (2H, s), 7.20 (1H, s), 7.30-7.50 (6H, m)
　５－ベンジルオキシ－２－ヨード－４－メトキシ安息香酸メチルの代わりに５－ベンジルオキシ－２－ヨード－４－メトキシベンズアルデヒド（参考例２－１）を用い、参考例３－１と同様の方法により、参考例３－２を合成した。構造式を表３に示した。 The same method as Reference Example 3-1, except that 5-benzyloxy-2-iodo-4-methoxybenzaldehyde (Reference Example 2-1) was used instead of methyl 5-benzyloxy-2-iodo-4-methoxybenzoate Thus, Reference Example 3-2 was synthesized. The structural formula is shown in Table 3.
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
　参考例３－２の物性値を以下に示した。 The physical property values of Reference Example 3-2 are shown below.
参考例３－２ 
１H-NMR（CDCl3）δ ppm：4.00 (3H, s), 5.24 (2H, s), 7.19 (1H, s), 7.30-7.50 (5H, m), 7.69 (1H, s), 10.25 (1H, s)　 Reference Example 3-2
1 H-NMR (CDCl 3 ) δ ppm: 4.00 (3H, s), 5.24 (2H, s), 7.19 (1H, s), 7.30-7.50 (5H, m), 7.69 (1H, s), 10.25 ( 1H, s)
参考例４－１
５－ベンジルオキシ－４－メトキシ－２－トリフルオロメチル安息香酸
　1mol/L硫酸(80mL)、アセトニトリル(135mL)、ジメチルスルホキシド(24mL)および５－ベンジルオキシ－４－メトキシ－２－トリフルオロメチルベンズアルデヒド（参考例３－２）(21.0g)の混合物に、亜塩素酸ナトリウム(9.32g)の水(82ｍL)溶液を19℃以下で加え、室温にて1.5時間撹拌した。反応混合物に水を加え、氷冷下で15分間撹拌した。不溶物を濾取して表題化合物(20.7g)を得た。構造式を表４に示した。
１H-NMR（CDCl3）δ ppm：3.98 (3H, s), 5.22 (2H, s), 7.25 (1H, s), 7.30-7.50 (5H, m), 7.58 (1H, s) Reference Example 4-1
5-Benzyloxy-4-methoxy-2-trifluoromethylbenzoic acid 1 mol / L sulfuric acid (80 mL), acetonitrile (135 mL), dimethyl sulfoxide (24 mL) and 5-benzyloxy-4-methoxy-2-trifluoromethylbenzaldehyde (Reference Example 3-2) To a mixture of (21.0 g), a solution of sodium chlorite (9.32 g) in water (82 mL) was added at 19 ° C. or lower and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was stirred for 15 minutes under ice cooling. The insoluble material was collected by filtration to give the title compound (20.7 g). The structural formula is shown in Table 4.
1 H-NMR (CDCl 3 ) δ ppm: 3.98 (3H, s), 5.22 (2H, s), 7.25 (1H, s), 7.30-7.50 (5H, m), 7.58 (1H, s)
　５－ベンジルオキシ－４－メトキシ－２－トリフルオロメチルベンズアルデヒドの代わりに５－ベンジルオキシ－２－クロロ－４－メトキシベンズアルデヒド（参考例１－２）を用い、参考例４－１と同様の方法により、参考例４－２を合成した。構造式を表４に示した。 The same method as Reference Example 4-1, except that 5-benzyloxy-2-chloro-4-methoxybenzaldehyde (Reference Example 1-2) was used instead of 5-benzyloxy-4-methoxy-2-trifluoromethylbenzaldehyde. Thus, Reference Example 4-2 was synthesized. The structural formula is shown in Table 4.
参考例５－１
５－ベンジルオキシ－２－ヨード－４－メトキシ安息香酸
　５－ベンジルオキシ－４－メトキシ－２－ヨード安息香酸メチル（参考例２－２）(1.50g)のテトラヒドロフラン(10mL)/エタノール(6mL)溶液に5mol/L水酸化ナトリウム水溶液(3mL)を加え、60℃にて4.5時間撹拌した。反応液を室温に冷却し、5mol/L塩酸にて中和した。反応混合物に水を加え、不溶物を濾取して表題化合物(1.42g)を得た。構造式を表４に示した。
１H-NMR（CDCl3）δ ppm：3.93 (3H, s), 5.16 (2H, s), 7.30-7.50 (6H, m), 7.67 (1H, s)　 Reference Example 5-1
5-Benzyloxy-2-iodo-4-methoxybenzoic acid Methyl 5-benzyloxy-4-methoxy-2-iodobenzoate (Reference Example 2-2) (1.50 g) in tetrahydrofuran (10 mL) / ethanol (6 mL) A 5 mol / L aqueous sodium hydroxide solution (3 mL) was added to the solution, and the mixture was stirred at 60 ° C. for 4.5 hours. The reaction solution was cooled to room temperature and neutralized with 5 mol / L hydrochloric acid. Water was added to the reaction mixture, and the insoluble material was collected by filtration to give the title compound (1.42 g). The structural formula is shown in Table 4.
1 H-NMR (CDCl 3 ) δ ppm: 3.93 (3H, s), 5.16 (2H, s), 7.30-7.50 (6H, m), 7.67 (1H, s)
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
　参考例４－２の物性値を以下に示した。 The physical property values of Reference Example 4-2 are shown below.
参考例４－２ 
１H-NMR（CDCl3）δ ppm：3.93 (3H, s), 5.15 (2H, s), 6.95 (1H, s), 7.30-7.50 (5H, m), 7.62 (1H, s)　 Reference Example 4-2
1 H-NMR (CDCl 3 ) δ ppm: 3.93 (3H, s), 5.15 (2H, s), 6.95 (1H, s), 7.30-7.50 (5H, m), 7.62 (1H, s)
参考例６－１ 
　５－ベンジルオキシ－４－メトキシ－２－トリフルオロメチルベンズアミド５－ベンジルオキシ－４－メトキシ－２－トリフルオロメチル安息香酸（参考例４－１）(19.6g)のＮ，Ｎ－ジメチルホルムアミド(80mL)溶液に、５℃以下にて１－ヒドロキシベンゾトリアゾール一水和物(11.2g)、１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩（13.9g）を加え、室温にて１時間撹拌した。反応混合物に28%アンモニア水(80mL)を加え、室温にて１時間撹拌した。反応混合物に水を加え、析出物を濾取して表題化合物(17.7g)を得た。構造式を表５に示した。
１H-NMR（CDCl3）δ ppm：3.95 (3H, s), 5.20 (2H, s), 5.72 (2H, br s), 7.10-7.20 (2H, m), 7.30-7.50 (5H, m)　 Reference Example 6-1
5-benzyloxy-4-methoxy-2-trifluoromethylbenzamide 5-benzyloxy-4-methoxy-2-trifluoromethylbenzoic acid (Reference Example 4-1) (19.6 g) in N, N-dimethylformamide ( 80 mL) solution was added 1-hydroxybenzotriazole monohydrate (11.2 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (13.9 g) at 5 ° C. or less at room temperature. Stir for 1 hour. 28% aqueous ammonia (80 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the precipitate was collected by filtration to give the title compound (17.7 g). The structural formula is shown in Table 5.
1 H-NMR (CDCl 3 ) δ ppm: 3.95 (3H, s), 5.20 (2H, s), 5.72 (2H, br s), 7.10-7.20 (2H, m), 7.30-7.50 (5H, m)
　５－ベンジルオキシ－４－メトキシ－２－トリフルオロメチル安息香酸の代わりに対応するカルボン酸を用い、28%アンモニア水の代わりに対応するアミンを用い、参考例６－１と同様の方法により、参考例６－２～参考例６－９を合成した。構造式を表５に示した。 By using the corresponding carboxylic acid instead of 5-benzyloxy-4-methoxy-2-trifluoromethylbenzoic acid and using the corresponding amine instead of 28% aqueous ammonia, in the same manner as in Reference Example 6-1, Reference Examples 6-2 to 6-9 were synthesized. The structural formula is shown in Table 5.
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
　参考例６－２～参考例６－９の物性値を以下に示した。 The physical property values of Reference Example 6-2 to Reference Example 6-9 are shown below.
参考例６－２ 
１H-NMR（CDCl3）δ ppm：2.90-3.10 (3H, m), 3.93 (3H, s), 5.18 (2H, s), 5.70 (1H, br s), 7.00-7.20 (2H, m), 7.30-7.50 (5H, m) Reference Example 6-2
1 H-NMR (CDCl 3 ) δ ppm: 2.90-3.10 (3H, m), 3.93 (3H, s), 5.18 (2H, s), 5.70 (1H, br s), 7.00-7.20 (2H, m) , 7.30-7.50 (5H, m)
参考例６－３ 
１H-NMR（CDCl3）δ ppm：0.90-1.00 (3H, m), 1.55-1.70 (2H, m), 3.30-3.45 (2H, m), 3.93 (3H, s), 5.20 (2H, s), 5.71 (1H, br s), 7.07 (1H, br s), 7.11 (1H, br s), 7.30-7.50 (5H, m) Reference Example 6-3
1 H-NMR (CDCl 3 ) δ ppm: 0.90-1.00 (3H, m), 1.55-1.70 (2H, m), 3.30-3.45 (2H, m), 3.93 (3H, s), 5.20 (2H, s ), 5.71 (1H, br s), 7.07 (1H, br s), 7.11 (1H, br s), 7.30-7.50 (5H, m)
参考例６－４ 
１H-NMR（CDCl3）δ ppm：3.36 (3H, s), 3.50-3.70 (4H, m), 3.93 (3H, s), 5.18 (2H, s), 6.00-6.20 (1H, m), 7.08 (1H, s), 7.12 (1H, s), 7.20-7.55 (5H, m) Reference Example 6-4
1 H-NMR (CDCl 3 ) δ ppm: 3.36 (3H, s), 3.50-3.70 (4H, m), 3.93 (3H, s), 5.18 (2H, s), 6.00-6.20 (1H, m), 7.08 (1H, s), 7.12 (1H, s), 7.20-7.55 (5H, m)
参考例６－５ 
１H-NMR（CDCl3）δ ppm：1.80-1.95 (2H, m), 3.31 (3H, s), 3.45-3.60 (4H, m), 3.93 (3H, s), 5.17 (2H, s), 6.20-6.35 (1H, m), 7.08 (1H, s), 7.11 (1H, s), 7.25-7.50 (5H, m)　 Reference Example 6-5
1 H-NMR (CDCl 3 ) δ ppm: 1.80-1.95 (2H, m), 3.31 (3H, s), 3.45-3.60 (4H, m), 3.93 (3H, s), 5.17 (2H, s), 6.20-6.35 (1H, m), 7.08 (1H, s), 7.11 (1H, s), 7.25-7.50 (5H, m)
参考例６－６ 
１H-NMR（CDCl3）δ ppm：3.92 (3H, s), 4.55-4.65 (2H, m), 5.18 (2H, s), 5.94 (1H, br s), 7.08 (1H, br s), 7.11 (1H, br s), 7.25-7.45 (10H, m) Reference Example 6-6
1 H-NMR (CDCl 3 ) δ ppm: 3.92 (3H, s), 4.55-4.65 (2H, m), 5.18 (2H, s), 5.94 (1H, br s), 7.08 (1H, br s), 7.11 (1H, br s), 7.25-7.45 (10H, m)
参考例６－７ 
１H-NMR（CDCl3）δ ppm：1.65-1.80 (2H, m), 2.15 (6H, s), 2.35-2.45 (2H, m), 3.45-3.60 (2H, m), 3.93 (3H, s), 5.17 (2H, s), 7.05 (1H, s), 7.11 (2H, br s), 7.25-7.50 (5H, m)　 Reference Example 6-7
1 H-NMR (CDCl 3 ) δ ppm: 1.65-1.80 (2H, m), 2.15 (6H, s), 2.35-2.45 (2H, m), 3.45-3.60 (2H, m), 3.93 (3H, s ), 5.17 (2H, s), 7.05 (1H, s), 7.11 (2H, br s), 7.25-7.50 (5H, m)
参考例６－８ 
１H-NMR（CDCl3）δ ppm：3.01 (3H d, J=4.9Hz), 3.89 (3H, s), 5.14 (2H, s), 6.40-6.60 (1H, m), 6.84 (1H, s), 7.25-7.50 (6H, m)  Reference Example 6-8
1 H-NMR (CDCl 3 ) δ ppm: 3.01 (3H d, J = 4.9 Hz), 3.89 (3H, s), 5.14 (2H, s), 6.40-6.60 (1H, m), 6.84 (1H, s ), 7.25-7.50 (6H, m)
参考例６－９ 
１H-NMR（CDCl3）δ ppm：2.99 (3H, d, J=5.0Hz), 3.88 (3H, s), 5.11 (2H, s), 5.75 (1H, br s), 7.04 (1H, s), 7.24 (1H, s), 7.25-7.45 (5H, m) Reference Example 6-9
1 H-NMR (CDCl 3 ) δ ppm: 2.99 (3H, d, J = 5.0 Hz), 3.88 (3H, s), 5.11 (2H, s), 5.75 (1H, br s), 7.04 (1H, s ), 7.24 (1H, s), 7.25-7.45 (5H, m)
参考例７－１
１－（５－ベンジルオキシ－２－クロロ－４－メトキシベンゾイル）－３－シクロプロピルメチル尿素
　５－ベンジルオキシ－２－クロロ－４－メトキシベンズアミド（参考例１－１）(0.500g)の１，２－ジクロロエタン(9mL)溶液に室温にて塩化オキサリル(0.429mL)を加えた。1時間加熱還流後、反応混合物に塩化オキサリル(0.214mL)を加え、2時間加熱還流した。反応混合物を減圧濃縮して５－ベンジルオキシ－２－クロロ－４－メトキシベンゾイルイソシアナートを得た。
　得られた５－ベンジルオキシ－２－クロロ－４－メトキシベンゾイルイソシアナートの塩化メチレン(3.4mL)溶液に氷冷下シクロプロパンメチルアミン(0.446mL)を加え、室温にて1時間撹拌した。反応混合物を水にて洗浄し、有機層を減圧濃縮した。残渣にメタノールを加え、不溶物を濾取して表題化合物(0.334g)を得た。構造式を表６に示した。
１H-NMR（CDCl3）δ ppm：0.20-0.35 (2H, m), 0.50-0.60 (2H, m), 1.00-1.15 (1H, m), 3.15-3.30 (2H, m), 3.92 (3H, s), 5.15 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.40-8.60 (2H, m)　 Reference Example 7-1
1- (5-benzyloxy-2-chloro-4-methoxybenzoyl) -3-cyclopropylmethylurea 5-benzyloxy-2-chloro-4-methoxybenzamide (Reference Example 1-1) (0.500 g) Oxalyl chloride (0.429 mL) was added to a solution of 2-dichloroethane (9 mL) at room temperature. After heating to reflux for 1 hour, oxalyl chloride (0.214 mL) was added to the reaction mixture and heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure to give 5-benzyloxy-2-chloro-4-methoxybenzoyl isocyanate.
To a solution of the obtained 5-benzyloxy-2-chloro-4-methoxybenzoyl isocyanate in methylene chloride (3.4 mL) was added cyclopropanemethylamine (0.446 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water, and the organic layer was concentrated under reduced pressure. Methanol was added to the residue, and the insoluble material was collected by filtration to give the title compound (0.334 g). The structural formula is shown in Table 6.
1 H-NMR (CDCl 3 ) δ ppm: 0.20-0.35 (2H, m), 0.50-0.60 (2H, m), 1.00-1.15 (1H, m), 3.15-3.30 (2H, m), 3.92 (3H , s), 5.15 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.40-8.60 (2H, m)
　５－ベンジルオキシ－２－クロロ－４－メトキシベンズアミドの代わりに対応するアミドを用い、シクロプロパンメチルアミンの代わりに対応するアミンを用い、参考例７－１と同様の方法により、参考例７－２～参考例７－５６を合成した。これらを表６に示した。 Using the corresponding amide instead of 5-benzyloxy-2-chloro-4-methoxybenzamide and the corresponding amine instead of cyclopropanemethylamine, the same procedure as in Reference Example 7-1 was carried out to give Reference Example 7- 2 to Reference Examples 7-56 were synthesized. These are shown in Table 6.
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-I000015
Figure JPOXMLDOC01-appb-I000016
Figure JPOXMLDOC01-appb-I000017
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-I000015
Figure JPOXMLDOC01-appb-I000016
Figure JPOXMLDOC01-appb-I000017
　参考例７－２～参考例７－１５、および参考例７－１７～参考例７－５６の物性値を以下に示した。 Physical property values of Reference Example 7-2 to Reference Example 7-15 and Reference Example 7-17 to Reference Example 7-56 are shown below.
参考例７－２
１H-NMR（CDCl3）δ ppm：0.90-1.05 (3H, m), 1.55-1.70 (2H, m), 3.25-3.35 (2H, m), 3.92 (3H, s), 5.15 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.40-8.55 (1H, m), 8.62 (1H, br s) Reference Example 7-2
1 H-NMR (CDCl 3 ) δ ppm: 0.90-1.05 (3H, m), 1.55-1.70 (2H, m), 3.25-3.35 (2H, m), 3.92 (3H, s), 5.15 (2H, s ), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.40-8.55 (1H, m), 8.62 (1H, br s)
参考例７－３
１H-NMR（CDCl3）δ ppm：0.90-1.00 (3H, m), 1.30-1.65 (4H, m), 3.25-3.40 (2H, m), 3.92 (3H, s), 5.15 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.35-8.50 (1H, m), 8.59 (1H, br s) Reference Example 7-3
1 H-NMR (CDCl 3 ) δ ppm: 0.90-1.00 (3H, m), 1.30-1.65 (4H, m), 3.25-3.40 (2H, m), 3.92 (3H, s), 5.15 (2H, s ), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.35-8.50 (1H, m), 8.59 (1H, br s)
参考例７－４
１H-NMR（CDCl3）δ ppm：0.85-1.00 (3H, m), 1.25-1.45 (4H, m), 1.50-1.70 (2H, m), 3.25-3.40 (2H, m), 3.92 (3H, s), 5.15 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.35-8.60 (2H, m) Reference Example 7-4
1 H-NMR (CDCl 3 ) δ ppm: 0.85-1.00 (3H, m), 1.25-1.45 (4H, m), 1.50-1.70 (2H, m), 3.25-3.40 (2H, m), 3.92 (3H , s), 5.15 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.35-8.60 (2H, m)
参考例７－５
１H-NMR（CDCl3）δ ppm：1.20-1.30 (6H, m), 3.92 (3H, s), 3.95-4.15 (1H, m), 5.15 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.25-8.40 (1H, m), 8.54 (1H, s) Reference Example 7-5
1 H-NMR (CDCl 3 ) δ ppm: 1.20-1.30 (6H, m), 3.92 (3H, s), 3.95-4.15 (1H, m), 5.15 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.25-8.40 (1H, m), 8.54 (1H, s)
参考例７－６
１H-NMR（CDCl3）δ ppm：1.41 (9H, m), 3.91 (3H, s), 5.13 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.35-8.55 (2H, m) Reference Example 7-6
1 H-NMR (CDCl 3 ) δ ppm: 1.41 (9H, m), 3.91 (3H, s), 5.13 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.35- 8.55 (2H, m)
参考例７－７
１H-NMR（CDCl3）δ ppm：0.90-1.00 (3H, m), 1.50-1.65 (2H, m), 3.20-3.35 (2H, m), 3.96 (3H, s), 5.20 (2H, s), 7.09 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.27 (1H, br s), 8.30-8.40 (1H, m) Reference Example 7-7
1 H-NMR (CDCl 3 ) δ ppm: 0.90-1.00 (3H, m), 1.50-1.65 (2H, m), 3.20-3.35 (2H, m), 3.96 (3H, s), 5.20 (2H, s ), 7.09 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.27 (1H, br s), 8.30-8.40 (1H, m)
参考例７－８
１H-NMR（CDCl3）δ ppm：0.85-1.00 (3H, m), 1.30-1.60 (4H, m), 3.20-3.35 (2H, m), 3.96 (3H, s), 5.21 (2H, s), 7.10 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.25-8.40 (1H, m), 8.50 (1H, br s) Reference Example 7-8
1 H-NMR (CDCl 3 ) δ ppm: 0.85-1.00 (3H, m), 1.30-1.60 (4H, m), 3.20-3.35 (2H, m), 3.96 (3H, s), 5.21 (2H, s ), 7.10 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.25-8.40 (1H, m), 8.50 (1H, br s)
参考例７－９
１H-NMR（CDCl3）δ ppm：0.80-1.00 (3H, m), 1.20-1.40 (4H, m), 1.50-1.65 (2H, m), 3.20-3.35 (2H, m), 3.96 (3H, s), 5.21 (2H, s), 7.10 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.25-8.40 (1H, m), 8.49 (1H, br s) Reference Example 7-9
1 H-NMR (CDCl 3 ) δ ppm: 0.80-1.00 (3H, m), 1.20-1.40 (4H, m), 1.50-1.65 (2H, m), 3.20-3.35 (2H, m), 3.96 (3H , s), 5.21 (2H, s), 7.10 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.25-8.40 (1H, m), 8.49 (1H, br s)
参考例７－１０
１H-NMR（CDCl3）δ ppm：0.80-0.95 (3H, m), 1.20-1.40 (6H, m), 1.50-1.60 (2H, m), 3.25-3.35 (2H, m), 3.96 (3H, s), 5.21 (2H, s), 7.09 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.25-8.40 (2H, m) Reference Example 7-10
1 H-NMR (CDCl 3 ) δ ppm: 0.80-0.95 (3H, m), 1.20-1.40 (6H, m), 1.50-1.60 (2H, m), 3.25-3.35 (2H, m), 3.96 (3H , s), 5.21 (2H, s), 7.09 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.25-8.40 (2H, m)
参考例７－１１
１H-NMR（CDCl3）δ ppm：0.85-0.95 (3H, m), 1.20-1.40 (8H, m), 1.50-1.60 (2H, m),  3.96 (3H, s), 5.21 (2H, s), 7.10 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.30-8.40 (1H, m), 8.43 (1H, br s) Reference Example 7-11
1 H-NMR (CDCl 3 ) δ ppm: 0.85-0.95 (3H, m), 1.20-1.40 (8H, m), 1.50-1.60 (2H, m), 3.96 (3H, s), 5.21 (2H, s ), 7.10 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.30-8.40 (1H, m), 8.43 (1H, br s)
参考例７－１２
１H-NMR（CDCl3）δ ppm：1.15-1.25 (6H, m), 3.90-4.00 (4H, m), 5.21 (2H, s), 7.11 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.15-8.30 (1H, m), 8.66 (1H, s) Reference Example 7-12
1 H-NMR (CDCl 3 ) δ ppm: 1.15-1.25 (6H, m), 3.90-4.00 (4H, m), 5.21 (2H, s), 7.11 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.15-8.30 (1H, m), 8.66 (1H, s)
参考例７－１３
１H-NMR（CDCl3）δ ppm：0.90-1.00 (6H, m), 1.75-1.90 (1H, m), 3.05-3.15 (2H, m), 3.96 (3H, s), 5.21 (2H, s), 7.10 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.35-8.50 (2H, m) Reference Example 7-13
1 H-NMR (CDCl 3 ) δ ppm: 0.90-1.00 (6H, m), 1.75-1.90 (1H, m), 3.05-3.15 (2H, m), 3.96 (3H, s), 5.21 (2H, s ), 7.10 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.35-8.50 (2H, m)
参考例７－１４
１H-NMR（CDCl3）δ ppm：1.39 (9H, s), 3.95 (3H, s), 5.18 (2H, s), 7.06 (1H, s), 7.17 (1H, s), 7.33-7.44 (5H, m), 7.93 (1H, s), 8.26 (1H, s)　 Reference Example 7-14
1 H-NMR (CDCl 3 ) δ ppm: 1.39 (9H, s), 3.95 (3H, s), 5.18 (2H, s), 7.06 (1H, s), 7.17 (1H, s), 7.33-7.44 ( 5H, m), 7.93 (1H, s), 8.26 (1H, s)
参考例７－１５
１H-NMR（CDCl3）δ ppm：0.85-1.00 (6H, m), 1.55-1.75 (4H, m), 3.20-3.40 (4H, m), 3.90 (3H, s), 5.13 (2H, s), 6.85 (1H, s), 7.25-7.50 (6H, m), 7.94 (1H, br s) Reference Example 7-15
1 H-NMR (CDCl 3 ) δ ppm: 0.85-1.00 (6H, m), 1.55-1.75 (4H, m), 3.20-3.40 (4H, m), 3.90 (3H, s), 5.13 (2H, s ), 6.85 (1H, s), 7.25-7.50 (6H, m), 7.94 (1H, br s)
参考例７－１７
１H-NMR（CDCl3）δ ppm：1.18 (6H, t, J=7.1Hz), 3.33 (4H, q, J=7.1Hz), 3.92 (3H, s), 5.16 (2H, s), 7.01 (1H, s), 7.10 (1H, s), 7.25-7.45 (5H, m), 7.76 (1H, br s)　 Reference Example 7-17
1 H-NMR (CDCl 3 ) δ ppm: 1.18 (6H, t, J = 7.1 Hz), 3.33 (4H, q, J = 7.1 Hz), 3.92 (3H, s), 5.16 (2H, s), 7.01 (1H, s), 7.10 (1H, s), 7.25-7.45 (5H, m), 7.76 (1H, br s)
参考例７－１８
１H-NMR（CDCl3）δ ppm：0.92 (3H, t, J=7.4Hz), 1.50-1.70 (2H, m), 2.99 (3H, s), 3.20-3.40 (2H, m), 3.94 (3H, s), 5.17 (2H, s), 7.05 (1H, s), 7.12 (1H, s), 7.25-7.50 (6H, m)　 Reference Example 7-18
1 H-NMR (CDCl 3 ) δ ppm: 0.92 (3H, t, J = 7.4 Hz), 1.50-1.70 (2H, m), 2.99 (3H, s), 3.20-3.40 (2H, m), 3.94 ( 3H, s), 5.17 (2H, s), 7.05 (1H, s), 7.12 (1H, s), 7.25-7.50 (6H, m)
参考例７－１９
１H-NMR（CDCl3）δ ppm：0.85-0.95 (6H, m), 1.50-1.70 (4H, m), 3.15-3.30 (4H, m), 3.92 (3H, s), 5.15 (2H, s), 7.00 (1H, s), 7.10 (1H, s), 7.25-7.45 (5H, m), 7.75 (1H, br s) Reference Example 7-19
1 H-NMR (CDCl 3 ) δ ppm: 0.85-0.95 (6H, m), 1.50-1.70 (4H, m), 3.15-3.30 (4H, m), 3.92 (3H, s), 5.15 (2H, s ), 7.00 (1H, s), 7.10 (1H, s), 7.25-7.45 (5H, m), 7.75 (1H, br s)
参考例７－２０
１H-NMR（CDCl3）δ ppm：0.90-1.00 (6H, m), 1.25-1.45 (4H, m), 1.50-1.65 (4H, m), 3.20-3.30 (4H, m), 3.93 (3H, s), 5.16 (2H, s), 7.01 (1H, s), 7.11 (1H, s), 7.30-7.45 (5H, m) Reference Example 7-20
1 H-NMR (CDCl 3 ) δ ppm: 0.90-1.00 (6H, m), 1.25-1.45 (4H, m), 1.50-1.65 (4H, m), 3.20-3.30 (4H, m), 3.93 (3H , s), 5.16 (2H, s), 7.01 (1H, s), 7.11 (1H, s), 7.30-7.45 (5H, m)
参考例７－２１
１H-NMR（CDCl3）δ ppm：1.20-1.35 (12H, m), 3.75-3.90 (2H, m), 3.92 (3H, s), 5.16 (2H, s), 7.07 (1H, s), 7.11 (1H, s), 7.25-7.45 (5H, m), 7.60 (1H, br s) Reference Example 7-21
1 H-NMR (CDCl 3 ) δ ppm: 1.20-1.35 (12H, m), 3.75-3.90 (2H, m), 3.92 (3H, s), 5.16 (2H, s), 7.07 (1H, s), 7.11 (1H, s), 7.25-7.45 (5H, m), 7.60 (1H, br s)
参考例７－２２
１H-NMR（CDCl3）δ ppm：0.60-0.70 (2H, m), 0.75-0.85 (2H, m), 2.70-2.85 (1H, m), 3.92 (3H, s), 5.14 (2H, s), 6.89 (1H, s), 7.20-7.50 (6H, m), 8.25-8.40 (1H, m), 8.40-8.55 (1H, m)　 Reference Example 7-22
1 H-NMR (CDCl 3 ) δ ppm: 0.60-0.70 (2H, m), 0.75-0.85 (2H, m), 2.70-2.85 (1H, m), 3.92 (3H, s), 5.14 (2H, s ), 6.89 (1H, s), 7.20-7.50 (6H, m), 8.25-8.40 (1H, m), 8.40-8.55 (1H, m)
参考例７－２３
１H-NMR（CDCl3）δ ppm：1.15-2.05 (10H, m), 3.70-3.85 (1H, m), 3.92 (3H, s), 5.14 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m) Reference Example 7-23
1 H-NMR (CDCl 3 ) δ ppm: 1.15-2.05 (10H, m), 3.70-3.85 (1H, m), 3.92 (3H, s), 5.14 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m)
参考例７－２４
１H-NMR（CDCl3）δ ppm：1.40-1.80 (10H, m), 1.90-2.10 (2H, m), 3.85-4.05 (4H, m), 5.14 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.35-8.50 (2H, m) Reference Example 7-24
1 H-NMR (CDCl 3 ) δ ppm: 1.40-1.80 (10H, m), 1.90-2.10 (2H, m), 3.85-4.05 (4H, m), 5.14 (2H, s), 6.89 (1H, s ), 7.30-7.50 (6H, m), 8.35-8.50 (2H, m)
参考例７－２５
１H-NMR（CDCl3）δ ppm：1.65-1.75 (6H, m), 2.00-2.15 (9H, m), 3.91 (3H, s), 5.13 (2H, s), 6.88 (1H, s), 7.30-7.50 (6H, m), 8.34 (1H, br s), 8.39 (1H, br s) Reference Example 7-25
1 H-NMR (CDCl 3 ) δ ppm: 1.65-1.75 (6H, m), 2.00-2.15 (9H, m), 3.91 (3H, s), 5.13 (2H, s), 6.88 (1H, s), 7.30-7.50 (6H, m), 8.34 (1H, br s), 8.39 (1H, br s)
参考例７－２６
１H-NMR（CDCl3）δ ppm：0.60-0.70 (2H, m), 0.75-0.85 (2H, m), 2.70-2.80 (1H, m), 3.96 (3H, s), 5.20 (2H, s), 7.05 (1H, s), 7.17 (1H, s), 7.30-7.50 (5H, m), 7.92 (1H, br s), 8.35 (1H, br s) Reference Example 7-26
1 H-NMR (CDCl 3 ) δ ppm: 0.60-0.70 (2H, m), 0.75-0.85 (2H, m), 2.70-2.80 (1H, m), 3.96 (3H, s), 5.20 (2H, s ), 7.05 (1H, s), 7.17 (1H, s), 7.30-7.50 (5H, m), 7.92 (1H, br s), 8.35 (1H, br s)
参考例７－２７
１H-NMR（CDCl3）δ ppm：1.40-1.80 (6H, m), 1.85-2.00 (2H, m),  3.96 (3H, s), 4.05-4.15 (1H, m), 5.21 (2H, s), 7.11 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.25-8.40 (1H, m), 8.60 (1H, br s) Reference Example 7-27
1 H-NMR (CDCl 3 ) δ ppm: 1.40-1.80 (6H, m), 1.85-2.00 (2H, m), 3.96 (3H, s), 4.05-4.15 (1H, m), 5.21 (2H, s ), 7.11 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.25-8.40 (1H, m), 8.60 (1H, br s)
参考例７－２８
１H-NMR（CDCl3）δ ppm：1.15-1.45 (5H, m), 1.55-1.65 (1H, m), 1.70-1.80 (2H, m), 1.95-2.00 (2H, m), 3.70-3.80 (1H, m), 3.96 (3H, s), 5.19 (2H, s), 7.06 (1H, s), 7.17 (1H, s), 7.30-7.45 (5H, m), 7.72 (1H, br s), 8.20-8.25 (1H, m) Reference Example 7-28
1 H-NMR (CDCl 3 ) δ ppm: 1.15-1.45 (5H, m), 1.55-1.65 (1H, m), 1.70-1.80 (2H, m), 1.95-2.00 (2H, m), 3.70-3.80 (1H, m), 3.96 (3H, s), 5.19 (2H, s), 7.06 (1H, s), 7.17 (1H, s), 7.30-7.45 (5H, m), 7.72 (1H, br s) , 8.20-8.25 (1H, m)
参考例７－２９
１H-NMR（CDCl3）δ ppm：1.00-1.90 (10H, m), 2.87 (3H, s), 3.90-4.00 (4H, m), 5.17 (2H, s), 7.05 (1H, s), 7.12 (1H, s), 7.25-7.50 (5H, m) Reference Example 7-29
1 H-NMR (CDCl 3 ) δ ppm: 1.00-1.90 (10H, m), 2.87 (3H, s), 3.90-4.00 (4H, m), 5.17 (2H, s), 7.05 (1H, s), 7.12 (1H, s), 7.25-7.50 (5H, m)
参考例７－３０
１H-NMR（CDCl3）δ ppm：1.40-1.70 (10H, m), 1.85-2.00 (2H, m), 3.80-3.95 (1H, m), 3.96 (3H, s), 5.20 (2H, s), 7.09 (1H, s), 7.17 (1H, s), 7.30-7.50 (5H, m), 8.25-8.45 (2H, m) Reference Example 7-30
1 H-NMR (CDCl 3 ) δ ppm: 1.40-1.70 (10H, m), 1.85-2.00 (2H, m), 3.80-3.95 (1H, m), 3.96 (3H, s), 5.20 (2H, s ), 7.09 (1H, s), 7.17 (1H, s), 7.30-7.50 (5H, m), 8.25-8.45 (2H, m)
参考例７－３１
１H-NMR（CDCl3）δ ppm：0.85-1.45 (8H, m), 1.65-1.80 (2H, m), 1.95-2.10 (2H, m), 3.50-3.70 (1H, m), 3.96 (3H, s), 5.20 (2H, s), 7.07 (1H, s), 7.17 (1H, s), 7.30-7.50 (5H, m), 8.00-8.20 (2H, m) Reference Example 7-31
1 H-NMR (CDCl 3 ) δ ppm: 0.85-1.45 (8H, m), 1.65-1.80 (2H, m), 1.95-2.10 (2H, m), 3.50-3.70 (1H, m), 3.96 (3H , s), 5.20 (2H, s), 7.07 (1H, s), 7.17 (1H, s), 7.30-7.50 (5H, m), 8.00-8.20 (2H, m)
参考例７－３２
１H-NMR（CDCl3）δ ppm：1.68 (6H, t, J=2.8Hz), 2.03 (6H, d, J=2.8Hz), 2.08 (3H, br s), 3.95 (3H, s), 5.18 (2H, s), 7.06 (1H, s), 7.16 (1H, s), 7.30-7.45 (5H, m), 7.98 (1H, s), 8.16 (1H, s)　 Reference Example 7-32
1 H-NMR (CDCl 3 ) δ ppm: 1.68 (6H, t, J = 2.8 Hz), 2.03 (6H, d, J = 2.8 Hz), 2.08 (3H, br s), 3.95 (3H, s), 5.18 (2H, s), 7.06 (1H, s), 7.16 (1H, s), 7.30-7.45 (5H, m), 7.98 (1H, s), 8.16 (1H, s)
参考例７－３３
１H-NMR（CDCl3）δ ppm：0.75-0.90 (2H, m), 0.90-1.00 (2H, m), 2.60-2.70 (1H, m), 2.88 (3H, s), 3.93 (3H, s), 5.17 (2H, s), 6.94 (1H, s), 7.11 (1H, s), 7.25-7.50 (5H, m), 8.31 (1H, br s)　 Reference Example 7-33
1 H-NMR (CDCl 3 ) δ ppm: 0.75-0.90 (2H, m), 0.90-1.00 (2H, m), 2.60-2.70 (1H, m), 2.88 (3H, s), 3.93 (3H, s ), 5.17 (2H, s), 6.94 (1H, s), 7.11 (1H, s), 7.25-7.50 (5H, m), 8.31 (1H, br s)
参考例７－３４
１H-NMR（CDCl3）δ ppm：1.05-1.85 (16H, m), 3.40-3.50 (1H, m), 3.75-3.85 (1H, m), 3.93 (3H, s), 5.16 (2H, s), 7.06 (1H, s), 7.11 (1H, s), 7.30-7.45 (6H, m) Reference Example 7-34
1 H-NMR (CDCl 3 ) δ ppm: 1.05-1.85 (16H, m), 3.40-3.50 (1H, m), 3.75-3.85 (1H, m), 3.93 (3H, s), 5.16 (2H, s ), 7.06 (1H, s), 7.11 (1H, s), 7.30-7.45 (6H, m)
参考例７－３５
１H-NMR（CDCl3）δ ppm：0.15-0.25 (2H, m), 0.45-0.60 (2H, m), 0.90-1.10 (1H, m), 3.10-3.20 (2H, m), 3.96 (3H, s), 5.21 (2H, s), 7.11 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.35-8.50 (2H, m) Reference Example 7-35
1 H-NMR (CDCl 3 ) δ ppm: 0.15-0.25 (2H, m), 0.45-0.60 (2H, m), 0.90-1.10 (1H, m), 3.10-3.20 (2H, m), 3.96 (3H , s), 5.21 (2H, s), 7.11 (1H, s), 7.18 (1H, s), 7.30-7.50 (5H, m), 8.35-8.50 (2H, m)
参考例７－３６
１H-NMR（CDCl3）δ ppm：1.55-1.70 (2H, m), 1.95-2.00 (2H, m), 3.45-3.55 (2H, m), 3.90-4.00 (6H, m), 5.19 (2H, s), 7.07 (1H, s), 7.18 (1H, s), 7.30-7.45 (5H, m), 7.79 (1H, s), 8.29 (1H, d, J=7.8Hz)　 Reference Example 7-36
1 H-NMR (CDCl 3 ) δ ppm: 1.55-1.70 (2H, m), 1.95-2.00 (2H, m), 3.45-3.55 (2H, m), 3.90-4.00 (6H, m), 5.19 (2H , s), 7.07 (1H, s), 7.18 (1H, s), 7.30-7.45 (5H, m), 7.79 (1H, s), 8.29 (1H, d, J = 7.8Hz)
参考例７－３７
１H-NMR（DMSO-d６）δ ppm：1.19 (3H, t, J=7.0Hz), 1.35-1.50 (2H, m), 1.80-1.90 (2H, m), 2.90-3.00 (2H, m), 3.75-3.90 (3H, m), 3.88 (3H, s), 4.03 (2H, q, J=7.0Hz), 5.20 (2H, s), 7.28 (1H, s), 7.35-7.50 (6H, m), 8.30-8.35 (1H, m), 10.87 (1H, br s) Reference Example 7-37
1 H-NMR (DMSO-d 6 ) δ ppm: 1.19 (3H, t, J = 7.0 Hz), 1.35-1.50 (2H, m), 1.80-1.90 (2H, m), 2.90-3.00 (2H, m ), 3.75-3.90 (3H, m), 3.88 (3H, s), 4.03 (2H, q, J = 7.0Hz), 5.20 (2H, s), 7.28 (1H, s), 7.35-7.50 (6H, m), 8.30-8.35 (1H, m), 10.87 (1H, br s)
参考例７－３８
１H-NMR（CDCl3）δ ppm：3.85-4.10 (5H, m), 5.16 (2H, s), 6.90 (1H, s), 7.30-7.50 (6H, m), 8.63 (1H, br s),  8.85-9.00 (1H, m) Reference Example 7-38
1 H-NMR (CDCl 3 ) δ ppm: 3.85-4.10 (5H, m), 5.16 (2H, s), 6.90 (1H, s), 7.30-7.50 (6H, m), 8.63 (1H, br s) , 8.85-9.00 (1H, m)
参考例７－３９
１H-NMR（CDCl3）δ ppm：3.98 (3H, s), 5.19 (2H, s), 7.10-7.15 (2H, m), 7.21 (1H, s), 7.30-7.40 (7H, m), 7.50-7.55 (2H, m), 8.43 (1H, s), 10.41 (1H, s) Reference Example 7-39
1 H-NMR (CDCl 3 ) δ ppm: 3.98 (3H, s), 5.19 (2H, s), 7.10-7.15 (2H, m), 7.21 (1H, s), 7.30-7.40 (7H, m), 7.50-7.55 (2H, m), 8.43 (1H, s), 10.41 (1H, s)
参考例７－４０
１H-NMR（CDCl3）δ ppm：3.98 (3H, s), 5.16 (2H, s), 7.15-7.25 (3H, m), 7.35-7.45 (7H, m), 8.36 (1H, br s), 10.05 (1H, br s) Reference Example 7-40
1 H-NMR (CDCl 3 ) δ ppm: 3.98 (3H, s), 5.16 (2H, s), 7.15-7.25 (3H, m), 7.35-7.45 (7H, m), 8.36 (1H, br s) , 10.05 (1H, br s)
参考例７－４１
１H-NMR（CDCl3）δ ppm：2.28 (6H, s), 3.98 (3H, s), 5.13 (2H, s), 7.05-7.15 (4H, m), 7.20 (1H, s), 7.30-7.45 (5H, m), 8.35 (1H, br s), 9.73 (1H, br s) Reference Example 7-41
1 H-NMR (CDCl 3 ) δ ppm: 2.28 (6H, s), 3.98 (3H, s), 5.13 (2H, s), 7.05-7.15 (4H, m), 7.20 (1H, s), 7.30- 7.45 (5H, m), 8.35 (1H, br s), 9.73 (1H, br s)
参考例７－４２
１H-NMR（CDCl3）δ ppm：1.44 (9H, s), 3.98 (3H, s), 5.16 (2H, s), 7.14 (1H, s), 7.15-7.25 (3H, m), 7.30-7.45 (6H, m), 7.50-7.55 (1H, m), 8.33 (1H, br s), 10.19 (1H, br s)　 Reference Example 7-42
1 H-NMR (CDCl 3 ) δ ppm: 1.44 (9H, s), 3.98 (3H, s), 5.16 (2H, s), 7.14 (1H, s), 7.15-7.25 (3H, m), 7.30- 7.45 (6H, m), 7.50-7.55 (1H, m), 8.33 (1H, br s), 10.19 (1H, br s)
参考例７－４３
１H-NMR（CDCl3）δ ppm：3.98 (3H, s), 3.99 (3H, s), 5.19 (2H, s), 7.10-7.20 (3H, m), 7.30-7.45 (5H, m), 7.50-7.55 (1H, m), 8.05-8.10 (1H, m), 8.17 (1H, br s), 8.45-8.50 (1H, m), 12.30 (1H, br s) Reference Example 7-43
1 H-NMR (CDCl 3 ) δ ppm: 3.98 (3H, s), 3.99 (3H, s), 5.19 (2H, s), 7.10-7.20 (3H, m), 7.30-7.45 (5H, m), 7.50-7.55 (1H, m), 8.05-8.10 (1H, m), 8.17 (1H, br s), 8.45-8.50 (1H, m), 12.30 (1H, br s)
参考例７－４４
１H-NMR（CDCl3）δ ppm：3.22 (3H, s), 3.93 (3H, s), 5.16 (2H, s), 6.89 (1H, s), 7.10 (1H, s), 7.20-7.30 (1H, m), 7.30-7.45 (7H, m), 7.45-7.50 (2H, m)　 Reference Example 7-44
1 H-NMR (CDCl 3 ) δ ppm: 3.22 (3H, s), 3.93 (3H, s), 5.16 (2H, s), 6.89 (1H, s), 7.10 (1H, s), 7.20-7.30 ( 1H, m), 7.30-7.45 (7H, m), 7.45-7.50 (2H, m)
参考例７－４５
１H-NMR（CDCl3）δ ppm：2.39 (3H, d, J=0.6Hz), 3.98 (3H, s), 5.20 (2H, s), 6.50 (1H, d, J=0.6Hz), 7.11 (1H, s), 7.20 (1H, s), 7.30-7.45 (5H, m), 8.25 (1H, s), 10.76 (1H, s)　 Reference Example 7-45
1 H-NMR (CDCl 3 ) δ ppm: 2.39 (3H, d, J = 0.6 Hz), 3.98 (3H, s), 5.20 (2H, s), 6.50 (1H, d, J = 0.6 Hz), 7.11 (1H, s), 7.20 (1H, s), 7.30-7.45 (5H, m), 8.25 (1H, s), 10.76 (1H, s)
参考例７－４６
１H-NMR（CDCl3）δ ppm：3.95 (3H, s), 4.52 (2H, d, J=5.8Hz), 5.19 (2H, s), 7.08 (1H, s), 7.18 (1H, s), 7.25-7.45 (10H, m), 8.13 (1H, s), 8.68 (1H, t, J=5.8Hz)　 Reference Example 7-46
1 H-NMR (CDCl 3 ) δ ppm: 3.95 (3H, s), 4.52 (2H, d, J = 5.8 Hz), 5.19 (2H, s), 7.08 (1H, s), 7.18 (1H, s) , 7.25-7.45 (10H, m), 8.13 (1H, s), 8.68 (1H, t, J = 5.8Hz)
参考例７－４７
１H-NMR（CDCl3）δ ppm： 2.85-2.95 (2H, m), 3.50-3.65 (2H, m), 3.95 (3H, s), 5.19 (2H, s), 7.04 (1H, s), 7.15-7.45 (11H, m), 7.81 (1H, br s), 8.35 (1H, br s) Reference Example 7-47
1 H-NMR (CDCl 3 ) δ ppm: 2.85-2.95 (2H, m), 3.50-3.65 (2H, m), 3.95 (3H, s), 5.19 (2H, s), 7.04 (1H, s), 7.15-7.45 (11H, m), 7.81 (1H, br s), 8.35 (1H, br s)
参考例７－４８
１H-NMR（CDCl3）δ ppm：2.96 (3H, s), 3.94 (3H, s), 4.55 (2H, s), 5.16 (2H, s), 7.04 (1H, br s), 7.13 (1H, s), 7.25-7.45 (10H, m), 7.54 (1H, br s)　 Reference Example 7-48
1 H-NMR (CDCl 3 ) δ ppm: 2.96 (3H, s), 3.94 (3H, s), 4.55 (2H, s), 5.16 (2H, s), 7.04 (1H, br s), 7.13 (1H , s), 7.25-7.45 (10H, m), 7.54 (1H, br s)
参考例７－４９
１H-NMR（DMSO-d６）δ ppm：1.81 (3H, s), 3.15-3.20 (2H, m), 3.25-3.30 (2H, m), 3.88 (3H, s), 5.20 (2H, s), 7.28 (1H, s), 7.35-7.50 (6H, m), 7.96 (1H, t, J=5.2Hz), 8.41 (1H, br s), 10.83 (1H, s) Reference Example 7-49
1 H-NMR (DMSO-d 6 ) δ ppm: 1.81 (3H, s), 3.15-3.20 (2H, m), 3.25-3.30 (2H, m), 3.88 (3H, s), 5.20 (2H, s ), 7.28 (1H, s), 7.35-7.50 (6H, m), 7.96 (1H, t, J = 5.2Hz), 8.41 (1H, br s), 10.83 (1H, s)
参考例７－５０
１H-NMR（CDCl3）δ ppm： 1.20-1.30 (3H, m), 3.50-3.65 (6H, m), 3.92 (3H, s), 5.15 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.55 (1H, br s), 8.60-8.75 (1H, m) Reference Example 7-50
1 H-NMR (CDCl 3 ) δ ppm: 1.20-1.30 (3H, m), 3.50-3.65 (6H, m), 3.92 (3H, s), 5.15 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.55 (1H, br s), 8.60-8.75 (1H, m)
参考例７－５１
１H-NMR（CDCl3）δ ppm： 1.20-1.30 (3H, m), 1.80-1.95 (2H, m), 3.40-3.60 (6H, m), 3.92 (3H, s), 5.15 (2H, s), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.34 (1H, br s), 8.50-8.65 (1H, m) Reference Example 7-51
1 H-NMR (CDCl 3 ) δ ppm: 1.20-1.30 (3H, m), 1.80-1.95 (2H, m), 3.40-3.60 (6H, m), 3.92 (3H, s), 5.15 (2H, s ), 6.89 (1H, s), 7.30-7.50 (6H, m), 8.34 (1H, br s), 8.50-8.65 (1H, m)
参考例７－５２
１H-NMR（CDCl3）δ ppm： 1.15-1.30 (3H, m), 3.45-3.65 (6H, m), 3.96 (3H, s), 5.19 (2H, s), 7.07 (1H, s), 7.17 (1H, s), 7.30-7.50 (5H, m), 7.92 (1H, br s), 8.45-8.55 (1H, m) Reference Example 7-52
1 H-NMR (CDCl 3 ) δ ppm: 1.15-1.30 (3H, m), 3.45-3.65 (6H, m), 3.96 (3H, s), 5.19 (2H, s), 7.07 (1H, s), 7.17 (1H, s), 7.30-7.50 (5H, m), 7.92 (1H, br s), 8.45-8.55 (1H, m)
参考例７－５３
１H-NMR（CDCl3）δ ppm： 1.05-1.25 (3H, m), 1.80-1.90 (2H, m), 3.40-3.55 (6H, m), 3.96 (3H, s), 5.20 (2H, s), 7.07 (1H, s), 7.17 (1H, s), 7.30-7.50 (5H, m), 8.05 (1H, br s), 8.45-8.55 (1H, m) Reference Example 7-53
1 H-NMR (CDCl 3 ) δ ppm: 1.05-1.25 (3H, m), 1.80-1.90 (2H, m), 3.40-3.55 (6H, m), 3.96 (3H, s), 5.20 (2H, s ), 7.07 (1H, s), 7.17 (1H, s), 7.30-7.50 (5H, m), 8.05 (1H, br s), 8.45-8.55 (1H, m)
参考例７－５４
１H-NMR（CDCl3）δ ppm：1.80-1.90 (2H, m), 3.36 (3H, s), 3.40-3.45 (2H, m), 3.47 (2H, t, J=6.0Hz), 3.96 (3H, s), 5.20 (2H, s), 7.07 (1H, s), 7.17 (1H, s), 7.30-7.45 (5H, m), 7.96 (1H, s), 8.48 (1H, br s)　 Reference Example 7-54
1 H-NMR (CDCl 3 ) δ ppm: 1.80-1.90 (2H, m), 3.36 (3H, s), 3.40-3.45 (2H, m), 3.47 (2H, t, J = 6.0Hz), 3.96 ( 3H, s), 5.20 (2H, s), 7.07 (1H, s), 7.17 (1H, s), 7.30-7.45 (5H, m), 7.96 (1H, s), 8.48 (1H, br s)
参考例７－５５
１H-NMR（CDCl3）δ ppm： 1.17 (6H, d, J=6.1Hz),  1.75-1.90 (2H, m), 3.35-3.55 (4H, m),  3.56 (1H, heptet, J=6.1Hz), 3.96 (3H, s), 5.20 (2H, s), 7.07 (1H, s), 7.17 (1H, s), 7.30-7.50 (5H, m), 8.10 (1H, br s), 8.40-8.45 (1H, m) Reference Example 7-55
1 H-NMR (CDCl 3 ) δ ppm: 1.17 (6H, d, J = 6.1 Hz), 1.75-1.90 (2H, m), 3.35-3.55 (4H, m), 3.56 (1H, heptet, J = 6.1 Hz), 3.96 (3H, s), 5.20 (2H, s), 7.07 (1H, s), 7.17 (1H, s), 7.30-7.50 (5H, m), 8.10 (1H, br s), 8.40- 8.45 (1H, m)
参考例７－５６
１H-NMR（DMSO-d６）δ ppm：1.45-1.60 (6H, m), 3.30-3.40 (4H, m), 3.87 (3H, s), 5.18 (2H, s), 7.18 (1H, s), 7.24 (1H, s), 7.35-7.50 (5H, m), 10.34 (1H, s) Reference Example 7-56
1 H-NMR (DMSO-d 6 ) δ ppm: 1.45-1.60 (6H, m), 3.30-3.40 (4H, m), 3.87 (3H, s), 5.18 (2H, s), 7.18 (1H, s ), 7.24 (1H, s), 7.35-7.50 (5H, m), 10.34 (1H, s)
参考例８－１ 
１－（５－ベンジルオキシ－４－メトキシ－２－トリフルオロメチルベンゾイル）－３－（３－メトキシプロピル）－１－メチル尿素
　５－ベンジルオキシ－４－メトキシ－Ｎ－メチル－２－トリフルオロメチルベンズアミド（参考例６－２）(0.518g)の塩化メチレン(10mL)溶液に氷冷下クロロトリメチルシラン(0.231mL)とトリエチルアミン(0.447mL)を加えた。1時間加熱還流後、反応混合物に氷冷下トリホスゲン(0.453g)を少しずつ加え、30分間加熱還流した。反応混合物を減圧濃縮して（５－ベンジルオキシ－４－メトキシ－２－トリフルオロメチルベンゾイル）メチルカルバミン酸クロリドを得た。
　得られた酸クロリドの塩化メチレン(10mL)溶液に氷冷下３－メトキシプロピルアミン(0.779mL)を加え、室温にて16.5時間撹拌した。反応混合物を水、飽和食塩水にて洗浄し、無水硫酸マグネシウムにて乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン/酢酸エチル＝19/1～0/1）にて精製して表題化合物(0.591g)を得た。構造式を表７に示した。
１H-NMR（CDCl3）δ ppm：1.85-1.90 (2H, m), 2.89 (3H, s), 3.36 (3H, s), 3.40-3.50 (4H, m), 3.96 (3H, s), 5.15-5.25 (2H, m), 6.76 (1H, s), 7.13 (1H, s), 7.30-7.45 (5H, m), 9.16 (1H, br s) Reference Example 8-1
1- (5-Benzyloxy-4-methoxy-2-trifluoromethylbenzoyl) -3- (3-methoxypropyl) -1-methylurea 5-benzyloxy-4-methoxy-N-methyl-2-trifluoro Chlorotrimethylsilane (0.231 mL) and triethylamine (0.447 mL) were added to a solution of methylbenzamide (Reference Example 6-2) (0.518 g) in methylene chloride (10 mL) under ice cooling. After heating under reflux for 1 hour, triphosgene (0.453 g) was added little by little to the reaction mixture under ice cooling, and the mixture was heated under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure to give (5-benzyloxy-4-methoxy-2-trifluoromethylbenzoyl) methylcarbamic acid chloride.
To a solution of the obtained acid chloride in methylene chloride (10 mL) was added 3-methoxypropylamine (0.779 mL) under ice cooling, and the mixture was stirred at room temperature for 16.5 hours. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 19 / 1-0 / 1) to give the title compound (0.591 g). The structural formula is shown in Table 7.
1 H-NMR (CDCl 3 ) δ ppm: 1.85-1.90 (2H, m), 2.89 (3H, s), 3.36 (3H, s), 3.40-3.50 (4H, m), 3.96 (3H, s), 5.15-5.25 (2H, m), 6.76 (1H, s), 7.13 (1H, s), 7.30-7.45 (5H, m), 9.16 (1H, br s)
　５－ベンジルオキシ－４－メトキシ－Ｎ－メチル－２－トリフルオロメチルベンズアミドの代わりに対応するアミドを用い、３－メトキシプロピルアミンの代わりに対応するアミンを用い、参考例８－１と同様の方法により、参考例８－２～参考例８－３２を合成した。これらを表７に示した。 Similar to Reference Example 8-1 except that the corresponding amide was used instead of 5-benzyloxy-4-methoxy-N-methyl-2-trifluoromethylbenzamide and the corresponding amine was used instead of 3-methoxypropylamine. According to the method, Reference Example 8-2 to Reference Example 8-32 were synthesized. These are shown in Table 7.
参考例９－１ 
４－ベンジルオキシ－２－（３－シクロプロピル－１－メチルウレイドカルボニル）－５－メトキシ安息香酸メチル
　トリス（ジベンジリデンアセトン）ジパラジウム（０）(67mg)と１，１’－ビス（ジフェニルホスフィノ）フェロセン(162mg)のＮ，Ｎ－ジメチルホルムアミド(5mL)懸濁液をアルゴン下室温にて10分間撹拌した。反応混合物に１－（５－ベンジルオキシ－２－ヨード－４－メトキシベンゾイル）－３－シクロプロピル－１－メチル尿素（参考例８－９）(0.700g)、メタノール(5mL)およびトリエチルアミン(0.610mL)を室温にて加え、一酸化炭素下80℃にて18時間還流した。反応混合物に室温にて2mol/L塩酸を加え、酢酸エチルにて抽出した。有機層を水、2mol/L水酸化ナトリウム水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムにて乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：塩化メチレン/酢酸エチル＝96/4～88/12）にて精製して表題化合物(0.256g)を得た。構造式を表７に示した。
１H-NMR（CDCl3）δ ppm：0.55-0.65 (2H, m), 0.75-0.85 (2H, m), 2.75-2.85 (1H, m), 2.90 (3H, s), 3.86 (3H, s), 3.95 (3H, s), 5.19 (2H, s), 6.72 (1H, s), 7.30-7.45 (5H, m), 7.53 (1H, s), 9.20 (1H, br s) Reference Example 9-1
4-Benzyloxy-2- (3-cyclopropyl-1-methylureidocarbonyl) -5-methoxybenzoic acid methyl tris (dibenzylideneacetone) dipalladium (0) (67 mg) and 1,1′-bis (diphenylphos A suspension of fino) ferrocene (162 mg) in N, N-dimethylformamide (5 mL) was stirred at room temperature under argon for 10 minutes. To the reaction mixture was added 1- (5-benzyloxy-2-iodo-4-methoxybenzoyl) -3-cyclopropyl-1-methylurea (Reference Example 8-9) (0.700 g), methanol (5 mL) and triethylamine (0.610 mL) was added at room temperature, and the mixture was refluxed at 80 ° C. for 18 hours under carbon monoxide. To the reaction mixture was added 2 mol / L hydrochloric acid at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, 2 mol / L aqueous sodium hydroxide solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride / ethyl acetate = 96/4 to 88/12) to obtain the title compound (0.256 g). The structural formula is shown in Table 7.
1 H-NMR (CDCl 3 ) δ ppm: 0.55-0.65 (2H, m), 0.75-0.85 (2H, m), 2.75-2.85 (1H, m), 2.90 (3H, s), 3.86 (3H, s ), 3.95 (3H, s), 5.19 (2H, s), 6.72 (1H, s), 7.30-7.45 (5H, m), 7.53 (1H, s), 9.20 (1H, br s)
参考例１０－１
１－（５－ベンジルオキシ－２－シアノ－４－メトキシベンゾイル）－３－シクロプロピル－１－メチル尿素
　１－（５－ベンジルオキシ－２－ヨード－４－メトキシベンゾイル）－３－シクロプロピル－１－メチル尿素（参考例８－９）(0.600g)、シアン化第一銅(5mL)、トリス（ジベンジリデンアセトン）ジパラジウム（０）(57mg)および１，１’－ビス（ジフェニルホスフィノ）フェロセン(139mg)の１，４－ジオキサン(10mL)懸濁液にアルゴン下室温にてシアン化テトラエチルアンモニウム(195mg)を加え、100℃にて40分間撹拌した。反応混合物に室温にて塩化メチレンを加え、不溶物をセライト（登録商標）にて濾別した。濾液にアミノプロピルシリカゲル(10g)を加え、室温にて10分間撹拌した。不溶物をセライト（登録商標）にて濾別した。濾液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：塩化メチレン/酢酸エチル＝1/0～7/3）にて精製して表題化合物(0.261g)を得た。構造式を表７に示した。
１H-NMR（CDCl3）δ ppm：0.55-0.65 (2H, m), 0.75-0.85 (2H, m), 2.75-2.85 (1H, m), 2.99 (3H, s), 3.95 (3H, s), 5.21 (2H, s), 6.84 (1H, s), 7.14 (1H, s), 7.30-7.40 (5H, m), 8.94 (1H, br s) Reference Example 10-1
1- (5-benzyloxy-2-cyano-4-methoxybenzoyl) -3-cyclopropyl-1-methylurea 1- (5-benzyloxy-2-iodo-4-methoxybenzoyl) -3-cyclopropyl- 1-methylurea (Reference Example 8-9) (0.600 g), cuprous cyanide (5 mL), tris (dibenzylideneacetone) dipalladium (0) (57 mg) and 1,1′-bis (diphenylphosphino) ) Tetraethylammonium cyanide (195 mg) was added to a suspension of ferrocene (139 mg) in 1,4-dioxane (10 mL) at room temperature under argon, and the mixture was stirred at 100 ° C. for 40 minutes. Methylene chloride was added to the reaction mixture at room temperature, and the insoluble material was filtered off through Celite (registered trademark). Aminopropyl silica gel (10 g) was added to the filtrate, and the mixture was stirred at room temperature for 10 minutes. Insoluble matter was filtered off through Celite (registered trademark). The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: methylene chloride / ethyl acetate = 1 / 0-7 / 3) to give the title compound (0.261 g). The structural formula is shown in Table 7.
1 H-NMR (CDCl 3 ) δ ppm: 0.55-0.65 (2H, m), 0.75-0.85 (2H, m), 2.75-2.85 (1H, m), 2.99 (3H, s), 3.95 (3H, s ), 5.21 (2H, s), 6.84 (1H, s), 7.14 (1H, s), 7.30-7.40 (5H, m), 8.94 (1H, br s)
参考例１１－１ 
１－（５－ベンジルオキシ－４－メトキシ－２－トリフルオロメチルベンゾイル）－３－メチルテトラヒドロピリミジン－２－オン
　５－ベンジルオキシ－Ｎ－（３－ジメチルアミノプロピル）－４－メトキシ－２－トリフルオロメチルベンズアミド（参考例６－７）(0.623g)の塩化メチレン(20mL)溶液に室温にてクロロトリメチルシラン(0.232mL)とトリエチルアミン(0.423mL)を加えた。0.5時間加熱還流後、反応混合物に室温にてトリホスゲン(0.463g)を加え、1.5時間加熱還流した。反応混合物に氷冷下シクロプロピルアミン(0.779mL)を加え、室温にて一晩撹拌した。反応混合物を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン/酢酸エチル＝8/2～0/1）にて精製して表題化合物(0.546g)を得た。構造式を表７に示した。
MS (ESI, m/z): 423 (M+H)+　 Reference Example 11-1
1- (5-Benzyloxy-4-methoxy-2-trifluoromethylbenzoyl) -3-methyltetrahydropyrimidin-2-one 5-benzyloxy-N- (3-dimethylaminopropyl) -4-methoxy-2- To a solution of trifluoromethylbenzamide (Reference Example 6-7) (0.623 g) in methylene chloride (20 mL) were added chlorotrimethylsilane (0.232 mL) and triethylamine (0.423 mL) at room temperature. After heating to reflux for 0.5 hour, triphosgene (0.463 g) was added to the reaction mixture at room temperature, and the mixture was heated to reflux for 1.5 hours. Cyclopropylamine (0.779 mL) was added to the reaction mixture under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 8 / 2-0 / 1) to give the title compound (0.546 g). The structural formula is shown in Table 7.
MS (ESI, m / z): 423 (M + H) +
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-I000019
Figure JPOXMLDOC01-appb-I000020
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-I000019
Figure JPOXMLDOC01-appb-I000020
　参考例８－２～参考例８－３２の物性値を以下に示した。 The physical property values of Reference Example 8-2 to Reference Example 8-32 are shown below.
参考例８－２
１H-NMR（CDCl3）δ ppm：0.55-0.85 (4H, m), 2.75-2.85 (1H, m), 3.01 (3H, s), 3.90 (3H, s), 5.11 (2H, s), 6.74 (1H, s), 6.90 (1H, s), 7.25-7.45 (5H, m), 9.14 (1H, br s) Reference Example 8-2
1 H-NMR (CDCl 3 ) δ ppm: 0.55-0.85 (4H, m), 2.75-2.85 (1H, m), 3.01 (3H, s), 3.90 (3H, s), 5.11 (2H, s), 6.74 (1H, s), 6.90 (1H, s), 7.25-7.45 (5H, m), 9.14 (1H, br s)
参考例８－３
１H-NMR（CDCl3）δ ppm：2.89 (3H, s), 2.90-3.00 (3H, m), 3.96 (3H, s), 5.00-5.40 (2H, m), 6.73 (1H, s), 7.14 (1H, s), 7.25-7.50 (5H, m), 8.97 (1H, br s) Reference Example 8-3
1 H-NMR (CDCl 3 ) δ ppm: 2.89 (3H, s), 2.90-3.00 (3H, m), 3.96 (3H, s), 5.00-5.40 (2H, m), 6.73 (1H, s), 7.14 (1H, s), 7.25-7.50 (5H, m), 8.97 (1H, br s)
参考例８－４
１H-NMR（CDCl3）δ ppm：0.90-1.00 (3H, m), 1.50-1.70 (2H, m), 2.89 (3H, s), 3.25-3.40 (2H, m), 3.96 (3H, s), 5.10-5.30 (2H, m), 6.75 (1H, br s), 7.14 (1H, br s), 7.25-7.50 (5H, m), 9.08 (1H, br s) Reference Example 8-4
1 H-NMR (CDCl 3 ) δ ppm: 0.90-1.00 (3H, m), 1.50-1.70 (2H, m), 2.89 (3H, s), 3.25-3.40 (2H, m), 3.96 (3H, s ), 5.10-5.30 (2H, m), 6.75 (1H, br s), 7.14 (1H, br s), 7.25-7.50 (5H, m), 9.08 (1H, br s)
参考例８－５
MS (ESI, m/z): 411 (M+H)+ Reference Example 8-5
MS (ESI, m / z): 411 (M + H) +
参考例８－６
１H-NMR（CDCl3）δ ppm：0.55-0.65 (2H, m), 0.75-0.85 (2H, m), 2.75-2.85 (1H, m), 2.89 (3H, s), 3.96 (3H, s), 5.10-5.30 (2H, m), 6.72 (1H, s), 7.13 (1H, s), 7.30-7.45 (5H, m), 9.09 (1H, br s) Reference Example 8-6
1 H-NMR (CDCl 3 ) δ ppm: 0.55-0.65 (2H, m), 0.75-0.85 (2H, m), 2.75-2.85 (1H, m), 2.89 (3H, s), 3.96 (3H, s ), 5.10-5.30 (2H, m), 6.72 (1H, s), 7.13 (1H, s), 7.30-7.45 (5H, m), 9.09 (1H, br s)
参考例８－７
１H-NMR（CDCl3）δ ppm： 0.55-0.65 (5H, m), 0.75-0.85 (2H, m), 1.00-1.20 (1H, m), 1.35-1.55 (1H, m), 2.70-2.85 (1H, m), 3.00-3.15 (1H, m), 3.40-3.55 (1H, m), 3.98 (3H, s),  5.05-5.35 (2H, m), 6.74 (1H, s), 7.12 (1H, s), 7.25-7.45 (5H, m), 9.02 (1H, br s) Reference Example 8-7
1 H-NMR (CDCl 3 ) δ ppm: 0.55-0.65 (5H, m), 0.75-0.85 (2H, m), 1.00-1.20 (1H, m), 1.35-1.55 (1H, m), 2.70-2.85 (1H, m), 3.00-3.15 (1H, m), 3.40-3.55 (1H, m), 3.98 (3H, s), 5.05-5.35 (2H, m), 6.74 (1H, s), 7.12 (1H , s), 7.25-7.45 (5H, m), 9.02 (1H, br s)
参考例８－８
MS (ESI, m/z): 465 (M+H)+ Reference Example 8-8
MS (ESI, m / z): 465 (M + H) +
参考例８－９
１H-NMR（CDCl3）δ ppm：0.55-0.65 (2H, m), 0.75-0.85 (2H, m), 2.75-2.85 (1H, m), 2.96 (3H, s), 3.90 (3H, s), 5.11 (2H, br s), 6.68 (1H, s), 7.23 (1H, s), 7.30-7.40 (5H, m), 9.15 (1H, br s) Reference Example 8-9
1 H-NMR (CDCl 3 ) δ ppm: 0.55-0.65 (2H, m), 0.75-0.85 (2H, m), 2.75-2.85 (1H, m), 2.96 (3H, s), 3.90 (3H, s ), 5.11 (2H, br s), 6.68 (1H, s), 7.23 (1H, s), 7.30-7.40 (5H, m), 9.15 (1H, br s)
参考例８－１０
MS (ESI, m/z): 479 (M+H)+ Reference Example 8-10
MS (ESI, m / z): 479 (M + H) +
参考例８－１１
１H-NMR（CDCl3）δ ppm：2.96 (3H, s), 3.98 (3H, s), 5.10-5.30 (2H, m), 6.79 (1H, s), 7.00-7.20 (2H, m), 7.30-7.50 (7H, m), 7.50-7.70 (2H, m), 11.27 (1H, br s) Reference Example 8-11
1 H-NMR (CDCl 3 ) δ ppm: 2.96 (3H, s), 3.98 (3H, s), 5.10-5.30 (2H, m), 6.79 (1H, s), 7.00-7.20 (2H, m), 7.30-7.50 (7H, m), 7.50-7.70 (2H, m), 11.27 (1H, br s)
参考例８－１２
MS (ESI, m/z): 473 (M+H)+ Reference Example 8-12
MS (ESI, m / z): 473 (M + H) +
参考例８－１３
１H-NMR（CDCl3）δ ppm：0.40-0.85 (4H, m), 2.60-2.85 (1H, m), 3.25 (3H, br s), 3.30-4.05 (7H, m), 5.15 (2H, s), 6.95 (1H, s), 7.09 (1H, s), 7.25-7.50 (5H, m)　 Reference Example 8-13
1 H-NMR (CDCl 3 ) δ ppm: 0.40-0.85 (4H, m), 2.60-2.85 (1H, m), 3.25 (3H, br s), 3.30-4.05 (7H, m), 5.15 (2H, s), 6.95 (1H, s), 7.09 (1H, s), 7.25-7.50 (5H, m)
参考例８－１４
１H-NMR（CDCl3）δ ppm：0.50-0.70 (2H, m), 0.70-0.85 (2H, m), 2.70-2.85 (1H, m), 3.10-3.80 (7H, m), 3.96 (3H, s), 5.00-5.45 (2H, m), 6.78 (1H, s), 7.12 (1H, s), 7.25-7.45 (5H, m)　 Reference Example 8-14
1 H-NMR (CDCl 3 ) δ ppm: 0.50-0.70 (2H, m), 0.70-0.85 (2H, m), 2.70-2.85 (1H, m), 3.10-3.80 (7H, m), 3.96 (3H , s), 5.00-5.45 (2H, m), 6.78 (1H, s), 7.12 (1H, s), 7.25-7.45 (5H, m)
参考例８－１５
１H-NMR（CDCl3）δ ppm：0.60-0.95 (4H, m), 2.80-2.95 (1H, m), 3.92 (3H, s),  4.10-4.40 (2H, m), 4.45-4.60 (1H, m), 5.25-5.40 (1H, m), 6.26 (1H, s), 6.90-7.00 (2H, m), 7.10 (1H, s), 7.20-7.40 (8H, m), 9.18 (1H, br s) Reference Example 8-15
1 H-NMR (CDCl 3 ) δ ppm: 0.60-0.95 (4H, m), 2.80-2.95 (1H, m), 3.92 (3H, s), 4.10-4.40 (2H, m), 4.45-4.60 (1H , m), 5.25-5.40 (1H, m), 6.26 (1H, s), 6.90-7.00 (2H, m), 7.10 (1H, s), 7.20-7.40 (8H, m), 9.18 (1H, br s)
参考例８－１６
１H-NMR（CDCl3）δ ppm：0.72-1.60 (5H, m), 2.60-3.45 (8H, m), 3.89 (3H, s), 5.09 (2H, s), 6.87 (1H, s), 6.96 (1H, br s), 7.28-7.45 (5H, m) Reference Example 8-16
1 H-NMR (CDCl 3 ) δ ppm: 0.72-1.60 (5H, m), 2.60-3.45 (8H, m), 3.89 (3H, s), 5.09 (2H, s), 6.87 (1H, s), 6.96 (1H, br s), 7.28-7.45 (5H, m)
参考例８－１７
１H-NMR（CDCl3）δ ppm：0.50 (2H, br s), 0.70-0.77 (2H, m), 2.05-2.60 (1H, m), 2.77 (3H, br s), 3.14 (3H, br s), 3.91 (3H, s), 5.10 (2H, s), 6.89 (1H, s), 6.94 (1H, br s), 7.27-7.43 (5H, m) Reference Example 8-17
1 H-NMR (CDCl 3 ) δ ppm: 0.50 (2H, br s), 0.70-0.77 (2H, m), 2.05-2.60 (1H, m), 2.77 (3H, br s), 3.14 (3H, br s), 3.91 (3H, s), 5.10 (2H, s), 6.89 (1H, s), 6.94 (1H, br s), 7.27-7.43 (5H, m)
参考例８－１８
１H-NMR（CDCl3）δ ppm：1.18 (3H, t, J=7.0Hz), 1.74 (2H, br s), 2.67-3.62 (12H, m), 3.89 (3H, s), 5.09 (2H, s), 6.87 (1H, s), 6.96 (1H, br s), 7.28-7.43 (5H, m) Reference Example 8-18
1 H-NMR (CDCl 3 ) δ ppm: 1.18 (3H, t, J = 7.0Hz), 1.74 (2H, br s), 2.67-3.62 (12H, m), 3.89 (3H, s), 5.09 (2H , s), 6.87 (1H, s), 6.96 (1H, br s), 7.28-7.43 (5H, m)
参考例８－１９
１H-NMR（CDCl3）δ ppm：0.80-1.60 (12H, m), 2.80-4.50 (8H, m), 5.06 (2H, br s), 6.88-7.21 (2H, m), 7.29-7.43 (5H, m) Reference Example 8-19
1 H-NMR (CDCl 3 ) δ ppm: 0.80-1.60 (12H, m), 2.80-4.50 (8H, m), 5.06 (2H, br s), 6.88-7.21 (2H, m), 7.29-7.43 ( 5H, m)
参考例８－２０
１H-NMR（CDCl3）δ ppm：2.82 (3H, br s), 3.17 (3H, br s), 3.91 (3H, s), 4.38 (2H, br s), 5.07 (2H, br s), 6.81-7.48 (12H, m) Reference Example 8-20
1 H-NMR (CDCl 3 ) δ ppm: 2.82 (3H, br s), 3.17 (3H, br s), 3.91 (3H, s), 4.38 (2H, br s), 5.07 (2H, br s), 6.81-7.48 (12H, m)
参考例８－２１
１H-NMR（CDCl3）δ ppm：1.35-1.60 (6H, m), 3.00-3.51 (7H, m), 3.89 (3H, s), 5.08 (2H, s), 6.87 (1H, s), 6.96 (1H, br s), 7.28-7.44 (5H, m) Reference Example 8-21
1 H-NMR (CDCl 3 ) δ ppm: 1.35-1.60 (6H, m), 3.00-3.51 (7H, m), 3.89 (3H, s), 5.08 (2H, s), 6.87 (1H, s), 6.96 (1H, br s), 7.28-7.44 (5H, m)
参考例８－２２
MS (ESI, m/z) : 419(M+H)+　 Reference Example 8-22
MS (ESI, m / z): 419 (M + H) +
参考例８－２３
１H-NMR（CDCl3）δ ppm：1.24 (9H, br s), 2.77 (3H, br s), 3.16 (3H, br s), 3.88 (3H, s), 5.08 (2H, br s), 6.85 (1H, s), 6.97 (1H, s), 7.28-7.43 (5H, m) Reference Example 8-23
1 H-NMR (CDCl 3 ) δ ppm: 1.24 (9H, br s), 2.77 (3H, br s), 3.16 (3H, br s), 3.88 (3H, s), 5.08 (2H, br s), 6.85 (1H, s), 6.97 (1H, s), 7.28-7.43 (5H, m)
参考例８－２４
MS (ESI, m/z) : 377(M+H)+　 Reference Example 8-24
MS (ESI, m / z): 377 (M + H) +
参考例８－２５
MS (ESI, m/z) : 391(M+H)+　 Reference Example 8-25
MS (ESI, m / z): 391 (M + H) +
参考例８－２６
MS (ESI, m/z) : 391(M+H)+　 Reference Example 8-26
MS (ESI, m / z): 391 (M + H) +
参考例８－２７
１H-NMR（CDCl3）δ ppm：0.95 (3H, t, J=7.5Hz), 1.36-1.45 (2H, m), 1.55-1.62 (2H, m), 3.01 (3H, s), 3.35 (2H, br s), 3.91 (3H, s), 5.12-5.13 (2H, m), 6.77 (1H, s), 6.90 (1H, s), 7.32-7.41 (5H, m), 9.12 (1H, br s)
MS(ESI, m/z):405 (M+H)+ Reference Example 8-27
1 H-NMR (CDCl 3 ) δ ppm: 0.95 (3H, t, J = 7.5Hz), 1.36-1.45 (2H, m), 1.55-1.62 (2H, m), 3.01 (3H, s), 3.35 ( 2H, br s), 3.91 (3H, s), 5.12-5.13 (2H, m), 6.77 (1H, s), 6.90 (1H, s), 7.32-7.41 (5H, m), 9.12 (1H, br s)
MS (ESI, m / z): 405 (M + H) +
参考例８－２８
１H-NMR（CDCl3）δ ppm：0.90-0.93 (3H, m), 1.33-1.38 (4H, m), 1.57-1.62 (2H, m), 3.01 (3H, s), 3.34 (2H, br s), 3.91 (3H, s), 5.12-5.13 (2H, m), 6.77 (1H, s), 6.91 (1H, s), 7.30-7.42 (5H, m), 9.11-9.13 (1H, m)　 Reference Example 8-28
1 H-NMR (CDCl 3 ) δ ppm: 0.90-0.93 (3H, m), 1.33-1.38 (4H, m), 1.57-1.62 (2H, m), 3.01 (3H, s), 3.34 (2H, br s), 3.91 (3H, s), 5.12-5.13 (2H, m), 6.77 (1H, s), 6.91 (1H, s), 7.30-7.42 (5H, m), 9.11-9.13 (1H, m)
参考例８－２９
１H-NMR（CDCl3）δ ppm：1.17 (6H, d, J=6.3Hz), 1.82-1.89 (2H, m), 3.01 (3H, s), 3.41-3.62 (5H, m), 3.91 (3H, s), 5.12 (2H, br s), 6.77 (1H, s), 6.90 (1H, s), 7.29-7.42 (5H, m), 9.19 (1H, t, J=5.4Hz) Reference Example 8-29
1 H-NMR (CDCl 3 ) δ ppm: 1.17 (6H, d, J = 6.3 Hz), 1.82-1.89 (2H, m), 3.01 (3H, s), 3.41-3.62 (5H, m), 3.91 ( 3H, s), 5.12 (2H, br s), 6.77 (1H, s), 6.90 (1H, s), 7.29-7.42 (5H, m), 9.19 (1H, t, J = 5.4Hz)
参考例８－３０
１H-NMR（CDCl3）δ ppm：3.05 (3H, s), 3.85-4.25 (5H, m), 5.14 (2H, br s), 6.79 (1H, s), 6.91 (1H, s), 7.30-7.43 (5H, m), 9.59 (1H, t, J=6.2Hz) Reference Example 8-30
1 H-NMR (CDCl 3 ) δ ppm: 3.05 (3H, s), 3.85-4.25 (5H, m), 5.14 (2H, br s), 6.79 (1H, s), 6.91 (1H, s), 7.30 -7.43 (5H, m), 9.59 (1H, t, J = 6.2Hz)
参考例８－３１
１H-NMR（CDCl3）δ ppm：1.25 (3H, t, J=7.2Hz), 1.55 (2H, br s), 1.86 (2H, br s), 2.42 (1H, br s), 2.80 (2H, br s), 3.14 (3H, br s), 3.84 (2H, br s), 3.90 (3H, s), 4.13 (2H, q, J=7.2Hz), 5.09 (2H, s), 6.87 (1H, s), 6.93 (1H, br s), 7.29-7.43(5H, m) Reference Example 8-31
1 H-NMR (CDCl 3 ) δ ppm: 1.25 (3H, t, J = 7.2Hz), 1.55 (2H, br s), 1.86 (2H, br s), 2.42 (1H, br s), 2.80 (2H , br s), 3.14 (3H, br s), 3.84 (2H, br s), 3.90 (3H, s), 4.13 (2H, q, J = 7.2Hz), 5.09 (2H, s), 6.87 (1H , s), 6.93 (1H, br s), 7.29-7.43 (5H, m)
参考例８－３２
１H-NMR（CDCl3）δ ppm：3.04 (3H, s), 3.92 (3H, s), 4.60 (2H, br s), 5.13 (2H, br s), 6.77 (1H, s), 6.92 (1H, s), 7.30-7.41 (5H, m), 7.45-7.48 (2H, m), 7.63-7.66 (2H, m), 9.64-9.67 (1H, m)　 Reference Example 8-32
1 H-NMR (CDCl 3 ) δ ppm: 3.04 (3H, s), 3.92 (3H, s), 4.60 (2H, br s), 5.13 (2H, br s), 6.77 (1H, s), 6.92 ( 1H, s), 7.30-7.41 (5H, m), 7.45-7.48 (2H, m), 7.63-7.66 (2H, m), 9.64-9.67 (1H, m)
参考例１２－１ 
１－（２－クロロ－５－ヒドロキシ－４－メトキシベンゾイル）－３－シクロプロピルメチル尿素
　１－（５－ベンジルオキシ－２－クロロ－４－メトキシベンゾイル）－３－シクロプロピルメチル尿素（参考例７－１）(0.334g) の塩化メチレン(10mL)溶液に氷冷下四塩化チタン(0.236mL)を加え、0℃にて15分撹拌した。反応混合物に氷(15g)と2mol/L塩酸(5mL)を加え、氷が溶けるまで撹拌した。分離した有機層を濃縮した。残渣に塩化メチレンとヘキサンを加え、析出物を濾取して表題化合物(0.227g)を得た。構造式を表８に示した。
１H-NMR（CDCl3）δ ppm：0.20-0.35 (2H, m), 0.45-0.65 (2H, m), 1.00-1.15 (1H, m), 3.15-3.30 (2H, m), 3.95 (3H, s), 5.92 (1H, s), 6.89 (1H, s), 7.31 (1H, s), 8.40-8.65 (2H, m)　 Reference Example 12-1
1- (2-Chloro-5-hydroxy-4-methoxybenzoyl) -3-cyclopropylmethylurea 1- (5-benzyloxy-2-chloro-4-methoxybenzoyl) -3-cyclopropylmethylurea (reference example) 7-1) Titanium tetrachloride (0.236 mL) was added to a methylene chloride (10 mL) solution of (0.334 g) under ice cooling, and the mixture was stirred at 0 ° C. for 15 minutes. Ice (15 g) and 2 mol / L hydrochloric acid (5 mL) were added to the reaction mixture, and the mixture was stirred until the ice melted. The separated organic layer was concentrated. Methylene chloride and hexane were added to the residue, and the precipitate was collected by filtration to give the title compound (0.227 g). The structural formula is shown in Table 8.
1 H-NMR (CDCl 3 ) δ ppm: 0.20-0.35 (2H, m), 0.45-0.65 (2H, m), 1.00-1.15 (1H, m), 3.15-3.30 (2H, m), 3.95 (3H , s), 5.92 (1H, s), 6.89 (1H, s), 7.31 (1H, s), 8.40-8.65 (2H, m)
　１－（５－ベンジルオキシ－２－クロロ－４－メトキシベンゾイル）－３－シクロプロピルメチル尿素の代わりに対応するベンジル誘導体を用い、参考例１２－１と同様の方法により、参考例１２－２～参考例１２－９１を合成した。これらを表８に示した。 Reference Example 12-2 was prepared in the same manner as Reference Example 12-1, except that the corresponding benzyl derivative was used instead of 1- (5-benzyloxy-2-chloro-4-methoxybenzoyl) -3-cyclopropylmethylurea. Reference Example 12-91 was synthesized. These are shown in Table 8.
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-I000022
Figure JPOXMLDOC01-appb-I000023
Figure JPOXMLDOC01-appb-I000024
Figure JPOXMLDOC01-appb-I000025
Figure JPOXMLDOC01-appb-I000026
Figure JPOXMLDOC01-appb-I000027
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-I000022
Figure JPOXMLDOC01-appb-I000023
Figure JPOXMLDOC01-appb-I000024
Figure JPOXMLDOC01-appb-I000025
Figure JPOXMLDOC01-appb-I000026
Figure JPOXMLDOC01-appb-I000027
　参考例１２－２～参考例１２－９１の物性値を以下に示した。 The physical property values of Reference Example 12-2 to Reference Example 12-91 are shown below.
参考例１２－２
１H-NMR（CDCl3）δ ppm：0.95-1.05 (3H, m), 1.55-1.70 (2H, m), 3.25-3.40 (2H, m), 3.95 (3H, s), 5.72 (1H, s), 6.88 (1H, s), 7.31 (1H, s),  8.27 (1H, br s), 8.35-8.55 (1H, m) Reference Example 12-2
1 H-NMR (CDCl 3 ) δ ppm: 0.95-1.05 (3H, m), 1.55-1.70 (2H, m), 3.25-3.40 (2H, m), 3.95 (3H, s), 5.72 (1H, s ), 6.88 (1H, s), 7.31 (1H, s), 8.27 (1H, br s), 8.35-8.55 (1H, m)
参考例１２－３
１H-NMR（CDCl3）δ ppm：0.90-1.00 (3H, m), 1.35-1.65 (4H, m), 3.30-3.40 (2H, m), 3.95 (3H, s), 5.66 (1H, s), 6.88 (1H, s), 7.32 (1H, s), 8.21 (1H, br s), 8.35-8.50 (1H, m) Reference Example 12-3
1 H-NMR (CDCl 3 ) δ ppm: 0.90-1.00 (3H, m), 1.35-1.65 (4H, m), 3.30-3.40 (2H, m), 3.95 (3H, s), 5.66 (1H, s ), 6.88 (1H, s), 7.32 (1H, s), 8.21 (1H, br s), 8.35-8.50 (1H, m)
参考例１２－４
１H-NMR（CDCl3）δ ppm：0.85-1.00 (3H, m), 1.25-1.45 (4H, m), 1.50-1.70 (2H, m), 3.25-3.40 (2H, m), 3.95 (3H, s), 5.85 (1H, s), 6.88 (1H, s), 7.31 (1H, s), 8.30-8.50 (2H, m) Reference Example 12-4
1 H-NMR (CDCl 3 ) δ ppm: 0.85-1.00 (3H, m), 1.25-1.45 (4H, m), 1.50-1.70 (2H, m), 3.25-3.40 (2H, m), 3.95 (3H , s), 5.85 (1H, s), 6.88 (1H, s), 7.31 (1H, s), 8.30-8.50 (2H, m)
参考例１２－５
１H-NMR（CDCl3）δ ppm：1.20-1.35 (6H, m), 3.95 (3H, s), 4.00-4.15 (1H, m), 5.80 (1H, s), 6.88 (1H, s), 7.30 (1H, s), 8.20-8.40 (2H, m) Reference Example 12-5
1 H-NMR (CDCl 3 ) δ ppm: 1.20-1.35 (6H, m), 3.95 (3H, s), 4.00-4.15 (1H, m), 5.80 (1H, s), 6.88 (1H, s), 7.30 (1H, s), 8.20-8.40 (2H, m)
参考例１２－６
１H-NMR（CDCl3）δ ppm：1.42 (9H, m), 3.95 (3H, s), 5.69 (1H, s), 6.88 (1H, s), 7.29 (1H, s), 8.18 (1H, br s), 8.42 (1H, br s) Reference Example 12-6
1 H-NMR (CDCl 3 ) δ ppm: 1.42 (9H, m), 3.95 (3H, s), 5.69 (1H, s), 6.88 (1H, s), 7.29 (1H, s), 8.18 (1H, br s), 8.42 (1H, br s)
参考例１２－７
１H-NMR（CDCl3）δ ppm：0.90-1.05 (3H, m), 1.55-1.70 (2H, m), 3.25-3.35 (2H, m), 3.99 (3H, s), 6.30 (1H, s), 7.13 (1H, s), 7.17 (1H, s), 8.18 (1H, br s), 8.30-8.40 (1H, m) Reference Example 12-7
1 H-NMR (CDCl 3 ) δ ppm: 0.90-1.05 (3H, m), 1.55-1.70 (2H, m), 3.25-3.35 (2H, m), 3.99 (3H, s), 6.30 (1H, s ), 7.13 (1H, s), 7.17 (1H, s), 8.18 (1H, br s), 8.30-8.40 (1H, m)
参考例１２－８
１H-NMR（CDCl3）δ ppm：0.90-1.00 (3H, m), 1.30-1.45 (2H, m), 1.50-1.65 (2H, m), 3.25-3.40 (2H, m), 3.99 (3H, s), 6.28 (1H, s), 7.12 (1H, s), 7.17 (1H, s), 8.16 (1H, br s), 8.25-8.40 (1H, m) Reference Example 12-8
1 H-NMR (CDCl 3 ) δ ppm: 0.90-1.00 (3H, m), 1.30-1.45 (2H, m), 1.50-1.65 (2H, m), 3.25-3.40 (2H, m), 3.99 (3H , s), 6.28 (1H, s), 7.12 (1H, s), 7.17 (1H, s), 8.16 (1H, br s), 8.25-8.40 (1H, m)
参考例１２－９
１H-NMR（CDCl3）δ ppm：0.85-0.95 (3H, m), 1.30-1.40 (4H, m), 1.50-1.65 (2H, m), 3.25-3.40 (2H, m), 4.00 (3H, s), 6.22 (1H, s), 7.12 (1H, s), 7.17 (1H, s), 8.05 (1H, br s), 8.25-8.35 (1H, m) Reference Example 12-9
1 H-NMR (CDCl 3 ) δ ppm: 0.85-0.95 (3H, m), 1.30-1.40 (4H, m), 1.50-1.65 (2H, m), 3.25-3.40 (2H, m), 4.00 (3H , s), 6.22 (1H, s), 7.12 (1H, s), 7.17 (1H, s), 8.05 (1H, br s), 8.25-8.35 (1H, m)
参考例１２－１０
１H-NMR（CDCl3）δ ppm：0.85-0.95 (3H, m), 1.25-1.45 (6H, m), 1.50-1.65 (2H, m), 3.25-3.40 (2H, m), 3.99 (3H, s), 6.24 (1H, br s), 7.12 (1H, s), 7.17 (1H, s), 8.05 (1H, br s), 8.25-8.35 (1H, m) Reference Example 12-10
1 H-NMR (CDCl 3 ) δ ppm: 0.85-0.95 (3H, m), 1.25-1.45 (6H, m), 1.50-1.65 (2H, m), 3.25-3.40 (2H, m), 3.99 (3H , s), 6.24 (1H, br s), 7.12 (1H, s), 7.17 (1H, s), 8.05 (1H, br s), 8.25-8.35 (1H, m)
参考例１２－１１
１H-NMR（CDCl3）δ ppm：0.85-0.95 (3H, m), 1.20-1.40 (8H, m), 1.50-1.65 (2H, m), 3.25-3.40 (2H, m), 3.99 (3H, s), 6.33 (1H, br s), 7.13 (1H, s), 7.17 (1H, s), 8.19 (1H, br s), 8.25-8.40 (1H, m) Reference Example 12-11
1 H-NMR (CDCl 3 ) δ ppm: 0.85-0.95 (3H, m), 1.20-1.40 (8H, m), 1.50-1.65 (2H, m), 3.25-3.40 (2H, m), 3.99 (3H , s), 6.33 (1H, br s), 7.13 (1H, s), 7.17 (1H, s), 8.19 (1H, br s), 8.25-8.40 (1H, m)
参考例１２－１２
１H-NMR（CDCl3）δ ppm：1.20-1.30 (6H, m), 3.95-4.10 (4H, m), 6.17 (1H, s), 7.12 (1H, s), 7.17 (1H, s), 7.99 (1H, br s), 8.10-8.20 (1H, m) Reference Example 12-12
1 H-NMR (CDCl 3 ) δ ppm: 1.20-1.30 (6H, m), 3.95-4.10 (4H, m), 6.17 (1H, s), 7.12 (1H, s), 7.17 (1H, s), 7.99 (1H, br s), 8.10-8.20 (1H, m)
参考例１２－１３
１H-NMR（CDCl3）δ ppm：0.90-1.00 (6H, m), 1.80-1.90 (1H, m), 3.10-3.20 (2H, m), 3.99 (3H, s), 6.53 (1H, br s), 7.14 (1H, s), 7.17 (1H, s), 8.40-8.50 (1H, m), 8.60 (1H, br s) Reference Example 12-13
1 H-NMR (CDCl 3 ) δ ppm: 0.90-1.00 (6H, m), 1.80-1.90 (1H, m), 3.10-3.20 (2H, m), 3.99 (3H, s), 6.53 (1H, br s), 7.14 (1H, s), 7.17 (1H, s), 8.40-8.50 (1H, m), 8.60 (1H, br s)
参考例１２－１４
１H-NMR（CDCl3）δ ppm：1.41 (9H, s), 3.99 (3H, s), 6.05 (1H, s), 7.11 (1H, s), 7.16 (1H, s), 7.83 (1H, br s), 8.25 (1H, br s)　 Reference Example 12-14
1 H-NMR (CDCl 3 ) δ ppm: 1.41 (9H, s), 3.99 (3H, s), 6.05 (1H, s), 7.11 (1H, s), 7.16 (1H, s), 7.83 (1H, br s), 8.25 (1H, br s)
参考例１２－１５
１H-NMR（CDCl3）δ ppm：0.85-1.00 (6H, m), 1.55-1.75 (4H, m), 3.20-3.35 (4H, m), 3.92 (3H, s), 5.71 (1H, br s), 6.83 (1H, s), 7.21 (1H, s), 7.82 (1H, br s) Reference Example 12-15
1 H-NMR (CDCl 3 ) δ ppm: 0.85-1.00 (6H, m), 1.55-1.75 (4H, m), 3.20-3.35 (4H, m), 3.92 (3H, s), 5.71 (1H, br s), 6.83 (1H, s), 7.21 (1H, s), 7.82 (1H, br s)
参考例１２－１６
１H-NMR（CDCl3）δ ppm：3.03 (6H, s), 3.97 (3H, s), 6.01 (1H, br s), 7.06 (1H, s), 7.12 (1H, s), 7.56 (1H, br s)　 Reference Example 12-16
1 H-NMR (CDCl 3 ) δ ppm: 3.03 (6H, s), 3.97 (3H, s), 6.01 (1H, br s), 7.06 (1H, s), 7.12 (1H, s), 7.56 (1H , br s)
参考例１２－１７
１H-NMR（CDCl3）δ ppm：1.20 (6H, t, J=7.2Hz), 3.34 (4H, q, J=7.2Hz), 3.96 (3H, s), 5.96 (1H, s), 7.01 (1H, s), 7.10 (1H, s),  7.52 (1H, br s)　 Reference Example 12-17
1 H-NMR (CDCl 3 ) δ ppm: 1.20 (6H, t, J = 7.2Hz), 3.34 (4H, q, J = 7.2Hz), 3.96 (3H, s), 5.96 (1H, s), 7.01 (1H, s), 7.10 (1H, s), 7.52 (1H, br s)
参考例１２－１８
１H-NMR（CDCl3）δ ppm：0.92 (3H, t, J=7.5Hz), 1.45-1.75 (2H, m), 3.00 (3H, br s), 3.29 (2H, t, J=7.6Hz), 3.97 (3H, s), 5.80-6.20 (1H, m), 7.04 (1H, s), 7.12 (1H, s), 7.40-7.60 (1H, m) 　 Reference Example 12-18
1 H-NMR (CDCl 3 ) δ ppm: 0.92 (3H, t, J = 7.5Hz), 1.45-1.75 (2H, m), 3.00 (3H, br s), 3.29 (2H, t, J = 7.6Hz ), 3.97 (3H, s), 5.80-6.20 (1H, m), 7.04 (1H, s), 7.12 (1H, s), 7.40-7.60 (1H, m)
参考例１２－１９
１H-NMR（CDCl3）δ ppm：0.80-1.00 (6H, m), 1.50-1.70 (4H, m), 3.15-3.30 (4H, m), 3.95 (3H, s), 6.04 (1H, br s), 6.99 (1H, s), 7.09 (1H, s), 7.65 (1H, br s) Reference Example 12-19
1 H-NMR (CDCl 3 ) δ ppm: 0.80-1.00 (6H, m), 1.50-1.70 (4H, m), 3.15-3.30 (4H, m), 3.95 (3H, s), 6.04 (1H, br s), 6.99 (1H, s), 7.09 (1H, s), 7.65 (1H, br s)
参考例１２－２０
１H-NMR（CDCl3）δ ppm：0.85-1.00 (6H, m), 1.20-1.40 (4H, m), 1.45-1.65 (4H, m), 3.20-3.30 (4H, m), 3.96 (3H, s), 6.02 (1H, br s), 7.00 (1H, s), 7.09 (1H, s), 7.60 (1H, br s) Reference Example 12-20
1 H-NMR (CDCl 3 ) δ ppm: 0.85-1.00 (6H, m), 1.20-1.40 (4H, m), 1.45-1.65 (4H, m), 3.20-3.30 (4H, m), 3.96 (3H , s), 6.02 (1H, br s), 7.00 (1H, s), 7.09 (1H, s), 7.60 (1H, br s)
参考例１２－２１
１H-NMR（CDCl3）δ ppm：1.31 (12H, t, J=6.8Hz), 3.86 (2H, heptet, J=6.8Hz), 3.96 (3H, s), 6.01 (1H, br s), 7.05 (1H, s), 7.09 (1H, s),  7.40 (1H, br s)　 Reference Example 12-21
1 H-NMR (CDCl 3 ) δ ppm: 1.31 (12H, t, J = 6.8 Hz), 3.86 (2H, heptet, J = 6.8 Hz), 3.96 (3H, s), 6.01 (1H, br s), 7.05 (1H, s), 7.09 (1H, s), 7.40 (1H, br s)
参考例１２－２２
１H-NMR（CDCl3）δ ppm：0.60-0.70 (2H, m), 0.75-0.90 (2H, m), 2.70-2.85 (1H, m), 3.95 (3H, s), 5.63 (1H, s), 6.88 (1H, s), 7.29 (1H, s), 8.10-8.25 (1H, m), 8.35-8.55 (1H, m)　 Reference Example 12-22
1 H-NMR (CDCl 3 ) δ ppm: 0.60-0.70 (2H, m), 0.75-0.90 (2H, m), 2.70-2.85 (1H, m), 3.95 (3H, s), 5.63 (1H, s ), 6.88 (1H, s), 7.29 (1H, s), 8.10-8.25 (1H, m), 8.35-8.55 (1H, m)
参考例１２－２３
１H-NMR（CDCl3）δ ppm：1.15-2.05 (10H, m), 3.65-3.85 (1H, m), 3.95 (3H, s), 6.88 (1H, s), 7.31 (1H, s) Reference Example 12-23
1 H-NMR (CDCl 3 ) δ ppm: 1.15-2.05 (10H, m), 3.65-3.85 (1H, m), 3.95 (3H, s), 6.88 (1H, s), 7.31 (1H, s)
参考例１２－２４
１H-NMR（CDCl3）δ ppm： 1.45-1.75 (10H, m), 1.90-2.10 (2H, m), 3.90-4.05 (4H, m), 5.70 (1H, s), 6.88 (1H, s), 7.31 (1H, s), 8.21 (1H, br s), 8.35-8.50 (1H, m) Reference Example 12-24
1 H-NMR (CDCl 3 ) δ ppm: 1.45-1.75 (10H, m), 1.90-2.10 (2H, m), 3.90-4.05 (4H, m), 5.70 (1H, s), 6.88 (1H, s ), 7.31 (1H, s), 8.21 (1H, br s), 8.35-8.50 (1H, m)
参考例１２－２５
１H-NMR（CDCl3）δ ppm： 1.60-1.75 (6H, m), 2.00-2.15 (9H, m), 3.94 (3H, s), 5.67 (1H, s), 6.87 (1H, s), 7.28 (1H, s), 8.22 (1H, br s), 8.33 (1H, br s) Reference Example 12-25
1 H-NMR (CDCl 3 ) δ ppm: 1.60-1.75 (6H, m), 2.00-2.15 (9H, m), 3.94 (3H, s), 5.67 (1H, s), 6.87 (1H, s), 7.28 (1H, s), 8.22 (1H, br s), 8.33 (1H, br s)
参考例１２－２６
１H-NMR（CDCl3）δ ppm：0.60-0.70 (2H, m), 0.75-0.85 (2H, m), 2.70-2.85 (1H, m), 3.99 (3H, s), 6.14 (1H, br s), 6.10 (1H, s), 7.17 (1H, s), 7.86 (1H, br s), 8.34 (1H, br s)　 Reference Example 12-26
1 H-NMR (CDCl 3 ) δ ppm: 0.60-0.70 (2H, m), 0.75-0.85 (2H, m), 2.70-2.85 (1H, m), 3.99 (3H, s), 6.14 (1H, br s), 6.10 (1H, s), 7.17 (1H, s), 7.86 (1H, br s), 8.34 (1H, br s)
参考例１２－２７
１H-NMR（CDCl3）δ ppm：1.50-1.80 (6H, m), 1.95-2.10 (2H, m), 4.00 (3H, s), 4.10-4.25 (1H, m), 6.24 (1H, s), 7.12 (1H, s), 7.17 (1H, s), 8.00 (1H, br s), 8.20-8.35 (1H, m) Reference Example 12-27
1 H-NMR (CDCl 3 ) δ ppm: 1.50-1.80 (6H, m), 1.95-2.10 (2H, m), 4.00 (3H, s), 4.10-4.25 (1H, m), 6.24 (1H, s ), 7.12 (1H, s), 7.17 (1H, s), 8.00 (1H, br s), 8.20-8.35 (1H, m)
参考例１２－２８
１H-NMR（CDCl3）δ ppm：1.15-1.45 (5H, m), 1.55-1.65 (1H, m), 1.70-1.80 (2H, m), 1.95-2.00 (2H, m), 3.70-3.80 (1H, m), 4.00 (3H, s), 6.10 (1H, s), 7.11 (1H, s), 7.16 (1H, s), 7.81 (1H, s), 8.20-8.25 (1H, m)　 Reference Example 12-28
1 H-NMR (CDCl 3 ) δ ppm: 1.15-1.45 (5H, m), 1.55-1.65 (1H, m), 1.70-1.80 (2H, m), 1.95-2.00 (2H, m), 3.70-3.80 (1H, m), 4.00 (3H, s), 6.10 (1H, s), 7.11 (1H, s), 7.16 (1H, s), 7.81 (1H, s), 8.20-8.25 (1H, m)
参考例１２－２９
１H-NMR（CDCl3）δ ppm：1.00-1.15 (1H, m), 1.20-1.55 (4H, m), 1.60-1.85 (5H, m), 2.88 (3H, s), 3.90-4.00 (4H, m), 6.00 (1H, s), 7.04 (1H, s), 7.10 (1H, s), 7.55 (1H, br s) Reference Example 12-29
1 H-NMR (CDCl 3 ) δ ppm: 1.00-1.15 (1H, m), 1.20-1.55 (4H, m), 1.60-1.85 (5H, m), 2.88 (3H, s), 3.90-4.00 (4H , m), 6.00 (1H, s), 7.04 (1H, s), 7.10 (1H, s), 7.55 (1H, br s)
参考例１２－３０
１H-NMR（CDCl3）δ ppm：1.45-1.75 (10H, m), 1.95-2.05 (2H, m), 3.85-4.05 (4H, m), 6.09 (1H, s), 7.11 (1H, s), 7.16 (1H, s), 7.78 (1H, br s), 8.20-8.35 (1H, m) Reference Example 12-30
1 H-NMR (CDCl 3 ) δ ppm: 1.45-1.75 (10H, m), 1.95-2.05 (2H, m), 3.85-4.05 (4H, m), 6.09 (1H, s), 7.11 (1H, s ), 7.16 (1H, s), 7.78 (1H, br s), 8.20-8.35 (1H, m)
参考例１２－３１
１H-NMR（CDCl3）δ ppm：0.85-1.15 (5H, m), 1.20-1.45 (3H, m), 1.70-1.80 (2H, m), 2.00-2.10 (2H, m), 3.55-3.75 (1H, m), 3.99 (3H, s), 6.13 (1H, s), 7.11 (1H, s), 7.16 (1H, s), 7.88 (1H, br s), 8.05-8.20 (1H, m) Reference Example 12-31
1 H-NMR (CDCl 3 ) δ ppm: 0.85-1.15 (5H, m), 1.20-1.45 (3H, m), 1.70-1.80 (2H, m), 2.00-2.10 (2H, m), 3.55-3.75 (1H, m), 3.99 (3H, s), 6.13 (1H, s), 7.11 (1H, s), 7.16 (1H, s), 7.88 (1H, br s), 8.05-8.20 (1H, m)
参考例１２－３２
１H-NMR（CDCl3）δ ppm：1.68 (6H, t, J=2.8Hz), 2.02 (6H, d, J=2.8Hz), 2.08 (3H, br s), 3.98 (3H, s), 6.07 (1H, s), 7.11 (1H, s), 7.15 (1H, s), 8.18 (1H, s), 8.27 (1H, s) Reference Example 12-32
1 H-NMR (CDCl 3 ) δ ppm: 1.68 (6H, t, J = 2.8 Hz), 2.02 (6H, d, J = 2.8 Hz), 2.08 (3H, br s), 3.98 (3H, s), 6.07 (1H, s), 7.11 (1H, s), 7.15 (1H, s), 8.18 (1H, s), 8.27 (1H, s)
参考例１２－３３
１H-NMR（CDCl3）δ ppm：0.80-0.90 (2H, m), 0.90-1.05 (2H, m), 2.60-2.75 (1H, m), 2.89 (3H, s), 3.96 (3H, s), 5.93 (1H, s), 6.96 (1H, s), 7.10 (1H, s), 8.25-8.45 (1H, m)　 Reference Example 12-33
1 H-NMR (CDCl 3 ) δ ppm: 0.80-0.90 (2H, m), 0.90-1.05 (2H, m), 2.60-2.75 (1H, m), 2.89 (3H, s), 3.96 (3H, s ), 5.93 (1H, s), 6.96 (1H, s), 7.10 (1H, s), 8.25-8.45 (1H, m)
参考例１２－３４
１H-NMR（CDCl3）δ ppm：1.05-1.15 (1H, m), 1.25-1.40 (7H, m), 1.60-1.85 (8H, m), 3.40-3.50 (1H, m), 3.75-3.85 (1H, m), 3.95 (3H, s), 7.03 (1H, s), 7.09 (1H, s), 7.45 (1H, br s)  Reference Example 12-34
1 H-NMR (CDCl 3 ) δ ppm: 1.05-1.15 (1H, m), 1.25-1.40 (7H, m), 1.60-1.85 (8H, m), 3.40-3.50 (1H, m), 3.75-3.85 (1H, m), 3.95 (3H, s), 7.03 (1H, s), 7.09 (1H, s), 7.45 (1H, br s)
参考例１２－３５
１H-NMR（CDCl3）δ ppm： 0.20-0.30 (2H, m), 0.50-0.60 (2H, m), 1.00-1.15 (1H, m), 3.15-3.25 (2H, m), 4.00 (3H, s), 6.15 (1H, s), 7.13 (1H, s), 7.17 (1H, s), 7.95 (1H, br s), 8.30-8.45 (1H, m) Reference Example 12-35
1 H-NMR (CDCl 3 ) δ ppm: 0.20-0.30 (2H, m), 0.50-0.60 (2H, m), 1.00-1.15 (1H, m), 3.15-3.25 (2H, m), 4.00 (3H , s), 6.15 (1H, s), 7.13 (1H, s), 7.17 (1H, s), 7.95 (1H, br s), 8.30-8.45 (1H, m)
参考例１２－３６
１H-NMR（DMSO-d６）δ ppm：1.45-1.55 (2H, m), 1.80-1.85 (2H, m), 3.35-3.45 (2H, m), 3.75-3.85 (3H, m), 3.87 (3H, s), 6.95 (1H, s), 7.22 (1H, s), 8.27 (1H, d, J=7.8Hz), 10.28 (1H, s), 10.79 (1H, s)　 Reference Example 12-36
1 H-NMR (DMSO-d 6 ) δ ppm: 1.45-1.55 (2H, m), 1.80-1.85 (2H, m), 3.35-3.45 (2H, m), 3.75-3.85 (3H, m), 3.87 (3H, s), 6.95 (1H, s), 7.22 (1H, s), 8.27 (1H, d, J = 7.8Hz), 10.28 (1H, s), 10.79 (1H, s)
参考例１２－３７
１H-NMR（DMSO-d６）δ ppm：1.26 (3H, t, J=7.0Hz), 1.45-1.55 (2H, m), 1.95-2.05 (2H, m), 3.00-3.10 (2H, m), 3.85-3.95 (1H, m), 3.93 (3H, s), 4.00-4.05 (2H, m), 4.12 (2H, q, J=7.0Hz), 6.96 (1H, s), 7.23 (1H, s) Reference Example 12-37
1 H-NMR (DMSO-d 6 ) δ ppm: 1.26 (3H, t, J = 7.0 Hz), 1.45-1.55 (2H, m), 1.95-2.05 (2H, m), 3.00-3.10 (2H, m ), 3.85-3.95 (1H, m), 3.93 (3H, s), 4.00-4.05 (2H, m), 4.12 (2H, q, J = 7.0Hz), 6.96 (1H, s), 7.23 (1H, s)
参考例１２－３８
１H-NMR（CDCl3）δ ppm： 3.95-4.10 (5H, m), 6.90 (1H, s), 7.38 (1H, s), 8.49 (1H, br s), 8.85-9.00 (1H, m) Reference Example 12-38
1 H-NMR (CDCl 3 ) δ ppm: 3.95-4.10 (5H, m), 6.90 (1H, s), 7.38 (1H, s), 8.49 (1H, br s), 8.85-9.00 (1H, m)
参考例１２－３９
１H-NMR（DMSO-d６）δ ppm：3.89 (3H, s), 7.05 (1H, s), 7.10-7.15 (1H, m), 7.26 (1H, s), 7.30-7.40 (2H, m), 7.55-7.60 (2H, m), 10.30 (1H, s), 10.39 (1H, s), 11.12 (1H, s) Reference Example 12-39
1 H-NMR (DMSO-d 6 ) δ ppm: 3.89 (3H, s), 7.05 (1H, s), 7.10-7.15 (1H, m), 7.26 (1H, s), 7.30-7.40 (2H, m ), 7.55-7.60 (2H, m), 10.30 (1H, s), 10.39 (1H, s), 11.12 (1H, s)
参考例１２－４０
１H-NMR（DMSO-d６）δ ppm：3.89 (3H, s), 7.03 (1H, s), 7.27 (1H, s), 7.38 (1H, t, J=8.4Hz), 7.57 (2H, d, J=8.4Hz), 9.99 (1H, br s), 10.33 (1H, s), 11.29 (1H, br s) Reference Example 12-40
1 H-NMR (DMSO-d 6 ) δ ppm: 3.89 (3H, s), 7.03 (1H, s), 7.27 (1H, s), 7.38 (1H, t, J = 8.4 Hz), 7.57 (2H, d, J = 8.4Hz), 9.99 (1H, br s), 10.33 (1H, s), 11.29 (1H, br s)
参考例１２－４１
１H-NMR（CDCl3）δ ppm：2.32 (6H, s), 4.02 (3H, s), 6.03 (1H, br s), 7.05-7.25 (5H, m), 7.83 (1H, br s), 9.68 (1H, br s) Reference Example 12-41
1 H-NMR (CDCl 3 ) δ ppm: 2.32 (6H, s), 4.02 (3H, s), 6.03 (1H, br s), 7.05-7.25 (5H, m), 7.83 (1H, br s), 9.68 (1H, br s)
参考例１２－４２
１H-NMR（DMSO-d６）δ ppm：1.38 (9H, s), 3.89 (3H, s), 7.04 (1H, s), 7.15-7.30 (3H, m), 7.40-7.45 (1H, m), 7.45-7.50 (1H, m), 10.21 (1H, s), 10.33 (1H, br s), 11.22 (1H, s) Reference Example 12-42
1 H-NMR (DMSO-d 6 ) δ ppm: 1.38 (9H, s), 3.89 (3H, s), 7.04 (1H, s), 7.15-7.30 (3H, m), 7.40-7.45 (1H, m ), 7.45-7.50 (1H, m), 10.21 (1H, s), 10.33 (1H, br s), 11.22 (1H, s)
参考例１２－４３
１H-NMR（DMSO-d６）δ ppm：3.89 (6H, s), 7.05 (1H, s), 7.20-7.25 (1H, m), 7.26 (1H, s), 7.60-7.65 (1H, m), 7.95-8.00 (1H, m), 8.40-8.45 (1H, m), 10.32 (1H, br s), 11.18 (1H, br s), 11.91 (1H, br s) Reference Example 12-43
1 H-NMR (DMSO-d 6 ) δ ppm: 3.89 (6H, s), 7.05 (1H, s), 7.20-7.25 (1H, m), 7.26 (1H, s), 7.60-7.65 (1H, m ), 7.95-8.00 (1H, m), 8.40-8.45 (1H, m), 10.32 (1H, br s), 11.18 (1H, br s), 11.91 (1H, br s)
参考例１２－４４
１H-NMR（CDCl3）δ ppm：3.23 (3H, s), 3.96 (3H, s), 5.92 (1H, s), 6.92 (1H, s), 7.09 (1H, s), 7.25-7.30 (2H, m), 7.40-7.55 (4H, m)　 Reference Example 12-44
1 H-NMR (CDCl 3 ) δ ppm: 3.23 (3H, s), 3.96 (3H, s), 5.92 (1H, s), 6.92 (1H, s), 7.09 (1H, s), 7.25-7.30 ( 2H, m), 7.40-7.55 (4H, m)
参考例１２－４５
１H-NMR（DMSO-d６）δ ppm：2.40 (3H, d, J=0.8Hz), 3.89 (3H, s), 6.62 (1H, d, J=0.8Hz), 7.07 (1H, s), 7.27 (1H, s), 10.34 (1H, s), 10.77 (1H, s), 11.39 (1H, s)　 Reference Example 12-45
1 H-NMR (DMSO-d 6 ) δ ppm: 2.40 (3H, d, J = 0.8 Hz), 3.89 (3H, s), 6.62 (1H, d, J = 0.8 Hz), 7.07 (1H, s) , 7.27 (1H, s), 10.34 (1H, s), 10.77 (1H, s), 11.39 (1H, s)
参考例１２－４６
１H-NMR（CDCl3）δ ppm：3.99 (3H, s), 4.54 (2H, d, J=5.7Hz), 6.05 (1H, s), 7.12 (1H, s), 7.17 (1H, s), 7.27-7.37 (5H, m), 7.94 (1H, s), 8.66 (1H, br s)　 Reference Example 12-46
1 H-NMR (CDCl 3 ) δ ppm: 3.99 (3H, s), 4.54 (2H, d, J = 5.7 Hz), 6.05 (1H, s), 7.12 (1H, s), 7.17 (1H, s) , 7.27-7.37 (5H, m), 7.94 (1H, s), 8.66 (1H, br s)
参考例１２－４７
 １H-NMR（CDCl3）δ ppm：2.80-2.95 (2H, m), 3.50-3.65 (2H, m), 3.97 (3H, s), 6.18 (1H, s), 7.11 (1H, s), 7.15-7.35 (6H, m), 8.34 (1H, br s), 8.35-8.45 (1H, m) Reference Example 12-47
1 H-NMR (CDCl 3 ) δ ppm: 2.80-2.95 (2H, m), 3.50-3.65 (2H, m), 3.97 (3H, s), 6.18 (1H, s), 7.11 (1H, s), 7.15-7.35 (6H, m), 8.34 (1H, br s), 8.35-8.45 (1H, m)
参考例１２－４８
１H-NMR（CDCl3）δ ppm：2.97 (3H, s), 3.97 (3H, s), 4.56 (2H, s), 6.00 (1H, br s), 7.04 (1H, br s), 7.12 (1H, s), 7.25-7.40 (5H, m), 7.61 (1H, br s)　 Reference Example 12-48
1 H-NMR (CDCl 3 ) δ ppm: 2.97 (3H, s), 3.97 (3H, s), 4.56 (2H, s), 6.00 (1H, br s), 7.04 (1H, br s), 7.12 ( 1H, s), 7.25-7.40 (5H, m), 7.61 (1H, br s)
参考例１２－４９
１H-NMR（DMSO-d６）δ ppm：1.80 (3H, s), 3.15-3.30 (4H, m), 3.87 (3H, s), 6.94 (1H, s), 7.22 (1H, s), 7.90-8.00 (1H, m), 8.35-8.40 (1H, m), 10.27 (1H, s), 10.77 (1H, s) Reference Example 12-49
1 H-NMR (DMSO-d 6 ) δ ppm: 1.80 (3H, s), 3.15-3.30 (4H, m), 3.87 (3H, s), 6.94 (1H, s), 7.22 (1H, s), 7.90-8.00 (1H, m), 8.35-8.40 (1H, m), 10.27 (1H, s), 10.77 (1H, s)
参考例１２－５０
１H-NMR（CDCl3）δ ppm：1.20-1.30 (3H, m), 3.50-3.65 (6H, m), 3.95 (3H, s), 5.74 (1H, s), 6.88 (1H, s), 7.33 (1H, s), 8.33 (1H, br s), 8.60-8.70 (1H, m) Reference Example 12-50
1 H-NMR (CDCl 3 ) δ ppm: 1.20-1.30 (3H, m), 3.50-3.65 (6H, m), 3.95 (3H, s), 5.74 (1H, s), 6.88 (1H, s), 7.33 (1H, s), 8.33 (1H, br s), 8.60-8.70 (1H, m)
参考例１２－５１
１H-NMR（CDCl3）δ ppm：1.20-1.30 (3H, m), 1.80-1.95 (2H, m), 3.40-3.60 (6H, m), 3.95 (3H, s), 5.71 (1H, s), 6.88 (1H, s), 7.32 (1H, s), 8.27 (1H, br s), 8.50-8.65 (1H, m) Reference Example 12-51
1 H-NMR (CDCl 3 ) δ ppm: 1.20-1.30 (3H, m), 1.80-1.95 (2H, m), 3.40-3.60 (6H, m), 3.95 (3H, s), 5.71 (1H, s ), 6.88 (1H, s), 7.32 (1H, s), 8.27 (1H, br s), 8.50-8.65 (1H, m)
参考例１２－５２
１H-NMR（CDCl3）δ ppm：1.15-1.30 (3H, m), 3.45-3.65 (6H, m), 3.99 (3H, s), 6.78 (1H, s), 7.15 (1H, s), 7.17 (1H, s), 8.55-8.65 (1H, m), 8.89 (1H, br s) Reference Example 12-52
1 H-NMR (CDCl 3 ) δ ppm: 1.15-1.30 (3H, m), 3.45-3.65 (6H, m), 3.99 (3H, s), 6.78 (1H, s), 7.15 (1H, s), 7.17 (1H, s), 8.55-8.65 (1H, m), 8.89 (1H, br s)
参考例１２－５３
１H-NMR（CDCl3）δ ppm：1.15-1.25 (3H, m), 1.80-1.95 (2H, m), 3.40-3.60 (6H, m), 3.99 (3H, s), 6.38 (1H, br s), 7.13 (1H, s), 7.16 (1H, s), 8.27 (1H br s), 8.45-8.55 (1H, m) Reference Example 12-53
1 H-NMR (CDCl 3 ) δ ppm: 1.15-1.25 (3H, m), 1.80-1.95 (2H, m), 3.40-3.60 (6H, m), 3.99 (3H, s), 6.38 (1H, br s), 7.13 (1H, s), 7.16 (1H, s), 8.27 (1H br s), 8.45-8.55 (1H, m)
参考例１２－５４
１H-NMR（CDCl3）δ ppm：1.85-1.90 (2H, m), 3.37 (3H, s), 3.40-3.50 (4H, m), 3.99 (3H, s), 6.26 (1H, s), 7.13 (1H, s), 7.17 (1H, s), 8.10 (1H, s), 8.48 (1H, br s) Reference Example 12-54
1 H-NMR (CDCl 3 ) δ ppm: 1.85-1.90 (2H, m), 3.37 (3H, s), 3.40-3.50 (4H, m), 3.99 (3H, s), 6.26 (1H, s), 7.13 (1H, s), 7.17 (1H, s), 8.10 (1H, s), 8.48 (1H, br s)
参考例１２－５５
１H-NMR（CDCl3）δ ppm： 1.15-1.20 (6H, m), 1.80-1.90 (2H, m), 3.40-3.65 (5H, m), 3.98 (3H, s), 6.52 (1H, br s), 7.13 (1H, s), 7.16 (1H, s), 8.40-8.60 (2H, m) Reference Example 12-55
1 H-NMR (CDCl 3 ) δ ppm: 1.15-1.20 (6H, m), 1.80-1.90 (2H, m), 3.40-3.65 (5H, m), 3.98 (3H, s), 6.52 (1H, br s), 7.13 (1H, s), 7.16 (1H, s), 8.40-8.60 (2H, m)
参考例１２－５６
１H-NMR（CDCl3）δ ppm：1.61-1.65 (6H, m), 3.45-3.50 (4H, m), 3.97 (3H, s), 6.00 (1H, br s), 7.07 (1H, s), 7.12 (1H, s), 7.49 (1H, br s)　 Reference Example 12-56
1 H-NMR (CDCl 3 ) δ ppm: 1.61-1.65 (6H, m), 3.45-3.50 (4H, m), 3.97 (3H, s), 6.00 (1H, br s), 7.07 (1H, s) , 7.12 (1H, s), 7.49 (1H, br s)
参考例１２－５７
１H-NMR（CDCl3）δ ppm：1.85-1.90 (2H, m), 3.04 (3H, s), 3.36 (3H, s), 3.45-3.50 (4H, m), 3.99 (3H, s), 6.02 (1H, s), 6.86 (1H, s), 7.12 (1H, s), 9.17 (1H, br s)　 Reference Example 12-57
1 H-NMR (CDCl 3 ) δ ppm: 1.85-1.90 (2H, m), 3.04 (3H, s), 3.36 (3H, s), 3.45-3.50 (4H, m), 3.99 (3H, s), 6.02 (1H, s), 6.86 (1H, s), 7.12 (1H, s), 9.17 (1H, br s)
参考例１２－５８
１H-NMR（CDCl3）δ ppm：0.55-0.70 (2H, m), 0.75-0.85 (2H, m), 2.75-2.85 (1H, m), 3.11 (3H, s), 3.93 (3H, s), 5.66 (1H, s), 6.82 (1H, s), 6.88 (1H, s), 9.17 (1H, br s)　 Reference Example 12-58
1 H-NMR (CDCl 3 ) δ ppm: 0.55-0.70 (2H, m), 0.75-0.85 (2H, m), 2.75-2.85 (1H, m), 3.11 (3H, s), 3.93 (3H, s ), 5.66 (1H, s), 6.82 (1H, s), 6.88 (1H, s), 9.17 (1H, br s)
参考例１２－５９
１H-NMR（CDCl3）δ ppm：2.80-3.00 (3H, m), 3.06 (3H, s), 3.99 (3H, s), 6.06 (1H, s), 6.85 (1H, s), 7.13 (1H, s), 9.01 (1H, br s) Reference Example 12-59
1 H-NMR (CDCl 3 ) δ ppm: 2.80-3.00 (3H, m), 3.06 (3H, s), 3.99 (3H, s), 6.06 (1H, s), 6.85 (1H, s), 7.13 ( 1H, s), 9.01 (1H, br s)
参考例１２－６０
１H-NMR（CDCl3）δ ppm：0.90-1.05 (3H, m), 1.55-1.70 (2H, m), 3.05 (3H, s), 3.25-3.40 (2H, m), 3.99 (3H, s), 6.04 (1H, s), 6.86 (1H, br s), 7.13 (1H, br s), 9.10 (1H, br s) Reference Example 12-60
1 H-NMR (CDCl 3 ) δ ppm: 0.90-1.05 (3H, m), 1.55-1.70 (2H, m), 3.05 (3H, s), 3.25-3.40 (2H, m), 3.99 (3H, s ), 6.04 (1H, s), 6.86 (1H, br s), 7.13 (1H, br s), 9.10 (1H, br s)
参考例１２－６１
１H-NMR（CDCl3）δ ppm：2.60-3.60 (9H, m), 3.97 (3H, s), 5.85-6.15(1H, m), 6.93 (1H, s), 7.11 (1H, br s) Reference Example 12-61
1 H-NMR (CDCl 3 ) δ ppm: 2.60-3.60 (9H, m), 3.97 (3H, s), 5.85-6.15 (1H, m), 6.93 (1H, s), 7.11 (1H, br s)
参考例１２－６２
１H-NMR（CDCl3）δ ppm：0.55-0.65 (2H, m), 0.75-0.85 (2H, m), 2.75-2.85 (1H, m), 3.05 (3H, s), 3.99 (3H, s), 6.05 (1H, s), 6.84 (1H, s), 7.12 (1H, s), 9.11 (1H, br s)　 Reference Example 12-62
1 H-NMR (CDCl 3 ) δ ppm: 0.55-0.65 (2H, m), 0.75-0.85 (2H, m), 2.75-2.85 (1H, m), 3.05 (3H, s), 3.99 (3H, s ), 6.05 (1H, s), 6.84 (1H, s), 7.12 (1H, s), 9.11 (1H, br s)
参考例１２－６３
１H-NMR（CDCl3）δ ppm：0.55-0.95 (7H, m), 1.35-1.70 (2H, m), 2.75-2.85 (1H, m), 3.15-3.30 (1H, m), 3.55-3.75 (1H, m), 3.99 (3H, s), 6.05 (1H, s), 6.87 (1H, s), 7.12 (1H, s), 9.05 (1H, br s) Reference Example 12-63
1 H-NMR (CDCl 3 ) δ ppm: 0.55-0.95 (7H, m), 1.35-1.70 (2H, m), 2.75-2.85 (1H, m), 3.15-3.30 (1H, m), 3.55-3.75 (1H, m), 3.99 (3H, s), 6.05 (1H, s), 6.87 (1H, s), 7.12 (1H, s), 9.05 (1H, br s)
参考例１２－６４
１H-NMR（CDCl3）δ ppm：1.00-2.10 (10H, m), 3.03 (3H, s), 3.70-3.85 (1H, m), 3.99 (3H, s), 6.03 (1H, s), 6.86 (1H, s), 7.12 (1H, s), 8.85-9.20 (1H,m)  Reference Example 12-64
1 H-NMR (CDCl 3 ) δ ppm: 1.00-2.10 (10H, m), 3.03 (3H, s), 3.70-3.85 (1H, m), 3.99 (3H, s), 6.03 (1H, s), 6.86 (1H, s), 7.12 (1H, s), 8.85-9.20 (1H, m)
参考例１２－６５
１H-NMR（DMSO-d６）δ ppm：0.40-0.50 (2H, m), 0.65-0.70 (2H, m), 2.60-2.70 (1H, m), 2.86 (3H, s), 3.77 (3H, s), 3.85 (3H, s), 6.75 (1H, s), 7.42 (1H, s), 8.81 (1H, br s), 10.37 (1H, br s) Reference Example 12-65
1 H-NMR (DMSO-d 6 ) δ ppm: 0.40-0.50 (2H, m), 0.65-0.70 (2H, m), 2.60-2.70 (1H, m), 2.86 (3H, s), 3.77 (3H , s), 3.85 (3H, s), 6.75 (1H, s), 7.42 (1H, s), 8.81 (1H, br s), 10.37 (1H, br s)
参考例１２－６６
１H-NMR（CDCl3）δ ppm：0.60-0.65 (2H, m), 0.75-0.85 (2H, m), 2.75-2.85 (1H, m), 3.16 (3H, s), 3.99 (3H, s), 6.29 (1H, s), 6.96 (1H, s), 7.15 (1H, s), 8.99 (1H, br s) Reference Example 12-66
1 H-NMR (CDCl 3 ) δ ppm: 0.60-0.65 (2H, m), 0.75-0.85 (2H, m), 2.75-2.85 (1H, m), 3.16 (3H, s), 3.99 (3H, s ), 6.29 (1H, s), 6.96 (1H, s), 7.15 (1H, s), 8.99 (1H, br s)
参考例１２－６７
MS (ESI, m/z): 389 (M+H)+
MS (ESI, m/z): 387 (M-H)- Reference Example 12-67
MS (ESI, m / z): 389 (M + H) +
MS (ESI, m / z): 387 (MH)-
参考例１２－６８
１H-NMR（CDCl3）δ ppm：3.13 (3H, s), 4.01 (3H, s), 6.05 (1H, s), 6.91 (1H, s), 7.00-7.20 (2H, m), 7.30-7.40 (2H, m), 7.50-7.70 (2H, m), 11.30 (1H, br s) Reference Example 12-68
1 H-NMR (CDCl 3 ) δ ppm: 3.13 (3H, s), 4.01 (3H, s), 6.05 (1H, s), 6.91 (1H, s), 7.00-7.20 (2H, m), 7.30- 7.40 (2H, m), 7.50-7.70 (2H, m), 11.30 (1H, br s)
参考例１２－６９
１H-NMR（CDCl3）δ ppm：2.95 (3H, s), 3.35 (3H, br s), 3.94 (3H, s), 5.87 (1H, s), 7.05 (1H, s), 7.10-7.50 (6H, m) Reference Example 12-69
1 H-NMR (CDCl 3 ) δ ppm: 2.95 (3H, s), 3.35 (3H, br s), 3.94 (3H, s), 5.87 (1H, s), 7.05 (1H, s), 7.10-7.50 (6H, m)
参考例１２－７０
１H-NMR（CDCl3）δ ppm：0.40-0.85 (4H, m), 2.60-2.90 (1H, m), 3.00-4.10 (10H, m), 5.94 (1H, s), 6.93 (1H, s), 7.07 (1H, s)　 Reference Example 12-70
1 H-NMR (CDCl 3 ) δ ppm: 0.40-0.85 (4H, m), 2.60-2.90 (1H, m), 3.00-4.10 (10H, m), 5.94 (1H, s), 6.93 (1H, s ), 7.07 (1H, s)
参考例１２－７１
１H-NMR（CDCl3）δ ppm：0.50-0.90 (4H, m), 1.70-1.95 (2H, m), 2.70-2.85 (1H, m), 3.20 (3H, s), 3.20-3.90 (4H, m), 3.98 (3H, s), 5.99 (1H, s), 6.87 (1H, s), 7.11 (1H, s)　 Reference Example 12-71
1 H-NMR (CDCl 3 ) δ ppm: 0.50-0.90 (4H, m), 1.70-1.95 (2H, m), 2.70-2.85 (1H, m), 3.20 (3H, s), 3.20-3.90 (4H , m), 3.98 (3H, s), 5.99 (1H, s), 6.87 (1H, s), 7.11 (1H, s)
参考例１２－７２
１H-NMR（CDCl3）δ ppm： 0.55-0.70 (2H, m), 0.75-0.85 (2H, m), 2.75-2.90 (1H, m), 3.97 (3H, s), 4.35-4.50 (1H, m), 5.10-5.25 (1H, m), 5.87 (1H, s), 6.51 (1H, s), 6.90-7.05 (2H, m), 7.08 (1H, s), 7.15-7.30 (3H, m), 9.10 (1H, br s) Reference Example 12-72
1 H-NMR (CDCl 3 ) δ ppm: 0.55-0.70 (2H, m), 0.75-0.85 (2H, m), 2.75-2.90 (1H, m), 3.97 (3H, s), 4.35-4.50 (1H , m), 5.10-5.25 (1H, m), 5.87 (1H, s), 6.51 (1H, s), 6.90-7.05 (2H, m), 7.08 (1H, s), 7.15-7.30 (3H, m ), 9.10 (1H, br s)
参考例１２－７３
１H-NMR（CDCl3）δ ppm：2.00-2.15 (2H, m), 2.90 (3H, s), 3.36 (2H, t, J=6.3Hz), 3.85-4.00 (5H, m), 5.85 (1H, s), 6.87 (1H, s), 7.04 (1H, s)　 Reference Example 12-73
1 H-NMR (CDCl 3 ) δ ppm: 2.00-2.15 (2H, m), 2.90 (3H, s), 3.36 (2H, t, J = 6.3 Hz), 3.85-4.00 (5H, m), 5.85 ( 1H, s), 6.87 (1H, s), 7.04 (1H, s)
参考例１２－７４
１H-NMR（CDCl3）δ ppm：3.90 (3H, s), 3.99 (3H, s), 5.87 (1H, s), 7.18 (1H, s), 7.39 (1H, s)　 Reference Example 12-74
1 H-NMR (CDCl 3 ) δ ppm: 3.90 (3H, s), 3.99 (3H, s), 5.87 (1H, s), 7.18 (1H, s), 7.39 (1H, s)
参考例１２－７５
１H-NMR（CDCl3）δ ppm：0.86 (3H, br s), 1.40-1.65 (2H, m), 2.70-3.40 (8H, m), 3.91 (3H, s), 5.71 (1H, br s), 6.85 (1H, s), 6.94 (1H, s) Reference Example 12-75
1 H-NMR (CDCl 3 ) δ ppm: 0.86 (3H, br s), 1.40-1.65 (2H, m), 2.70-3.40 (8H, m), 3.91 (3H, s), 5.71 (1H, br s ), 6.85 (1H, s), 6.94 (1H, s)
参考例１２－７６
１H-NMR（CDCl3）δ ppm：0.55 (2H, br s), 0.75-0.85 (2H, m), 2.15-2.72 (1H, m), 2.89 (3H, br s), 3.18 (3H, br s), 3.92 (3H, s), 5.69 (1H, s), 6.87 (1H, s), 6.95 (1H, s) Reference Example 12-76
1 H-NMR (CDCl 3 ) δ ppm: 0.55 (2H, br s), 0.75-0.85 (2H, m), 2.15-2.72 (1H, m), 2.89 (3H, br s), 3.18 (3H, br s), 3.92 (3H, s), 5.69 (1H, s), 6.87 (1H, s), 6.95 (1H, s)
参考例１２－７７
１H-NMR（CDCl3）δ ppm：1.18 (3H, t, J=7.0Hz), 1.78 (2H, br s), 2.83-3.63 (12H, m), 3.91 (3H, s), 5.68 (1H, s), 6.85 (1H, s), 6.94 (1H, s) Reference Example 12-77
1 H-NMR (CDCl 3 ) δ ppm: 1.18 (3H, t, J = 7.0 Hz), 1.78 (2H, br s), 2.83-3.63 (12H, m), 3.91 (3H, s), 5.68 (1H , s), 6.85 (1H, s), 6.94 (1H, s)
参考例１２－７８
１H-NMR（CDCl3）δ ppm：：1.10-1.65 (12H, m), 2.90-4.50 (8H, m), 5.70 (1H, br s), 6.86 (1H, s), 7.03 (1H, br s) Reference Example 12-78
1 H-NMR (CDCl 3 ) δ ppm: 1.10-1.65 (12H, m), 2.90-4.50 (8H, m), 5.70 (1H, br s), 6.86 (1H, s), 7.03 (1H, br s)
参考例１２－７９
１H-NMR（CDCl3）δ ppm：2.90 (3H, br s), 3.18 (3H, br s), 3.92 (3H, s), 4.49 (2H, br s), 5.70 (1H, s), 6.84 (1H, s), 6.96-7.40 (6H, m) Reference Example 12-79
1 H-NMR (CDCl 3 ) δ ppm: 2.90 (3H, br s), 3.18 (3H, br s), 3.92 (3H, s), 4.49 (2H, br s), 5.70 (1H, s), 6.84 (1H, s), 6.96-7.40 (6H, m)
参考例１２－８０
１H-NMR（CDCl3）δ ppm：1.45-1.63 (6H, m), 3.17 (3H, br s), 3.38 (4H, br s), 3.91 (3H, s), 5.65 (1H, br s), 6.85 (1H, s), 6.94 (1H, s) Reference Example 12-80
1 H-NMR (CDCl 3 ) δ ppm: 1.45-1.63 (6H, m), 3.17 (3H, br s), 3.38 (4H, br s), 3.91 (3H, s), 5.65 (1H, br s) , 6.85 (1H, s), 6.94 (1H, s)
参考例１２－８１
１H-NMR（CDCl3）δ ppm：3.17(3H, brs), 3.25-3.90(8H, m), 3.93(3H, s), 5.63(1H, s), 6.87(1H, s), 6.94(1H, s) Reference Example 12-81
1 H-NMR (CDCl 3 ) δ ppm: 3.17 (3H, brs), 3.25-3.90 (8H, m), 3.93 (3H, s), 5.63 (1H, s), 6.87 (1H, s), 6.94 ( 1H, s)
参考例１２－８２
１H-NMR（CDCl3）δ ppm：1.27 (9H, s), 2.88 (3H, s), 3.18 (3H, s), 3.91 (3H, s), 5.59 (1H, s), 6.84 (1H, s), 6.94 (1H, s) Reference Example 12-82
1 H-NMR (CDCl 3 ) δ ppm: 1.27 (9H, s), 2.88 (3H, s), 3.18 (3H, s), 3.91 (3H, s), 5.59 (1H, s), 6.84 (1H, s), 6.94 (1H, s)
参考例１２－８３
１H-NMR（CDCl3）δ ppm：1.24(3H, t, J=7.2Hz), 3.11(3H, s), 3.30-3.50(2H, m), 3.94(3H, s), 5.68(1H, s), 6.84(1H, s), 6.89(1H, s), 9.12(1H, br)　 Reference Example 12-83
1 H-NMR (CDCl 3 ) δ ppm: 1.24 (3H, t, J = 7.2 Hz), 3.11 (3H, s), 3.30-3.50 (2H, m), 3.94 (3H, s), 5.68 (1H, s), 6.84 (1H, s), 6.89 (1H, s), 9.12 (1H, br)
参考例１２－８４
１H-NMR（CDCl3）δ ppm：0.98(3H, t, J=7.4Hz), 1.50-1.75(2H, m), 3.11(3H, s), 3.20-3.45(2H, m), 3.94(3H, s), 5.68(1H, s), 6.85(1H, s), 6.89(1H, s), 9.17(1H, br) Reference Example 12-84
1 H-NMR (CDCl 3 ) δ ppm: 0.98 (3H, t, J = 7.4 Hz), 1.50-1.75 (2H, m), 3.11 (3H, s), 3.20-3.45 (2H, m), 3.94 ( 3H, s), 5.68 (1H, s), 6.85 (1H, s), 6.89 (1H, s), 9.17 (1H, br)
参考例１２－８５
１H-NMR（CDCl3）δ ppm：1.25(6H, d, J=6.6Hz), 3.10(3H, s), 3.94(3H, s), 3.95-4.20(1H, m), 5.67(1H, s), 6.84(1H, s), 6.88(1H, s), 9.04(1H, br) Reference Example 12-85
1 H-NMR (CDCl 3 ) δ ppm: 1.25 (6H, d, J = 6.6 Hz), 3.10 (3H, s), 3.94 (3H, s), 3.95-4.20 (1H, m), 5.67 (1H, s), 6.84 (1H, s), 6.88 (1H, s), 9.04 (1H, br)
参考例１２－８６
１H-NMR（CDCl3）δ ppm：0.95 (3H, t, J=7.3Hz), 1.36-1.46 (2H, m), 1.56-1.63 (2H, m), 3.11 (3H, s), 3.36 (2H, br s), 3.93 (3H, s), 5.71 (1H, s), 6.85 (1H, s), 6.88 (1H, s), 9.15 (1H, br s) Reference Example 12-86
1 H-NMR (CDCl 3 ) δ ppm: 0.95 (3H, t, J = 7.3 Hz), 1.36-1.46 (2H, m), 1.56-1.63 (2H, m), 3.11 (3H, s), 3.36 ( 2H, br s), 3.93 (3H, s), 5.71 (1H, s), 6.85 (1H, s), 6.88 (1H, s), 9.15 (1H, br s)
参考例１２－８７
１H-NMR（CDCl3）δ ppm：0.90-0.93 (3H, m), 1.34-1.38 (4H, m), 1.55-1.65 (2H, m), 3.11 (3H, s), 3.35 (2H, br s), 3.93 (3H, s), 5.68 (1H, s), 6.85 (1H, s), 6.89 (1H, s), 9.15 (1H, br s) Reference Example 12-87
1 H-NMR (CDCl 3 ) δ ppm: 0.90-0.93 (3H, m), 1.34-1.38 (4H, m), 1.55-1.65 (2H, m), 3.11 (3H, s), 3.35 (2H, br s), 3.93 (3H, s), 5.68 (1H, s), 6.85 (1H, s), 6.89 (1H, s), 9.15 (1H, br s)
参考例１２－８８
１H-NMR（CDCl3）δ ppm：1.17 (6H, d, J=6.0Hz), 1.82-1.90 (2H, m), 3.11 (3H, s), 3.42-3.63 (5H, m), 3.93 (3H, s), 5.71 (1H, s), 6.84 (1H, s), 6.88 (1H, s), 9.22 (1H, br s) Reference Example 12-88
1 H-NMR (CDCl 3 ) δ ppm: 1.17 (6H, d, J = 6.0 Hz), 1.82-1.90 (2H, m), 3.11 (3H, s), 3.42-3.63 (5H, m), 3.93 ( 3H, s), 5.71 (1H, s), 6.84 (1H, s), 6.88 (1H, s), 9.22 (1H, br s)
参考例１２－８９
１H-NMR（CDCl3）δ ppm：3.15 (3H, s), 3.90-4.20 (5H, m), 5.70 (1H, s), 6.87 (1H, s), 6.90 (1H, s), 9.61 (1H, t, J=6.0Hz) Reference Example 12-89
1 H-NMR (CDCl 3 ) δ ppm: 3.15 (3H, s), 3.90-4.20 (5H, m), 5.70 (1H, s), 6.87 (1H, s), 6.90 (1H, s), 9.61 ( (1H, t, J = 6.0Hz)
参考例１２－９０
１H-NMR（CDCl3）δ ppm：1.25 (3H, t, J=7.1Hz), 1.52-1.67 (2H, m), 1.90-1.93 (2H, m), 2.47 (1H, br s), 2.97 (2H, br s), 3.16 (3H, br s), 3.91 (3H, s), 3.94 (2H, br s), 4.14 (2H, q, J=7.1Hz), 5.63 (1H, br s), 6.85 (1H, s), 6.94 (1H, s) Reference Example 12-90
1 H-NMR (CDCl 3 ) δ ppm: 1.25 (3H, t, J = 7.1 Hz), 1.52-1.67 (2H, m), 1.90-1.93 (2H, m), 2.47 (1H, br s), 2.97 (2H, br s), 3.16 (3H, br s), 3.91 (3H, s), 3.94 (2H, br s), 4.14 (2H, q, J = 7.1Hz), 5.63 (1H, br s), 6.85 (1H, s), 6.94 (1H, s)
参考例１２－９１
１H-NMR（CDCl3）δ ppm：3.14 (3H, s), 3.94 (3H, s), 4.61 (2H, br s), 5.69 (1H, s), 6.86 (1H, s), 6.90 (1H, s), 7.46-7.48 (2H, m), 7.64-7.66 (2H, m), 9.66-9.69 (1H, m) Reference Example 12-91
1 H-NMR (CDCl 3 ) δ ppm: 3.14 (3H, s), 3.94 (3H, s), 4.61 (2H, br s), 5.69 (1H, s), 6.86 (1H, s), 6.90 (1H , s), 7.46-7.48 (2H, m), 7.64-7.66 (2H, m), 9.66-9.69 (1H, m)
参考例１３－１ 
１－（６－クロロ－３－ヒドロキシ－４－メトキシ－２－ニトロベンゾイル）－３－シクロプロピルメチル尿素
　１－（２－クロロ－５－ヒドロキシ－４－メトキシベンゾイル）－３－シクロプロピルメチル尿素（参考例１２－１）(0.227g) の塩化メチレン(5mL)溶液に氷冷下発煙硝酸 (0.039mL)を加え、室温にて1時間撹拌した。反応混合物を水で洗浄し、有機層を濃縮して表題化合物(0.227g)を得た。構造式を表９に示した。
１H-NMR（CDCl3）δ ppm：0.20-0.30 (2H, m), 0.50-0.60 (2H, m), 0.95-1.10 (1H, m), 3.10-3.20 (2H, m), 3.99 (3H, s), 7.09 (1H, s), 8.20-8.30 (1H, m), 8.76 (1H, br s), 10.58 (1H, br s)　 Reference Example 13-1
1- (6-Chloro-3-hydroxy-4-methoxy-2-nitrobenzoyl) -3-cyclopropylmethylurea 1- (2-chloro-5-hydroxy-4-methoxybenzoyl) -3-cyclopropylmethylurea (Reference Example 12-1) To a solution of (0.227 g) in methylene chloride (5 mL) was added fuming nitric acid (0.039 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water and the organic layer was concentrated to give the title compound (0.227 g). The structural formula is shown in Table 9.
1 H-NMR (CDCl 3 ) δ ppm: 0.20-0.30 (2H, m), 0.50-0.60 (2H, m), 0.95-1.10 (1H, m), 3.10-3.20 (2H, m), 3.99 (3H , s), 7.09 (1H, s), 8.20-8.30 (1H, m), 8.76 (1H, br s), 10.58 (1H, br s)
　１－（２－クロロ－５－ヒドロキシ－４－メトキシベンゾイル）－３－シクロプロピルメチル尿素の代わりに対応するフェノール誘導体を用い、参考例１３－１と同様の方法により、参考例１３－２～参考例１３－９１を合成した。これらを表９に示した。 In the same manner as in Reference Example 13-1, using the corresponding phenol derivative instead of 1- (2-chloro-5-hydroxy-4-methoxybenzoyl) -3-cyclopropylmethylurea, Reference Example 13-2 to Reference Examples 13-91 were synthesized. These are shown in Table 9.
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-I000029
Figure JPOXMLDOC01-appb-I000030
Figure JPOXMLDOC01-appb-I000031
Figure JPOXMLDOC01-appb-I000032
Figure JPOXMLDOC01-appb-I000033
Figure JPOXMLDOC01-appb-I000034
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-I000029
Figure JPOXMLDOC01-appb-I000030
Figure JPOXMLDOC01-appb-I000031
Figure JPOXMLDOC01-appb-I000032
Figure JPOXMLDOC01-appb-I000033
Figure JPOXMLDOC01-appb-I000034
　参考例１３－２～参考例１３－５９、参考例１３－６１、および参考例１３－６３～参考例１３－９１の物性値を以下に示した。 Physical property values of Reference Example 13-2 to Reference Example 13-59, Reference Example 13-61, and Reference Example 13-63 to Reference Example 13-91 are shown below.
参考例１３－２
１H-NMR（CDCl3）δ ppm：0.90-1.05 (3H, m), 1.50-1.70 (2H, m), 3.20-3.30 (2H, m), 3.99 (3H, s), 7.09 (1H, s), 8.10-8.25 (1H, m), 8.59 (1H, br s), 10.58 (1H, br s) Reference Example 13-2
1 H-NMR (CDCl 3 ) δ ppm: 0.90-1.05 (3H, m), 1.50-1.70 (2H, m), 3.20-3.30 (2H, m), 3.99 (3H, s), 7.09 (1H, s ), 8.10-8.25 (1H, m), 8.59 (1H, br s), 10.58 (1H, br s)
参考例１３－３
１H-NMR（CDCl3）δ ppm：0.90-1.00 (3H, m), 1.30-1.65 (4H, m), 3.25-3.35 (2H, m), 3.99 (3H, s), 7.09 (1H, s), 8.10-8.20 (1H, m), 8.37 (1H, br s), 10.56 (1H, br s) Reference Example 13-3
1 H-NMR (CDCl 3 ) δ ppm: 0.90-1.00 (3H, m), 1.30-1.65 (4H, m), 3.25-3.35 (2H, m), 3.99 (3H, s), 7.09 (1H, s ), 8.10-8.20 (1H, m), 8.37 (1H, br s), 10.56 (1H, br s)
参考例１３－４
１H-NMR（CDCl3）δ ppm：0.85-1.00 (3H, m), 1.25-1.70 (6H, m), 3.20-3.35 (2H, m), 3.99 (3H, s), 7.09 (1H, s), 8.10-8.20 (1H, m), 8.48 (1H, br s), 10.57 (1H, br s) Reference Example 13-4
1 H-NMR (CDCl 3 ) δ ppm: 0.85-1.00 (3H, m), 1.25-1.70 (6H, m), 3.20-3.35 (2H, m), 3.99 (3H, s), 7.09 (1H, s ), 8.10-8.20 (1H, m), 8.48 (1H, br s), 10.57 (1H, br s)
参考例１３－５
１H-NMR（CDCl3）δ ppm：1.15-1.30 (6H, m), 3.85-4.05 (4H, m), 7.09 (1H, s), 7.95-8.10 (1H, m), 8.95 (1H, br s), 10.60 (1H, br s) Reference Example 13-5
1 H-NMR (CDCl 3 ) δ ppm: 1.15-1.30 (6H, m), 3.85-4.05 (4H, m), 7.09 (1H, s), 7.95-8.10 (1H, m), 8.95 (1H, br s), 10.60 (1H, br s)
参考例１３－６
１H-NMR（CDCl3）δ ppm：1.30 (9H, m), 3.97 (3H, s), 7.08 (1H, s), 8.15 (1H, br s), 9.55 (1H, br s), 10.65 (1H, br s) Reference Example 13-6
1 H-NMR (CDCl 3 ) δ ppm: 1.30 (9H, m), 3.97 (3H, s), 7.08 (1H, s), 8.15 (1H, br s), 9.55 (1H, br s), 10.65 ( 1H, br s)
参考例１３－７
１H-NMR（DMSO-d６）δ ppm：0.75-0.95 (3H, m), 1.40-1.60 (2H, m), 3.10-3.20 (2H, m), 4.00 (3H, s), 7.47 (1H, s), 8.05-8.15 (1H, m), 11.13 (1H, br s), 11.76 (1H, br s) Reference Example 13-7
1 H-NMR (DMSO-d 6 ) δ ppm: 0.75-0.95 (3H, m), 1.40-1.60 (2H, m), 3.10-3.20 (2H, m), 4.00 (3H, s), 7.47 (1H , s), 8.05-8.15 (1H, m), 11.13 (1H, br s), 11.76 (1H, br s)
参考例１３－８
１H-NMR（DMSO-d６）δ ppm：0.75-1.00 (3H, m), 1.15-1.60 (4H, m), 3.10-3.30 (2H, m), 4.00 (3H, s), 7.47 (1H, s), 8.00-8.15 (1H, m), 11.12 (1H, br s), 11.76 (1H, br s) Reference Example 13-8
1 H-NMR (DMSO-d 6 ) δ ppm: 0.75-1.00 (3H, m), 1.15-1.60 (4H, m), 3.10-3.30 (2H, m), 4.00 (3H, s), 7.47 (1H , s), 8.00-8.15 (1H, m), 11.12 (1H, br s), 11.76 (1H, br s)
参考例１３－９
１H-NMR（CDCl3）δ ppm：0.85-1.00 (3H, m), 1.25-1.40 (4H, m), 1.50-1.65 (2H, m), 3.20-3.35 (2H, m), 4.05 (3H, s), 7.30 (1H, s), 8.05-8.15 (1H, m), 8.58 (1H, br s), 10.51 (1H, br s) Reference Example 13-9
1 H-NMR (CDCl 3 ) δ ppm: 0.85-1.00 (3H, m), 1.25-1.40 (4H, m), 1.50-1.65 (2H, m), 3.20-3.35 (2H, m), 4.05 (3H , s), 7.30 (1H, s), 8.05-8.15 (1H, m), 8.58 (1H, br s), 10.51 (1H, br s)
参考例１３－１０
１H-NMR（DMSO-d６）δ ppm：0.80-0.95 (3H, m), 1.00-1.55 (8H, m), 3.10-3.25 (2H, m), 4.00 (3H, s), 7.47 (1H, s), 8.05-8.15 (1H, m), 11.13 (1H, br s), 11.78 (1H, br s) Reference Example 13-10
1 H-NMR (DMSO-d 6 ) δ ppm: 0.80-0.95 (3H, m), 1.00-1.55 (8H, m), 3.10-3.25 (2H, m), 4.00 (3H, s), 7.47 (1H , s), 8.05-8.15 (1H, m), 11.13 (1H, br s), 11.78 (1H, br s)
参考例１３－１１
１H-NMR（DMSO-d６）δ ppm：0.80-0.95 (3H, m), 1.15-1.55 (10H, m), 3.10-3.25 (2H, m), 4.00 (3H, s), 7.47 (1H, s), 8.05-8.15 (1H, m), 11.13 (1H, br s), 11.78 (1H, br s) Reference Example 13-11
1 H-NMR (DMSO-d 6 ) δ ppm: 0.80-0.95 (3H, m), 1.15-1.55 (10H, m), 3.10-3.25 (2H, m), 4.00 (3H, s), 7.47 (1H , s), 8.05-8.15 (1H, m), 11.13 (1H, br s), 11.78 (1H, br s)
参考例１３－１２
１H-NMR（CDCl3）δ ppm：1.15-1.25 (6H, m), 3.80-3.95 (1H, m), 4.04 (3H, s), 7.30 (1H, s), 7.90-8.00 (1H, m), 9.14 (1H, s), 10.59 (1H, br s) Reference Example 13-12
1 H-NMR (CDCl 3 ) δ ppm: 1.15-1.25 (6H, m), 3.80-3.95 (1H, m), 4.04 (3H, s), 7.30 (1H, s), 7.90-8.00 (1H, m ), 9.14 (1H, s), 10.59 (1H, br s)
参考例１３－１３
１H-NMR（DMSO-d６）δ ppm：0.70-0.95 (6H, m), 1.70-1.85 (1H, m), 3.00-3.10 (2H, m), 4.00 (3H, s), 7.47 (1H, s), 8.10-8.20 (1H, m), 11.17 (1H, br s), 11.79 (1H, br s) Reference Example 13-13
1 H-NMR (DMSO-d 6 ) δ ppm: 0.70-0.95 (6H, m), 1.70-1.85 (1H, m), 3.00-3.10 (2H, m), 4.00 (3H, s), 7.47 (1H , s), 8.10-8.20 (1H, m), 11.17 (1H, br s), 11.79 (1H, br s)
参考例１３－１４
１H-NMR（DMSO-d６）δ ppm：1.32 (9H, s), 4.00 (3H, s), 7.46 (1H, s), 8.01 (1H, s), 11.01 (1H, s), 11.76 (1H, br s)　 Reference Example 13-14
1 H-NMR (DMSO-d 6 ) δ ppm: 1.32 (9H, s), 4.00 (3H, s), 7.46 (1H, s), 8.01 (1H, s), 11.01 (1H, s), 11.76 ( 1H, br s)
参考例１３－１５
１H-NMR（CDCl3）δ ppm：0.80-1.15 (6H, m), 1.45-1.90 (4H, m), 3.10-3.25 (4H, m), 3.94 (3H, s), 7.06 (1H, s), 7.86 (1H, br s), 10.89 (1H, br s) Reference Example 13-15
1 H-NMR (CDCl 3 ) δ ppm: 0.80-1.15 (6H, m), 1.45-1.90 (4H, m), 3.10-3.25 (4H, m), 3.94 (3H, s), 7.06 (1H, s ), 7.86 (1H, br s), 10.89 (1H, br s)
参考例１３－１６
１H-NMR（CDCl3）δ ppm：2.97 (6H, s), 4.00 (3H, s), 8.02 (1H, s), 11.11 (1H, s) Reference Example 13-16
1 H-NMR (CDCl 3 ) δ ppm: 2.97 (6H, s), 4.00 (3H, s), 8.02 (1H, s), 11.11 (1H, s)
参考例１３－１７
１H-NMR（CDCl3）δ ppm：1.10-1.25 (6H, m), 3.20-3.40 (4H, m),  4.00 (3H, s), 7.27 (1H, s), 7.96 (1H, br s), 11.10 (1H, br s)　 Reference Example 13-17
1 H-NMR (CDCl 3 ) δ ppm: 1.10-1.25 (6H, m), 3.20-3.40 (4H, m), 4.00 (3H, s), 7.27 (1H, s), 7.96 (1H, br s) , 11.10 (1H, br s)
参考例１３－１８
１H-NMR（DMSO-d６）δ ppm：0.60-1.00 (3H, m), 1.30-1.60 (2H, m), 2.84 (3H, br s), 2.95-3.50 (2H, m), 3.98 (3H, s), 7.30-7.50 (1H, m), 10.35-10.70 (1H, m), 11.20-11.80 (1H, m)  Reference Example 13-18
1 H-NMR (DMSO-d 6 ) δ ppm: 0.60-1.00 (3H, m), 1.30-1.60 (2H, m), 2.84 (3H, br s), 2.95-3.50 (2H, m), 3.98 ( 3H, s), 7.30-7.50 (1H, m), 10.35-10.70 (1H, m), 11.20-11.80 (1H, m)
参考例１３－１９
１H-NMR（DMSO-d６）δ ppm：0.60-1.00 (6H, m), 1.30-1.60 (4H, m), 2.95-3.30 (4H, m), 3.98 (3H, s), 7.39 (1H, br s), 10.53 (1H, br s), 11.44 (1H, br s) Reference Example 13-19
1 H-NMR (DMSO-d 6 ) δ ppm: 0.60-1.00 (6H, m), 1.30-1.60 (4H, m), 2.95-3.30 (4H, m), 3.98 (3H, s), 7.39 (1H , br s), 10.53 (1H, br s), 11.44 (1H, br s)
参考例１３－２０
１H-NMR（DMSO-d６）δ ppm：0.75-1.00 (6H, m), 1.10-1.50 (8H, m), 3.00-3.30 (4H, m), 3.99 (3H, s), 7.39 (1H, br s), 10.52 (1H, br s), 11.45 (1H, br s) Reference Example 13-20
1 H-NMR (DMSO-d 6 ) δ ppm: 0.75-1.00 (6H, m), 1.10-1.50 (8H, m), 3.00-3.30 (4H, m), 3.99 (3H, s), 7.39 (1H , br s), 10.52 (1H, br s), 11.45 (1H, br s)
参考例１３－２１
１H-NMR（CDCl3）δ ppm：1.20-1.35 (12H, m), 3.80-3.95 (2H, m), 4.00 (3H, s), 7.26 (1H, s), 7.76 (1H, br s), 11.10 (1H, br s)　 Reference Example 13-21
1 H-NMR (CDCl 3 ) δ ppm: 1.20-1.35 (12H, m), 3.80-3.95 (2H, m), 4.00 (3H, s), 7.26 (1H, s), 7.76 (1H, br s) , 11.10 (1H, br s)
参考例１３－２２
１H-NMR（DMSO-d６）δ ppm：0.35-0.80 (4H, m), 2.55-2.80 (1H, m), 3.93 (3H, s), 7.35 (1H, s), 8.09 (1H, br s), 10.99 (1H, br s), 11.15 (1H, br s)　 Reference Example 13-22
1 H-NMR (DMSO-d 6 ) δ ppm: 0.35-0.80 (4H, m), 2.55-2.80 (1H, m), 3.93 (3H, s), 7.35 (1H, s), 8.09 (1H, br s), 10.99 (1H, br s), 11.15 (1H, br s)
参考例１３－２３
１H-NMR（CDCl3）δ ppm：1.10-1.90 (10H, m), 3.45-3.60 (1H, m), 3.98 (3H, s), 7.08 (1H, s), 8.16 (1H, br s), 10.63 (1H, br s) Reference Example 13-23
1 H-NMR (CDCl 3 ) δ ppm: 1.10-1.90 (10H, m), 3.45-3.60 (1H, m), 3.98 (3H, s), 7.08 (1H, s), 8.16 (1H, br s) , 10.63 (1H, br s)
参考例１３－２４
１H-NMR（CDCl3）δ ppm：1.40-1.75 (10H, m), 1.85-2.05 (2H, m), 3.70-3.90 (1H, m), 3.98 (3H, s), 7.08 (1H, s), 8.10-8.25 (1H, m), 9.06 (1H, br s), 10.61 (1H, br s) Reference Example 13-24
1 H-NMR (CDCl 3 ) δ ppm: 1.40-1.75 (10H, m), 1.85-2.05 (2H, m), 3.70-3.90 (1H, m), 3.98 (3H, s), 7.08 (1H, s ), 8.10-8.25 (1H, m), 9.06 (1H, br s), 10.61 (1H, br s)
参考例１３－２５
１H-NMR（CDCl3）δ ppm：1.45-1.75 (6H, m), 1.85-2.15 (9H, m), 3.96 (3H, s), 7.08 (1H, s), 8.07 (1H, br s), 9.58 (1H, br s), 10.65 (1H, br s) Reference Example 13-25
1 H-NMR (CDCl 3 ) δ ppm: 1.45-1.75 (6H, m), 1.85-2.15 (9H, m), 3.96 (3H, s), 7.08 (1H, s), 8.07 (1H, br s) , 9.58 (1H, br s), 10.65 (1H, br s)
参考例１３－２６
１H-NMR（CDCl3）δ ppm：0.60-0.70 (2H, m), 0.75-0.85 (2H, m), 2.65-2.75 (1H, m), 4.04 (3H, s), 7.30 (1H, s),  8.13 (1H, br s),  8.53 (1H, br s), 10.48 (1H, br s)　 Reference Example 13-26
1 H-NMR (CDCl 3 ) δ ppm: 0.60-0.70 (2H, m), 0.75-0.85 (2H, m), 2.65-2.75 (1H, m), 4.04 (3H, s), 7.30 (1H, s ), 8.13 (1H, br s), 8.53 (1H, br s), 10.48 (1H, br s)
参考例１３－２７
１H-NMR（DMSO-d６）δ ppm：1.25-2.00 (8H, m), 3.90-4.10 (4H, m), 7.47 (1H, s), 7.95-8.05 (1H, m), 11.18 (1H, br s), 11.80 (1H, br s) Reference Example 13-27
1 H-NMR (DMSO-d 6 ) δ ppm: 1.25-2.00 (8H, m), 3.90-4.10 (4H, m), 7.47 (1H, s), 7.95-8.05 (1H, m), 11.18 (1H , br s), 11.80 (1H, br s)
参考例１３－２８
１H-NMR（DMSO-d６）δ ppm：1.20-1.36 (5H, m), 1.51-1.54 (1H, m), 1.62-1.64 (2H, m), 1.80-1.82 (2H, m), 3.54-3.59 (1H, m), 3.81 (3H, s), 6.96 (1H, s), 8.12 (1H, d, J=7.2Hz), 10.82 (1H, s) Reference Example 13-28
1 H-NMR (DMSO-d 6 ) δ ppm: 1.20-1.36 (5H, m), 1.51-1.54 (1H, m), 1.62-1.64 (2H, m), 1.80-1.82 (2H, m), 3.54 -3.59 (1H, m), 3.81 (3H, s), 6.96 (1H, s), 8.12 (1H, d, J = 7.2Hz), 10.82 (1H, s)
参考例１３－２９
１H-NMR（CDCl3）δ ppm：1.00-1.15 (1H, m), 1.20-1.85 (9H, m), 2.83 (3H, s), 3.70-4.05 (4H, m), 8.06 (1H, s), 11.10 (1H, br s) Reference Example 13-29
1 H-NMR (CDCl 3 ) δ ppm: 1.00-1.15 (1H, m), 1.20-1.85 (9H, m), 2.83 (3H, s), 3.70-4.05 (4H, m), 8.06 (1H, s ), 11.10 (1H, br s)
参考例１３－３０
１H-NMR（DMSO-d６）δ ppm：1.35-1.65 (10H, m), 1.75-1.90 (2H, m), 3.70-3.85 (1H, m), 4.00 (3H, s), 7.46 (1H, s), 8.00-8.10 (1H, m), 11.15 (1H, br s), 11.78 (1H, br s) Reference Example 13-30
1 H-NMR (DMSO-d 6 ) δ ppm: 1.35-1.65 (10H, m), 1.75-1.90 (2H, m), 3.70-3.85 (1H, m), 4.00 (3H, s), 7.46 (1H , s), 8.00-8.10 (1H, m), 11.15 (1H, br s), 11.78 (1H, br s)
参考例１３－３１
１H-NMR（CDCl3）δ ppm：0.85-1.10 (5H, m), 1.20-1.45 (3H, m), 1.65-1.80 (2H, m), 1.95-2.05 (2H, m), 3.45-3.60 (1H, m), 4.04 (3H, s), 7.29 (1H, s), 7.85-8.00 (1H, m), 8.79 (1H, br s), 10.54 (1H, br s) Reference Example 13-31
1 H-NMR (CDCl 3 ) δ ppm: 0.85-1.10 (5H, m), 1.20-1.45 (3H, m), 1.65-1.80 (2H, m), 1.95-2.05 (2H, m), 3.45-3.60 (1H, m), 4.04 (3H, s), 7.29 (1H, s), 7.85-8.00 (1H, m), 8.79 (1H, br s), 10.54 (1H, br s)
参考例１３－３２
１H-NMR（DMSO-d６）δ ppm：1.64 (6H, br s), 1.95 (6H, br s), 2.04 (3H, br s), 3.99 (3H, s), 7.45 (1H, s), 7.96 (1H, s), 11.00 (1H, s), 11.80 (1H, br s)　 Reference Example 13-32
1 H-NMR (DMSO-d 6 ) δ ppm: 1.64 (6H, br s), 1.95 (6H, br s), 2.04 (3H, br s), 3.99 (3H, s), 7.45 (1H, s) , 7.96 (1H, s), 11.00 (1H, s), 11.80 (1H, br s)
参考例１３－３３
１H-NMR（DMSO-d６）δ ppm：0.50-0.90 (4H, m), 2.60-2.90 (4H, m), 3.97 (3H, s), 7.38 (1H, br s), 10.44 (1H, br s), 11.40-11.70 (1H, m)  Reference Example 13-33
1 H-NMR (DMSO-d 6 ) δ ppm: 0.50-0.90 (4H, m), 2.60-2.90 (4H, m), 3.97 (3H, s), 7.38 (1H, br s), 10.44 (1H, br s), 11.40-11.70 (1H, m)
参考例１３－３４
１H-NMR（DMSO-d６）δ ppm：1.00-1.80 (16H, m), 3.60-3.70 (1H, m), 3.99 (3H, s), 7.35-7.50 (1H, m), 10.35-10.65 (1H, m), 11.40-11.70 (1H, m) Reference Example 13-34
1 H-NMR (DMSO-d 6 ) δ ppm: 1.00-1.80 (16H, m), 3.60-3.70 (1H, m), 3.99 (3H, s), 7.35-7.50 (1H, m), 10.35-10.65 (1H, m), 11.40-11.70 (1H, m)
参考例１３－３５
１H-NMR（DMSO-d６）δ ppm：0.05-0.55 (4H, m), 0.95-1.10 (1H, m), 3.00-3.15 (2H, m), 4.00 (3H, s), 7.47 (1H, s), 8.10-8.20 (1H, m), 11.14 (1H, br s), 11.77 (1H, br s) Reference Example 13-35
1 H-NMR (DMSO-d 6 ) δ ppm: 0.05-0.55 (4H, m), 0.95-1.10 (1H, m), 3.00-3.15 (2H, m), 4.00 (3H, s), 7.47 (1H , s), 8.10-8.20 (1H, m), 11.14 (1H, br s), 11.77 (1H, br s)
参考例１３－３６
１H-NMR（DMSO-d６）δ ppm：1.45-1.55 (2H, m), 1.75-1.85 (2H, m), 3.75-3.85 (3H, m), 4.00 (3H, s), 7.47 (1H, s), 8.02 (1H, d, J=7.6Hz), 11.22 (1H, s), 11.80 (1H, br s) Reference Example 13-36
1 H-NMR (DMSO-d 6 ) δ ppm: 1.45-1.55 (2H, m), 1.75-1.85 (2H, m), 3.75-3.85 (3H, m), 4.00 (3H, s), 7.47 (1H , s), 8.02 (1H, d, J = 7.6Hz), 11.22 (1H, s), 11.80 (1H, br s)
参考例１３－３７
１H-NMR（DMSO-d６）δ ppm：1.18 (3H, t, J=7.0Hz), 1.35-1.45 (2H, m), 1.80-1.85 (2H, m), 2.85-3.00 (2H, m), 3.70-3.90 (3H, m), 4.00-4.05 (5H, m), 7.47 (1H, s), 8.01 (1H, d, J=7.6Hz), 11.22 (1H, s), 11.80 (1H, br s)　 Reference Example 13-37
1 H-NMR (DMSO-d 6 ) δ ppm: 1.18 (3H, t, J = 7.0 Hz), 1.35-1.45 (2H, m), 1.80-1.85 (2H, m), 2.85-3.00 (2H, m ), 3.70-3.90 (3H, m), 4.00-4.05 (5H, m), 7.47 (1H, s), 8.01 (1H, d, J = 7.6Hz), 11.22 (1H, s), 11.80 (1H, br s)
参考例１３－３８
１H-NMR（CDCl3）δ ppm：3.85-4.05 (5H, m), 7.10 (1H, s), 8.55-8.70 (1H, m), 9.00 (1H, br s), 10.57 (1H, br s) Reference Example 13-38
1 H-NMR (CDCl 3 ) δ ppm: 3.85-4.05 (5H, m), 7.10 (1H, s), 8.55-8.70 (1H, m), 9.00 (1H, br s), 10.57 (1H, br s )
参考例１３－３９
１H-NMR（DMSO-d６）δ ppm：3.95 (3H, s), 7.10-7.15 (1H, m), 7.30-7.40 (3H, m), 7.55-7.60 (2H, m), 10.23 (1H, s), 11.51 (1H, s), 11.94 (1H, br s)　 Reference Example 13-39
1 H-NMR (DMSO-d 6 ) δ ppm: 3.95 (3H, s), 7.10-7.15 (1H, m), 7.30-7.40 (3H, m), 7.55-7.60 (2H, m), 10.23 (1H , s), 11.51 (1H, s), 11.94 (1H, br s)
参考例１３－４０
１H-NMR（DMSO-d６）δ ppm：4.02 (3H, s), 7.38 (1H, t, J=8.0Hz), 7.51 (1H, s), 7.56 (2H, d, J=8.0Hz), 9.75 (1H, br s), 11.65 (1H, br s), 11.85 (1H, br s) Reference Example 13-40
1 H-NMR (DMSO-d 6 ) δ ppm: 4.02 (3H, s), 7.38 (1H, t, J = 8.0 Hz), 7.51 (1H, s), 7.56 (2H, d, J = 8.0 Hz) , 9.75 (1H, br s), 11.65 (1H, br s), 11.85 (1H, br s)
参考例１３－４１
１H-NMR（DMSO-d６）δ ppm：2.18 (6H, s), 4.02 (3H, s), 6.95-7.20 (3H, m), 7.52 (1H, s), 9.45 (1H, br s), 11.47 (1H, br s), 11.84 (1H, br s) Reference Example 13-41
1 H-NMR (DMSO-d 6 ) δ ppm: 2.18 (6H, s), 4.02 (3H, s), 6.95-7.20 (3H, m), 7.52 (1H, s), 9.45 (1H, br s) , 11.47 (1H, br s), 11.84 (1H, br s)
参考例１３－４２
１H-NMR（DMSO-d６）δ ppm：1.36 (9H, s), 4.02 (3H, s), 7.15-7.30 (2H, m), 7.40-7.50 (3H, m), 9.94 (1H, s), 11.63 (1H, s)　 Reference Example 13-42
1 H-NMR (DMSO-d 6 ) δ ppm: 1.36 (9H, s), 4.02 (3H, s), 7.15-7.30 (2H, m), 7.40-7.50 (3H, m), 9.94 (1H, s ), 11.63 (1H, s)
参考例１３－４３
１H-NMR（DMSO-d６）δ ppm：3.88 (3H, s), 4.03 (3H, s), 7.20-7.30 (1H, m), 7.51 (1H, s), 7.60-7.70 (1H, m), 7.95-8.00 (1H, m), 8.40-8.45 (1H, m), 11.60 (1H, s), 11.78 (1H, s), 11.84 (1H, br s) Reference Example 13-43
1 H-NMR (DMSO-d 6 ) δ ppm: 3.88 (3H, s), 4.03 (3H, s), 7.20-7.30 (1H, m), 7.51 (1H, s), 7.60-7.70 (1H, m ), 7.95-8.00 (1H, m), 8.40-8.45 (1H, m), 11.60 (1H, s), 11.78 (1H, s), 11.84 (1H, br s)
参考例１３－４４
１H-NMR（DMSO-d６）δ ppm：3.18 (3H, s), 3.98 (3H, s), 7.20-7.30 (3H, m), 7.35-7.45 (3H, m), 10.48 (1H, br s), 11.56 (1H, br s)　 Reference Example 13-44
1 H-NMR (DMSO-d 6 ) δ ppm: 3.18 (3H, s), 3.98 (3H, s), 7.20-7.30 (3H, m), 7.35-7.45 (3H, m), 10.48 (1H, br s), 11.56 (1H, br s)
参考例１３－４５
１H-NMR（DMSO-d６）δ ppm：2.35-2.45 (3H, m), 4.02 (3H, s), 6.62 (1H, s), 7.52 (1H, s), 10.49 (1H, s), 11.97 (1H, s)　 Reference Example 13-45
1 H-NMR (DMSO-d 6 ) δ ppm: 2.35-2.45 (3H, m), 4.02 (3H, s), 6.62 (1H, s), 7.52 (1H, s), 10.49 (1H, s), 11.97 (1H, s)
参考例１３－４６
１H-NMR（DMSO-d６）δ ppm：4.00 (3H, s), 4.41 (2H, d, J=6.0Hz), 7.20-7.40 (5H, m), 7.47 (1H, s), 8.55 (1H, t, J=6.0Hz), 11.24 (1H, s), 11.77 (1H, br s)　 Reference Example 13-46
1 H-NMR (DMSO-d 6 ) δ ppm: 4.00 (3H, s), 4.41 (2H, d, J = 6.0 Hz), 7.20-7.40 (5H, m), 7.47 (1H, s), 8.55 ( 1H, t, J = 6.0Hz), 11.24 (1H, s), 11.77 (1H, br s)
参考例１３－４７
１H-NMR（CDCl3）δ ppm：2.75-2.85 (2H, m), 3.40-3.50 (2H, m), 3.97 (3H, s), 7.15-7.40 (6H, m), 8.15-8.30 (1H, m), 9.45 (1H, br s), 10.60 (1H, br s) Reference Example 13-47
1 H-NMR (CDCl 3 ) δ ppm: 2.75-2.85 (2H, m), 3.40-3.50 (2H, m), 3.97 (3H, s), 7.15-7.40 (6H, m), 8.15-8.30 (1H , m), 9.45 (1H, br s), 10.60 (1H, br s)
参考例１３－４８
１H-NMR（DMSO-d６）δ ppm：2.81 (3H, br s), 3.99 (3H, s), 4.35-4.55 (2H, m), 7.15-7.45 (6H, m), 10.79 (1H, br s), 11.51 (1H, br s)　 Reference Example 13-48
1 H-NMR (DMSO-d 6 ) δ ppm: 2.81 (3H, br s), 3.99 (3H, s), 4.35-4.55 (2H, m), 7.15-7.45 (6H, m), 10.79 (1H, br s), 11.51 (1H, br s)
参考例１３－４９
１H-NMR（DMSO-d６）δ ppm：1.80 (3H, s), 3.10-3.30 (4H, m), 4.00 (3H, s), 7.46 (1H, s), 7.93 (1H, t, J=5.0Hz), 8.14 (1H, t, J=5.0Hz), 11.15 (1H, s), 11.77 (1H, br s) Reference Example 13-49
1 H-NMR (DMSO-d 6 ) δ ppm: 1.80 (3H, s), 3.10-3.30 (4H, m), 4.00 (3H, s), 7.46 (1H, s), 7.93 (1H, t, J = 5.0Hz), 8.14 (1H, t, J = 5.0Hz), 11.15 (1H, s), 11.77 (1H, br s)
参考例１３－５０
１H-NMR（CDCl3）δ ppm：1.15-1.30 (3H, m), 3.45-3.65 (6H, m), 3.99 (3H, s), 7.09 (1H, s), 8.25 (1H, br s), 8.35-8.45 (1H, m), 10.55 (1H, br s) Reference Example 13-50
1 H-NMR (CDCl 3 ) δ ppm: 1.15-1.30 (3H, m), 3.45-3.65 (6H, m), 3.99 (3H, s), 7.09 (1H, s), 8.25 (1H, br s) , 8.35-8.45 (1H, m), 10.55 (1H, br s)
参考例１３－５１
１H-NMR（CDCl3）δ ppm：1.15-1.30 (3H, m), 1.80-1.95 (2H, m), 3.35-3.60 (6H, m), 3.98 (3H, s), 7.09 (1H, s), 8.30-8.40 (1H, m), 8.60 (1H, br s), 10.57 (1H, br s) Reference Example 13-51
1 H-NMR (CDCl 3 ) δ ppm: 1.15-1.30 (3H, m), 1.80-1.95 (2H, m), 3.35-3.60 (6H, m), 3.98 (3H, s), 7.09 (1H, s ), 8.30-8.40 (1H, m), 8.60 (1H, br s), 10.57 (1H, br s)
参考例１３－５２
１H-NMR（DMSO-d６）δ ppm：1.05-1.20 (3H, m), 3.20-3.50 (6H, m), 4.00 (3H, s), 7.47 (1H, s), 8.10-8.25 (1H, m), 11.18 (1H, br s), 11.78 (1H, br s) Reference Example 13-52
1 H-NMR (DMSO-d 6 ) δ ppm: 1.05-1.20 (3H, m), 3.20-3.50 (6H, m), 4.00 (3H, s), 7.47 (1H, s), 8.10-8.25 (1H , m), 11.18 (1H, br s), 11.78 (1H, br s)
参考例１３－５３
１H-NMR（DMSO-d６）δ ppm：1.05-1.20 (3H, m), 1.60-1.80 (2H, m), 3.20-3.50 (6H, m), 4.00 (3H, s), 7.46 (1H, s), 8.10-8.25 (1H, m), 11.10 (1H, br s), 11.75 (1H, br s) Reference Example 13-53
1 H-NMR (DMSO-d 6 ) δ ppm: 1.05-1.20 (3H, m), 1.60-1.80 (2H, m), 3.20-3.50 (6H, m), 4.00 (3H, s), 7.46 (1H , s), 8.10-8.25 (1H, m), 11.10 (1H, br s), 11.75 (1H, br s)
参考例１３－５４
１H-NMR（DMSO-d６）δ ppm：1.65-1.75 (2H, m), 3.20-3.40 (7H, m), 3.95 (3H, s), 7.34 (1H, s), 8.18 (1H, t, J=5.6Hz), 11.03 (1H, s), 11.70 (1H, br s)　 Reference Example 13-54
1 H-NMR (DMSO-d 6 ) δ ppm: 1.65-1.75 (2H, m), 3.20-3.40 (7H, m), 3.95 (3H, s), 7.34 (1H, s), 8.18 (1H, t , J = 5.6Hz), 11.03 (1H, s), 11.70 (1H, br s)
参考例１３－５５
１H-NMR（DMSO-d６）δ ppm：1.00-1.15 (6H, m), 1.60-1.75 (2H, m), 3.20-3.55 (5H, m), 4.00 (3H, s), 7.47 (1H, s), 8.10-8.25 (1H, m), 11.11 (1H, br s), 11.77 (1H, br s) Reference Example 13-55
1 H-NMR (DMSO-d 6 ) δ ppm: 1.00-1.15 (6H, m), 1.60-1.75 (2H, m), 3.20-3.55 (5H, m), 4.00 (3H, s), 7.47 (1H , s), 8.10-8.25 (1H, m), 11.11 (1H, br s), 11.77 (1H, br s)
参考例１３－５６
１H-NMR（DMSO-d６）δ ppm：1.40-1.55 (6H, m), 3.25-3.35 (4H, m), 3.99 (3H, s), 7.40 (1H, s), 10.80 (1H, s), 11.47 (1H, s)　 Reference Example 13-56
1 H-NMR (DMSO-d 6 ) δ ppm: 1.40-1.55 (6H, m), 3.25-3.35 (4H, m), 3.99 (3H, s), 7.40 (1H, s), 10.80 (1H, s ), 11.47 (1H, s)
参考例１３－５７
１H-NMR（DMSO-d６）δ ppm：1.65-1.75 (2H, m), 2.96 (3H, s), 3.22 (3H, s), 3.25-3.40 (4H, m), 3.71 (3H, s), 6.63 (1H, s), 8.92 (1H, t, J=5.7Hz)　 Reference Example 13-57
1 H-NMR (DMSO-d 6 ) δ ppm: 1.65-1.75 (2H, m), 2.96 (3H, s), 3.22 (3H, s), 3.25-3.40 (4H, m), 3.71 (3H, s ), 6.63 (1H, s), 8.92 (1H, t, J = 5.7Hz)
参考例１３－５８
MS (ESI, m/z): 344 (M+H)+　
MS (ESI, m/z): 342 (M-H)- Reference Example 13-58
MS (ESI, m / z): 344 (M + H) +
MS (ESI, m / z): 342 (MH)-
参考例１３－５９
１H-NMR（CDCl3）δ ppm：2.95-3.00 (3H, m), 3.07 (3H, s), 4.05 (3H, s), 7.32 (1H, s), 8.76 (1H, br s) Reference Example 13-59
1 H-NMR (CDCl 3 ) δ ppm: 2.95-3.00 (3H, m), 3.07 (3H, s), 4.05 (3H, s), 7.32 (1H, s), 8.76 (1H, br s)
参考例１３－６１
MS (ESI, m/z): 366 (M+H)+ Reference Example 13-61
MS (ESI, m / z): 366 (M + H) +
参考例１３－６３
MS (ESI, m/z): 406 (M+H)+
MS (ESI, m/z): 404 (M-H)- Reference Example 13-63
MS (ESI, m / z): 406 (M + H) +
MS (ESI, m / z): 404 (MH)-
参考例１３－６４
MS (ESI, m/z): 420 (M+H)+ Reference Example 13-64
MS (ESI, m / z): 420 (M + H) +
参考例１３－６５
MS (ESI, m/z): 366 (M-H)- Reference Example 13-65
MS (ESI, m / z): 366 (MH)-
参考例１３－６６
１H-NMR（DMSO-d６）δ ppm：0.45-0.65 (4H, m), 2.50-2.55 (1H, m), 3.16 (3H, s), 3.96 (3H, s), 7.68 (1H, s), 8.07 (1H, br s) Reference Example 13-66
1 H-NMR (DMSO-d 6 ) δ ppm: 0.45-0.65 (4H, m), 2.50-2.55 (1H, m), 3.16 (3H, s), 3.96 (3H, s), 7.68 (1H, s ), 8.07 (1H, br s)
参考例１３－６７
MS (ESI, m/z): 432 (M-H)- Reference Example 13-67
MS (ESI, m / z): 432 (MH)-
参考例１３－６８
１H-NMR（CDCl3）δ ppm：3.14 (3H, s), 4.07 (3H, s), 7.00-7.20 (1H, m), 7.30-7.50 (3H, m), 7.50-7.70 (2H, m) Reference Example 13-68
1 H-NMR (CDCl 3 ) δ ppm: 3.14 (3H, s), 4.07 (3H, s), 7.00-7.20 (1H, m), 7.30-7.50 (3H, m), 7.50-7.70 (2H, m )
参考例１３－６９
MS (ESI, m/z): 428 (M+H)+ Reference Example 13-69
MS (ESI, m / z): 428 (M + H) +
参考例１３－７０
MS (ESI, m/z): 420 (M-H)- Reference Example 13-70
MS (ESI, m / z): 420 (MH)-
参考例１３－７１
MS (ESI, m/z): 434 (M-H)- Reference Example 13-71
MS (ESI, m / z): 434 (MH)-
参考例１３－７２
MS (ESI, m/z): 454 (M+H)+
MS (ESI, m/z): 452 (M-H)- Reference Example 13-72
MS (ESI, m / z): 454 (M + H) +
MS (ESI, m / z): 452 (MH)-
参考例１３－７３
１H-NMR（DMSO-d６）δ ppm：1.80-2.00 (2H, m), 2.77 (3H, s), 3.74 (2H, t, J=5.7Hz), 3.97 (3H, s), 7.38 (1H, s), 11.30-11.60 (1H, m) Reference Example 13-73
1 H-NMR (DMSO-d 6 ) δ ppm: 1.80-2.00 (2H, m), 2.77 (3H, s), 3.74 (2H, t, J = 5.7 Hz), 3.97 (3H, s), 7.38 ( 1H, s), 11.30-11.60 (1H, m)
参考例１３－７４
１H-NMR（CDCl3）δ ppm：3.96 (3H, s), 4.03 (3H, s), 7.29 (1H, s), 10.39 (1H, s) Reference Example 13-74
1 H-NMR (CDCl 3 ) δ ppm: 3.96 (3H, s), 4.03 (3H, s), 7.29 (1H, s), 10.39 (1H, s)
参考例１３－７５
MS (ESI, m/z):360 (M+H)+ Reference Example 13-75
MS (ESI, m / z): 360 (M + H) +
参考例１３－７６
MS (ESI, m/z):358 (M+H)+ Reference Example 13-76
MS (ESI, m / z): 358 (M + H) +
参考例１３－７７
MS (ESI, m/z):404 (M+H)+ Reference Example 13-77
MS (ESI, m / z): 404 (M + H) +
参考例１３－７８
MS (ESI, m/z):388 (M+H)+ Reference Example 13-78
MS (ESI, m / z): 388 (M + H) +
参考例１３－７９
MS (ESI, m/z):408 (M+H)+ Reference Example 13-79
MS (ESI, m / z): 408 (M + H) +
参考例１３－８０
MS (ESI, m/z):372 (M+H)+ Reference Example 13-80
MS (ESI, m / z): 372 (M + H) +
参考例１３－８１
MS (ESI, m/z):374 (M+H)+ Reference Example 13-81
MS (ESI, m / z): 374 (M + H) +
参考例１３－８２
MS (ESI, m/z):374(M+H)+ Reference Example 13-82
MS (ESI, m / z): 374 (M + H) +
参考例１３－８３
MS (ESI, m/z):332 (M+H)+ Reference Example 13-83
MS (ESI, m / z): 332 (M + H) +
参考例１３－８４
NEID0876
MS (ESI, m/z):346 (M+H)+ Reference Example 13-84
NEID0876
MS (ESI, m / z): 346 (M + H) +
参考例１３－８５
MS (ESI, m/z):346 (M+H)+ Reference Example 13-85
MS (ESI, m / z): 346 (M + H) +
参考例１３－８６
MS (ESI, m/z):360 (M+H)+ Reference Example 13-86
MS (ESI, m / z): 360 (M + H) +
参考例１３－８７
MS (ESI, m/z):374 (M+H)+ Reference Example 13-87
MS (ESI, m / z): 374 (M + H) +
参考例１３－８８
MS (ESI, m/z):404 (M+H)+ Reference Example 13-88
MS (ESI, m / z): 404 (M + H) +
参考例１３－８９
MS (ESI, m/z):386 (M+H)+ Reference Example 13-89
MS (ESI, m / z): 386 (M + H) +
参考例１３－９０
MS (ESI, m/z):444 (M+H)+ Reference Example 13-90
MS (ESI, m / z): 444 (M + H) +
参考例１３－９１
MS (ESI, m/z):419 (M+H)+ Reference Example 13-91
MS (ESI, m / z): 419 (M + H) +
参考例１４－１ 
３，４－ジメトキシ－２－ニトロ－６－トリフルオロメチル安息香酸メチル
　３－ヒドロキシ－４－メトキシ－２－ニトロ－６－トリフルオロメチル安息香酸メチル（参考例１３－７４）(4.33g)のアセトン(150mL)溶液に室温にて炭酸水素ナトリウム(6.15g)およびジメチル硫酸(6.95mL)を加え、3日間加熱還流した。反応混合物に水を加え、アセトンを減圧下留去した。残渣を酢酸エチルにて抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。残渣をアミノプロピルシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン/酢酸エチル＝19/1～1/1）にて精製して表題化合物(4.23g)を得た。構造式を表１０に示した。
１H-NMR（CDCl3）δ ppm：3.89 (3H, s), 4.007 (3H, s), 4.013 (3H, s), 7.29 (1H, s) Reference Example 14-1
Methyl 3,4-dimethoxy-2-nitro-6-trifluoromethylbenzoate Methyl 3-hydroxy-4-methoxy-2-nitro-6-trifluoromethylbenzoate (Reference Example 13-74) (4.33 g) Sodium bicarbonate (6.15 g) and dimethyl sulfate (6.95 mL) were added to an acetone (150 mL) solution at room temperature, and the mixture was heated to reflux for 3 days. Water was added to the reaction mixture, and acetone was distilled off under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: hexane / ethyl acetate = 19/1 to 1/1) to give the title compound (4.23 g). The structural formula is shown in Table 10.
1 H-NMR (CDCl 3 ) δ ppm: 3.89 (3H, s), 4.007 (3H, s), 4.013 (3H, s), 7.29 (1H, s)
参考例１５－１ 
３，４－ジメトキシ－２－ニトロ－６－トリフルオロメチル安息香酸
　５－ベンジルオキシ－４－メトキシ－２－トリフルオロメチル安息香酸メチルの代わりに３，４－ジメトキシ－２－ニトロ－６－トリフルオロメチル安息香酸メチル（参考例１４－１）を用い、参考例５－１と同様の方法により、表題化合物を合成した。構造式を表１０に示した。
１H-NMR（CDCl3）δ ppm：3.94 (3H, s), 4.04 (3H, s), 7.63 (1H, s) Reference Example 15-1
3,4-Dimethoxy-2-nitro-6-trifluoromethylbenzoic acid Instead of methyl 5-benzyloxy-4-methoxy-2-trifluoromethylbenzoate, 3,4-dimethoxy-2-nitro-6-trimethyl The title compound was synthesized in the same manner as in Reference Example 5-1, using methyl fluoromethylbenzoate (Reference Example 14-1). The structural formula is shown in Table 10.
1 H-NMR (CDCl 3 ) δ ppm: 3.94 (3H, s), 4.04 (3H, s), 7.63 (1H, s)
参考例１６－１ 
３，４－ジメトキシ－２－ニトロ－６－トリフルオロメチルベンズアミド
　５－ベンジルオキシ－４－メトキシ－２－トリフルオロメチル安息香酸の代わりに３，４－ジメトキシ－２－ニトロ－６－トリフルオロメチル安息香酸（参考例１５－１）を用い、参考例６－１と同様の方法により、表題化合物を合成した。構造式を表１０に示した。
１H-NMR（DMSO-d６）δ ppm：3.93 (3H, s), 4.02 (3H, s), 7.60 (1H, s), 7.88 (1H, br s), 8.14 (1H, br s) Reference Example 16-1
3,4-Dimethoxy-2-nitro-6-trifluoromethylbenzamide 3,4-Dimethoxy-2-nitro-6-trifluoromethyl instead of 5-benzyloxy-4-methoxy-2-trifluoromethylbenzoic acid The title compound was synthesized in the same manner as in Reference Example 6-1 using benzoic acid (Reference Example 15-1). The structural formula is shown in Table 10.
1 H-NMR (DMSO-d 6 ) δ ppm: 3.93 (3H, s), 4.02 (3H, s), 7.60 (1H, s), 7.88 (1H, br s), 8.14 (1H, br s)
参考例１７－１
１－（３，４－ジメトキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）－３－インダン－２－イル尿素
　５－ベンジルオキシ－２－クロロ－４－メトキシベンズアミドの代わりに３，４－ジメトキシ－２－ニトロ－６－トリフルオロメチルベンズアミド（参考例１６－１）を用い、参考例７－１と同様の方法により、表題化合物を合成した。構造式を表１０に示した。
１H-NMR（DMSO-d６）δ ppm：2.85-2.95 (2H, m), 3.20-3.30 (2H, m), 3.95 (3H, s), 4.04 (3H, s), 4.45-4.55 (1H, m), 7.15-7.25 (4H, m), 7.66 (1H, s), 8.18 (1H, d, J=7.3Hz), 11.32 (1H, s)　 Reference Example 17-1
1- (3,4-Dimethoxy-2-nitro-6-trifluoromethylbenzoyl) -3-indan-2-ylurea 3,4-dimethoxy instead of 5-benzyloxy-2-chloro-4-methoxybenzamide The title compound was synthesized in the same manner as in Reference Example 7-1 using -2-nitro-6-trifluoromethylbenzamide (Reference Example 16-1). The structural formula is shown in Table 10.
1 H-NMR (DMSO-d 6 ) δ ppm: 2.85-2.95 (2H, m), 3.20-3.30 (2H, m), 3.95 (3H, s), 4.04 (3H, s), 4.45-4.55 (1H , m), 7.15-7.25 (4H, m), 7.66 (1H, s), 8.18 (1H, d, J = 7.3Hz), 11.32 (1H, s)
参考例１８－１ 
１－（３－ヒドロキシ－４－メトキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）－３－インダン－２－イル尿素
　１－（３，４－ジメトキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）－３－インダン－２－イル尿素（参考例１７－１）(0.191g)のＮ，Ｎ－ジメチルホルムアミド(7mL)溶液にアルゴン下室温にて塩化リチウム(179mg)を加え、反応混合物を外温130℃にて1時間20分加熱撹拌した。反応混合物に2mol/L塩酸を加え、酢酸エチルにて抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去して表題化合物(0.185g)を得た。構造式を表１０に示した。
MS (ESI, m/z): 440 (M+H)+
MS (ESI, m/z): 438 (M-H)-　 Reference Example 18-1
1- (3-hydroxy-4-methoxy-2-nitro-6-trifluoromethylbenzoyl) -3-indan-2-ylurea 1- (3,4-dimethoxy-2-nitro-6-trifluoromethylbenzoyl) ) 3-Indan-2-ylurea (Reference Example 17-1) (0.191 g) in N, N-dimethylformamide (7 mL) was added lithium chloride (179 mg) at room temperature under argon, and the reaction mixture was removed. The mixture was heated and stirred at a temperature of 130 ° C. for 1 hour and 20 minutes. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.185 g). The structural formula is shown in Table 10.
MS (ESI, m / z): 440 (M + H) +
MS (ESI, m / z): 438 (MH)-
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
実施例１－１
１－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）－３－シクロプロピルメチル尿素（化合物１－１）
　１－（６－クロロ－３－ヒドロキシ－４－メトキシ－２－ニトロベンゾイル）－３－シクロプロピルメチル尿素（参考例１３－１）(0.248g)および酢酸エチル(10mL)の混合物に室温撹拌下、塩化アルミニウム(0.299g)およびピリジン(0.248mL)を加え、2時間加熱還流した。反応混合物を室温に冷却後、5mol/L塩酸(3mL)を加えた。反応混合物を室温にて30分撹拌した。分離した有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。得られた残渣に塩化メチレンとヘキサンを加え、析出物を濾取して表題化合物(0.153g)を得た。構造式を表１１に示した。
１H-NMR（DMSO-d6）δ ppm：0.15-0.30 (2H, m), 0.35-0.50 (2H, m), 0.90-1.10 (1H, m), 3.00-3.15 (2H, m), 7.02 (1H, s), 8.15-8.30 (1H, m), 10.35-11.50 (3H, m) Example 1-1
1- (6-Chloro-3,4-dihydroxy-2-nitrobenzoyl) -3-cyclopropylmethylurea (Compound 1-1)
A mixture of 1- (6-chloro-3-hydroxy-4-methoxy-2-nitrobenzoyl) -3-cyclopropylmethylurea (Reference Example 13-1) (0.248 g) and ethyl acetate (10 mL) was stirred at room temperature. , Aluminum chloride (0.299 g) and pyridine (0.248 mL) were added, and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, and 5 mol / L hydrochloric acid (3 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Methylene chloride and hexane were added to the obtained residue, and the precipitate was collected by filtration to give the title compound (0.153 g). The structural formula is shown in Table 11.
1 H-NMR (DMSO-d 6 ) δ ppm: 0.15-0.30 (2H, m), 0.35-0.50 (2H, m), 0.90-1.10 (1H, m), 3.00-3.15 (2H, m), 7.02 (1H, s), 8.15-8.30 (1H, m), 10.35-11.50 (3H, m)
　１－（６－クロロ－３－ヒドロキシ－４－メトキシ－２－ニトロベンゾイル）－３－シクロプロピルメチル尿素の代わりに対応する２－メトキシ－６－ニトロフェノールを用い実施例１－１と同様の方法により、化合物１－２～化合物１－９１を合成した。構造式を表１１に示した。 1- (6-Chloro-3-hydroxy-4-methoxy-2-nitrobenzoyl) -3-cyclopropylmethylurea was replaced with the corresponding 2-methoxy-6-nitrophenol in the same manner as in Example 1-1. According to the method, compounds 1-2 to 1-91 were synthesized. The structural formula is shown in Table 11.
実施例２－１
２，２－ジメチルプロピオン酸=４－クロロ－３－（３－シクロヘプチルウレイドカルボニル）－６－（２，２－ジメチルプロピオニルオキシ）－２－ニトロフェニル（化合物２－１）
　１－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）－３－シクロヘプチル尿素（化合物１－２４）(121mg)のテトラヒドロフラン(2mL)溶液に、トリメチルアセチルクロリド(0.092mL)およびトリエチルアミン(0.100mL)を氷冷撹拌下にて加えた。その混合物を30分間撹拌した後、室温まで昇温させ、一晩撹拌した。その反応混合物を酢酸エチルで希釈し、1mol/L塩酸および飽和食塩水で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン/酢酸エチル＝19/1～1/1）にて精製して表題化合物(0.156mg)を得た。構造式を表１１に示した。
１H-NMR（CDCl3）δ ppm：1.33 (9H, s), 1.34 (9H, s), 1.40-1.70 (10H, m),  1.85-1.95 (2H, m), 3.65-3.80 (1H, m), 7.51 (1H, s), 8.06 (1H, d, J=7.6Hz), 10.43 (1H, br s) Example 2-1
2,2-dimethylpropionic acid = 4-chloro-3- (3-cycloheptylureidocarbonyl) -6- (2,2-dimethylpropionyloxy) -2-nitrophenyl (compound 2-1)
To a solution of 1- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) -3-cycloheptylurea (compound 1-24) (121 mg) in tetrahydrofuran (2 mL) was added trimethylacetyl chloride (0.092 mL) and triethylamine. (0.100 mL) was added under ice-cooling stirring. The mixture was stirred for 30 minutes, then warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with 1 mol / L hydrochloric acid and saturated brine. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 19 / 1-1 / 1) to give the title compound (0.156 mg). The structural formula is shown in Table 11.
1 H-NMR (CDCl 3 ) δ ppm: 1.33 (9H, s), 1.34 (9H, s), 1.40-1.70 (10H, m), 1.85-1.95 (2H, m), 3.65-3.80 (1H, m ), 7.51 (1H, s), 8.06 (1H, d, J = 7.6Hz), 10.43 (1H, br s)
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-I000037
Figure JPOXMLDOC01-appb-I000038
Figure JPOXMLDOC01-appb-I000039
Figure JPOXMLDOC01-appb-I000040
Figure JPOXMLDOC01-appb-I000041
Figure JPOXMLDOC01-appb-I000042
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-I000037
Figure JPOXMLDOC01-appb-I000038
Figure JPOXMLDOC01-appb-I000039
Figure JPOXMLDOC01-appb-I000040
Figure JPOXMLDOC01-appb-I000041
Figure JPOXMLDOC01-appb-I000042
　化合物１－２～化合物１－９１の物性値を以下に示した。 The physical property values of Compound 1-2 to Compound 1-91 are shown below.
化合物１－２
１H-NMR（DMSO-d６）δ ppm：0.75-0.95 (3H, m), 1.40-1.60 (2H, m), 3.05-3.25 (2H, m), 7.02 (1H, s), 8.05-8.25 (1H, m), 10.25-11.65 (3H, m) Compound 1-2
1 H-NMR (DMSO-d 6 ) δ ppm: 0.75-0.95 (3H, m), 1.40-1.60 (2H, m), 3.05-3.25 (2H, m), 7.02 (1H, s), 8.05-8.25 (1H, m), 10.25-11.65 (3H, m)
化合物１－３
１H-NMR（DMSO-d６）δ ppm：0.80-1.00 (3H, m), 1.20-1.55 (4H, m), 3.10-3.30 (2H, m), 7.01 (1H, s), 8.05-8.20 (1H, m), 10.30-11.65 (3H, m) Compound 1-3
1 H-NMR (DMSO-d 6 ) δ ppm: 0.80-1.00 (3H, m), 1.20-1.55 (4H, m), 3.10-3.30 (2H, m), 7.01 (1H, s), 8.05-8.20 (1H, m), 10.30-11.65 (3H, m)
化合物１－４
１H-NMR（DMSO-d６）δ ppm：0.80-0.95 (3H, m), 1.15-1.55 (6H, m), 3.10-3.25 (2H, m), 7.01 (1H, s), 8.05-8.25 (1H, m), 10.30-11.65 (3H, m) Compound 1-4
1 H-NMR (DMSO-d 6 ) δ ppm: 0.80-0.95 (3H, m), 1.15-1.55 (6H, m), 3.10-3.25 (2H, m), 7.01 (1H, s), 8.05-8.25 (1H, m), 10.30-11.65 (3H, m)
化合物１－５
１H-NMR（DMSO-d６）δ ppm：1.05-1.25 (6H, m), 3.75-3.95 (1H, m), 7.01 (1H, s), 7.90-8.10 (1H, m), 9.65-11.85 (3H, m) Compound 1-5
1 H-NMR (DMSO-d 6 ) δ ppm: 1.05-1.25 (6H, m), 3.75-3.95 (1H, m), 7.01 (1H, s), 7.90-8.10 (1H, m), 9.65-11.85 (3H, m)
化合物１－６
１H-NMR（DMSO-d６）δ ppm：1.32 (9H, s), 7.01 (1H, s), 8.10 (1H, br s), 10.10-11.50 (3H, m) Compound 1-6
1 H-NMR (DMSO-d 6 ) δ ppm: 1.32 (9H, s), 7.01 (1H, s), 8.10 (1H, br s), 10.10-11.50 (3H, m)
化合物１－７
１H-NMR（DMSO-d６）δ ppm：0.80-0.95 (3H, m), 1.40-1.55 (2H, m), 3.10-3.20 (2H, m), 7.23 (1H, s), 8.05-8.20 (1H, m), 11.06 (1H, br s), 11.38 (2H, br s) Compound 1-7
1 H-NMR (DMSO-d 6 ) δ ppm: 0.80-0.95 (3H, m), 1.40-1.55 (2H, m), 3.10-3.20 (2H, m), 7.23 (1H, s), 8.05-8.20 (1H, m), 11.06 (1H, br s), 11.38 (2H, br s)
化合物１－８
１H-NMR（DMSO-d６）δ ppm：0.80-0.95 (3H, m), 1.20-1.55 (4H, m), 3.10-3.25 (2H, m), 7.23 (1H, s), 8.00-8.15 (1H, m), 11.05 (1H, br s), 11.38 (2H, br s) Compound 1-8
1 H-NMR (DMSO-d 6 ) δ ppm: 0.80-0.95 (3H, m), 1.20-1.55 (4H, m), 3.10-3.25 (2H, m), 7.23 (1H, s), 8.00-8.15 (1H, m), 11.05 (1H, br s), 11.38 (2H, br s)
化合物１－９
１H-NMR（DMSO-d６）δ ppm：0.80-0.95 (3H, m), 1.10-1.55 (6H, m), 3.10-3.25 (2H, m), 7.24 (1H, s), 8.05-8.15 (1H, m), 11.06 (1H, br s), 11.41 (2H, br s) Compound 1-9
1 H-NMR (DMSO-d 6 ) δ ppm: 0.80-0.95 (3H, m), 1.10-1.55 (6H, m), 3.10-3.25 (2H, m), 7.24 (1H, s), 8.05-8.15 (1H, m), 11.06 (1H, br s), 11.41 (2H, br s)
化合物１－１０
１H-NMR（DMSO-d６）δ ppm：0.80-0.95 (3H, m), 1.00-1.55 (8H, m), 3.10-3.25 (2H, m), 7.22 (1H, s), 8.05-8.15 (1H, m), 11.04 (1H, br s), 11.34 (1H, br s) Compound 1-10
1 H-NMR (DMSO-d 6 ) δ ppm: 0.80-0.95 (3H, m), 1.00-1.55 (8H, m), 3.10-3.25 (2H, m), 7.22 (1H, s), 8.05-8.15 (1H, m), 11.04 (1H, br s), 11.34 (1H, br s)
化合物１－１１
１H-NMR（DMSO-d６）δ ppm：0.80-0.95 (3H, m), 1.15-1.55 (10H, m), 3.10-3.25 (2H, m), 7.22 (1H, s), 8.00-8.15 (1H, m), 11.04 (1H, br s), 11.36 (1H, br s) Compound 1-11
1 H-NMR (DMSO-d 6 ) δ ppm: 0.80-0.95 (3H, m), 1.15-1.55 (10H, m), 3.10-3.25 (2H, m), 7.22 (1H, s), 8.00-8.15 (1H, m), 11.04 (1H, br s), 11.36 (1H, br s)
化合物１－１２
１H-NMR（DMSO-d６）δ ppm：0.95-1.30 (6H, m), 3.75-3.90 (1H, m), 7.24 (1H, s), 7.85-7.95 (1H, m), 11.07 (1H, br s), 11.42 (2H, br s) Compound 1-12
1 H-NMR (DMSO-d 6 ) δ ppm: 0.95-1.30 (6H, m), 3.75-3.90 (1H, m), 7.24 (1H, s), 7.85-7.95 (1H, m), 11.07 (1H , br s), 11.42 (2H, br s)
化合物１－１３
１H-NMR（DMSO-d６）δ ppm：0.75-0.95 (6H, m), 1.70-1.85 (1H, m), 2.95-3.10 (2H, m), 7.24 (1H, s), 8.05-8.20 (1H, m), 11.08 (1H, br s), 11.36 (1H, br s) Compound 1-13
1 H-NMR (DMSO-d 6 ) δ ppm: 0.75-0.95 (6H, m), 1.70-1.85 (1H, m), 2.95-3.10 (2H, m), 7.24 (1H, s), 8.05-8.20 (1H, m), 11.08 (1H, br s), 11.36 (1H, br s)
化合物１－１４
１H-NMR（DMSO-d６）δ ppm：1.32 (9H, s), 7.23 (1H, s), 8.03 (1H, s), 10.94 (1H, s), 11.37 (1H, br s)　 Compound 1-14
1 H-NMR (DMSO-d 6 ) δ ppm: 1.32 (9H, s), 7.23 (1H, s), 8.03 (1H, s), 10.94 (1H, s), 11.37 (1H, br s)
化合物１－１５
１H-NMR（DMSO-d６）δ ppm：0.75-0.95 (6H, m), 1.35-1.60 (4H, m), 3.05-3.30 (4H, m), 6.97 (1H, s), 10.39 (1H, br s), 10.74 (2H, br s) Compound 1-15
1 H-NMR (DMSO-d 6 ) δ ppm: 0.75-0.95 (6H, m), 1.35-1.60 (4H, m), 3.05-3.30 (4H, m), 6.97 (1H, s), 10.39 (1H , br s), 10.74 (2H, br s)
化合物１－１６
１H-NMR（DMSO-d６）δ ppm：2.84 (6H, br s), 7.20 (1H, s), 10.59 (1H, br s), 11.13 (2H, br s)　 Compound 1-16
1 H-NMR (DMSO-d 6 ) δ ppm: 2.84 (6H, br s), 7.20 (1H, s), 10.59 (1H, br s), 11.13 (2H, br s)
化合物１－１７
１H-NMR（DMSO-d６）δ ppm：0.90-1.15 (6H, m), 3.10-3.35 (4H, m), 7.19 (1H, br s), 10.48 (1H, br s), 11.13 (2H, br s) Compound 1-17
1 H-NMR (DMSO-d 6 ) δ ppm: 0.90-1.15 (6H, m), 3.10-3.35 (4H, m), 7.19 (1H, br s), 10.48 (1H, br s), 11.13 (2H , br s)
化合物１－１８
１H-NMR（DMSO-d６）δ ppm：0.70-1.00 (3H, m), 1.30-1.60 (2H, m), 2.83 (3H, s), 2.95-3.70 (2H, m), 7.18 (1H, br s), 10.20-11.70 (3H, m) Compound 1-18
1 H-NMR (DMSO-d 6 ) δ ppm: 0.70-1.00 (3H, m), 1.30-1.60 (2H, m), 2.83 (3H, s), 2.95-3.70 (2H, m), 7.18 (1H , br s), 10.20-11.70 (3H, m)
化合物１－１９
１H-NMR（DMSO-d６）δ ppm：0.65-0.95 (6H, m), 1.30-1.60 (4H, m), 3.00-3.30 (4H, m), 7.19 (1H, br s), 10.44 (1H, br s), 11.12 (2H, br s) Compound 1-19
1 H-NMR (DMSO-d 6 ) δ ppm: 0.65-0.95 (6H, m), 1.30-1.60 (4H, m), 3.00-3.30 (4H, m), 7.19 (1H, br s), 10.44 ( 1H, br s), 11.12 (2H, br s)
化合物１－２０
１H-NMR（DMSO-d６）δ ppm： 0.75-1.00 (6H, m), 1.10-1.55 (8H, m), 3.00-3.35 (4H, m), 7.19 (1H, s), 10.42 (1H, br s), 11.11 (2H, br s) Compound 1-20
1 H-NMR (DMSO-d 6 ) δ ppm: 0.75-1.00 (6H, m), 1.10-1.55 (8H, m), 3.00-3.35 (4H, m), 7.19 (1H, s), 10.42 (1H , br s), 11.11 (2H, br s)
化合物１－２１
１H-NMR（DMSO-d６）δ ppm：1.00-1.30 (12H, m), 3.60-3.80 (2H, m), 7.20 (1H, br s), 10.25-10.60 (1H, m), 11.00-11.40 (2H, m) Compound 1-21
1 H-NMR (DMSO-d 6 ) δ ppm: 1.00-1.30 (12H, m), 3.60-3.80 (2H, m), 7.20 (1H, br s), 10.25-10.60 (1H, m), 11.00- 11.40 (2H, m)
化合物１－２２
１H-NMR（DMSO-d６）δ ppm：0.30-0.80 (4H, m), 2.50-2.80 (1H, m), 7.01 (1H, s), 8.10 (1H, br s), 10.00-12.00 (2H, m)　 Compound 1-22
1 H-NMR (DMSO-d 6 ) δ ppm: 0.30-0.80 (4H, m), 2.50-2.80 (1H, m), 7.01 (1H, s), 8.10 (1H, br s), 10.00-12.00 ( 2H, m)
化合物１－２３
１H-NMR（DMSO-d６）δ ppm：1.10-1.90 (10H, m), 3.45-3.60 (1H, m), 7.01 (1H, s), 8.06 (1H, br s), 11.05 (1H, br s) Compound 1-23
1 H-NMR (DMSO-d 6 ) δ ppm: 1.10-1.90 (10H, m), 3.45-3.60 (1H, m), 7.01 (1H, s), 8.06 (1H, br s), 11.05 (1H, br s)
化合物１－２４
１H-NMR（DMSO-d６）δ ppm：1.35-1.65 (10H, m), 1.75-1.90 (2H, m), 3.65-3.85 (1H, m), 7.01 (1H, s), 8.00-8.20 (1H, m), 10.15-12.40 (3H, m) Compound 1-24
1 H-NMR (DMSO-d 6 ) δ ppm: 1.35-1.65 (10H, m), 1.75-1.90 (2H, m), 3.65-3.85 (1H, m), 7.01 (1H, s), 8.00-8.20 (1H, m), 10.15-12.40 (3H, m)
化合物１－２５
１H-NMR（DMSO-d６）δ ppm：1.55-1.70 (6H, m), 1.85-2.10 (9H, m), 7.01 (1H, s), 8.04 (1H, br s), 10.35-11.50 (2H, m) Compound 1-25
1 H-NMR (DMSO-d 6 ) δ ppm: 1.55-1.70 (6H, m), 1.85-2.10 (9H, m), 7.01 (1H, s), 8.04 (1H, br s), 10.35-11.50 ( 2H, m)
化合物１－２６
１H-NMR（DMSO-d６）δ ppm：0.50-0.75 (4H, m), 2.60-2.75 (1H, m), 7.22 (1H, br s), 8.04 (1H, br s), 11.12 (1H, br s), 11.34 (1H, br s) Compound 1-26
1 H-NMR (DMSO-d 6 ) δ ppm: 0.50-0.75 (4H, m), 2.60-2.75 (1H, m), 7.22 (1H, br s), 8.04 (1H, br s), 11.12 (1H , br s), 11.34 (1H, br s)
化合物１－２７
１H-NMR（DMSO-d６）δ ppm：1.20-2.00 (8H, m), 3.90-4.10 (1H, m), 7.23 (1H, s), 7.95-8.10 (1H, m), 11.09 (1H, br s), 11.40 (1H, br s) Compound 1-27
1 H-NMR (DMSO-d 6 ) δ ppm: 1.20-2.00 (8H, m), 3.90-4.10 (1H, m), 7.23 (1H, s), 7.95-8.10 (1H, m), 11.09 (1H , br s), 11.40 (1H, br s)
化合物１－２８
１H-NMR（DMSO-d６）δ ppm：1.15-1.35 (5H, m), 1.50-1.55 (1H, m), 1.60-1.65 (2H, m), 1.75-1.85 (2H, m), 3.50-3.60 (1H, m), 7.23 (1H, s), 8.00 (1H, d, J=7.6Hz), 11.07 (1H, s), 11.36 (1H, br s)　 Compound 1-28
1 H-NMR (DMSO-d 6 ) δ ppm: 1.15-1.35 (5H, m), 1.50-1.55 (1H, m), 1.60-1.65 (2H, m), 1.75-1.85 (2H, m), 3.50 -3.60 (1H, m), 7.23 (1H, s), 8.00 (1H, d, J = 7.6Hz), 11.07 (1H, s), 11.36 (1H, br s)
化合物１－２９
１H-NMR（DMSO-d６）δ ppm：0.95-1.80 (10H, m), 2.70 (3H, br s), 3.72 (1H, br s), 7.19 (1H, br s), 10.56 (1H, br s), 11.13 (2H, br s) Compound 1-29
1 H-NMR (DMSO-d 6 ) δ ppm: 0.95-1.80 (10H, m), 2.70 (3H, br s), 3.72 (1H, br s), 7.19 (1H, br s), 10.56 (1H, br s), 11.13 (2H, br s)
化合物１－３０
１H-NMR（DMSO-d６）δ ppm：1.30-1.90 (12H, m), 3.70-3.85 (1H, m), 7.23 (1H, s), 8.00-8.15 (1H, m), 11.08 (1H, br s), 11.38 (2H, br s) Compound 1-30
1 H-NMR (DMSO-d 6 ) δ ppm: 1.30-1.90 (12H, m), 3.70-3.85 (1H, m), 7.23 (1H, s), 8.00-8.15 (1H, m), 11.08 (1H , br s), 11.38 (2H, br s)
化合物１－３１
１H-NMR（DMSO-d６）δ ppm：0.75-1.45 (8H, m), 1.65-1.95 (4H, m), 7.85-7.95 (1H, m), 11.08 (1H, br s), 11.39 (2H, br s) Compound 1-31
1 H-NMR (DMSO-d 6 ) δ ppm: 0.75-1.45 (8H, m), 1.65-1.95 (4H, m), 7.85-7.95 (1H, m), 11.08 (1H, br s), 11.39 ( 2H, br s)
化合物１－３２
１H-NMR（DMSO-d６）δ ppm：1.64 (6H, br s), 1.95 (6H, br s), 2.04 (3H, br s), 7.22 (1H, s), 7.97 (1H, s), 10.92 (1H, s)　 Compound 1-32
1 H-NMR (DMSO-d 6 ) δ ppm: 1.64 (6H, br s), 1.95 (6H, br s), 2.04 (3H, br s), 7.22 (1H, s), 7.97 (1H, s) , 10.92 (1H, s)
化合物１－３３
１H-NMR（DMSO-d６）δ ppm：0.50-0.70 (2H, m), 0.70-0.90 (2H, m), 2.60-2.80 (4H, m), 7.19 (1H, s), 10.35 (1H, s), 10.80-11.50 (2H, m) Compound 1-33
1 H-NMR (DMSO-d 6 ) δ ppm: 0.50-0.70 (2H, m), 0.70-0.90 (2H, m), 2.60-2.80 (4H, m), 7.19 (1H, s), 10.35 (1H , s), 10.80-11.50 (2H, m)
化合物１－３４
１H-NMR（MeOH-d4）δ ppm：1.10-1.45 (9H, m), 1.60-1.85 (7H, m), 3.47 (1H, br s), 3.75 (1H, br s), 7.22 (1H, s) Compound 1-34
1 H-NMR (MeOH-d 4 ) δ ppm: 1.10-1.45 (9H, m), 1.60-1.85 (7H, m), 3.47 (1H, br s), 3.75 (1H, br s), 7.22 (1H , s)
化合物１－３５
１H-NMR（DMSO-d６）δ ppm：0.05-0.55 (4H, m), 0.90-1.10 (1H, m), 3.00-3.15 (2H, m), 7.23 (1H, s), 8.10-8.25 (1H, m), 11.07 (1H, br s), 11.38 (2H, br s) Compound 1-35
1 H-NMR (DMSO-d 6 ) δ ppm: 0.05-0.55 (4H, m), 0.90-1.10 (1H, m), 3.00-3.15 (2H, m), 7.23 (1H, s), 8.10-8.25 (1H, m), 11.07 (1H, br s), 11.38 (2H, br s)
化合物１－３６
１H-NMR（DMSO-d６）δ ppm：1.40-1.55 (2H, m), 1.75-1.80 (2H, m), 3.75-3.85 (3H, m), 7.21 (1H, s), 8.04 (1H, d, J=7.3Hz), 11.12 (1H, s) Compound 1-36
1 H-NMR (DMSO-d 6 ) δ ppm: 1.40-1.55 (2H, m), 1.75-1.80 (2H, m), 3.75-3.85 (3H, m), 7.21 (1H, s), 8.04 (1H , d, J = 7.3Hz), 11.12 (1H, s)
化合物１－３７
１H-NMR（DMSO-d６）δ ppm：1.18 (3H, t, J=7.2Hz), 1.35-1.45 (2H, m), 1.80-1.85 (2H, m), 2.93 (2H, br s), 3.70-3.90 (3H, m), 4.03 (2H, q, J=7.2Hz), 7.22 (1H, s), 8.02 (1H, d, J=7.6Hz), 11.13 (1H, s) Compound 1-37
1 H-NMR (DMSO-d 6 ) δ ppm: 1.18 (3H, t, J = 7.2 Hz), 1.35-1.45 (2H, m), 1.80-1.85 (2H, m), 2.93 (2H, br s) , 3.70-3.90 (3H, m), 4.03 (2H, q, J = 7.2Hz), 7.22 (1H, s), 8.02 (1H, d, J = 7.6Hz), 11.13 (1H, s)
化合物１－３８
１H-NMR（DMSO-d６）δ ppm：3.90-4.20 (2H, m), 7.04 (1H, s), 8.56 (1H, br s), 10.00-11.95 (3H, m) Compound 1-38
1 H-NMR (DMSO-d 6 ) δ ppm: 3.90-4.20 (2H, m), 7.04 (1H, s), 8.56 (1H, br s), 10.00-11.95 (3H, m)
化合物１－３９
１H-NMR（DMSO-d６）δ ppm：7.10-7.15 (1H, m), 7.25-7.60 (5H, m), 10.16 (1H, s), 11.55 (1H, s)　 Compound 1-39
1 H-NMR (DMSO-d 6 ) δ ppm: 7.10-7.15 (1H, m), 7.25-7.60 (5H, m), 10.16 (1H, s), 11.55 (1H, s)
化合物１－４０
１H-NMR（DMSO-d６）δ ppm：7.24 (1H, s), 7.34 (1H, t, J=7.8Hz), 7.56 (2H, d, J=7.8Hz), 9.76 (1H, s), 11.39 (1H, br s), 11.58 (1H, s) Compound 1-40
1 H-NMR (DMSO-d 6 ) δ ppm: 7.24 (1H, s), 7.34 (1H, t, J = 7.8Hz), 7.56 (2H, d, J = 7.8Hz), 9.76 (1H, s) , 11.39 (1H, br s), 11.58 (1H, s)
化合物１－４１
１H-NMR（DMSO-d６）δ ppm： 2.17 (6H, s), 7.00-7.20 (3H, m), 7.28 (1H, s), 9.46 (1H, br s), 10.80-12.15 (3H, m) Compound 1-41
1 H-NMR (DMSO-d 6 ) δ ppm: 2.17 (6H, s), 7.00-7.20 (3H, m), 7.28 (1H, s), 9.46 (1H, br s), 10.80-12.15 (3H, m)
化合物１－４２
１H-NMR（DMSO-d６）δ ppm：1.36 (9H, s), 7.15-7.30 (3H, m), 7.40-7.50 (2H, m), 9.95 (1H, s), 11.56 (1H, s)　 Compound 1-42
1 H-NMR (DMSO-d 6 ) δ ppm: 1.36 (9H, s), 7.15-7.30 (3H, m), 7.40-7.50 (2H, m), 9.95 (1H, s), 11.56 (1H, s )
化合物１－４３
１H-NMR（DMSO-d６）δ ppm：3.88 (3H, s), 7.20-7.30 (2H, m), 7.60-7.70 (1H, m), 7.95-7.80 (1H, m), 8.35-8.45 (1H, m), 11.43 (1H, br s), 11.53 (1H, s), 11.78 (1H, s) Compound 1-43
1 H-NMR (DMSO-d 6 ) δ ppm: 3.88 (3H, s), 7.20-7.30 (2H, m), 7.60-7.70 (1H, m), 7.95-7.80 (1H, m), 8.35-8.45 (1H, m), 11.43 (1H, br s), 11.53 (1H, s), 11.78 (1H, s)
化合物１－４４
１H-NMR（DMSO-d６）δ ppm：3.18 (3H, s), 7.20- 7.30 (4H, m), 7.35-7.45 (2H, m), 10.40 (1H, br s), 11.18 (2H, br s)　 Compound 1-44
1 H-NMR (DMSO-d 6 ) δ ppm: 3.18 (3H, s), 7.20-7.30 (4H, m), 7.35-7.45 (2H, m), 10.40 (1H, br s), 11.18 (2H, br s)
化合物１－４５
１H-NMR（DMSO-d６）δ ppm：2.39 (3H, s), 6.55-6.65 (1H, m), 7.27 (1H, s), 10.51 (1H, s), 11.89 (1H, s) Compound 1-45
1 H-NMR (DMSO-d 6 ) δ ppm: 2.39 (3H, s), 6.55-6.65 (1H, m), 7.27 (1H, s), 10.51 (1H, s), 11.89 (1H, s)
化合物１－４６
１H-NMR（DMSO-d６）δ ppm：4.40 (2H, d, J=6.0Hz), 7.20-7.40 (6H, m), 8.56 (1H, t, J=6.0Hz), 11.17 (1H, s)　 Compound 1-46
1 H-NMR (DMSO-d 6 ) δ ppm: 4.40 (2H, d, J = 6.0 Hz), 7.20-7.40 (6H, m), 8.56 (1H, t, J = 6.0 Hz), 11.17 (1H, s)
化合物１－４７
１H-NMR（DMSO-d６）δ ppm：2.70-2.85 (2H, m), 7.15-7.35 (6H, m), 8.10-8.20 (1H, m), 11.08 (1H, br s), 11.30 (1H, br s) Compound 1-47
1 H-NMR (DMSO-d 6 ) δ ppm: 2.70-2.85 (2H, m), 7.15-7.35 (6H, m), 8.10-8.20 (1H, m), 11.08 (1H, br s), 11.30 ( 1H, br s)
化合物１－４８
１H-NMR（DMSO-d６）δ ppm：2.80 (3H, br s), 4.45 (2H, br s), 7.15-7.40 (6H, m), 10.70 (1H, br s), 11.18 (2H, br s)　 Compound 1-48
1 H-NMR (DMSO-d 6 ) δ ppm: 2.80 (3H, br s), 4.45 (2H, br s), 7.15-7.40 (6H, m), 10.70 (1H, br s), 11.18 (2H, br s)
化合物１－４９
１H-NMR（DMSO-d６）δ ppm：1.80 (3H, s), 3.10-3.30 (4H, m), 7.23 (1H, s), 7.90-7.95 (1H, m), 8.10-8.20 (1H, m), 11.07 (1H, s)　 Compound 1-49
1 H-NMR (DMSO-d 6 ) δ ppm: 1.80 (3H, s), 3.10-3.30 (4H, m), 7.23 (1H, s), 7.90-7.95 (1H, m), 8.10-8.20 (1H , m), 11.07 (1H, s)
化合物１－５０
１H-NMR（DMSO-d６）δ ppm：1.05-1.20 (3H, m), 3.30-3.55 (6H, m), 7.02 (1H, s), 8.15-8.35 (1H, m), 10.20-11.60 (3H, m) Compound 1-50
1 H-NMR (DMSO-d 6 ) δ ppm: 1.05-1.20 (3H, m), 3.30-3.55 (6H, m), 7.02 (1H, s), 8.15-8.35 (1H, m), 10.20-11.60 (3H, m)
化合物１－５１
１H-NMR（DMSO-d６）δ ppm：1.05-1.20 (3H, m), 1.60-1.80 (2H, m), 3.15-3.50 (6H, m), 7.01 (1H, s), 8.15-8.30 (1H, m), 10.30-11.60 (3H, m) Compound 1-51
1 H-NMR (DMSO-d 6 ) δ ppm: 1.05-1.20 (3H, m), 1.60-1.80 (2H, m), 3.15-3.50 (6H, m), 7.01 (1H, s), 8.15-8.30 (1H, m), 10.30-11.60 (3H, m)
化合物１－５２
１H-NMR（DMSO-d６）δ ppm： 1.05-1.20 (3H, m), 3.25-3.55 (6H, m), 7.23 (1H, s), 8.10-8.25 (1H, m), 11.11 (1H, br s), 11.40 (2H, br s) Compound 1-52
1 H-NMR (DMSO-d 6 ) δ ppm: 1.05-1.20 (3H, m), 3.25-3.55 (6H, m), 7.23 (1H, s), 8.10-8.25 (1H, m), 11.11 (1H , br s), 11.40 (2H, br s)
化合物１－５３
１H-NMR（DMSO-d６）δ ppm： 1.05-1.15 (3H, m), 1.65-1.80 (2H, m), 3.20-3.50 (6H, m), 7.23 (1H, s), 8.15-8.25 (1H, m), 11.04 (1H, br s), 11.38 (2H, br s) Compound 1-53
1 H-NMR (DMSO-d 6 ) δ ppm: 1.05-1.15 (3H, m), 1.65-1.80 (2H, m), 3.20-3.50 (6H, m), 7.23 (1H, s), 8.15-8.25 (1H, m), 11.04 (1H, br s), 11.38 (2H, br s)
化合物１－５４
１H-NMR（DMSO-d６）δ ppm：1.65-1.75 (2H, m), 3.20-3.40 (7H, m), 7.23 (1H, s), 8.16 (1H, t, J=5.7Hz), 11.03 (1H, s), 11.36 (1H, br s) Compound 1-54
1 H-NMR (DMSO-d 6 ) δ ppm: 1.65-1.75 (2H, m), 3.20-3.40 (7H, m), 7.23 (1H, s), 8.16 (1H, t, J = 5.7 Hz), 11.03 (1H, s), 11.36 (1H, br s)
化合物１－５５
１H-NMR（DMSO-d６）δ ppm：1.00-1.15 (6H, m), 1.60-1.75 (2H, m), 3.10-3.60 (5H, m), 7.23 (1H, s), 8.10-8.25 (1H, m), 11.02 (1H, br s), 11.38 (2H, br s) Compound 1-55
1 H-NMR (DMSO-d 6 ) δ ppm: 1.00-1.15 (6H, m), 1.60-1.75 (2H, m), 3.10-3.60 (5H, m), 7.23 (1H, s), 8.10-8.25 (1H, m), 11.02 (1H, br s), 11.38 (2H, br s)
化合物１－５６
MS (ESI, m/z): 378 (M+H)+
MS (ESI, m/z): 376 (M-H)- Compound 1-56
MS (ESI, m / z): 378 (M + H) +
MS (ESI, m / z): 376 (MH)-
化合物１－５７
MS (ESI, m/z): 396 (M+H)+
MS (ESI, m/z): 394 (M-H)- Compound 1-57
MS (ESI, m / z): 396 (M + H) +
MS (ESI, m / z): 394 (MH)-
化合物１－５８
１H-NMR（DMSO-d６）δ ppm：0.30-0.90 (4H, m), 3.09 (3H, s), 7.04 (1H, br s) Compound 1-58
1 H-NMR (DMSO-d 6 ) δ ppm: 0.30-0.90 (4H, m), 3.09 (3H, s), 7.04 (1H, br s)
化合物１－５９
１H-NMR（DMSO-d６）δ ppm：2.50-2.90 (3H, m), 2.90-3.20 (3H, m), 7.10-7.40 (1H, m), 7.40-8.70 (1H, m), 11.05 (2H, br s) Compound 1-59
1 H-NMR (DMSO-d 6 ) δ ppm: 2.50-2.90 (3H, m), 2.90-3.20 (3H, m), 7.10-7.40 (1H, m), 7.40-8.70 (1H, m), 11.05 (2H, br s)
化合物１－６０
１H-NMR（DMSO-d６）δ ppm：0.75-0.90 (3H, m), 1.30-1.55 (2H, m), 2.85-3.25 (5H, m), 7.15-7.35 (1H, m), 7.60 (1H, br s), 8.68 (1H, br s), 11.02 (1H, br s) Compound 1-60
1 H-NMR (DMSO-d 6 ) δ ppm: 0.75-0.90 (3H, m), 1.30-1.55 (2H, m), 2.85-3.25 (5H, m), 7.15-7.35 (1H, m), 7.60 (1H, br s), 8.68 (1H, br s), 11.02 (1H, br s)
化合物１－６１
１H-NMR（DMSO-d６）δ ppm：2.70-3.10 (9H, m), 7.15-7.30 (1H, m) Compound 1-61
1 H-NMR (DMSO-d 6 ) δ ppm: 2.70-3.10 (9H, m), 7.15-7.30 (1H, m)
化合物１－６２
MS (ESI, m/z): 364 (M+H)+ Compound 1-62
MS (ESI, m / z): 364 (M + H) +
化合物１－６３
１H-NMR（DMSO-d６）δ ppm：0.30-0.90 (7H, m), 1.35-1.55 (2H, m), 2.35-2.50 (1H, m), 3.50-3.70 (2H, m), 7.17 (1H, s), 7.69 (1H, s), 11.07 (2H, br s) Compound 1-63
1 H-NMR (DMSO-d 6 ) δ ppm: 0.30-0.90 (7H, m), 1.35-1.55 (2H, m), 2.35-2.50 (1H, m), 3.50-3.70 (2H, m), 7.17 (1H, s), 7.69 (1H, s), 11.07 (2H, br s)
化合物１－６４
１H-NMR（DMSO-d６）δ ppm：0.90-1.90 (10H, m), 2.90-3.20 (3H, m), 7.10-7.30 (1H, m), 7.25-8.75 (1H, m) Compound 1-64
1 H-NMR (DMSO-d 6 ) δ ppm: 0.90-1.90 (10H, m), 2.90-3.20 (3H, m), 7.10-7.30 (1H, m), 7.25-8.75 (1H, m)
化合物１－６５
MS (ESI, m/z): 352 (M-H)- Compound 1-65
MS (ESI, m / z): 352 (MH)-
化合物１－６６
１H-NMR（DMSO-d６）δ ppm：0.45-0.55 (2H, m), 0.60-0.65 (2H, m), 2.50-2.60 (1H, m), 7.25 (1H, s), 8.08 (1H, br s), 11.27 (1H, br s) Compound 1-66
1 H-NMR (DMSO-d 6 ) δ ppm: 0.45-0.55 (2H, m), 0.60-0.65 (2H, m), 2.50-2.60 (1H, m), 7.25 (1H, s), 8.08 (1H , br s), 11.27 (1H, br s)
化合物１－６７
MS (ESI, m/z): 420 (M+H)+
MS (ESI, m/z): 418 (M-H)- Compound 1-67
MS (ESI, m / z): 420 (M + H) +
MS (ESI, m / z): 418 (MH)-
化合物１－６８
MS (ESI, m/z): 400 (M+H)+
MS (ESI, m/z): 398 (M-H)- Compound 1-68
MS (ESI, m / z): 400 (M + H) +
MS (ESI, m / z): 398 (MH)-
化合物１－６９
１H-NMR（DMSO-d６）δ ppm：2.85 (3H, s), 3.10-3.30 (3H, m), 7.10-7.55 (6H, m) Compound 1-69
1 H-NMR (DMSO-d 6 ) δ ppm: 2.85 (3H, s), 3.10-3.30 (3H, m), 7.10-7.55 (6H, m)
化合物１－７０
１H-NMR（DMSO-d６）δ ppm：0.30-0.80 (4H, m), 2.30-2.60 (1H, m), 3.27 (3H, s), 3.10-3.60 (2H, m), 3.75-3.95 (2H, m), 7.18 (1H, s), 7.55-7.70 (1H, m), 10.50-11.50 (2H, m) Compound 1-70
1 H-NMR (DMSO-d 6 ) δ ppm: 0.30-0.80 (4H, m), 2.30-2.60 (1H, m), 3.27 (3H, s), 3.10-3.60 (2H, m), 3.75-3.95 (2H, m), 7.18 (1H, s), 7.55-7.70 (1H, m), 10.50-11.50 (2H, m)
化合物１－７１
１H-NMR（DMSO-d６）δ ppm：0.25-0.80 (4H, m), 1.50-1.85 (2H, m), 2.35-2.60 (1H, m), 3.22 (3H, s), 3.15-3.60 (2H, m), 3.60-3.80 (2H, m), 7.18 (1H, s), 7.65-7.80 (1H, m), 10.50-11.50 (2H, m) Compound 1-71
1 H-NMR (DMSO-d 6 ) δ ppm: 0.25-0.80 (4H, m), 1.50-1.85 (2H, m), 2.35-2.60 (1H, m), 3.22 (3H, s), 3.15-3.60 (2H, m), 3.60-3.80 (2H, m), 7.18 (1H, s), 7.65-7.80 (1H, m), 10.50-11.50 (2H, m)
化合物１－７２
１H-NMR（DMSO-d６）δ ppm：-0.05-0.15 (2H, m), 0.35-0.50 (2H, m), 2.25-2.35 (1H, m), 4.85-5.05 (2H, m), 7.15-7.40 (6H, m), 7.75-7.85 (1H, m), 11.15 (2H, br s) Compound 1-72
1 H-NMR (DMSO-d 6 ) δ ppm: -0.05-0.15 (2H, m), 0.35-0.50 (2H, m), 2.25-2.35 (1H, m), 4.85-5.05 (2H, m), 7.15-7.40 (6H, m), 7.75-7.85 (1H, m), 11.15 (2H, br s)
化合物１－７３
１H-NMR（DMSO-d６）δ ppm：1.80-2.00 (2H, m), 2.77 (3H, s), 3.20-3.50 (2H, m), 3.72 (2H, t, J=5.7Hz), 7.17 (1H, s), 10.50-11.50 (2H, m)　 Compound 1-73
1 H-NMR (DMSO-d 6 ) δ ppm: 1.80-2.00 (2H, m), 2.77 (3H, s), 3.20-3.50 (2H, m), 3.72 (2H, t, J = 5.7 Hz), 7.17 (1H, s), 10.50-11.50 (2H, m)
化合物１－７４
１H-NMR（DMSO-d６）δ ppm：2.85-2.90 (2H, m), 4.45-4.55 (1H, m), 7.15-7.30 (5H, m), 8.24 (1H, d, J=7.3Hz), 11.16 (1H, s)　 Compound 1-74
1 H-NMR (DMSO-d 6 ) δ ppm: 2.85-2.90 (2H, m), 4.45-4.55 (1H, m), 7.15-7.30 (5H, m), 8.24 (1H, d, J = 7.3 Hz ), 11.16 (1H, s)
化合物１－７５
１H-NMR（DMSO-d６）δ ppm：0.70-0.91 (3H, m), 1.38-1.60 (2H, m), 2.81-3.30 (8H, m), 6.97-7.06 (1H, m), 10.99 (2H, br s)  Compound 1-75
1 H-NMR (DMSO-d 6 ) δ ppm: 0.70-0.91 (3H, m), 1.38-1.60 (2H, m), 2.81-3.30 (8H, m), 6.97-7.06 (1H, m), 10.99 (2H, br s)
化合物１－７６
１H-NMR（DMSO-d６）δ ppm：0.50-0.85 (4H, m), 2.55-3.20 (7H, m), 6.97-7.05 (1H, m), 10.95 (2H, br s)  Compound 1-76
1 H-NMR (DMSO-d 6 ) δ ppm: 0.50-0.85 (4H, m), 2.55-3.20 (7H, m), 6.97-7.05 (1H, m), 10.95 (2H, br s)
化合物１－７７
１H-NMR（DMSO-d６）δ ppm：1.03-1.13 (3H, m), 1.58-1.82 (2H, m), 2.82-3.50 (12H, m), 6.97-7.06 (1H, m), 11.01 (2H, br s)  Compound 1-77
1 H-NMR (DMSO-d 6 ) δ ppm: 1.03-1.13 (3H, m), 1.58-1.82 (2H, m), 2.82-3.50 (12H, m), 6.97-7.06 (1H, m), 11.01 (2H, br s)
化合物１－７８
１H-NMR（DMSO-d６）δ ppm：1.02-1.40 (12H, m), 2.93-3.04 (3H, m), 3.23-4.33 (2H, m), 7.02-7.05 (1H, m), 10.99 (2H, br s) Compound 1-78
1 H-NMR (DMSO-d 6 ) δ ppm: 1.02-1.40 (12H, m), 2.93-3.04 (3H, m), 3.23-4.33 (2H, m), 7.02-7.05 (1H, m), 10.99 (2H, br s)
化合物１－７９
１H-NMR（DMSO-d６）δ ppm：2.72-3.16 (6H, m), 4.05-4.85 (2H, m), 6.99-7.40 (6H, m), 11.05 (2H, br s) Compound 1-79
1 H-NMR (DMSO-d 6 ) δ ppm: 2.72-3.16 (6H, m), 4.05-4.85 (2H, m), 6.99-7.40 (6H, m), 11.05 (2H, br s)
化合物１－８０
１H-NMR（DMSO-d６）δ ppm：1.40-1.65 (6H, m), 2.96-3.50 (7H, m), 6.98-7.05 (1H, m), 10.92 (2H, br s)  Compound 1-80
1 H-NMR (DMSO-d 6 ) δ ppm: 1.40-1.65 (6H, m), 2.96-3.50 (7H, m), 6.98-7.05 (1H, m), 10.92 (2H, br s)
化合物１－８１
１H-NMR（DMSO-d６）δ ppm：.90-3.80(11H, m), 6.95-7.10(1H, m), 10.00-12.00(2H, br) Compound 1-81
1 H-NMR (DMSO-d 6 ) δ ppm: .90-3.80 (11H, m), 6.95-7.10 (1H, m), 10.00-12.00 (2H, br)
化合物１－８２
１H-NMR（DMSO-d６）δ ppm：2.75 (3H, br s), 3.10 (3H, s), 7.06 (1H, br s), 8.65 (1H, br s), 11.00 (2H, br s) Compound 1-82
1 H-NMR (DMSO-d 6 ) δ ppm: 2.75 (3H, br s), 3.10 (3H, s), 7.06 (1H, br s), 8.65 (1H, br s), 11.00 (2H, br s )
化合物１－８３
１H-NMR（DMSO-d６）δ ppm：0.80-1.40(3H, br), 2.80-3.60(5H, m), 6.80-7.20(1H, br), 8.50-9.00(1H, br), 10.00-12.00(2H, br) Compound 1-83
1 H-NMR (DMSO-d 6 ) δ ppm: 0.80-1.40 (3H, br), 2.80-3.60 (5H, m), 6.80-7.20 (1H, br), 8.50-9.00 (1H, br), 10.00 -12.00 (2H, br)
化合物１－８４
１H-NMR（DMSO-d６）δ ppm：0.70-0.95(3H, m), 1.30-1.60(2H, m), 2.80-3.60(5H, m), 6.80-7.25(1H, br), 8.50-9.00(1H, br), 10.00-12.00(2H, br) Compound 1-84
1 H-NMR (DMSO-d 6 ) δ ppm: 0.70-0.95 (3H, m), 1.30-1.60 (2H, m), 2.80-3.60 (5H, m), 6.80-7.25 (1H, br), 8.50 -9.00 (1H, br), 10.00-12.00 (2H, br)
化合物１－８５
１H-NMR（DMSO-d６）δ ppm：0.80-1.35(6H, br), 3.09(3H, brs), 3.60-4.00(1H, br), 6.80-7.20(1H, br), 8.40-8.80(1H, br), 10.00-12.00(2H, br) Compound 1-85
1 H-NMR (DMSO-d 6 ) δ ppm: 0.80-1.35 (6H, br), 3.09 (3H, brs), 3.60-4.00 (1H, br), 6.80-7.20 (1H, br), 8.40-8.80 (1H, br), 10.00-12.00 (2H, br)
化合物１－８６
MS(ESI, m/z):346 (M+H)+ Compound 1-86
MS (ESI, m / z): 346 (M + H) +
化合物１－８７
MS(ESI, m/z):360 (M+H)+ Compound 1-87
MS (ESI, m / z): 360 (M + H) +
化合物１－８８
１H-NMR（DMSO-d６）δ ppm：.06 (6H, d, J=6.1Hz), 1.67 (2H, br s), 3.00-3.55 (8H, m), 7.08 (1H, br s), 7.57-8.84 (1H, m), 11.07 (2H, br s) Compound 1-88
1 H-NMR (DMSO-d 6 ) δ ppm: .06 (6H, d, J = 6.1 Hz), 1.67 (2H, br s), 3.00-3.55 (8H, m), 7.08 (1H, br s) , 7.57-8.84 (1H, m), 11.07 (2H, br s)
化合物１－８９
１H-NMR（DMSO-d６）δ ppm：3.15 (3H, s), 4.05 (2H, br s), 7.08 (1H, br s), 9.10 (1H, br s), 11.14 (2H, br s) Compound 1-89
1 H-NMR (DMSO-d 6 ) δ ppm: 3.15 (3H, s), 4.05 (2H, br s), 7.08 (1H, br s), 9.10 (1H, br s), 11.14 (2H, br s )
化合物１－９０
MS(ESI, m/z):430 (M+H)+ Compound 1-90
MS (ESI, m / z): 430 (M + H) +
化合物１－９１
MS(ESI, m/z):405 (M+H)+ Compound 1-91
MS (ESI, m / z): 405 (M + H) +
試験例１
ヒトCOMT阻害活性
１）組換えヒトＣＯＭＴの調製
（１）組換えヒトカテコール－Ｏ－メチルトランスフェラーゼの調製
　完全長のヒトカテコール－Ｏ－メチルトランスフェラーゼ（以下、ＣＯＭＴ）をコードする、ＮＣＢＩ（National Center for Biotechnology Information）上に登録されている受入番号ＢＣ０１１９３５のＤＮＡ配列に基づき、配列番号１記載の組換えヒトＣＯＭＴをコードするＤＮＡ配列を増幅するために２つのオリゴヌクレオチドプライマーを設計した。５’プライマーの配列を配列番号３に、３’プライマーの配列を配列番号４に示した。これらのプライマーは、所望のベクター中に該当ＰＣＲ産物を挿入しやすくするために制限酵素部位（５’側はＢａｍＨ　Ｉ、３’側はＥｃｏＲ　Ｉ）を含んでいる。
　配列番号３記載の５’プライマーおよび配列番号４記載の３’プライマーの各々を、ＴＥ緩衝液で希釈して15pmol/μL溶液とした。Ｈ２Ｏ（ＰＣＲ用, 34.8μL）、25mmol/L　ＭｇＳＯ４ (2.0μL)、2mmol/L ｄＮＴＰｓ (5.0μL)、１０倍濃縮のＤＮＡポリメラーゼ　ＫＯＤ　ｐｌｕｓ緩衝液 (5.0μL、東洋紡)を混合し、ＰＣＲ反応用混合物を調製した。次いでヒト肝臓ｃＤＮＡ（5.0μL、Ｃｌｏｎｔｅｃｈ）、更に各々のプライマー対（1μL、15pmol）を上記混合物に加え、最後に1.0μLのＫＯＤ　ｐｌｕｓ（東洋紡）を加えた。その後、ＰＣＲ反応を行なった。ＰＣＲ反応は９４℃２分間の処置後、９４℃１５秒間、５９℃３０秒間、６８℃１分間でこのサイクルを４０サイクル行った。次いで６８℃５分間、４℃１０分間で終了した。
　ＰＣＲ産物をＱＩＡｑｕｉｃｋ　ＰＣＲ　Ｐｕｒｉｆｉｃａｔｉｏｎ　Ｋｉｔ（ＱＩＡＧＥＮ）にて精製した。所望のインサートＤＮＡは同キットのＥＢ緩衝液（30μL）で溶出した。 Test example 1
Human COMT Inhibitory Activity 1) Preparation of Recombinant Human COMT (1) Preparation of Recombinant Human Catechol-O-Methyltransferase NCBI (National Center for NC) encoding full-length human catechol-O-methyltransferase (hereinafter referred to as COMT) Based on the DNA sequence of Accession No. BC011935 registered on Biotechnology Information), two oligonucleotide primers were designed to amplify the DNA sequence encoding the recombinant human COMT described in SEQ ID NO: 1. The sequence of the 5 ′ primer is shown in SEQ ID NO: 3, and the sequence of the 3 ′ primer is shown in SEQ ID NO: 4. These primers contain a restriction enzyme site (BamH I on the 5 ′ side and EcoR I on the 3 ′ side) to facilitate insertion of the PCR product into the desired vector.
Each of the 5 ′ primer described in SEQ ID NO: 3 and the 3 ′ primer described in SEQ ID NO: 4 was diluted with TE buffer to obtain a 15 pmol / μL solution. H 2 O (for PCR, 34.8 μL), 25 mmol / L MgSO 4 (2.0 μL), 2 mmol / L dNTPs (5.0 μL), 10-fold concentrated DNA polymerase KOD plus buffer (5.0 μL, Toyobo) were mixed, A PCR reaction mixture was prepared. Then human liver cDNA (5.0 μL, Clontech) and each primer pair (1 μL, 15 pmol) were added to the above mixture, and finally 1.0 μL of KOD plus (Toyobo) was added. Thereafter, a PCR reaction was performed. The PCR reaction was carried out at 94 ° C. for 2 minutes, followed by 40 cycles of 94 ° C. for 15 seconds, 59 ° C. for 30 seconds, and 68 ° C. for 1 minute. Subsequently, it was completed at 68 ° C. for 5 minutes and at 4 ° C. for 10 minutes.
The PCR product was purified with QIAquick PCR Purification Kit (QIAGEN). The desired insert DNA was eluted with EB buffer (30 μL) of the same kit.
（２）組換えヒトＣＯＭＴインサートＤＮＡおよびｐＧＥＸ－２Ｔベクターの二重消化
　組換えヒトＣＯＭＴインサートＤＮＡ(1.5μg)に、１０倍濃縮のＥｃｏＲ　Ｉ緩衝液 (3.0μL、Ｎｅｗ　Ｅｎｇｌａｎｄ　Ｂｉｏｌａｂ)、Ｈ２Ｏ(11.1μL)、ＢａｍＨ　Ｉ(1.5μL、15U、10U/μL)とＥｃｏＲ　Ｉ(1.0μL、15U、10U/μL)を加え混合した。その混合溶液を３７℃で１．５時間加熱した。更にその溶液に１０倍濃縮のローディング緩衝液を加えた。混合溶液を電気泳動にて分離し、当該消化断片を有するＤＮＡを含むゲルの部分を切り出し、ＭｉｎＥｌｕｔｅ　Ｇｅｌ　Ｅｘｔｒａｃｔｉｏｎ　Ｋｉｔ（ＱＩＡＧＥＮ）を使用して精製した。　ｐＧＥＸ－２ＴベクターＤＮＡ(1.5μg、Ａｍｅｒｓｈａｍ)についても同様に二重消化を行い精製した。 (2) Double digestion of recombinant human COMT insert DNA and pGEX-2T vector To recombinant human COMT insert DNA (1.5 μg), 10-fold concentrated EcoR I buffer (3.0 μL, New England Biolab), H 2 O (11.1 μL), BamH I (1.5 μL, 15 U, 10 U / μL) and EcoR I (1.0 μL, 15 U, 10 U / μL) were added and mixed. The mixed solution was heated at 37 ° C. for 1.5 hours. Further, a 10-fold concentrated loading buffer was added to the solution. The mixed solution was separated by electrophoresis, and the gel portion containing the DNA having the digested fragment was excised and purified using MinElute Gel Extraction Kit (QIAGEN). pGEX-2T vector DNA (1.5 μg, Amersham) was similarly purified by double digestion.
（３）ライゲーションと大腸菌ＪＭ１０９の形質転換
　二重消化したｐＧＥＸ－２Ｔベクター（2.0μL、50ng）およびインサートＤＮＡ(1.24μL、33.4ng)を、２倍濃縮のライゲーション緩衝液(3.24μL、Ｐｒｏｍｅｇａ)に加えて混合した。次いで、Ｔ４リガーゼ(1.0μL、3U/μL、Ｐｒｏｍｅｇａ)を混合溶液に加え、その混合物を２５℃で１時間インキュベーションした。次に、大腸菌ＪＭ１０９(100μL)を０℃にて溶解し、リガーゼで反応させた上記混合溶液(5μL)をＪＭ１０９懸濁液に加え、穏やかに混合し、０℃で３０分間静置した。この混合物に強く振盪すること無しに４２℃で４０秒間の熱ショックを与え、０℃で１０分間冷却した。次いで、450μLのＳＯＣ溶液を熱ショック後の溶液に加え３７℃で１時間振盪した。振盪後、混合溶液の50μLと200μLを、ＬＢ－アンピシリン培地のプレート上(直径9cm、アンピシリン濃度100μg/mL)にそれぞれ播種し、３７℃で１６時間の静置培養をおこなった。その結果、プレート上にはコロニーが出現していた。 (3) Ligation and transformation of E. coli JM109 Double-digested pGEX-2T vector (2.0 μL, 50 ng) and insert DNA (1.24 μL, 33.4 ng) were added to 2-fold concentrated ligation buffer (3.24 μL, Promega). Added and mixed. T4 ligase (1.0 μL, 3 U / μL, Promega) was then added to the mixed solution and the mixture was incubated at 25 ° C. for 1 hour. Next, E. coli JM109 (100 μL) was dissolved at 0 ° C., and the above mixed solution (5 μL) reacted with ligase was added to the JM109 suspension, gently mixed, and allowed to stand at 0 ° C. for 30 minutes. The mixture was heat shocked at 42 ° C. for 40 seconds without vigorous shaking and cooled at 0 ° C. for 10 minutes. Next, 450 μL of the SOC solution was added to the solution after the heat shock and shaken at 37 ° C. for 1 hour. After shaking, 50 μL and 200 μL of the mixed solution were respectively seeded on a plate of LB-ampicillin medium (diameter 9 cm, ampicillin concentration 100 μg / mL), and static culture was performed at 37 ° C. for 16 hours. As a result, colonies appeared on the plate.
（４）ＧＳＴ融合組換えヒトＣＯＭＴプラスミドによるＪＭ１０９形質転換後のコロニーセレクション
　上記の静置培養後のプレートから適当数のコロニーを選択し、それらを滅菌爪楊枝にてＬＢ－アンピシリン液体培地（各2mL、アンピシリン濃度100μg/mL）に植菌し、３７℃で１６時間振盪培養した。それぞれから200μLを1.5mLマイクロチューブに分取し、フェノール抽出法によってプラスミドを抽出した。抽出されたプラスミドは、ＴＥ緩衝液に再溶解し、電気泳動に供した。検出されたバンドの泳動位置が、インサートＤＮＡのないｐＧＥＸ－２Ｔベクターのそれと近いものを一次陽性コロニーと判定し、以下の制限酵素二重消化による再確認を行なった。
　上記の一次陽性コロニー由来のＤＮＡ溶液（各7μL）を、１０倍濃縮のＥｃｏＲ　Ｉ緩衝液（0.9μL、Ｎｅｗ　Ｅｎｇｌａｎｄ　Ｂｉｏｌａｂ）と混和し、次いでＢａｍＨ　Ｉ(0.5μL、10U/μL) とＥｃｏＲ　Ｉ(0.5μL、15U/μL)を添加した。その溶液は、３７℃で１時間加温した後、電気泳動を行なった。およそ６７０ｂｐの位置にバンドが検出された試料が由来するコロニーを、二次陽性コロニーと判定した。 (4) Colony Selection after JM109 Transformation with GST-Fused Recombinant Human COMT Plasmid An appropriate number of colonies are selected from the plate after stationary culture described above, and they are sterilized with a toothpick in LB-ampicillin liquid medium (each 2 mL, Ampicillin concentration 100 μg / mL), and cultured with shaking at 37 ° C. for 16 hours. 200 μL of each was dispensed into 1.5 mL microtubes, and the plasmid was extracted by the phenol extraction method. The extracted plasmid was redissolved in TE buffer and subjected to electrophoresis. A detected band having a migration position close to that of the pGEX-2T vector having no insert DNA was determined as a primary positive colony, and reconfirmation was performed by the following restriction enzyme double digestion.
The DNA solution derived from the primary positive colonies (7 μL each) was mixed with 10-fold concentrated EcoR I buffer (0.9 μL, New England Biolab), then BamHI (0.5 μL, 10 U / μL) and EcoR I ( 0.5 μL, 15 U / μL) was added. The solution was heated at 37 ° C. for 1 hour and then subjected to electrophoresis. A colony from which a sample in which a band was detected at a position of about 670 bp was determined as a secondary positive colony.
（５）ＧＳＴ融合組換えヒトＣＯＭＴプラスミドの大腸菌ＪＭ１０９からの抽出と精製
　（４）で二次陽性コロニーと判定された、ＧＳＴ融合組換えヒトＣＯＭＴプラスミドでの形質転換ＪＭ１０９の培養液は、一部(100μL)をグリセロールストックとし、残りの培養液は12000rpmで１０分間遠心を行い、大腸菌ペレットを得た。得られた大腸菌ペレットから、ＱＩＡＧＥＮ　Ｐｌａｓｍｉｄ　ｍｉｎｉ　ｋｉｔ（ＱＩＡＧＥＮ）を用いてプラスミドＤＮＡを精製した。その濃度はＯＤ２６０ｎｍによって決定され247ng/μLであった。常法に従い配列確認を行ったところ、配列番号２のＤＮＡ配列が所望の位置に挿入されていた。 (5) Extraction and purification of GST fusion recombinant human COMT plasmid from Escherichia coli JM109 A part of the culture solution of JM109 transformed with GST fusion recombinant human COMT plasmid, which was determined as a secondary positive colony in (4), was partially (100 μL) was used as a glycerol stock, and the remaining culture was centrifuged at 12000 rpm for 10 minutes to obtain an E. coli pellet. Plasmid DNA was purified from the resulting E. coli pellet using QIAGEN Plasmid mini kit (QIAGEN). Its concentration was determined by OD260nm and was 247ng / μL. When the sequence was confirmed according to a conventional method, the DNA sequence of SEQ ID NO: 2 was inserted at the desired position.
（６）ＧＳＴ融合組換えヒトＣＯＭＴプラスミドＤＮＡの大腸菌ＢＬ２１　ＣＯＤＯＮ　ＰＬＵＳ　（ＤＥ３）ＲＰへの形質転換
　（５）で精製され配列確認が終了したＧＳＴ融合組換えヒトＣＯＭＴプラスミドＤＮＡ1μL(1ng/μL)を０℃で融解した大腸菌ＢＬ２１　ＣＯＤＯＮ　ＰＬＵＳ　（ＤＥ３）ＲＰ細胞懸濁液50μLに加え、（３）と同様に形質転換を行い、プレート培養を行った。 (6) Transformation of GST-fused recombinant human COMT plasmid DNA into E. coli BL21 CODEN PLUS (DE3) RP GST-fused recombinant human COMT plasmid DNA 1 μL (1 ng / μL) purified in (5) and sequence confirmed In addition to 50 μL of E. coli BL21 CODEN PLUS (DE3) RP cell suspension thawed at 0 ° C., transformation was performed in the same manner as in (3), and plate culture was performed.
（７）ＧＳＴ融合組換えヒトＣＯＭＴの発現
　形質転換後の大腸菌ＢＬ２１　ＣＯＤＯＮ　ＰＬＵＳ　（ＤＥ３）ＲＰのプレートからコロニーを拾い上げ、5mLのＬＢ－アンピシリン培地（アンピシリン濃度100μg/mL）に投入し、３７℃にて１５時間振盪培養を行った。培養液の一部50μLをグリセロールストックとし、－８０℃で保存した。使用時にこのグリセロールストックの一部を150mLのＬＢ－アンピシリン培地（アンピシリン濃度100μg/mL）に植菌し、３７℃にて１６時間振盪培養を行った。この培養液を500mLずつ７本のＬＢ－アンピシリン培地（アンピシリン濃度100μg/mL）で希釈し、２０℃にて４．５時間振盪培養を行った。培養液の６００ｎｍ吸光度が０．４４となっていることを確認した後、各50μLのイソプロピル－β－Ｄ－チオガラクトピラノシド（1mol/L）を添加し、２０℃にて１８時間振盪培養を行った。この培養液を9000rpmで２０分間遠心して大腸菌ペレットを回収し、4gずつ４本に分けて使用時まで－８０℃で凍結保存した。 (7) Expression of GST-fused recombinant human COMT Colonies were picked up from the transformed E. coli BL21 CODON PLUS (DE3) RP plate, placed in 5 mL of LB-ampicillin medium (ampicillin concentration 100 μg / mL), For 15 hours. A 50 μL portion of the culture was used as a glycerol stock and stored at −80 ° C. At the time of use, a part of this glycerol stock was inoculated into 150 mL of LB-ampicillin medium (ampicillin concentration 100 μg / mL) and cultured at 37 ° C. for 16 hours with shaking. This culture solution was diluted with 7 LB-ampicillin media (ampicillin concentration 100 μg / mL) in 500 mL portions, and cultured with shaking at 20 ° C. for 4.5 hours. After confirming that the absorbance at 600 nm of the culture solution was 0.44, 50 μL of isopropyl-β-D-thiogalactopyranoside (1 mol / L) was added and shake culture at 20 ° C. for 18 hours. Went. The culture broth was centrifuged at 9000 rpm for 20 minutes to recover the E. coli pellet, and divided into 4 pieces of 4 g and stored frozen at −80 ° C. until use.
（８）ＧＳＴ融合組換えヒトＣＯＭＴのトロンビン処理
　（７）から得られた大腸菌ペレットに40mLのＢｕｇＢｕｓｔｅｒ溶液(Ｎｏｖａｇｅｎ)、30μLのＢｅｎｚｏｎａｓｅ(Ｎｏｖａｇｅｎ)および1μLのｒＬｙｓｏｚｙｍｅ(Ｎｏｖａｇｅｎ)を添加し、１５分間室温にて穏やかに撹拌しながら処理した。得られたライゼートを12000rpm、４℃、２０分間遠心し、上澄み液を回収した。次いで、予めＤ－ＰＢＳ（Dulbecco’s Phosphate Buffered Saline）にて平衡化し、Ｄ－ＰＢＳで５０％に再懸濁させた、20mLのグルタチオン４ＢＳｅｐｈａｒｏｓｅ（レジンベッドボリューム10mL）を上記上澄み溶液に加え、得られた混合物を４℃にて1時間振盪した。振盪後の混合物をフィルターによりレジンと濾液に分別した。得られたレジンを30mLのＤ－ＰＢＳで5回洗浄し、30mLのトロンビン処理用緩衝液（150mmol/L　ＮａＣｌ、50mmol/L　Ｔｒｉｓ－ＨＣｌ、ｐＨ８．０、10%ｇｌｙｃｅｒｏｌ、2.5mmol/L　ＣａＣｌ２、0.5%　β－オクチル－Ｄ－グルコピラノシド）で３回洗浄した。次いで、レジンにトロンビン処理用緩衝液を加え30mLとし、トロンビン（アマシャムバイオサイエンス）３０ユニットを加えた。レジン混合液を４℃で１５時間穏やかに撹拌した後、レジンを濾過し、濾液として得られた組換えヒトＣＯＭＴの溶液を使用時まで－８０℃で保管した。 (8) Thrombin treatment of GST-fused recombinant human COMT To the E. coli pellet obtained from (7), 40 mL of BugBuster solution (Novagen), 30 μL of Benzonase (Novagen) and 1 μL of rLysozyme (Novagen) were added, and room temperature for 15 minutes Treated with gentle agitation. The obtained lysate was centrifuged at 12000 rpm, 4 ° C. for 20 minutes, and the supernatant was recovered. Next, 20 mL of glutathione 4B Sepharose (resin bed volume 10 mL), which had been equilibrated in advance with D-PBS (Dulbecco's Phosphate Buffered Saline) and resuspended to 50% with D-PBS, was added to the supernatant solution to obtain The mixture was shaken at 4 ° C. for 1 hour. The mixture after shaking was separated into a resin and a filtrate by a filter. The obtained resin was washed 5 times with 30 mL of D-PBS, and 30 mL of thrombin treatment buffer (150 mmol / L NaCl, 50 mmol / L Tris-HCl, pH 8.0, 10% glycerol, 2.5 mmol / L CaCl 2). , 0.5% β-octyl-D-glucopyranoside). Next, thrombin treatment buffer was added to the resin to make 30 mL, and 30 units of thrombin (Amersham Biosciences) were added. After the resin mixture was gently stirred at 4 ° C. for 15 hours, the resin was filtered, and the resulting recombinant human COMT solution was stored at −80 ° C. until use.
２）ヒトCOMT阻害作用の測定
ヒトCOMT阻害作用の測定は、Zurcher Gらの方法（J. Neurochem., 1982年, 38巻, P.191-195）を一部改変して実施した。１）で調製した組換えヒトCOMT（約1mg/mL）0.25μL、リン酸カリウム緩衝液（500mmol/L、pH7.6）40μL、塩化マグネシウム（100mmol/L）10μL、ジチオスレイトール（62.5mmol/L）10μL、アデノシンデアミナーゼ（2550ユニット/mL）0.5μLと試験化合物の混合物を３７℃で５分間プレインキュベートした。対照サンプルは同様の方法で調製したが、試験化合物の代わりにジメチルスルホキシド（5μL）を加えた。[3H]-S-アデノシル-L-メチオニン（12.5mmol/L、1.2Ci/mol；アマシャムバイオサイエンス社製）20μLの添加後、カテコール基質（7mmol/L）25μLを加えることにより反応を開始した。反応混合液（終容量0.25mL）は、３７℃で３０分間インキュベートした。反応は氷冷した0.1g/Lのグアイアコールを含む1mol/L塩酸(0.25mL)を加えることで停止させた。シンチレーター（オプティフロー（登録商標）0；パッカード社製）2.5mLを加え、次いで1分間勢い良く振とうした後、パッカード社製液体シンチレーションカウンター（TRICARB 1900CA）で有機層に存在する放射活性を直接計数した。ブランクはカテコール基質の非存在下でインキュベートした（基質を反応停止後に加えた）。IC50値は酵素活性を50％阻害するのに要した濃度を示す。比較例として、トルカポンおよびエンタカポンを同様に試験した。これらの結果を表１２に示した。 2) Measurement of human COMT inhibitory activity Human COMT inhibitory activity was measured by partially modifying the method of Zurcher G et al. (J. Neurochem., 1982, 38, P.191-195). Recombinant human COMT (about 1 mg / mL) 0.25 μL prepared in 1), potassium phosphate buffer (500 mmol / L, pH 7.6) 40 μL, magnesium chloride (100 mmol / L) 10 μL, dithiothreitol (62.5 mmol / L) A mixture of 10 μL, adenosine deaminase (2550 units / mL) 0.5 μL and the test compound was preincubated at 37 ° C. for 5 minutes. A control sample was prepared in a similar manner, but dimethyl sulfoxide (5 μL) was added instead of the test compound. [ 3 H] -S-adenosyl-L-methionine (12.5 mmol / L, 1.2 Ci / mol; manufactured by Amersham Biosciences) 20 μL, and then the reaction was started by adding 25 μL of catechol substrate (7 mmol / L) . The reaction mixture (final volume 0.25 mL) was incubated at 37 ° C. for 30 minutes. The reaction was stopped by adding ice-cooled 1 mol / L hydrochloric acid (0.25 mL) containing 0.1 g / L guaiacol. Add 2.5 mL of scintillator (Optiflow (registered trademark) 0; Packard), shake vigorously for 1 minute, and then directly count the radioactivity present in the organic layer with a Packard liquid scintillation counter (TRICARB 1900CA) did. Blanks were incubated in the absence of catechol substrate (substrate was added after the reaction was stopped). The IC 50 value indicates the concentration required to inhibit enzyme activity by 50%. As comparative examples, tolcapone and entacapone were similarly tested. These results are shown in Table 12.
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
試験例２
ラット肝細胞毒性
　-150℃に保存されたラット凍結肝細胞３ｘ１０－６cells/vialを37℃に暖め、グルコース含有thawing medium (10mL)に加えて混合した後、1000rpmで１分間遠心した。上清を除去した後、細胞沈査をWilliams E.medium (15mL)に懸濁させた。薬物はジメチルスルホキシド用いて45、15、4.5、1.5、0.45mmol/Lに調製後、各薬物溶液およびコントロール（ジメチルスルホキシド）を2.0μLずつ試験管に分注した、この試験管に上記の細胞の懸濁液(300μL)を分注して混合させた。各懸濁液を９６ウェルプレートに100μLずつ分注し、37℃にて４時間CO２インキュベータ中でインキュベートした。Promega社のCell Viability Assay法に従いATP活性を測定した。コントロールの５０％ATP活性を示す濃度をEC５０値として表した。これらの結果を表１３に示した。 Test example 2
Rat hepatotoxicity 3 × 10 −6 cells / vial of rat frozen hepatocytes stored at −150 ° C. were warmed to 37 ° C., added to a glucose-containing thawing medium (10 mL), mixed, and then centrifuged at 1000 rpm for 1 minute. After removing the supernatant, the cell pellet was suspended in Williams E. medium (15 mL). Drugs were prepared to 45, 15, 4.5, 1.5, and 0.45 mmol / L using dimethyl sulfoxide, and each drug solution and control (dimethyl sulfoxide) were dispensed in 2.0 μL aliquots into the test tube. The suspension (300 μL) was dispensed and mixed. Each suspension was dispensed at 100 μL into a 96-well plate and incubated at 37 ° C. for 4 hours in a CO 2 incubator. ATP activity was measured according to Cell Viability Assay method of Promega. The concentration showing 50% ATP activity of the control was expressed as an EC 50 value. These results are shown in Table 13.
Figure JPOXMLDOC01-appb-T000044
  　これらの試験の結果、本発明の化合物は、極めて軽微な肝細胞毒性しか示さないことが示唆された。
Figure JPOXMLDOC01-appb-T000044
 As a result of these tests, it was suggested that the compound of the present invention shows very slight hepatotoxicity.
　本発明の化合物は、優れたＣＯＭＴ阻害作用を有するので、パーキンソン病、うつ病、高血圧症の治療または予防剤として有用である。特に本発明の化合物と、Ｌ－ドパとを組み合わせて使用することにより、Ｌ－ドパの生体内利用率を増加させ、その作用時間を延長させることができるので、パーキンソン病の治療および予防に好適である。 Since the compound of the present invention has an excellent COMT inhibitory action, it is useful as a therapeutic or prophylactic agent for Parkinson's disease, depression and hypertension. In particular, by using the compound of the present invention in combination with L-dopa, the bioavailability of L-dopa can be increased and the action time can be extended, so that the treatment and prevention of Parkinson's disease can be achieved. It is suitable for.
<配列番号１>
　配列番号１は、組換えヒトカテコール－Ｏ－メチルトランスフェラーゼの配列である。
<配列番号２>
　配列番号２は、配列番号１の組換えヒトカテコール－Ｏ－メチルトランスフェラーゼを発現するように配列番号３および４のプライマーを用いて増幅されたＤＮＡ配列である。
<配列番号３>
　配列番号３は、配列番号２のＤＮＡを増幅するために使用された５’プライマーの配列である。
<配列番号４>
　配列番号４は、配列番号２のＤＮＡを増幅するために使用された３’プライマーの配列である。 <SEQ ID NO: 1>
SEQ ID NO: 1 is the sequence of recombinant human catechol-O-methyltransferase.
<SEQ ID NO: 2>
SEQ ID NO: 2 is a DNA sequence amplified using the primers of SEQ ID NOs: 3 and 4 to express the recombinant human catechol-O-methyltransferase of SEQ ID NO: 1.
<SEQ ID NO: 3>
SEQ ID NO: 3 is the sequence of the 5 ′ primer used to amplify the DNA of SEQ ID NO: 2.
<SEQ ID NO: 4>
SEQ ID NO: 4 is the sequence of the 3 ′ primer used to amplify the DNA of SEQ ID NO: 2.

Claims (10)

  1. 一般式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
      〔式中、
    　Ｒ１およびＲ２は、それぞれ独立して、水素原子、低級アシル基、低級アルコキシカルボニル基、または－Ｃ（Ｏ）ＮＲ７Ｒ８を表すか、あるいはＲ１およびＲ２が一緒になって－Ｃ（Ｏ）－を形成し；
    　Ｒ３は、ハロゲン原子、ハロ低級アルキル基、低級アルコキシカルボニル基、またはシアノ基であり；
    　Ｒ４は、水素原子、低級アルキル基、低級アルコキシ低級アルキル基またはアラルキル基であり；
    　Ｒ５およびＲ６は、それぞれ独立して、以下のａ）～ｌ）：
    　ａ）水素原子、
    　ｂ）アルキル基、
    　ｃ）シクロアルキル基、
    　ｄ）シクロアルキル低級アルキル基、
    　ｅ）橋かけ環状炭化水素基、
    　ｆ）ヘテロシクロアルキル基、
    　ｇ）ハロ低級アルキル基、
    　ｈ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基および低級アルコキシカルボニル基から独立して選択される１～５個の基で環が置換されるアリール基、
    　ｉ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、および低級アルコキシ基から独立して選択される１～３個の基で環が置換されるヘテロアリール基、
    　ｊ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、シアノ基および低級アルコキシ基から独立して選択される１～５個の基で環が置換されるアラルキル基、
    　ｋ）低級アシルアミノ低級アルキル基、または
    　ｌ）低級アルコキシ低級アルキル基であるか、あるいは
    　Ｒ５およびＲ６が、それらが結合している窒素原子と一緒になって、環状アミノ基を形成するか、あるいは
    　Ｒ４およびＲ５が、－（ＣＨ２）ｍ－で表される基を形成する場合、Ｒ６は水素原子または低級アルキル基であり；
    　Ｒ７およびＲ８は、それぞれ独立して、水素原子、低級アルキル基またはアラルキル基を表すか、あるいはＲ７およびＲ８が、それらが結合している窒素原子と一緒になって、環状アミノ基を形成し；
    　ｍは、２～４である〕
    で表される化合物またはその薬理学的に許容される塩。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
     [Where,
    R 1 and R 2 each independently represents a hydrogen atom, a lower acyl group, a lower alkoxycarbonyl group, or —C (O) NR 7 R 8 , or R 1 and R 2 taken together— Forming C (O)-;
    R 3 is a halogen atom, a halo lower alkyl group, a lower alkoxycarbonyl group, or a cyano group;
    R 4 is a hydrogen atom, a lower alkyl group, a lower alkoxy lower alkyl group or an aralkyl group;
    R 5 and R 6 are each independently the following a) to l):
    a) a hydrogen atom,
    b) an alkyl group,
    c) a cycloalkyl group,
    d) a cycloalkyl lower alkyl group,
    e) a bridged cyclic hydrocarbon group,
    f) a heterocycloalkyl group,
    g) a halo lower alkyl group,
    h) unsubstituted or group consisting of: aryl having a ring substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Group,
    i) unsubstituted or a group consisting of the following: a heteroaryl group in which the ring is substituted with 1 to 3 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group,
    j) The group consisting of unsubstituted or the following: an aralkyl group in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a cyano group and a lower alkoxy group,
    k) a lower acylamino lower alkyl group, or 1) a lower alkoxy lower alkyl group, or R 5 and R 6 together with the nitrogen atom to which they are attached form a cyclic amino group, Or when R 4 and R 5 form a group represented by — (CH 2 ) m —, R 6 is a hydrogen atom or a lower alkyl group;
    R 7 and R 8 each independently represents a hydrogen atom, a lower alkyl group or an aralkyl group, or R 7 and R 8 together with the nitrogen atom to which they are bonded, a cyclic amino group Forming;
    m is 2-4]
    Or a pharmacologically acceptable salt thereof.
  2. Ｒ１およびＲ２が、水素原子である、請求項１に記載の化合物またはその薬理学的に許容される塩。 The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R 1 and R 2 are hydrogen atoms.
  3. Ｒ５が、水素原子であり、
    Ｒ６が、以下のａ）～ｋ）：
    　ａ）アルキル基、
    　ｂ）シクロアルキル基、
    　ｃ）シクロアルキル低級アルキル基、
    　ｄ）橋かけ環状炭化水素基、
    　ｅ）ヘテロシクロアルキル基、
    　ｆ）ハロ低級アルキル基、
    　ｇ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基および低級アルコキシカルボニル基から独立して選択される１～５個の基で環が置換されるアリール基、
    　ｈ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、および低級アルコキシ基から独立して選択される１～３個の基で環が置換されるヘテロアリール基、
    　ｉ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、シアノ基、および低級アルコキシ基から独立して選択される１～５個の基で環が置換されるアラルキル基、
    　ｊ）低級アシルアミノ低級アルキル基、または
    　ｋ）低級アルコキシ低級アルキル基である、請求項２に記載の化合物またはその薬理学的に許容される塩。     R 5 is a hydrogen atom,
    R 6 represents the following a) to k):
    a) an alkyl group,
    b) a cycloalkyl group,
    c) a cycloalkyl lower alkyl group,
    d) a bridged cyclic hydrocarbon group,
    e) a heterocycloalkyl group,
    f) a halo lower alkyl group,
    g) Unsubstituted or group consisting of: aryl having a ring substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Group,
    h) an unsubstituted or group consisting of the following: a heteroaryl group in which the ring is substituted with 1 to 3 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group;
    i) An unsubstituted or group consisting of the following: an aralkyl group in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a cyano group, and a lower alkoxy group ,
    The compound or pharmacologically acceptable salt thereof according to claim 2, which is j) a lower acylamino lower alkyl group, or k) a lower alkoxy lower alkyl group.
  4. Ｒ６が、以下のａ）～ｈ）：
    　ａ）アルキル基、
    　ｂ）シクロアルキル基、
    　ｃ）シクロアルキル低級アルキル基、
    　ｄ）橋かけ環状炭化水素基、
    　ｅ）ヘテロシクロアルキル基、
    　ｆ）ハロ低級アルキル基、
    　ｇ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基および低級アルコキシカルボニル基から独立して選択される１～５個の基で環が置換されるアリール基、または
    　ｈ）低級アルコキシ低級アルキル基である、請求項３に記載の化合物またはその薬理学的に許容される塩。     R 6 represents the following a) to h):
    a) an alkyl group,
    b) a cycloalkyl group,
    c) a cycloalkyl lower alkyl group,
    d) a bridged cyclic hydrocarbon group,
    e) a heterocycloalkyl group,
    f) a halo lower alkyl group,
    g) Unsubstituted or group consisting of: aryl having a ring substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Or h) a compound or a pharmaceutically acceptable salt thereof according to claim 3, which is a lower alkoxy lower alkyl group.
  5. Ｒ４が、水素原子、低級アルキル基またはアラルキル基である、請求項４に記載の化合物またはその薬理学的に許容される塩。 The compound or pharmacologically acceptable salt thereof according to claim 4 , wherein R 4 is a hydrogen atom, a lower alkyl group or an aralkyl group.
  6. Ｒ６が、以下のａ）～ｅ）：
    　ａ）アルキル基、
    　ｂ）シクロアルキル基、
    　ｃ）シクロアルキル低級アルキル基、
    　ｄ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基および低級アルコキシカルボニル基から独立して選択される１～５個の基で環が置換されるアリール基、または
    　ｅ）低級アルコキシ低級アルキル基である、請求項５に記載の化合物またはその薬理学的に許容される塩。     R 6 represents the following a) to e):
    a) an alkyl group,
    b) a cycloalkyl group,
    c) a cycloalkyl lower alkyl group,
    d) Unsubstituted or the group consisting of: aryl in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group and a lower alkoxycarbonyl group Group or e) the compound or pharmacologically acceptable salt thereof according to claim 5, which is a lower alkoxy lower alkyl group.
  7. Ｒ３が、ハロゲン原子またはハロ低級アルキル基であり、
    Ｒ４が、水素原子である、請求項６に記載の化合物またはその薬理学的に許容される塩。　　     R 3 is a halogen atom or a halo lower alkyl group,
    The compound according to claim 6, wherein R 4 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
  8. 以下からなる群：
    　１－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）－３－シクロプロピルメチル尿素；
    　１－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）－３－プロピル尿素；
    　１－ブチル－３－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）尿素；
    　１－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）－３－ペンチル尿素； 
    　１－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）－３－イソプロピル尿素；
    　１－ｔｅｒｔ－ブチル－３－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）尿素；
    　１－ブチル－３－（３，４－ジヒドロキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）尿素；
    　１－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）－３－シクロヘプチル尿素；
    　１－シクロヘキシル－３－（３，４－ジヒドロキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）尿素；
    　１－シクロヘプチル－３－（３，４－ジヒドロキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）尿素；
    　１－（３，４－ジヒドロキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）－３－フェニル尿素；
    　１－（３，４－ジヒドロキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）－３－（２，６－ジメチルフェニル）尿素；
    　２－［３－（３，４－ジヒドロキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）ウレイド］安息香酸メチル；
    　１－（３，４－ジヒドロキシ－２－ニトロ－６－トリフルオロメチルベンゾイル）－３－（３－メトキシプロピル）－１－メチル尿素；
    　２－（３－シクロプロピル－１－メチルウレイドカルボニル）－４，５－ジヒドロキシ－３－ニトロ安息香酸メチル；および
    　１－（６－クロロ－３，４－ジヒドロキシ－２－ニトロベンゾイル）－３－（３－エトキシプロピル）尿素、
    から選択される化合物またはその薬理学的に許容される塩。     The group consisting of:
    1- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) -3-cyclopropylmethylurea;
    1- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) -3-propylurea;
    1-butyl-3- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) urea;
    1- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) -3-pentylurea;
    1- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) -3-isopropylurea;
    1-tert-butyl-3- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) urea;
    1-butyl-3- (3,4-dihydroxy-2-nitro-6-trifluoromethylbenzoyl) urea;
    1- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) -3-cycloheptylurea;
    1-cyclohexyl-3- (3,4-dihydroxy-2-nitro-6-trifluoromethylbenzoyl) urea;
    1-cycloheptyl-3- (3,4-dihydroxy-2-nitro-6-trifluoromethylbenzoyl) urea;
    1- (3,4-dihydroxy-2-nitro-6-trifluoromethylbenzoyl) -3-phenylurea;
    1- (3,4-dihydroxy-2-nitro-6-trifluoromethylbenzoyl) -3- (2,6-dimethylphenyl) urea;
    2- [3- (3,4-dihydroxy-2-nitro-6-trifluoromethylbenzoyl) ureido] methyl benzoate;
    1- (3,4-dihydroxy-2-nitro-6-trifluoromethylbenzoyl) -3- (3-methoxypropyl) -1-methylurea;
    Methyl 2- (3-cyclopropyl-1-methylureidocarbonyl) -4,5-dihydroxy-3-nitrobenzoate; and 1- (6-chloro-3,4-dihydroxy-2-nitrobenzoyl) -3- (3-ethoxypropyl) urea,
    Or a pharmacologically acceptable salt thereof.
  9. 請求項１～８のいずれか一項に記載の化合物またはその薬理学的に許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition comprising as an active ingredient the compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt thereof.
  10. 請求項１～８のいずれか一項に記載の化合物またはその薬理学的に許容される塩と、Ｌ－ドパおよび芳香族Ｌ－アミノ酸デカルボキシラーゼ阻害剤から選択される少なくとも１種とを組み合わせてなる医薬。
          A combination of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and at least one selected from L-dopa and an aromatic L-amino acid decarboxylase inhibitor The medicine which becomes
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150096392A (en) * 2012-11-08 2015-08-24 루트거스, 더 스테이트 유니버시티 오브 뉴 저지 Antimicrobial agents
US9458128B2 (en) 2012-05-24 2016-10-04 Orion Corporation Catechol O-methyltransferase activity inhibiting compounds
US10071082B2 (en) 2013-11-08 2018-09-11 Rutgers, The State University Of New Jersey Antimicrobial agents
US10513528B2 (en) 2016-02-25 2019-12-24 Taxis Pharmaceuticals, Inc. Synthetic processes and intermediates
US10774093B2 (en) 2017-03-30 2020-09-15 Taxis Pharmaceuticals, Inc. Synthetic processes and synthetic intermediates

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0733652A (en) * 1990-09-10 1995-02-03 Duphar Internatl Res Bv Medical preparation containing benzoyl urea derivative
JP2004525951A (en) * 2001-04-03 2004-08-26 テリック，インコーポレイテッド Antagonists of MCP-1 function and methods of using the same
JP2006516971A (en) * 2003-01-23 2006-07-13 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Carbonyl-amino-substituted acylphenylurea derivatives, their production and use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0733652A (en) * 1990-09-10 1995-02-03 Duphar Internatl Res Bv Medical preparation containing benzoyl urea derivative
JP2004525951A (en) * 2001-04-03 2004-08-26 テリック，インコーポレイテッド Antagonists of MCP-1 function and methods of using the same
JP2006516971A (en) * 2003-01-23 2006-07-13 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Carbonyl-amino-substituted acylphenylurea derivatives, their production and use

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
THE JOURNAL OF ANTIBIOTICS, vol. 40, no. 1, 1987, pages 22 - 28 *
YAKUGAKU ZASSHI, vol. 107, no. 10, 1987, pages 814 - 818 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9458128B2 (en) 2012-05-24 2016-10-04 Orion Corporation Catechol O-methyltransferase activity inhibiting compounds
KR20150096392A (en) * 2012-11-08 2015-08-24 루트거스, 더 스테이트 유니버시티 오브 뉴 저지 Antimicrobial agents
JP2016501190A (en) * 2012-11-08 2016-01-18 ラトガーズ， ザ ステイト ユニバーシティ オブ ニュー ジャージー Antibacterial agent
AU2013342095B2 (en) * 2012-11-08 2017-09-28 Rutgers, The State University Of New Jersey Antimicrobial agents
KR102163608B1 (en) * 2012-11-08 2020-10-07 루트거스, 더 스테이트 유니버시티 오브 뉴 저지 Antimicrobial agents
US10071082B2 (en) 2013-11-08 2018-09-11 Rutgers, The State University Of New Jersey Antimicrobial agents
US11129814B2 (en) 2013-11-08 2021-09-28 Taxis Pharmaceuticals, Inc. Antimicrobial agents
US10513528B2 (en) 2016-02-25 2019-12-24 Taxis Pharmaceuticals, Inc. Synthetic processes and intermediates
US10774093B2 (en) 2017-03-30 2020-09-15 Taxis Pharmaceuticals, Inc. Synthetic processes and synthetic intermediates

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