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WO2009081892A1 - Nouveau dérivé du catéchol, composition pharmaceutique le contenant et leur utilisation - Google Patents

Nouveau dérivé du catéchol, composition pharmaceutique le contenant et leur utilisation 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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Prior art keywords
group
alkyl group
lower alkyl
nmr
ppm
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PCT/JP2008/073270
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English (en)
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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Priority to JP2009547093A priority Critical patent/JP5369000B2/ja
Publication of WO2009081892A1 publication Critical patent/WO2009081892A1/fr

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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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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

L'invention porte sur un composé représenté par la formule générale (I) ci-après qui possède un effet inhibiteur puissant vis-à-vis de la COMT, ou un sel pharmacologiquement acceptable de celui-ci. L'invention porte également sur une composition pharmaceutique contenant un tel composé ou un sel pharmacologiquement acceptable de celui-ci, et sur leur utilisation. (Dans la formule, R1 et R2 représentent indépendamment un hydrogène, un acyle inférieur, un (alcoxy inférieur)carbonyle ou similaire; R3 représente un halogène, un halo-alkyle inférieur, un cyano ou similaire; R4 représente un hydrogène, un alkyle inférieur ou similaire; et R5 et R6 représentent indépendamment un hydrogène, un alkyle, un cycloalkyle, un hétérocycloalkyle, un halo-alkyle inférieur, un aryle éventuellement substitué, un hétéroaryle éventuellement substitué ou similaire.)
PCT/JP2008/073270 2007-12-25 2008-12-22 Nouveau dérivé du catéchol, composition pharmaceutique le contenant et leur utilisation WO2009081892A1 (fr)

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
KR20150096392A (ko) * 2012-11-08 2015-08-24 루트거스, 더 스테이트 유니버시티 오브 뉴 저지 항균제
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

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JP2004525951A (ja) * 2001-04-03 2004-08-26 テリック，インコーポレイテッド Ｍｃｐ−１機能のアンタゴニストおよびその使用方法
JP2006516971A (ja) * 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 カルボニル−アミノ置換アシルフェニル尿素誘導体、その製造方法及び使用

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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 (ko) * 2012-11-08 2015-08-24 루트거스, 더 스테이트 유니버시티 오브 뉴 저지 항균제
JP2016501190A (ja) * 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 抗菌剤
AU2013342095B2 (en) * 2012-11-08 2017-09-28 Rutgers, The State University Of New Jersey Antimicrobial agents
KR102163608B1 (ko) * 2012-11-08 2020-10-07 루트거스, 더 스테이트 유니버시티 오브 뉴 저지 항균제
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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