WO2017164173A1 - Composé imidazole et médicament comprenant celui-ci - Google Patents

Composé imidazole et médicament comprenant celui-ci Download PDF

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WO2017164173A1
WO2017164173A1 PCT/JP2017/011233 JP2017011233W WO2017164173A1 WO 2017164173 A1 WO2017164173 A1 WO 2017164173A1 JP 2017011233 W JP2017011233 W JP 2017011233W WO 2017164173 A1 WO2017164173 A1 WO 2017164173A1
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salt
group
compound
alkyl group
imidazole compound
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Japanese (ja)
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金井　求
洋平 相馬
卓士 新谷
柳人 城野
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国立研究開発法人科学技術振興機構
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to an imidazole compound and a pharmaceutical for preventing or treating a disease involving amyloid deposition such as Alzheimer's disease containing the imidazole compound.
  • Alzheimer's disease is a neurodegenerative disease having the pathological features of senile plaque formation and neurofibrillary tangles along with the degeneration and loss of nerve cells. Alzheimer's disease causes cognitive symptoms that result in progressive loss of memory, cognition, thinking, judgment, etc., and ultimately leads to death.
  • the main protein constituting senile plaques deposited in the brain is amyloid ⁇ peptide (A ⁇ ), which consists of 39-43 amino acids.
  • a ⁇ exhibits cytotoxicity, which is thought to cause Alzheimer's disease (Non-patent Document 1).
  • a ⁇ secreted from cells is a polypeptide composed mainly of 40 or 42 amino acids, and in particular, A ⁇ consisting of 42 is more cohesive and deposits early in the brain and is highly cytotoxic. Is known (Non-Patent Document 2). Therefore, a drug that inhibits A ⁇ aggregation is expected as a preventive or therapeutic drug for Alzheimer's disease.
  • Non-patent Document 3 L- [Lys-Leu-Val-Phe-Phe], which is a partial sequence of A ⁇ , is known to have aggregation inhibitory activity against A ⁇ .
  • the present inventor has reported that cyclic oligopeptides and picolinic acid amide derivatives have A ⁇ aggregation inhibitory activity (Non-patent Document 4).
  • an object of the present invention is to provide a new compound having an excellent A ⁇ aggregation inhibitory action and useful as a medicine.
  • the present inventor has conducted various studies to find a low molecular compound having an A ⁇ aggregation inhibitory activity superior to that of the pentapeptide and the like.
  • the imidazole compound represented by the following general formula (1) or a salt thereof is excellent. It has been found that it has aggregation inhibitory activity, has high water solubility, and is useful as a prophylactic and therapeutic agent for various diseases caused by amyloid deposition such as Alzheimer's disease.
  • A, B and C are the same or different and each represents a nitrogen atom or a carbon atom;
  • X 1 and X 2 are the same or different and each represents —CH 2 —, —O— or —S—;
  • R 1 and R 2 are the same or different and each represents a cyclic alkyl group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, or a heterocycle that may have a substituent.
  • R 3 represents a hydrogen atom or a linear or branched alkyl group
  • R 4 represents a linear or branched alkyl group or a cyclic alkyl group
  • R 3 and R 4 together with the adjacent nitrogen atom may form a saturated heterocyclic ring
  • R 5 represents a linear or branched alkyl group or a cyclic alkyl group
  • One of R 6 and R 7 represents a hydrogen atom or an alkyl group
  • the dashed line in the imidazole ring indicates that there is one double bond.
  • an salt thereof [2]
  • the ring containing A, B and C is the following (a), (c), (d) or (e)
  • the ring containing A, B and C is the following (c), (d) or (e)
  • the ring containing A, B and C is the following (c)
  • R 1 and R 2 are the same or different and each represents an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, a nitro group, an amino group, mono C 1-4 1 to 5 selected from an alkylamino group, a di-C 1-4 alkylamino group and a halogeno C 1-4 alkyl group may be substituted, an aromatic hydrocarbon group having 6 to 14 carbon atoms, 8.
  • the imidazole compound or salt thereof according to any one of [1] to [7], which is a cyclic alkyl group or a heterocyclic group.
  • R 3 is a hydrogen atom or a linear or branched alkyl group having 1 to 12 carbon atoms
  • R 4 and R 5 are the same or different and are a hydrogen atom or a linear chain having 1 to 12 carbon atoms. Or a branched alkyl group or a cyclic alkyl group having 3 to 8 carbon atoms; R 3 and R 4 may form a saturated heterocyclic ring together with an adjacent nitrogen atom, [1] to [8 ]
  • the imidazole compound or its salt in any one of.
  • R 3 is a hydrogen atom
  • R 4 and R 5 are the same or different and are a branched alkyl group having 3 to 8 carbon atoms. salt.
  • the imidazole ring in the general formula (1) has one of the following structures:
  • An amyloid ⁇ peptide aggregation inhibitor comprising the imidazole compound or salt thereof according to any one of [1] to [12] as an active ingredient.
  • a medicament comprising the imidazole compound or salt thereof according to any one of [1] to [12].
  • the medicament according to [14] which is an Alzheimer's disease preventive or therapeutic drug.
  • a pharmaceutical composition comprising the imidazole compound or a salt thereof according to any one of [1] to [12] and a pharmaceutically acceptable carrier.
  • [18] Use of the imidazole compound or a salt thereof according to any one of [1] to [12] for the manufacture of an agent for preventing or treating Alzheimer's disease.
  • a method for inhibiting amyloid ⁇ peptide aggregation comprising administering the imidazole compound or salt thereof according to any one of [1] to [12].
  • a method for preventing or treating Alzheimer's disease comprising administering the imidazole compound or a salt thereof according to any one of [1] to [12].
  • the imidazole compound represented by the formula (1) or a salt thereof has an extremely excellent A ⁇ aggregation inhibitory activity and is excellent in water solubility, and therefore prevents or treats diseases caused by amyloid deposition such as Alzheimer's disease and Down's syndrome. It is useful as a medicinal product.
  • the A ⁇ aggregation inhibitory activity of the compound of the present invention is shown. 2 shows the concentration dependency of the A ⁇ aggregation inhibitory activity of compound (1-3).
  • A, B and C are the same or different and represent a nitrogen atom or a carbon atom. Therefore, the ring containing A, B and C includes the following benzene rings and heterocycles.
  • X 1 and X 2 are the same or different and represent —CH 2 —, —O— or —S—. Of these, —CH 2 — or —O— is preferable. Furthermore, one of X 1 and X 2 is -O-, the other is -CH 2 - and more preferably from or -O-, further preferably both X 1 and X 2 is -O- .
  • R 1 and R 2 are the same or different and have a cyclic alkyl group which may have a substituent, an aromatic hydrocarbon group which may have a substituent or a substituent.
  • the heterocyclic group which may be carried out is shown.
  • the aromatic hydrocarbon group include aromatic hydrocarbon groups having 6 to 14 carbon atoms, and specific examples include a phenyl group, an indenyl group, a naphthyl group, a biphenyl group, a phenanthrenyl group, and an anthracenyl group. Among these, a phenyl group, a naphthyl group, and a biphenyl group are more preferable, and a phenyl group is more preferable.
  • cyclic alkyl group a cyclic alkyl group having 5 to 8 carbon atoms is preferable, and a cyclic alkyl group having 5 to 6 carbon atoms is more preferable. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • the heterocyclic group is preferably a heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • pyrrolyl group imidazolyl group, thienyl group, furyl group, pyridyl group, pyrimidyl group, triazinyl group, quinolyl group, morpholinyl group, piperidinyl group, piperazinyl group and the like.
  • Examples of the group which can be substituted with an aromatic hydrocarbon group, a cyclic alkyl group or a heterocyclic group include an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, a nitro group, amino 1-5 selected from a group, a mono C 1-4 alkylamino group, a di C 1-4 alkylamino group and a halogeno C 1-4 alkyl group.
  • examples of the alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and tert-butyl group.
  • examples of the alkoxy group having 1 to 4 carbon atoms include methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, and n-butyloxy group.
  • examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Examples of the mono C 1-4 alkylamino group include a methylamino group, an ethylamino group, and an isopropylamino group.
  • Examples of the diC 1-4 alkylamino group include a dimethylamino group, a diethylamino group, and a diisopropylamino group.
  • Examples of the halogeno C 1-4 alkyl group include a chloromethyl group, a trichloromethyl group, and a trifluoromethyl group.
  • R 3 represents a hydrogen atom or a linear or branched alkyl group.
  • R 4 and R 5 are the same or different and each represents a linear or branched alkyl group or a cyclic alkyl group.
  • examples of the linear or branched alkyl group include a linear or branched alkyl group having 1 to 12 carbon atoms, preferably a linear or branched alkyl group having 1 to 8 carbon atoms, More preferred are 8 branched alkyl groups.
  • Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, an isohexyl group, an isooctyl group, and a 2-ethylhexyl group.
  • Examples of the cyclic alkyl group include cyclic alkyl groups having 3 to 8 carbon atoms, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • R 3 and R 4 may be combined with an adjacent nitrogen atom to form a saturated heterocyclic ring.
  • the saturated heterocycle formed by R 3 , R 4 and a nitrogen atom is preferably a 5- or 6-membered saturated heterocycle containing one nitrogen atom and further containing an oxygen atom.
  • pyrrolidine, piperidine And morpholine for example, pyrrolidine, piperidine And morpholine.
  • R 3 is preferably a hydrogen atom, and R 4 and R 5 are preferably the same or different and are a linear or branched alkyl group or a cyclic alkyl group. More preferably, R 3 is a hydrogen atom, and R 4 and R 5 are the same or different and are a linear or branched alkyl group having 3 to 8 carbon atoms or a cyclic alkyl group having 3 to 8 carbon atoms. More preferably, R 3 is a hydrogen atom, R 4 and R 5 are the same or different, and are a branched alkyl group having 3 to 8 carbon atoms.
  • R 6 and R 7 represents a hydrogen atom or an alkyl group.
  • the alkyl group is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, more preferably a methyl group or an ethyl group.
  • the dashed line of the imidazole ring indicates that there is one double bond. This imidazole ring may have the following structure depending on the position of the double bond.
  • X 1 and X 2 are preferably —CH 2 — or —O—, and particularly preferably both X 1 and X 2 are —O—.
  • R 1 and R 2 are preferably an aromatic hydrocarbon group having 6 to 14 carbon atoms, and more preferably a phenyl group.
  • R 3 is a hydrogen atom
  • R 4 and R 5 are the same or different and are preferably a branched alkyl group having 3 to 8 carbon atoms or a cyclic alkyl group having 3 to 8 carbon atoms
  • R 3 is a hydrogen atom More preferably, R 4 and R 5 are the same or different and are branched alkyl groups having 3 to 8 carbon atoms.
  • a and C are carbon atoms
  • B is a nitrogen atom
  • X 1 and X 2 are —O—
  • R 1 and R 2 are phenyl groups
  • More preferred are compounds wherein 3 is a hydrogen atom
  • R 4 and R 5 are branched alkyl groups having 3 to 8 carbon atoms.
  • Examples of the salt of the imidazole compound of the formula (1) include pharmaceutically acceptable salts such as inorganic acid salts such as hydrochloride, sulfate, nitrate, carbonate, phosphate, trifluoroacetate, acetate, Acid addition salts such as organic acid salts such as acid salts and succinic acid salts.
  • pharmaceutically acceptable salts such as inorganic acid salts such as hydrochloride, sulfate, nitrate, carbonate, phosphate, trifluoroacetate, acetate, Acid addition salts such as organic acid salts such as acid salts and succinic acid salts.
  • the imidazole compound of the formula (1) or a salt thereof may have an asymmetric carbon atom, and in this case, each optically active substance and a mixture thereof are included.
  • imidazole compound or a salt thereof of the present invention are the compounds or salts thereof described in Examples described later.
  • the imidazole compound or salt thereof of the present invention can be produced, for example, according to the following reaction formula.
  • Hal represents a halogen atom
  • Bpin represents a pinacolboranyl group
  • R a , R b and R c are the same or different and represent an amino protecting group
  • A, B, C, X 1 , X 2 And R 1 to R 7 are the same as the above, but only one of R a and R b is present.
  • compound (4) is obtained by cross-coupling compound (2) and compound (3), and compound (1) is obtained by removing the amino protecting group.
  • Compound (2) can be produced according to a known method.
  • Compound (3) can be produced from imidazole, for example, according to the following reaction formula.
  • amino protecting groups include protecting groups that can be removed under acidic conditions such as trifluoroacetic acid, for example, silylalkyl groups such as trimethylsilylethoxymethyl group, and tert-butoxycarbonyl groups.
  • the reaction for bonding the protecting group can be carried out, for example, by reacting a halogenated protecting group with imidazole (5) in the presence of a strong base. Specifically, the reaction may be performed at room temperature for 10 to 24 hours in the presence of a strong base such as sodium hydride.
  • Compound (6) is reacted with n-butyllithium and a copper bromide dimethylsulfide complex, and then reacted with an alkyl halide such as methylallyl bromide to obtain compound (7).
  • This reaction is performed, for example, by reacting compound (6) with n-butyllithium, reacting with a copper bromide dimethylsulfide complex, and then reacting with methylallyl bromide.
  • the reaction may be carried out in an ether solvent such as tetrahydrofuran at a temperature of ⁇ 80 to ⁇ 150 ° C. for 1 hour to 10 hours.
  • Compound (8) is obtained by reducing Compound (7).
  • This reaction is carried out by hydrogenation in the presence of a catalyst such as palladium / carbon.
  • the reaction may be carried out in an alcohol solvent such as methanol at room temperature for 10 to 48 hours.
  • Compound (9) is obtained by reacting Compound (8) with a halogenating agent such as N-bromosuccinimide.
  • a halogenating agent such as N-bromosuccinimide.
  • Halogenation may be carried out with chlorine as well as bromine.
  • the halogenation reaction may be performed in a solvent such as chloroform at room temperature for 5 to 30 minutes.
  • Compound (10) is obtained by reacting compound (9) with n-butyllithium and then with a formylating agent.
  • a formylating agent dimethylformamide, orthoformate, N-ethoxymethyleneaniline and the like can be used.
  • the reaction may be performed in a solvent such as tetrahydrofuran at ⁇ 80 ° C. to room temperature for 30 minutes to 3 hours.
  • Compound (11) is obtained by reducing compound (10).
  • reducing compound (10) for example, diisobutylaluminum hydride, lithium aluminum hydride, sodium borohydride and the like can be used.
  • the reaction may be carried out in an ether solvent such as tetrahydrofuran at room temperature for 30 minutes to 3 hours.
  • Compound (12) is obtained by halogenating the imidazole ring of compound (11).
  • the halogenation reaction can be performed using a halogenating agent such as N-bromosuccinimide.
  • the reaction can be carried out at room temperature in a solvent such as chloroform.
  • Compound (13) is obtained by halogenating the hydroxy group of compound (12).
  • the halogenation reaction of the hydroxy group is performed using a halogenating agent such as thionyl chloride.
  • the reaction can be performed at room temperature in a solvent such as toluene.
  • Compound (14) is obtained by amination of compound (13).
  • the amination reaction can be performed by reacting an N-protected alkylamine such as N-benzylisopropylamine.
  • Examples of the amino-protecting group used herein include protecting groups that can be eliminated by a hydrogenation reaction such as a benzyl group or a benzyloxycarbonyl group.
  • the reaction may be performed in a solvent such as dimethylformamide at room temperature for 10 to 36 hours.
  • Compound (15) is obtained by reacting compound (14) with a boron compound such as pinacol borane.
  • a boron compound such as pinacol borane.
  • an organic boron compound used for Suzuki Miyaura cross-coupling reaction is used.
  • the compound (15) is an example of the compound (3), and R 4 and R 5 can be appropriately changed.
  • the reaction can be carried out in a solvent such as tetrahydrofuran at ⁇ 80 ° C. to room temperature.
  • the reaction of the compound (2) and the compound (3) in the above reaction formula is a Suzuki Miyaura cross-coupling reaction, and is performed in the presence of a palladium catalyst and a base.
  • a palladium catalyst include Pd (PPh 3 ) 4 , PdCl 2 (dppf), and the like.
  • the base potassium phosphate or the like is used.
  • the reaction can be carried out at 30 to 100 ° C. in a solvent such as water and toluene.
  • Compound (1) is obtained by removing the amino protecting group of compound (4).
  • the elimination reaction of the amino protecting group varies depending on the type of the protecting group.
  • a protecting group that is eliminated by a reduction reaction such as a benzyl group or a benzyloxycarbonyl group
  • hydrogenation is performed under a palladium / carbon catalyst. It can be eliminated by the method.
  • a protecting group such as a silylalkyl group or a t-butoxycarbonyl group that can be eliminated under acidic conditions, it can be eliminated by reacting with trifluoroacetic acid.
  • the compound (1) can be produced by the following reaction formula.
  • THP represents a tetrahydropyranyl group
  • R 1 to R 7 , A, B, C, X 1 , X 2 , Hal, Bpin, and R b are the same as described above.
  • the compound (16) is obtained by reacting the compound (12) with 3,4-dihydropyran in the presence of an acid to tetrahydropyranylate, and then reacting this with pinacolborane. can get.
  • Compound (17) is obtained by coupling compound (2) and compound (16). This reaction is a Suzuki Miyaura cross-coupling reaction, and is performed in the same manner as the reaction of the compound (2) and the compound (3).
  • reaction By removing the hydroxy protecting group (THP) and amino protecting group (R b ) of compound (17), compound (18) is obtained.
  • This reaction can be performed by reacting an acid such as trifluoroacetic acid. Specifically, it can be performed at room temperature in a solvent such as dichloromethane.
  • Compound (19) is obtained by Dess-Martin oxidation of compound (18).
  • Dess-Martin periodinane (DMP) can be used for the Dess-Martin oxidation reaction.
  • the reaction can be easily carried out at room temperature in a solvent such as dichloromethane.
  • Compound (20) and compound (21) are obtained by reacting compound (19) with an alkylating agent typified by a methylating agent such as methyl trifluoromethanesulfonate. This reaction proceeds easily at ⁇ 80 ° C. to room temperature in a solvent such as dichloromethane.
  • an alkylating agent such as methyl trifluoromethanesulfonate.
  • Compound (1a) and Compound (1b) can be obtained by reacting Compound (20) or Compound (21) with alkylamine or the like. This reaction can be performed at room temperature by adding decaborane or the like in a solvent such as methanol.
  • the imidazole compound of the present invention or a salt thereof has an excellent A ⁇ aggregation inhibitory activity as shown in the examples below, and as an A ⁇ aggregation inhibitor, and diseases involving amyloid deposition and A ⁇ aggregation in animals including humans, such as It is useful as a preventive and therapeutic drug for Alzheimer's disease, Down's syndrome and the like.
  • the dosage is 1 mg to 1 g per day for an adult, preferably 10 mg to 300 mg.
  • the pharmaceutical composition containing the imidazole compound or a salt thereof of the present invention can be prepared by selecting an appropriate preparation according to the administration method and preparing various preparations using a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for example, tablets, powders, granules, capsules, liquids, syrups, elixirs, oily or aqueous suspensions and the like are used orally. It can be illustrated as a formulation.
  • stabilizers As injections, stabilizers, preservatives, and solubilizing aids may be used in the preparation. After storing a solution that may contain these adjuvants in a container, it may be prepared as a solid preparation by lyophilization or the like. It is good also as a formulation. Further, a single dose may be stored in one container, and multiple doses may be stored in one container.
  • liquid preparations suspensions, emulsions, ointments, gels, creams, lotions, sprays, patches and the like can be exemplified as external preparations.
  • the solid preparation includes amide compounds of the present invention or salts thereof and pharmaceutically acceptable additives.
  • additives for example, fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents, lubricants Agents and the like can be selected and mixed as necessary to prepare a formulation.
  • liquid preparations include solutions, suspensions, emulsions and the like, but additives may include suspending agents, emulsifiers and the like.
  • Phenol (20 g) and sodium metal 300 mg, 12.5 mmol were placed in a thick vial for a microwave synthesizer and stirred at 60 ° C. for 1 hour. After cooling to 0 ° C., 2,4,6-tribromopyridine (2.00 g, 6.33 mmol) was added and stirred at 80 ° C. for 1 hour, then set in a microwave synthesizer and 195 ° C. under microwave irradiation. For 24 hours. The mixture was cooled to 80 ° C., dropped into 100 mL of 1M aqueous sodium hydroxide solution, and stirred until the supernatant became transparent.
  • Test Example 1 (A ⁇ aggregation inhibition test) To a 0.1 M phosphate buffer solution (pH 7.4, 50 ⁇ L) containing A ⁇ O-acyl isopeptide (10 ⁇ M), a test sample solution (DMSO solution) was added (sample final concentration 50 ⁇ M, 1% DMSO), 37 After incubating at 0 ° C. for an arbitrary time, a part of the reaction solution (10 ⁇ L) is added to a mixed solution of thioflavin T solution (50 ⁇ M thioflavin T, 10 ⁇ L) and 50 mM glycine-NaOH buffer (pH 8.5, 396 ⁇ L) and immediately mixed. The fluorescence intensity of thioflavin T was measured. In the fluorescence intensity measurement, an excitation wavelength of 440 nm and a fluorescence wavelength of 480 nm were used.
  • the obtained results are shown in FIG. 1 as the aggregation inhibition ratio when the activity of the DMSO solution used for the control is 100.
  • the compound (1b-1), the compound (1-2) and the compound (1-3) of the present invention are more excellent in inhibiting A ⁇ aggregation than the cyclic oligopeptides and picolinic acid amides described in Non-Patent Document 4. showed that.
  • FIG. 2 shows the concentration dependency of the A ⁇ aggregation inhibitory activity of the compound (1-3).

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  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un nouveau composé qui présente une excellente activité d'inhibition de l'agrégation des peptides Aβ et qui est utile comme médicament. Un composé imidazole représenté par la formule générale (1) (dans laquelle A, B et C peuvent être identiques ou différents les uns des autres et représentent indépendamment un atome d'azote ou un atome de carbone ; X1 et X2 peuvent être identiques ou différents les uns des autres et représentent indépendamment -CH2-, -O- ou -S- ; R1 et R2 peuvent être identiques ou différents les uns des autres et représentent indépendamment un groupe hydrocarboné aromatique qui peut avoir un substituant, ou similaire ; R3 représente un atome d'hydrogène ou un groupe alkyle linéaire ou ramifié, et R4 représente un groupe alkyle linéaire ou ramifié ou un groupe alkyle cyclique, R3 et R4 pouvant former ensemble avec un atome d'azote adjacent un noyau hétérocyclique saturé ; R5 représente un groupe alkyle linéaire ou ramifié ou un groupe alkyle cyclique ; l'un quelconque parmi R6 et R7 représente un atome d'hydrogène ou un groupe alkyle ; et la ligne de tirets dans le noyau imidazole représente la présence d'une double liaison) ou un sel de celui-ci.
PCT/JP2017/011233 2016-03-22 2017-03-21 Composé imidazole et médicament comprenant celui-ci WO2017164173A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001009118A2 (fr) * 1999-07-29 2001-02-08 Patrick T Prendergast Composes dithiolthione pour le traitement de troubles neurologiques et pour renforcer la memoire
US20070219181A1 (en) * 2006-03-09 2007-09-20 Eisai R&D Management Co., Ltd. Multi-cyclic cinnamide derivatives
WO2007116092A1 (fr) * 2006-04-12 2007-10-18 Probiodrug Ag Inhibiteurs d'enzyme
WO2009067493A2 (fr) * 2007-11-19 2009-05-28 Envivo Pharmaceuticals, Inc. Benzènes 1,3,5-trisubstitués pour le traitement de la maladie d'alzheimer et d'autres troubles

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Publication number Priority date Publication date Assignee Title
WO2001009118A2 (fr) * 1999-07-29 2001-02-08 Patrick T Prendergast Composes dithiolthione pour le traitement de troubles neurologiques et pour renforcer la memoire
US20070219181A1 (en) * 2006-03-09 2007-09-20 Eisai R&D Management Co., Ltd. Multi-cyclic cinnamide derivatives
WO2007116092A1 (fr) * 2006-04-12 2007-10-18 Probiodrug Ag Inhibiteurs d'enzyme
WO2009067493A2 (fr) * 2007-11-19 2009-05-28 Envivo Pharmaceuticals, Inc. Benzènes 1,3,5-trisubstitués pour le traitement de la maladie d'alzheimer et d'autres troubles

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