+

WO2016006593A1 - Nouveau dérivé de benzoxazine et médicament le contenant - Google Patents

Nouveau dérivé de benzoxazine et médicament le contenant Download PDF

Info

Publication number
WO2016006593A1
WO2016006593A1 PCT/JP2015/069487 JP2015069487W WO2016006593A1 WO 2016006593 A1 WO2016006593 A1 WO 2016006593A1 JP 2015069487 W JP2015069487 W JP 2015069487W WO 2016006593 A1 WO2016006593 A1 WO 2016006593A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
substituted
unsubstituted
mmol
Prior art date
Application number
PCT/JP2015/069487
Other languages
English (en)
Japanese (ja)
Inventor
勝彦 柳澤
昭好 河合
古谷　利夫
喜好 ▲高▼山
朋子 清水
Original Assignee
国立研究開発法人国立長寿医療研究センター
株式会社ファルマデザイン
株式会社エヌビィー健康研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 国立研究開発法人国立長寿医療研究センター, 株式会社ファルマデザイン, 株式会社エヌビィー健康研究所 filed Critical 国立研究開発法人国立長寿医療研究センター
Publication of WO2016006593A1 publication Critical patent/WO2016006593A1/fr

Links

Classifications

    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems

Definitions

  • the present invention relates to an amyloid fibril formation inhibitor.
  • the present invention particularly relates to a therapeutic or prophylactic agent for neurodegenerative diseases containing an amyloid fibril formation inhibitor.
  • Alzheimer's disease patients Pathological features commonly seen in Alzheimer's disease patients include (1) brain atrophy, (2) formation of patchy amyloid deposits (senile plaques), and (3) fibrous mass in nerve cells ( There are three accumulations of neurofibrillary tangles, which cause cognitive impairment (Alzheimer-type dementia), a clinical manifestation of Alzheimer's disease.
  • As treatment for Alzheimer-type dementia symptomatic treatment for temporarily improving symptoms of dementia is performed using a cholinesterase inhibitor, an NMDA inhibitor or the like.
  • the effect is extremely limited, and establishment of a fundamental therapy that suppresses the onset and progression of Alzheimer's disease is strongly desired.
  • Alzheimer's disease In order to establish the basic therapy for Alzheimer's disease, it is necessary to elucidate the pathogenesis of Alzheimer's disease.
  • Alzheimer's disease is known to be familial (hereditary) Alzheimer's disease caused by genetic factors and sporadic Alzheimer's disease without genetic background. And risk factors are being clarified. Since familial Alzheimer's disease and sporadic Alzheimer's disease share the same clinical symptoms, it is predicted that a common mechanism exists in the onset process. Research is expected to lead to the elucidation of the pathogenesis of sporadic Alzheimer's disease.
  • a ⁇ amyloid Precursor Protein
  • mutant APP increases the expression ratio of A ⁇ 42 and that A ⁇ 42 is more likely to aggregate than A ⁇ 40.
  • a ⁇ 42 aggregates first, and A ⁇ 40 aggregates and accumulates using it as a nucleus, so that amyloid fibril formation proceeds and Alzheimer's disease develops.
  • Non-Patent Documents 1 and 2 GM1 ganglioside (GM1) constituting the nerve cell membrane to form a complex
  • GM1-binding A ⁇ : GA ⁇ GM1-binding A ⁇
  • Non-Patent Documents 1 and 2 GM1 aggregates depending on the cholesterol concentration in the nerve cell membrane to form a cluster, and that A ⁇ specifically binds to this GM1 cluster to form GA ⁇ . It has been confirmed by analysis using vesicles (Non-patent Document 3). Furthermore, analysis using an antibody that specifically recognizes GA ⁇ has confirmed that GA ⁇ has a structure different from that of soluble A ⁇ (Non-patent Document 4).
  • Patent Documents 2 to 6 Many low molecular weight compounds that inhibit A ⁇ polymerization have also been developed (Patent Documents 2 to 6). These compounds inhibit the elongation of amyloid fibrils or disrupt the fibrils by inhibiting A ⁇ polymerization. However, it has been suggested that if the administration of the compound is stopped, the polymerization of A ⁇ is resumed, and a sufficient inhibitory effect on amyloid fibril formation has not been obtained.
  • an amyloid fibril formation inhibitor using an antibody (4396C antibody) that specifically binds to GA ⁇ has been developed (Patent Document 7).
  • the 4396C antibody specifically recognizes and binds to GA ⁇ and fundamentally suppresses the formation of amyloid fibrils by inhibiting the polymerization of A ⁇ with respect to GA ⁇ .
  • a drug using the antibody has a problem that it is difficult to use clinically because its administration method is limited. is there.
  • the present invention has been made for the purpose of solving various problems of the prior art and providing a fundamental prevention / treatment method for neurodegenerative diseases such as Alzheimer's disease. Specifically, the polymerization of A ⁇ is specifically performed.
  • An object of the present invention is to provide an amyloid fibril formation inhibitor that can be inhibited and is excellent in clinical application.
  • the present inventors have succeeded in obtaining a low molecular weight compound that inhibits the polymerization of A ⁇ by specifically binding to GA ⁇ .
  • the present invention is represented by the general formula (I): [Where: X is an oxygen atom or a carbon atom, Y is —C (O) — or —CH 2 —, Z is — (CH 2 ) 1 —, — (CH 2 ) 1 —NH— (CH 2 ) m —, — (CH 2 ) 1 —C (O) — (CH 2 ) m —NH— (CH 2 ) N —, — (CH 2 ) 1 —C (O) — (CH 2 ) m —NH— (CH 2 ) n —O—, —C (O) — (CH 2 ) m —N (CH 3 ) — (CH 2 ) n —, — (CH 2 ) 1 —C (O) — (CH 2 ) m —N (CH 3 ) — (CH 2 ) n —, — (CH 2 ) 1 —C (O) — (
  • Ar is a substituted or unsubstituted C 5-14 aryl group or a substituted or unsubstituted C 1-14 heteroaryl group;
  • R 1 and R 2 are each independently a hydrogen atom, a substituted or unsubstituted C 1-20 alkyl group, a substituted or unsubstituted C 3-20 cycloalkyl group, a C 1-20 alkoxyalkyl group, C 1 A -20 hydroxyalkyl group, a C 1-20 aminoalkyl group, a C 1-20 alky
  • X is an oxygen atom
  • Y is —CH 2 —
  • Z represents — (CH 2 ) 1 —C (O) — (CH 2 ) m —NH— (CH 2 ) n —, — (CH 2 ) 1 —C (O) — (CH 2 ) m —, — (CH 2 ) 1 —SO 2 — (CH 2 ) m —, — (CH 2 ) 1 —CH ⁇ CH—C (O) — (CH 2 ) m —, or — (CH 2 ) 1 —C ( O) —CH ⁇ CH— (CH 2 ) m ⁇
  • the substituent may be a C 1-20 alkyl group, a C
  • Ar is a substituted or unsubstituted C 5-14 aryl group or a substituted or unsubstituted C 1-14 heteroaryl group;
  • R 1 and R 2 are each independently a hydrogen atom, a substituted or unsubstituted C 1-20 alkyl group, a C 1-20 alkoxyalkyl group, a C 1-20 alkoxycarbonylalkyl group, or a C 1-20 acyl group.
  • R 1 and R 2 may jointly form a ring
  • R 3 represents a hydrogen atom, a halogen atom, a substituted or unsubstituted C 1-20 alkyl group, a substituted or unsubstituted C 3-20 cycloalkyl group, a C 1-20 alkoxy group, a C 1-20 hydroxyalkyl group, A C 1-20 aminoalkyl group, a C 1-20 alkylaminoalkyl group, a C 1-20 alkoxyalkyl group or a hydroxyl group, R 4 is preferably a hydrogen atom or a C 1-20 alkyl group.
  • X is an oxygen atom
  • Y is —CH 2 —
  • Z represents — (CH 2 ) 1 —C (O) — (CH 2 ) m —NH— (CH 2 ) n —, — (CH 2 ) 1 —C (O) — (CH 2 ) m —, — (CH 2 ) 1 —SO 2 — (CH 2 ) m —, — (CH 2 ) 1 —CH ⁇ CH—C (O) — (CH 2 ) m —, or — (CH 2 ) 1 —C ( O) —CH ⁇ CH— (CH 2 ) m ⁇
  • the substituent may be a C 1-20 alkyl group, a C
  • Ar is a substituted or unsubstituted phenyl group, naphthyl group, pyridyl group, quinolyl group, indolyl group, thieno group, furyl group, imidazolyl group, triazolyl group, oxadiazolyl group or oxazolyl group
  • R 1 and R 2 are each independently a hydrogen atom, a substituted or unsubstituted C 1-20 alkyl group or a C 1-20 alkoxyalkyl group, wherein R 1 and
  • a compound selected from the group consisting of compounds Nos. 1-122 listed in Tables 1A to 1E, or a pharmaceutically acceptable salt thereof, or a solvate thereof provides an amyloid fibril formation inhibitor comprising a product.
  • the compounds are compound numbers 1, 3 to 6, 8, 10 to 15, 17 to 23, 26, 32 to 42, 44 to 46, 48, 57, 59 to 61, 64 to 66, 69 to 76, 79, Preferably selected from the group consisting of 89, 92-94, 97-99, 102, 105, 106, 110-115 and 119 compounds.
  • the compound has compound numbers 3, 4, 8, 10, 11, 13, 14, 17, 18, 20, 23, 26, 32 to 34, 36, 37, 41, 42, 44, 45, 57, Preferably, it is selected from the group consisting of compounds of 60, 66, 69, 70, 72-76, 79, 93, 97, 105 and 111.
  • a therapeutic or prophylactic agent for a neurodegenerative disease containing the amyloid fibril formation inhibitor.
  • the neurodegenerative disease is preferably Alzheimer's disease.
  • the present invention also provides, according to one embodiment, a compound selected from the group consisting of compound numbers 1-122, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the compound is preferably selected from the group consisting of compound numbers 47-56, 59-93 and 118-122.
  • the amyloid fibril formation inhibitor according to the present invention like the existing anti-GA ⁇ antibody (4396C antibody), specifically binds to GA ⁇ and blocks the initiation of polymerization of amyloid fibrils, thereby reliably forming amyloid fibrils. Can be suppressed.
  • the active ingredient of the amyloid fibril formation inhibitor according to the present invention is a low-molecular compound, (1) it can be easily synthesized and can be prepared in large quantities at low cost, and (2) it does not exhibit antigenicity. Therefore, it is superior to antibodies in that it is highly safe, (3) has high molecular stability, and can secure a stable GA ⁇ binding ability in various dosage forms.
  • amyloid fibril formation inhibitor according to the present invention, it is possible to provide a fundamental method for preventing and treating neurodegenerative diseases such as Alzheimer's disease.
  • the present invention has the general formula (I): [Where: X is an oxygen atom or a carbon atom, Y is —C (O) — or —CH 2 —, Z is — (CH 2 ) 1 —, — (CH 2 ) 1 —NH— (CH 2 ) m —, — (CH 2 ) 1 —C (O) — (CH 2 ) m —NH— (CH 2 ) N —, — (CH 2 ) 1 —C (O) — (CH 2 ) m —NH— (CH 2 ) n —O—, —C (O) — (CH 2 ) m —N (CH 3 ) — (CH 2 ) n —, — (CH 2 ) 1 —C (O) — (CH 2 ) m —N (CH 3 ) — (CH 2 ) n —, — (CH 2 ) 1 —C (O) — (CH 2
  • Ar is a substituted or unsubstituted C 5-14 aryl group or a substituted or unsubstituted C 1-14 heteroaryl group;
  • R 1 and R 2 are each independently a hydrogen atom, a substituted or unsubstituted C 1-20 alkyl group, a substituted or unsubstituted C 3-20 cycloalkyl group, a C 1-20 alkoxyalkyl group, C 1 A -20 hydroxyalkyl group, a C 1-20 aminoalkyl group, a C 1-20 alky
  • Amyloid fibrils are insoluble substances formed by aggregation of amyloid ⁇ (hereinafter referred to as “A ⁇ ” in the present specification) into a fibrous form.
  • the amyloid fibrils first form a complex (GM1-binding A ⁇ : GA ⁇ ) by binding A ⁇ to GM1 ganglioside (hereinafter referred to as “GM1” in the present specification) that constitutes the nerve cell membrane. Is formed by aggregation of A ⁇ using “seed” as a seed.
  • the amyloid fibril formation inhibitor according to this embodiment suppresses the formation of amyloid fibrils by inhibiting the aggregation of A ⁇ with respect to GA ⁇ .
  • a ⁇ is a peptide produced by cleaving amyloid precursor protein (hereinafter referred to as “APP” in the present specification) with ⁇ -secretase and ⁇ -secretase. A ⁇ 40 and A ⁇ 42 with different numbers are included.
  • APP includes RefSeq accession numbers NP_001129601.1, NP_001129602.1, NP_0011191232.2, NP_9588177.1 in the NCBI RefSeq database (http://www.ncbi.nlm.nih.gov/RefSeq/).
  • human APP consisting of the amino acid sequences registered as NP_0011921231.1, NP_958816.1, NP_0011921230.1, NP_0004755.1, NP_001129488.1, NP_0011299603.1, it is cleaved by ⁇ -secretase and ⁇ -secretase to produce A ⁇ .
  • amino acid sequence is 80% or more, preferably 90% or more, more preferably about 95 Protein comprising the amino acid sequence having an identity of greater than may be included.
  • Amino acid sequence identity can be calculated using sequence analysis software or using programs routine in the art (FASTA, BLAST, etc.).
  • APP includes substitution, deletion, insertion and / or substitution of one to several amino acids in the amino acid sequence, as long as it is cleaved by ⁇ -secretase and ⁇ -secretase to produce A ⁇ .
  • Proteins consisting of added amino acid sequences can be included.
  • “1 to several” is, for example, “1 to 30”, preferably “1 to 10”, and particularly preferably “1 to 5”.
  • the amyloid fibril formation inhibitor of this embodiment comprises compound (I) or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • X is an oxygen atom or a carbon atom, preferably an oxygen atom.
  • Y is —C (O) — or —CH 2 —, preferably —CH 2 —.
  • -(CH 2 ) 1 -,-(CH 2 ) m- and-(CH 2 ) n - may optionally have one or more hydrogen atoms substituted by a substituent.
  • Substituents include C 1-20 alkyl group, C 1-20 alkoxy group, C 1-20 alkoxyalkyl group, C 1-20 hydroxyalkyl group, C 1-20 aminoalkyl group, C 1-20 alkylaminoalkyl group.
  • C 1-20 alkoxycarbonyl group C 1-20 alkoxycarbonylalkyl group, C 1-20 acyl group, C 1-20 acylalkyl group, C 1-20 alkylthio group, C 1-20 alkylenedioxy group, halogen It is selected from the group consisting of an atom, amino group, nitro group, cyano group, thiol group and hydroxyl group.
  • C 1-20 alkyl group, C 1-20 alkoxy group, C 1-20 alkoxyalkyl group, C 1-20 hydroxyalkyl group, C 1-20 aminoalkyl group, C 1-20 alkylaminoalkyl group, C 1 A -20 alkoxycarbonyl group, a C 1-20 alkoxycarbonylalkyl group, a C 1-20 acyl group, a C 1-20 acylalkyl group, a C 1-20 alkylthio group and a C 1-20 alkylenedioxy group are preferably C 1-10 , particularly preferably C 1-5 .
  • the alkyl group and hydroxyalkyl group include both linear and branched chain forms.
  • the number of substituents and the substitution position are not particularly limited, but the number of substituents is preferably 0 to 3.
  • Ar is a substituted or unsubstituted C 5-14 aryl group or a substituted or unsubstituted C 1-14 heteroaryl group, preferably a substituted or unsubstituted C 6-10 aryl group Or a substituted or unsubstituted C 4-10 heteroaryl group.
  • the “aryl group” means an aromatic hydrocarbon ring group.
  • the aryl group in this embodiment may be one in which two or more aromatic hydrocarbon rings are condensed.
  • Examples of the aryl group include a phenyl group, an indenyl group, a naphthyl group, a phenanthryl group, and an anthryl group, and a phenyl group or a naphthyl group is preferable.
  • heteroaryl group means a group in which one or more carbon atoms on the ring of the aryl group are substituted with a heteroatom.
  • Preferred heteroatoms are selected from the group consisting of oxygen atoms, nitrogen atoms and sulfur atoms.
  • heteroaryl group examples include pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, triazinyl group, tetrazolyl group, oxazolyl group, indolizinyl group, indolyl group, isoindolyl group, Indazolyl group, purinyl group, quinolidinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, oxadiazolyl group, thiazolyl group, thiadiazolyl group, benzimidazolyl group, thieno group, furyl group, thienyl group, etc.
  • the aryl group and heteroaryl group may not be substituted, and one or more hydrogen atoms may be substituted with a substituent.
  • the substituent is a C 1-20 alkyl group, a C 1-20 alkoxy group, a C 1-20 alkoxyalkyl group, a C 1-20 hydroxyalkyl group, a C 1-20 aminoalkyl group, or a C 1-20 alkyl.
  • Aminoalkyl group C 1-20 alkylaminocarbonyl group, C 1-20 alkoxycarbonyl group, C 1-20 alkoxycarbonylalkyl group, C 1-20 acyl group, C 1-20 acylalkyl group, C 1-20 alkylthio Selected from the group consisting of a group, a C 1-20 alkylenedioxy group, a C 1-20 haloalkyl group, a halogen atom, an amino group, a nitro group, an aminosulfonyl group, a cyano group, a thiol group, and a hydroxyl group.
  • R 1 and R 2 are each independently a hydrogen atom, a substituted or unsubstituted C 1-20 alkyl group, a substituted or unsubstituted C 3-20 cycloalkyl group, C 1-20 alkoxyalkyl group, C 1-20 hydroxyalkyl group, C 1-20 aminoalkyl group, C 1-20 alkylaminoalkyl group, C 1-20 alkoxycarbonyl group, C 1-20 acyl or C 1-20 acyl
  • An alkyl group preferably a hydrogen atom, a substituted or unsubstituted C 1-20 alkyl group, a C 1-20 alkoxyalkyl group, a C 1-20 alkoxycarbonylalkyl group, a C 1-20 acyl group or a C 1- 20 is an acyl group, particularly preferably a hydrogen atom, a substituted or unsubstituted C 1-20 alkyl group or It is a 1-20 alkoxyalkyl group.
  • each of R 1 and R 2 may be the same or different, and R 1 and R 2 may jointly form a ring.
  • R 3 represents a hydrogen atom, a halogen atom, a substituted or unsubstituted C 1-20 alkyl group, a substituted or unsubstituted C 3-20 cycloalkyl group, a C 1-20 alkoxy group, C 1 -20 hydroxyalkyl group, C 1-20 aminoalkyl group, C 1-20 alkylaminoalkyl group, C 1-20 alkoxyalkyl group, C 1-20 alkoxycarbonyl group, C 1-20 alkoxycarbonylalkyl group, C 1 A -20 acyl group, a C 1-20 acylalkyl group, a C 1-20 alkylthio group, a C 1-20 alkylenedioxy group, an amino group, a nitro group, a cyano group, a thiol group or a hydroxyl group, preferably a hydrogen atom , Halogen atom, substituted or unsubstituted C 1-20 alkyl group, substituted or unsubsti
  • the alkyl group and hydroxyalkyl group include both linear and branched chain forms.
  • the alkyl group and cycloalkyl group may not be substituted, and one or more hydrogen atoms may be substituted with a substituent.
  • the substituents in this case are the same as those defined above.
  • R 4 is a hydrogen atom, a substituted or unsubstituted C 1-20 alkyl group, a C 1-20 hydroxyalkyl group, a C 1-20 aminoalkyl group, a C 1-20 alkylaminoalkyl group, A C 1-20 alkoxyalkyl group, a substituted or unsubstituted C 5-14 aryl group or a substituted or unsubstituted C 4-14 heteroaryl group, preferably a hydrogen atom.
  • the compound (I) used in the present embodiment also includes stereoisomers such as tautomers, geometric isomers (for example, E isomer, Z isomer, etc.), enantiomers and the like. .
  • the compound (I) used in the present embodiment can be synthesized by appropriately combining various conventionally known methods with the chemical synthesis methods described in the following examples and the chemical synthesis methods corresponding thereto.
  • the compound (I) used in the present embodiment is selected from commercially available compounds
  • a commercially available compound may be purchased.
  • Commercially available compounds are, for example, domestically through Namiki Shoji Co., Ltd. or Kishida Chemical Co., Ltd., Amberter, Enamine, Aurora Fine Chemicals LLC, UORSY, Vitas-M Laboratory, Interbios Inc., Interchim Inc., Rync Inc. , ChemDiv etc. can be purchased.
  • amyloid fibril formation inhibitor of the present embodiment includes not only those comprising the above compound (I) but also those comprising a pharmaceutically acceptable salt of the above compound (I) or a solvate thereof. Is done.
  • “pharmaceutically acceptable” means not harmful when using a drug.
  • the pharmaceutically acceptable salt in the present embodiment is, for example, an alkali metal salt such as a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt or the like when an acidic group is present in the compound (I) Alkaline earth metal salts; ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, Examples include amine addition salts such as ethanolamine, N-methylglucamine and L-glucamine; or basic amino acid addition salts such as lysine, ⁇ -hydroxylysine and arginine.
  • inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc .; methanesulfonic acid, benzenesulfonic acid, P-Toluenesulfonic acid, acetic acid, propionate, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbine
  • organic acid salts such as acid, nicotinic acid and salicylic acid
  • acidic amino acid addition salts such as aspartic acid and glutamic acid.
  • the pharmaceutically acceptable “solvate” in the present embodiment includes, for example, hydrate, alcoholate, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, chloroform, dichloroethane, dichloromethane, Diethyl ether, methyl t-butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, isobutyl methyl ketone, toluene, benzene, o-xylene , M-xylene, p-xylene, ethyl acetate, propyl acetate, butyl acetate, propylene carbonate, diethyl carbonate, dimethyl carbonate, hexane, Pentane
  • the compound represented by compound (I) or a pharmaceutically acceptable salt thereof or a solvate thereof may be used alone or a mixture of two or more thereof as an active ingredient of an amyloid fibril formation inhibitor. it can.
  • the amyloid fibril formation inhibitor of the present embodiment may be composed of only an active ingredient, but generally, as an optional ingredient, a known pharmaceutically acceptable diluent, carrier, excipient, etc. May be included.
  • the compound represented by Compound (I) or a pharmaceutically acceptable salt thereof or a solvate thereof is publicly known according to a conventional method. What is necessary is just to formulate in combination with these carriers.
  • the compound represented by Compound (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof has an appropriate intake amount in a range corresponding to each form as an active ingredient. So long as it is contained.
  • the compound represented by Compound (I) or a pharmaceutically acceptable salt thereof or a solvate thereof is usually administered at a dose of 0.001 mg / kg (body weight) per day for an adult.
  • the content in the drug is preferably determined so as to be preferably 0.01 mg / kg (body weight) or more.
  • the content is not limited to this range, and may be appropriately determined depending on the patient's symptoms, age, sex, and the like. It can be adjusted.
  • the upper limit of the dose is preferably 100 mg / kg (body weight) or less, more preferably 10 mg / kg (body weight) or less per day.
  • the amyloid fibril formation inhibitor of the present embodiment can be formulated into various dosage forms.
  • the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, Examples include ointments, creams, gels, patches, inhalants, injections and the like. Therefore, the amyloid fibril formation inhibitor of this embodiment can be administered by various methods such as oral administration, intraperitoneal administration, intradermal administration, intravenous administration, intramuscular administration, and intracerebral administration.
  • the amyloid fibril formation inhibitor when used as an oral preparation, it can be a solid preparation such as a tablet, capsule, powder, granule or the like.
  • suitable additives such as additives such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts, and if desired, binders, disintegrants, lubricants, colorants, fragrances Etc. can be blended.
  • the solid preparation is a tablet or pill, it may be coated with a sugar coating such as sucrose, gelatin or hydroxypropylcellulose, or a film of a gastric or enteric substance, if desired.
  • the oral preparation of an amyloid fibril formation inhibitor can be a liquid such as a syrup, and in this case, sterile water, physiological saline, ethanol, or the like can be used as a carrier.
  • auxiliary agents such as suspending agents, sweetening agents, flavoring agents, preservatives and the like may be added.
  • the amyloid fibril formation inhibitor when used as a parenteral preparation, it can be a liquid such as an injection or a rectal agent.
  • the active ingredient is dissolved in a diluent such as distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. by conventional methods.
  • a diluent such as distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc.
  • it can be prepared by suspending and adding a disinfectant, a stabilizer, an isotonic agent, a soothing agent, or the like, if necessary.
  • a solid composition can be produced and dissolved in sterile water or a sterile solvent for injection before use.
  • the parenteral preparation of the amyloid fibril formation inhibitor can be, for example, a sustained release preparation such as a microcapsule and can be directly administered into the brain.
  • Sustained-release preparations can be prepared using a carrier that can prevent immediate release from the body.
  • a carrier for example, a biodegradable / biocompatible polymer such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester, and polylactic acid can be used. Liposomes can also be used as the carrier.
  • Preferred liposomes may be, but are not limited to, those that have been purified and prepared by the reverse phase evaporation method using a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE).
  • a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE).
  • amyloid fibril formation inhibitor of this embodiment may contain a pharmaceutically acceptable additive such as a coloring agent, a preservative, a fragrance, a flavoring agent, and a sweetening agent and other therapeutic agents as desired. it can.
  • a stabilizer in the preparation of the amyloid fibril formation inhibitor.
  • the stabilizer include albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol and the like.
  • the amount of the active ingredient contained in the preparation varies depending on various conditions such as the type of extraction solvent and the amount of solvent used. Therefore, the amount of the active ingredient may be sufficient in an amount smaller than the above preferable intake amount or may be necessary beyond the range.
  • the amyloid fibril formation inhibitor of this embodiment can fundamentally and reliably suppress the formation of amyloid fibrils. Therefore, it is useful for uses such as treatment and prevention of diseases associated with amyloid fibril formation.
  • the present invention relates to an amyloid fibril comprising a compound selected from the group consisting of compounds of compound Nos. 1-122, or a pharmaceutically acceptable salt thereof, or a solvate thereof. It is a formation inhibitor.
  • Compounds Nos. 1-122 shown below can inhibit the polymerization of A ⁇ with respect to GA ⁇ and suppress the formation of amyloid fibrils.
  • the compound used in the present embodiment is compound numbers 1, 3 to 6, 8, 10 to 15, 17 to 23, 26, 32 to 42, 44 to 46, 48, 57, 59 to 61, 64 to 66, 69 to 76, 79, 89, 92 to 94, 97 to 99, 102, 105, 106, 110 to 115 and 119 compounds.
  • the above compounds have a strong inhibitory effect on amyloid fibril formation.
  • the compounds used in this embodiment are particularly preferably compound numbers 3, 4, 8, 10, 11, 13, 14, 17, 18, 20, 23, 26, 32-34, 36, 37, 41, 42, 44, 45, 57, 60, 66, 69, 70, 72 to 76, 79, 93, 97, 105 and 111.
  • the above compounds have a particularly strong inhibitory effect on amyloid fibril formation.
  • the compounds of Compound Nos. 1 to 122 are appropriately combined with various conventionally known methods in the chemical synthesis methods described in the following Examples and the chemical synthesis methods equivalent thereto. Can be synthesized. Or when selecting from a commercially available compound, you may purchase a commercially available compound.
  • the amyloid fibril formation inhibitor of the present embodiment includes those comprising the above specific compound, as well as those comprising a pharmaceutically acceptable salt of the above compound or a solvate thereof.
  • the “pharmaceutically acceptable salt” and “solvate” in the present embodiment are the same as those defined in the first embodiment.
  • the amyloid fibril formation inhibitor of the present embodiment is the amyloid fibril of the first embodiment except that the specific compound is used as the compound (I) in the first embodiment or instead of the compound (I). It may be prepared in the same manner as the formation inhibitor.
  • Compounds 1 to 42, 44 to 96, 98 to 116, and 118 to 122 are compounds having a structure represented by the general formula (I).
  • Compounds 43, 97 and 117 are compounds having a structure similar to the structure represented by formula (I), and can be used in place of compound (I).
  • the present invention is a therapeutic or prophylactic agent for neurodegenerative diseases containing the amyloid fibril formation inhibitor.
  • the therapeutic or prophylactic agent for neurodegenerative diseases according to this embodiment is a compound represented by compound (I) or a compound selected from compound numbers 1-122, or a pharmaceutically acceptable salt thereof, or a solvent thereof.
  • An amyloid fibril formation inhibitor comprising a single substance or a mixture of two or more selected from Japanese and an optional component.
  • the arbitrary component referred to here may be a normal pharmaceutical ingredient, and is prepared as various commonly used forms such as tablets, capsules, powders, granules, liquids and the like.
  • the therapeutic agent or preventive agent for neurodegenerative diseases according to this embodiment may further contain other active ingredients for treating or preventing neurodegenerative diseases as optional components.
  • ⁇ treatment '' means to prevent or alleviate the progression and worsening of the disease state in an animal suffering from a neurodegenerative disease, and not only completely cure the disease, It also includes alleviating the symptoms of the disease.
  • prevention means to prevent the disease from occurring in an animal that may suffer from a neurodegenerative disease.
  • the “neurodegenerative disease” means all diseases associated with (or resulting from) neuronal tissue degeneration associated with A ⁇ aggregation and amyloid fibril formation. Although it does not specifically limit as a neurodegenerative disease, For example, Alzheimer's disease, Parkinson's disease, Down's syndrome, cerebral amyloid angiopathy, Huntington's disease etc. are mentioned.
  • the neurodegenerative disease that is the target of the therapeutic or prophylactic agent of this embodiment is preferably Alzheimer's disease.
  • Alzheimer's disease includes familial (hereditary) Alzheimer's disease as well as so-called Alzheimer's disease (spontaneous Alzheimer's disease).
  • the animal that is the target of the therapeutic or prophylactic agent of the present embodiment is, for example, a mammal such as a mouse, rat, rabbit, dog, cow, pig, sheep, non-human primate, human, and preferably a human. .
  • the therapeutic agent or preventive agent for neurodegenerative diseases according to this embodiment is useful for the fundamental treatment or prevention of neurodegenerative diseases associated with the formation of amyloid fibrils.
  • the present invention is a compound selected from the group consisting of compounds of compound numbers 1-122, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the compound of the present embodiment is preferably selected from the group consisting of compounds Nos. 47 to 56, 59 to 93, and 118 to 122.
  • the compound of the present embodiment can be synthesized by appropriately combining various conventionally known methods with the chemical synthesis methods described in the following examples and the chemical synthesis methods corresponding thereto.
  • the compound according to the present embodiment or a pharmaceutically acceptable salt thereof or a solvate thereof can inhibit the polymerization of A ⁇ with respect to GA ⁇ and suppress the formation of amyloid fibrils. Therefore, it is useful for uses such as treatment and prevention of diseases associated with amyloid fibril formation.
  • the three-dimensional coordinate data and partial charge values of each atom of these optimized structures are incorporated into the ff99 parameter set of the empirical force field used in AMBER, and a molecule of 5 ns in a molecular system in which water molecules are arranged Kinetic calculations were performed.
  • Molecular dynamics calculation was performed on the sugar chain region of GM1, and trajectory poses were sampled.
  • trajectory poses were sampled.
  • docking with the three-dimensional structure of A ⁇ 40 (PDB ID: 1AML) registered in the Protein Data Bank was performed.
  • 2 million docking poses were obtained.
  • a docking pose with the least structural distortion and the most stable energy is extracted and used as an atomic model of GA ⁇ .
  • the inhibitory activity with respect to GA (beta) dependence amyloid fibril formation was evaluated in the in vitro reproduction system mentioned later.
  • the hit compound having the highest priority among those included in the series of hit compound groups is represented by the following general formula (I): It was suggested that the compound represented by these has inhibitory activity with respect to GA ⁇ -dependent amyloid fibril formation. Thereafter, a similarity search for compounds having inhibitory activity was performed and the inhibitory activity against GA ⁇ -dependent amyloid fibril formation was evaluated. As a result, the compound represented by the above general formula (I) was found to be GA ⁇ -dependent amyloid fibril formation. It became clear that it has inhibitory activity against.
  • compounds 1-42, 44-46, 57, 58, 94-96 and 98-116 are compounds having a structure represented by the general formula (I), and compounds 43, 97 and 117 are And a compound having a structure similar to the structure represented by the general formula (I).
  • LC / MS analysis was performed using a quadrupole mass spectrometer LCMS-2010 (Shimadzu Corporation) (column: Shim-pack XR-ODS (3.0 ⁇ 30 mm, 2.2 ⁇ m)) using ESI (+) ions. Mode or APCI (+) ion mode. Flow rate conditions: 0.3 to 0.8 mL / min, acquisition time: 3 to 5 minutes, detection wavelength: 220 nm, oven temperature: 40 to 50 ° C.
  • Prep-HPLC was performed under the following conditions.
  • Silica gel column Fuji C18 (300 ⁇ 25), YMC 250 ⁇ 20; wavelength: 220 nm; moving bed A: acetonitrile (0.1% HCl); moving bed B: water; flow rate condition: 25 mL / min, injection amount: 2 mL Run time: 20 minutes; equilibration time: 3 minutes.
  • the resulting solid was triturated with petroleum ether / dichloromethane (75 mL, 20: 1) to give 4.45 g of compound 78-b (24.7%) as a red solid.
  • Example 4 Synthesis of compounds 119 to 122 [Synthesis of Compound 119] (1) Synthesis of compound 119-a To a 2-aminophenol (5 g) / dimethylformamide solution (50 mL) were added potassium carbonate (19 g) and diethyl 2-bromo-2-methylmalonate (7.1 mL) at room temperature, and the mixture was stirred at 100 ° C. for 8 hours. The end of the reaction was confirmed by TLC. 10 mL of water was added, the reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (60 mL ⁇ 2) and saturated brine (60 mL), and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give compound 119-a (7.5 g, 70%) as a yellow solid.
  • Test Example 1 Evaluation of amyloid fibril formation inhibitory activity by thioflavin T (ThT) assay> The inhibitory activity of the compounds 1-122 on GA ⁇ -dependent amyloid fibril formation was evaluated by ThT assay.
  • GM1-containing liposome Using a chloroform / methanol mixture (1: 1) as a solvent, a mixed solution of 100 mM cholesterol and sphingomyelin (both manufactured by Sigma-Aldrich) was prepared. In this mixed solution, GM1 (cat. # 1061, manufactured by Matreya) was dissolved to a concentration of 50 mM. The lipid mixture solution was aliquoted into glass test tubes and stored at ⁇ 20 ° C. until use. After melting before use, chloroform / methanol mixture (1: 1) was added and mixed, and then the solvent was removed by applying nitrogen gas to the suspension.
  • chloroform / methanol mixture (1: 1) was added and mixed, and then the solvent was removed by applying nitrogen gas to the suspension.
  • the dried lipid mixture was resuspended in PBS so that the GM1 concentration was 2.5 mM, and freeze-thawed 5 times using liquid nitrogen. This lipid suspension was centrifuged at 15,000 rpm for 10 minutes, and the precipitate was resuspended in PBS so that GM1 was 2.5 mM. Using an ultrasonic crusher equipped with a microchip (XL-2000, manufactured by MISONIX), sonication for 10 seconds was repeated on ice until the suspension became transparent to prepare GM1-containing liposomes. PBS was added immediately before use to dilute the GM1 concentration to 750 ⁇ M.
  • ThT assay ThT (manufactured by Sigma-Aldrich) was prepared to 5 ⁇ M using 50 mM glycine-NaOH buffer (pH 8.5). Immediately before the measurement, 10 ⁇ l from each well in (4) was transferred to a 96-well black plate. Using a multi-plate reader (ARVO-HTS, manufactured by PerkinElmer), 50 ⁇ l of 5 ⁇ M ThT solution was added to each well from an injector, and optimum fluorescence of ThT bound to amyloid fibrils (excitation wavelength: 430 nm, fluorescence wavelength) 490 nm).
  • the fluorescence intensity of ThT indicates the degree of amyloid fibril formation.
  • Table 4 shows the ABC evaluation of GA ⁇ -dependent amyloid fibril formation inhibition rate (%) of typical compounds and the amyloid fibril formation inhibitory activity of compounds 1-122. Compounds 1 to 122 were all confirmed to have inhibitory activity against amyloid fibril formation.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un inhibiteur de la formation de fibrilles amyloïdes et un médicament thérapeutique ou prophylactique pour les maladies neurodégénératives, ledit inhibiteur et ledit médicament comprenant un composé représenté par la formule générale (I), un sel pharmaceutiquement acceptable de celui-ci ou un solvate de celui-ci. Dans la formule générale (I) : X représente un atome d'oxygène, etc.; Y représente -CH2-, etc. ; Z représente -(CH2)l-C(O)-(CH2)m-NH-(CH2)n- ; Ar représente un groupe aryle ou un groupe hétéroaryle ; R1 et R2 représentent indépendamment un atome d'hydrogène, un groupe alkyle, un groupe alcoxyalkyle, etc., ou R1 et R2 peuvent ensemble former un cycle ; R3 représente un atome d'hydrogène, un atome d'halogène, un groupe alkyle, un groupe cycloalkyle, un groupe alcoxy, etc. ; et R4 représente un atome d'hydrogène, etc.
PCT/JP2015/069487 2014-07-08 2015-07-07 Nouveau dérivé de benzoxazine et médicament le contenant WO2016006593A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2014-140625 2014-07-08
JP2014140625A JP2016017049A (ja) 2014-07-08 2014-07-08 新規ベンズオキサジン誘導体及びこれを含有する医薬

Publications (1)

Publication Number Publication Date
WO2016006593A1 true WO2016006593A1 (fr) 2016-01-14

Family

ID=55064224

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2015/069487 WO2016006593A1 (fr) 2014-07-08 2015-07-07 Nouveau dérivé de benzoxazine et médicament le contenant

Country Status (2)

Country Link
JP (1) JP2016017049A (fr)
WO (1) WO2016006593A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113527172A (zh) * 2020-04-21 2021-10-22 上海交通大学医学院附属仁济医院 M2乙酰胆碱受体拮抗剂及其用途
CN117384091A (zh) * 2023-12-08 2024-01-12 四川大学华西第二医院 一类酰胺衍生物、合成方法及用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003113147A (ja) * 1997-02-27 2003-04-18 Takeda Chem Ind Ltd アミン誘導体、その製造法および剤
WO2007062007A1 (fr) * 2005-11-21 2007-05-31 Amgen Inc. Modulateurs de la bêta-secrétase et procédés d'utilisation de ceux-ci
JP2012514038A (ja) * 2008-12-30 2012-06-21 バーテックス ファーマシューティカルズ インコーポレイテッド 嚢胞性線維症膜コンダクタンス調節因子のモジュレーター
WO2015080904A1 (fr) * 2013-11-27 2015-06-04 Vanderbilt University Analogues substitués du 4-benzyl-3,4-dihydro-2h-benzo[b] [1,4] oxazine-2-carboxamide, utilisés comme modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m1

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003113147A (ja) * 1997-02-27 2003-04-18 Takeda Chem Ind Ltd アミン誘導体、その製造法および剤
WO2007062007A1 (fr) * 2005-11-21 2007-05-31 Amgen Inc. Modulateurs de la bêta-secrétase et procédés d'utilisation de ceux-ci
JP2012514038A (ja) * 2008-12-30 2012-06-21 バーテックス ファーマシューティカルズ インコーポレイテッド 嚢胞性線維症膜コンダクタンス調節因子のモジュレーター
WO2015080904A1 (fr) * 2013-11-27 2015-06-04 Vanderbilt University Analogues substitués du 4-benzyl-3,4-dihydro-2h-benzo[b] [1,4] oxazine-2-carboxamide, utilisés comme modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m1

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY [o] retrieved from STN Database accession no. 924142-40-5 *
DATABASE REGISTRY [o] retrieved from STN Database accession no. 950150-67-1 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113527172A (zh) * 2020-04-21 2021-10-22 上海交通大学医学院附属仁济医院 M2乙酰胆碱受体拮抗剂及其用途
CN117384091A (zh) * 2023-12-08 2024-01-12 四川大学华西第二医院 一类酰胺衍生物、合成方法及用途
CN117384091B (zh) * 2023-12-08 2024-02-20 四川大学华西第二医院 一类酰胺衍生物、合成方法及用途

Also Published As

Publication number Publication date
JP2016017049A (ja) 2016-02-01

Similar Documents

Publication Publication Date Title
JP6870869B2 (ja) 新規オキサジアゾール誘導体及びこれを含有する医薬
KR102331422B1 (ko) 아이소인돌린 조성물 및 신경퇴행성 질환을 치료하는 방법
BR112017027798B1 (pt) Compostos de derivado de 1,3,4-oxadiazol sulfamida como inibidor de histona desacetilase 6 e a composição farmacêutica que compreende os mesmos
AU2016299485A1 (en) 1,3,4-oxadiazole amide derivative compound as histone deacetylase 6 inhibitor, and pharmaceutical composition containing same
JP2019512474A (ja) シアノ置換インドール化合物およびｌｓｄ１阻害剤としてのその使用
CN103097340A (zh) 治疗活性组合物及其使用方法
KR20200139702A (ko) 칼페인 조정자 및 그 치료학적 용도
TW201536793A (zh) Ｂａｃｅ抑制劑
US20180092866A1 (en) Substituted n-([1,1'-biphenyl]-3-yl)-[1,1'-biphenyl]-3-carboxamide analogs as inhibitors for beta-catenin/b-cell lymphoma 9 interactions
CN105246887A (zh) 香豆素衍生物以及用于治疗过度增生性疾病的方法
TW200817319A (en) Sulfonamide compound or salt thereof
KR20150130392A (ko) 구아니디노벤조산 에스테르 화합물
CN117580831A (zh) Grk2抑制剂及其用途
JP7642859B2 (ja) ヒストン脱アセチル化酵素６阻害剤としての１，３，４－オキサジアゾールチオカルボニル化合物およびこれを含む薬剤学的組成物
WO2016006593A1 (fr) Nouveau dérivé de benzoxazine et médicament le contenant
JP6983875B2 (ja) 細胞内カルシウムホメオスタシスを調節するためのトリアゾール
TWI619719B (zh) 選擇性ｂａｃｅ１抑制劑
US11718592B2 (en) Oxadiazole derivative
CN115477626B (zh) N-取代苯基磺酰胺类化合物及其用途
JP7624745B2 (ja) Ｔｒｐｖ４受容体リガンド
JP2022553443A (ja) Ｇｌｕｔ１欠損症症候群の治療に使用するためのイソキノリン誘導体
TWI857698B (zh) 作為組蛋白去乙醯酶6抑制劑之1,3,4-二唑三唑化合物及包含其之醫藥組合物
WO2014062204A1 (fr) Inhibiteurs de métalloprotéinases matricielles et méthodes de traitement de la douleur et d'autres maladies
JP2008156313A (ja) アミロイド疾患の治療およびモニタリングのための薬剤
JP2018168083A (ja) 新規キノリンカルボン酸誘導体及びこれを含有する医薬

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15818132

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15818132

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载