WO1994020476A1 - Nouveau compose heterocyclique - Google Patents

Nouveau compose heterocyclique Download PDF

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Publication number
WO1994020476A1
WO1994020476A1 PCT/JP1993/001233 JP9301233W WO9420476A1 WO 1994020476 A1 WO1994020476 A1 WO 1994020476A1 JP 9301233 W JP9301233 W JP 9301233W WO 9420476 A1 WO9420476 A1 WO 9420476A1
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WIPO (PCT)
Prior art keywords
formula
lower alkyl
group
salt
compound
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PCT/JP1993/001233
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English (en)
Japanese (ja)
Inventor
Hisashi Takasugi
Atsushi Kuno
Mitsuru Ohkubo
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Fujisawa Pharmaceutical Co., Ltd.
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Publication date
Priority claimed from JP4081393A external-priority patent/JPH05345772A/ja
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU49822/93A priority Critical patent/AU4982293A/en
Publication of WO1994020476A1 publication Critical patent/WO1994020476A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel heterocyclic compound having an acetylcholinesterase inhibitory action and a strong affinity for a muscarinic receptor, and is used in the medical field.
  • acetylcholinesterase inhibitors are known, the present invention has been made with the aim of developing even more excellent pharmaceuticals.
  • the present invention relates to a novel heterocyclic compound and a pharmaceutically acceptable salt thereof.
  • the present invention relates to acetylcholinesterase inhibitors, and thus to amnesia and dementia (for example, senile dementia of Alzheimer type, vascular dementia, etc.).
  • the present invention relates to a novel heterocyclic compound which is useful for the prevention and treatment of diseases of the central nervous system such as cerebrovascular disorders, and pharmaceutically acceptable salts thereof.
  • heterocyclic compounds targeted by the present invention are novel and are represented by the following general formula (I): M-W-Y-A-Q (I)
  • R 1 is hydrogen, lower alkyl, a heterocyclic group which may have a suitable substituent, or a heterocyclic group which may have a suitable substituent.
  • R 2 represents hydrogen, lower alkyl, a heterocyclic group which may have a suitable substituent, or phenyl which may have a suitable substituent;
  • R ⁇ and R 2 combine with each other to form the formula:
  • Z represents S or 0, respectively) or a group represented by
  • W represents a bond, lower alkylene or lower alkylene
  • Y is lower alkylene
  • R 3 represents hydrogen or lower alkyl.
  • R 7 represents hydroxy or protected hydroxy.
  • A represents a bond or lower alkylene
  • R 9 wherein R 8 represents lower alkyl and R 9 represents alk (lower) alkyl.
  • a target compound of the present invention ( I) can be manufactured by the following methods. Manufacturing method (1)
  • Y is each as defined above
  • RI is lower alkyl
  • X 1 and X 2 each represent an acid residue
  • w 1 is a bond, a ⁇ c 5 A Ruki-les-down or is c 2 C 5 Anoreke two-les-down, R 7
  • the starting compounds or their salts can be produced by the following methods. Manufacturing method (A)
  • R R M, W, W 1 Z, Y, A, Q and X ⁇ are each as defined above,
  • R 5 is carboxyl or protected carboxyl
  • R 6 is lower alkyl
  • R 10 is a low-grade alkoxy
  • R is lower alkyl
  • W 2 represents a bond, c] to c 4 alkylene or c 2 -C alkylene,
  • Suitable pharmaceutically acceptable salts of the compound (I) are conventional non-toxic salts, for example, salts with inorganic bases, such as alkali metal salts (eg, For example, sodium salt, potassium salt, etc., alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), ammonium salt; organic base and Salts, for example, organic base salts (for example, triethylamine salt, pyridin salt, picolinate salt, ethanolamine salt, triethanolamine salt, diethanolamine salt)
  • Inorganic acid addition salts for example, hydrochloride, hydrobromide, sulfate, phosphoric acid
  • cyclohexylamine and N, N'-dibenzylethylenediamine such as cyclohexylamine and N, N'-dibenzylethylenediamine.
  • Organic carboxylic acid or sulfonate addition salts for example, formate, acetate, Li Furuo Russia ⁇ salt, Maleate, tartrate, fumarate, methansulfonate, benzenesulfonate, toluenesulfonate, etc.
  • basic And salts with bases or acid addition salts such as salts with acidic amino acids (eg, arginine, asno, laginic acid, glutamic acid, etc.).
  • lower is used to mean a group having 1 to 6, preferably 1 to 4 carbon atoms, unless otherwise specified.
  • Suitable lower alkyl moieties in the terms “lower alkyl” and “al (lower) alkyl” include methyl, ethinole, propinole, isopro pinole. Linear or branched having 1 to 6 carbon atoms, such as butyl, butynole, isobutyl, secondary butyl, tertiary butyl, pentyl, tertiary pentyl, hexyl, etc. Among them, preferred are those having 1 to 4 carbon atoms.
  • Suitable “lower grades” include methoxy, ethoxy, proboxy, isoproboxy, butoxy, isobutoxy, and secondary butoxy. , Tertiary butoxy, pentoxy, tertiary pentoxy, hexyloxy, etc., linear or branched having 1 to 6 carbon atoms. Others are listed.
  • Preferred “heterocyclic groups” are saturated or unsaturated monocyclic or polycyclic heterocycles containing at least one heteroatom, such as an oxygen, sulfur or nitrogen atom. It means a ring group.
  • heterocyclic groups include the following heterocyclic groups: 3- to 8-membered unsaturated heterocyclic groups containing 1-4 nitrogen atoms, For example, pyrrolyl, pyrrolinole, imidazolinole, virazolinole, pyridyl and its N-oxide, dihydroxypyridyl, tetrahydrolin Pyridyl, pyrimidinole, pyrazinyl, pyridazinyl, triazolinole (for example, 4H—1, 2, 41 triazole, 1H-11, 2,3—triazolinole, 2H—1,2,3—triazolinole, etc., tetrazole (for example, 1H—tetrazole), 2 H — tetrazolinol, etc.), dihydrotriazine (for example, 4, 5 — dihydro1-1, 2, 4-triazine) Les, 2, 5 - di-heat mud-1, 2, 4 one Application Benefit
  • 3- to 8-membered saturated heterocyclic group containing 1 to 4 nitrogen atoms such as azetidinyl, pyrrolidinole, imidazolidinyl, piperidinole, virazolidinyl, piperazinyl What
  • a fused unsaturated heterocyclic group containing 1 to 5 nitrogen atoms for example, indolinole, isoindolinole, indlizinyl, benzoimidazolinole, quino Linole, Isoquinolinole, Indazolinole, Benzotriazolinole, Tetrazolopyridyl, Tetrazolopyridinil (for example, Tetozo) La Zoro [1, 5 — b] pyridazinyl), dihydrotriazolopyridazinyl, etc .;
  • a 3- to 8-membered unsaturated heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms such as oxazolyl, isoxozolinole, oxaziazolinole (for example, 1,2,4-oxaziazinolole, 1,3,41-oxaziazinolyl, 1,2,5—oxaziazinolinole, etc.);
  • 3- to 8-membered unsaturated heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms for example, 1,3—thiazolinole, 1,2—thiazolinole, thiazo Linole, thiadiazolyl (for example, 1,2,4-thiadiazolinole, 1,3,4-thiadiazolinole, 1,2,5—thiadiazolinole, 1,2,3— Thia diazo linole);
  • Condensed unsaturated heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as benzothiazolyl and benzothiadiazolinole;
  • Suitable "lower alkylenes" include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and hexaalkylene. Examples thereof include straight-chain or branched-chain ones having 1 to 6 carbon atoms, such as methylene, methylenolethylene, ethynoleethylene, and propylene, and more.
  • a good example is
  • Suitable “lower alkenylene” include vinylene, plorenylene, 1 — (or 2 —) butenylene, 1 — (or 2 — or 3 —) Pentenlen, 1 — (or 2 — or 3 —) Hexenylene, Methynorebiren, Ethilbiniren, 1 (or 2 — or 3 —) methylprodilelen, 1-1 (or 2 — or 3 —) ethynoleprodilene, 1 — (or 2 — or 3 — or 4)
  • aryl in the word “aryl” and “al (lower) alkyl” include phenyl, naphthyl and the like. A more preferred example is finninore.
  • Suitable “protected carboxyls” include esterified potato reboxes and the like.
  • Suitable examples of the ester moiety of the esterified carboxy include lower alkyl esters (eg, methyl ether tenol, etinoles tenenole, propyles tenore, isopro).
  • Lower alkyl esters having at least one suitable substituent for example, lower alkyl esters, for example, lower alkyl esters [for example, acetoxyl methyl esters, propioninoleo, etc.] Kisme Chinoles Tenoré, Butyri Luo Kisime Chinoles Tenoré, Valle Rinoréo Kisime Chinoles Tenoré, Pinot Roy Norero Kisime Chinoles Tenoré, Hexano y Noreo Kisime Chinoles Tener, 1 (or 2 —) Acetoki Sheil Estel, 1 (or 2 — or 3 —) Acetoki Propirester, 1 1 (or Is 2 — or 3 — or 4 1) acetoxybutyl
  • Suitable “acid residues” include halogen (eg, chlorine, bromine, iodine or fluorine); alkanoyloxy (eg, acetoxy, etc.). ), Low-grade alkanols (e.g., methansulfoninoleux), and more preferably halogen. is there.
  • halogen eg, chlorine, bromine, iodine or fluorine
  • alkanoyloxy eg, acetoxy, etc.
  • Low-grade alkanols e.g., methansulfoninoleux
  • Suitable "protected hydroxy” include acyloxy; phenyl-lower alkyl optionally having one or more suitable substituents (e.g., benzyloxy). And hydroxy substituted with a conventional protecting group such as tetramethylhydrobilanyl.
  • a preferred "acyl moiety" in the expression “acyloxy” includes carbamoyl, an aliphatic acyl group, and an aromatic or heterocyclic ring-containing amino acid. And a sil group.
  • Preferable examples of the acyl include lower-alkanols (for example, honole minole, acetyl, propionyl, butyrinole, isobutylinole, norenorinole).
  • Suitable rC—Cranolylene includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, methylene, and the like. Examples thereof include linear or branched ones such as chinolemethylene, ethynoleethylene, and propylene.
  • Suitable “Ju-Ju alkylene” includes methylene, ethylene, trimethylene, tetramethylene, ethylethylene, propylene And straight-chain or branched-chain ones.
  • Preferred “c 2 to C r alkenylene” include vinylene, prophenylene, 1- (or 2 —) butenylene, 1- 1 (or 2 — or Or 3-) pentenelen, methylvinylene, ethylvinylene, 11 (or 2 — or 3 —) methylpropenylene, 11 ( Or 2 — or 3 —) Chilpropenylene, 1 (or 2 — or 3 — or 4 1) Methynole 1 — (or 2 —) Straight chain or branched, such as butenylene Examples include chain-like ones.
  • Suitable “c 2 to alkenylene” includes vinylene, propylene, 11- (or 2-) butenylene, methylvinylene, ethynolevine. Examples thereof include straight-chain or branched-chain compounds such as len, and 11 (or 2 — or 3 —) methylprobenylene.
  • a preferred "substituent" in the expression “optionally substituted aryl” is a lower alkyl (for example, methyl, ethylenol, Propyl, Isopropynole, Butyl, Isobutyl, Tertiary Butynole, Pentinole, Neopentyl, Tertiary Pentyl, Hexyl, etc., Lower Alkoxy (for example) Methoxy, ethoxy, proboxy, isopropoxy, isobutoxy, tertiary butoxy, pentyloxy, neopentinoreoxy, tertiary pentinoleo Kish, hexyloxy, etc.), lower alkenyl (for example, vinyl, 1-vinyl, 1-methyl, 1- or 2-- or 3—Butenyl, 1 1 or 2 — or 3 — or 4 1 pen Tenyl, 1 or 2 — or 3 — or 4 1 or 5> xenyl, etc.), lower
  • Hydroxy lower alkyl protected hydroxy lower phenol, acyl ole, cyano, mentole, lower alkyl thio (eg, methyl thio, ethyl thio, etc.) , Propiorchio, Isopropiorchio, Buti Norchio ), Imino, etc.
  • Suitable "protected amino” includes acylamino (for the acyl part, the one exemplified above is cited).
  • a preferred “substituent” in the expression “heterocyclic group optionally having substituent (s)” is a lower alkyl (for example, methyl, ethyl, and methyl).
  • a suitable “substituent” in the expression “Alkyl (lower alkyl) which may have a suitable substituent” includes lower alkyl (for example, methylol, ethyl, Propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl, hexyl, etc., lower phenolic (eg, methoxy) , Ethoxy, propoxy, isopro box, isobutoki, tertiary butoxy, pentyloxy, neopentyloxy, tertiary pentyloxy, Hexyloxy, etc.), lower alkenyl (for example, vinyl, 1-propene, aryl, 1-methyl phenol) Nole, 1 or 2 — or 3 — butenyl, 1 or 2 1 or 3 — or 4 1-pentenyl, 1 1 or 2 — or
  • the compound (Ia) or a salt thereof is a compound (Ila) or a reactive derivative of the carboxyl group or a salt thereof with the compound (III) or a reactive derivative thereof. Alternatively, it can be produced by reacting with a salt thereof.
  • a Schiff base-type imine formed by the reaction of the compound (III) with a phenolic compound such as phenolic anhydride or ketone can be used.
  • compound (III) bis (trimethylinoleyl) acetamide, mono (trimethylinolecillin) acetamide Toamide [for example, N— (trimethylsilyl) acetamide], bis (trimethyltinsilino) or bis (trimethyltinsilino) is due to its reaction with silyl compounds such as urine.
  • a derivative formed by the reaction of compound (III) with phosphorus trichloride or phosgene is due to its reaction with silyl compounds such as urine.
  • Suitable reactive derivatives at the carboxyl group of the compound (IIa) include acid halides, acid anhydrides, active amides, active esters, and the like.
  • Preferred examples of such reactive derivatives include acid chlorides; acid azides; substituted phosphoric acids (eg, dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, Benzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (For example, methansulphonic acid), aliphatic carboxylic acids
  • a mixed acid anhydride with an acid such as an aromatic carboxylic acid (for example, benzoic acid); a symmetrical acid anhydride
  • Imidazole 4-monosubstituted imidazole, dimethylpyrazole, triazonole, 1-hydroxyl-1H-benzotriazole or tetrazole
  • the reaction is usually carried out in a conventional solvent, for example, water, alcohol (for example, methanol, ethanol, etc.), acetate, dioxane, acetone. Tonitrinole, chlorophonolem, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethinole honolem amide,
  • a conventional solvent for example, water, alcohol (for example, methanol, ethanol, etc.), acetate, dioxane, acetone.
  • Tonitrinole, chlorophonolem methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethinole honolem amide
  • the reaction should be performed in an organic solvent that does not adversely affect pyridin or other reactions.
  • These conventional solvents may be used as a mixture with water.
  • the N, N'-dicyclohexyl phenol can be used.
  • the starting compound When the starting compound is in a liquid state, it can be used as a solvent.
  • reaction is carried out using alkali metal bicarbonate, tri (lower) alkylamines, pyridines, N—lower alkylmonohololin, N,
  • the reaction temperature is not particularly limited, but usually the reaction is performed without cooling or under caloric heat.
  • Compound (Ic) or a salt thereof can be produced by reacting compound (Ib) or a salt thereof with compound (IV) or a salt thereof.
  • the reaction is usually carried out in a conventional solvent, for example, alcohol (for example, methanol, ethanol, ethylene glycol, etc.), chlorofonolem, and ethanol.
  • alcohol for example, methanol, ethanol, ethylene glycol, etc.
  • chlorofonolem for example, ethanol
  • -Tenore tetrahydrofuran, benzene, N, N-dimethinole honoleum amide, or any other organic solvent that does not adversely affect the reaction.
  • the reaction temperature is not particularly limited, but the reaction is usually performed without cooling or heating.
  • the reaction is usually carried out with an alkali metal hydroxide, alkaline metal bicarbonate, alkaline metal carbonate, alkaline metal acetate, tri (lower) alkylamine, alkaline metal Hydride, pyridin, norethidin, picolin, dimethinorea minopyridine, N-lower alkylmorpholine, N, N-di (lower) alkylben Performed in the presence of an inorganic or organic base such as ziramine, N, N-di (lower) alkylaniline.
  • an inorganic or organic base such as ziramine, N, N-di (lower) alkylaniline.
  • Compound (Id) or a salt thereof can be produced by reacting compound (V) or a salt thereof with compound (VIII) or a salt thereof.
  • the reaction is usually carried out with alcohol (for example, methanol, ethanol, etc.), benzene, N, N, N-dimethylformamide, tetrahydrofuran.
  • alcohol for example, methanol, ethanol, etc.
  • benzene N, N, N-dimethylformamide
  • tetrahydrofuran The reaction is performed in a solvent such as lofuran, toluene, methylene chloride, ethylene dichloride, chloroformolem, or getyl ether, or any other solvent that does not adversely influence the reaction.
  • the reaction temperature is not particularly limited, but the reaction is usually carried out without heating or under heating.
  • Compound (Ie) or a salt thereof is compound (IX) or Can be produced by reacting the salt thereof with the compound (IIIa) or a salt thereof, and subjecting the resulting compound to a reduction reaction.
  • This reduction is carried out by a conventional method, including chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used for chemical reduction include hydrides (eg, hydrogen iodide, hydrogen sulfide, aluminum hydride, sodium borohydride, cyanoborohydride) Sodium or a metal (for example, tin, zinc, iron, etc.) or a metal compound (for example, chromium chloride, chromium acetate, etc.) and an organic acid Is a combination with an inorganic acid (for example, formic acid, acetic acid, propionic acid, triphenolic acetic acid, p-tonolenosorenoic acid, hydrochloric acid, hydrobromic acid, etc.) .
  • hydrides eg, hydrogen iodide, hydrogen sulfide, aluminum hydride, sodium borohydride, cyanoborohydride
  • Sodium or a metal for example, tin, zinc, iron, etc.
  • a metal compound for example, chromium chloride, chromium acetate
  • Suitable catalysts to be used for the catalytic reduction are platinum catalysts (for example, platinum plate, spongy platinum, platinum black, platinum in the form of colloid, platinum oxide, platinum wire, etc.), palladium catalysts (for example, For example, spongy, 0 radium, no, 0 radium black, palladium oxide, palladium charcoal, colloidal palladium, palladium palladium sulfate, palladium Z carbonate
  • Nickel catalysts for example, reduced nickel oxide, nickel oxide, and Raney nickel
  • cobalt catalysts for example, reduced nickel oxide, and Raney nickel.
  • reactions are usually performed in water, alcohol (eg, methanol, ethanol), N, N—dimethylmethonolone amide, tetrahydrofuran
  • alcohol eg, methanol, ethanol
  • N N—dimethylmethonolone amide
  • tetrahydrofuran The reaction is carried out in a solvent such as lan, a mixture thereof, or any other solvent that does not adversely influence the reaction.
  • the acids to be used for the chemical reduction are liquid, they can be used as a solvent.
  • the reaction temperature is not particularly limited, but usually the reaction is carried out without cooling or heating.
  • Compound (Ig) or a salt thereof can be produced by subjecting compound (I () or a salt thereof to an elimination reaction of a hydroxy protecting group.
  • Suitable methods for this elimination reaction include conventional methods such as hydrolysis and reduction.
  • the hydrolysis is preferably performed in the presence of a base or an acid, including Lewis acid.
  • Suitable bases include alkali metals (for example, sodium, potassium, etc.), alkaline earth metals (for example, magnesium, canoleum, etc.). ), These hydroxides, carbonates or bicarbonates, tri (lower) alkylamines (such as trimethinoreamin, triethinoreamin), Inorganic and organic bases such as picolin, 1,5—diazabicyclo [4.3.0] non-5-ene I can do it.
  • alkali metals for example, sodium, potassium, etc.
  • alkaline earth metals for example, magnesium, canoleum, etc.
  • Inorganic and organic bases such as picolin, 1,5—diazabicyclo [4.3.0] non-5-ene I can do it.
  • Suitable acids include organic acids (eg, formic acid, diacid, propionic acid, trichloroacetic acid, trifluoroacetic acid) and inorganic acids (eg, hydrochloric acid). , Hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.).
  • a Lewis acid such as trihalodiacid (eg, trichlorosulfuric acid, trifluoacetic acid, etc.) requires a cation trapping agent (eg, Aniso It is preferable to carry out the program in the presence of a file or a folder.
  • a Lewis acid such as trihalodiacid (eg, trichlorosulfuric acid, trifluoacetic acid, etc.)
  • a cation trapping agent eg, Aniso It is preferable to carry out the program in the presence of a file or a folder.
  • the reaction is usually carried out in water, alcohol (eg, methanol, ethanol, isopropynoreal), tetrahydrofuran, zeolite, etc.
  • alcohol eg, methanol, ethanol, isopropynoreal
  • tetrahydrofuran zeolite
  • Conventional such as xan, dichloromethane, ethylene dichloride, chlorofonolem, N, N-dimethylformamide, N, N-dimethylacetamide Perform in a solvent or any other organic solvent that does not adversely affect the reaction.
  • hydrophilic solvents may be used as a mixture with water.
  • the reaction temperature is not particularly limited, but the reaction is usually performed without cooling or heating.
  • the reduction is carried out by standard methods including chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used for chemical reduction are metals (eg, tin, zinc, iron, etc.) or metal compounds (eg, chlorides). Chromium, chromium acetate, etc.) and organic or inorganic acids (for example, formic acid, acetic acid, propionic acid, trifluoric acid, P-toluenesulfonic acid, hydrochloric acid, bromide) Hydrogen acid, etc.).
  • metals eg, tin, zinc, iron, etc.
  • metal compounds eg, chlorides
  • organic or inorganic acids for example, formic acid, acetic acid, propionic acid, trifluoric acid, P-toluenesulfonic acid, hydrochloric acid, bromide) Hydrogen acid, etc.
  • Suitable catalysts to be used for the catalytic reduction are platinum catalysts (for example, platinum plate, spongy platinum, platinum black, platinum in the form of colloid, platinum oxide, platinum wire, etc.), palladium catalysts (such as For example, spongy palladium, palladium black, palladium oxide, phosphorus, 0- radio charcoal, colloidal palladium, palladium palladium sulfate, palladium palladium carbonate, etc.
  • platinum catalysts for example, platinum plate, spongy platinum, platinum black, platinum in the form of colloid, platinum oxide, platinum wire, etc.
  • palladium catalysts such as For example, spongy palladium, palladium black, palladium oxide, phosphorus, 0- radio charcoal, colloidal palladium, palladium palladium sulfate, palladium palladium carbonate, etc.
  • Nickel catalysts for example, reduced nickel, nickel oxide, Raney 12
  • cobalt catalysts for example, reduced cobalt, Ranekobalt, etc.
  • Conventional catalysts such as copper catalysts (eg, reduced copper, Raney copper, Ullman copper) and iron catalysts (eg, reduced iron, Raney iron, Ullman iron).
  • This reduction is usually carried out with water, methanol, ethanol, prono, and so on. Performed in conventional solvents that do not adversely affect the reaction, such as phenolic, N, N—dimethinolehonoleamide, dimethyl ether, dioxane, tetrahydrofuran, and mixtures thereof. I do.
  • the acids to be used for the chemical reduction are liquid, they can be used as a solvent.
  • the reaction temperature for this reduction is not particularly limited, but usually the reaction is carried out without cooling or heating.
  • Compound (Ih) or a salt thereof can be produced by subjecting compound (Ig) or a salt thereof to an oxidation reaction.
  • Oxidation is carried out according to a conventional method.
  • Suitable oxidizing agents include dimethinoles norrexide and N, N, -dicyclohexylcarbodiimide, lower alkanoic anhydrides (eg, anhydrous acetic acid), and the like. Pentoxide, sulfur trioxide pyridin, N-nitrosuccinimide (for example, N-chlorosuccinimide), oxalyl chloride, etc. Combinations.
  • the reaction is carried out in the presence of an acid.
  • Suitable acids include organic acids (eg, formic acid, sulfuric acid, propionic acid, dichloroacetic acid, trifluoroacetic acid, etc.) and inorganic acids (eg, hydrochloric acid) , Hydrobromic acid, phosphoric acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.).
  • the reaction may be an alkali metal (for example, sodium, potassium hydroxide), an alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide, etc.). ), Alkaline metal bicarbonates (eg, sodium bicarbonate, potassium bicarbonate), alkaline metal bicarbonates (eg, sodium carbonate, potassium carbonate, etc.) ), Tri-lower alkylamines (for example, trimethylamine, triethylamine, diisopropinoleamine, etc.), alkali metal hydrides (for example, hydrogenated Aluminum, etc.), Alkali metal lower-grade alkoxy (for example, sodium methoxide, sodium ethoxy) ), Pyridines (eg, pyridin, norethidin, picolin, dimethylaminopyridine), N—lower alkynole
  • the reaction may be performed in the presence of an inorganic base or an organic base such as phosphorus, N, N—di-lower phenol benzoylamin,
  • This reaction is usually carried out in water, alcohol (for example, methanol, ethanol, etc.), benzene, N, N-dimethyl-honolemamide, tetrahydro.
  • Solvents such as Drofuran, Toluene, Methylene Chloride, Ethylene Dichloride, Chlorohonolem, Dioxan, and Jethyl Ether, and adversely affect other reactions Not performed in any solvent.
  • solvents may be used by mixing with water.
  • the reaction temperature is not particularly limited, but the reaction is usually performed without cooling or heating.
  • Compound (IIb) or a salt thereof can be produced by reacting compound (V) or a salt thereof with compound (VI) or a salt thereof.
  • the reaction is usually carried out with water, ethanol (for example, methanol, ethanol, ethanol), tetrahydrofuran, zeolite, etc.
  • ethanol for example, methanol, ethanol, ethanol
  • Conventional solvents such as xan, black formaldehyde, methylene chloride, dimethyl acetate amide, N, N-dimethylformamide, and other adverse effects on the reaction Perform in any organic solvent that does not.
  • hydrophilic solvents may be used by mixing with water.
  • the reaction temperature is not particularly limited, but usually the reaction is performed without cooling or heating.
  • Compound (IId) or a salt thereof can be produced by reacting compound (IIc) or a salt thereof with compound (VII) or a salt thereof.
  • the reaction is usually alcohol (for example, methanol, ethanol, ethylene glycol, etc.), chlorophonolem, ethereal, tetrahydro.
  • the reaction is carried out in a conventional solvent such as drofuran, benzene, and acetate, or any other organic solvent that does not adversely influence the reaction.
  • the reaction temperature is not particularly limited, but usually the reaction is performed without cooling or heating.
  • Reactions include alkali metal hydroxides, alkali metal carbonates, alkali metal carbonates, alkali metal acetates, tri (lower) alkylamines, pyridines, and lutidines.
  • Inorganic bases such as, picolin, dimethylaminopyrrolidine, N-lower alkyl morpholine, N, N-di-lower alkylbenzilamin, N, N-di-lower alkyl aniline Can be performed even in the presence of an organic base. When the base and / or the starting compound are liquid, they can be used as a solvent. Manufacturing method (C)
  • Compound (IIe) or a salt thereof is compound (IId) Alternatively, it can be produced by subjecting the salt to a reduction reaction.
  • the reduction is carried out in accordance with the usual methods of reducing pyridin rings to 1,2,5,6—tetrahydropyridinine rings, including chemical and catalytic reductions.
  • Suitable reducing agents to be used for chemical reduction are hydrides (eg, hydrogen iodide, hydrogen sulfide, aluminum hydride, sodium borohydride, etc.) or Metals (for example, tin, zinc, iron, etc.) or metal compounds, substances (for example, chromium chloride, chromium acetate, etc.) and organic or inorganic acids (for example, formic acid, Combination with acetic acid, propionic acid, trifluoroacetic acid, P-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
  • hydrides eg, hydrogen iodide, hydrogen sulfide, aluminum hydride, sodium borohydride, etc.
  • Metals for example, tin, zinc, iron, etc.
  • metal compounds for example, chromium chloride, chromium acetate, etc.
  • organic or inorganic acids for example, formic acid, Combination with acetic acid
  • Suitable catalysts to be used for catalytic reduction are platinum catalysts (for example, platinum plate, spongy platinum, platinum black, platinum-like platinum, platinum oxide, platinum wire, etc.), palladium catalysts (for example, Spongy palladium, no, .radium black, no oxide, 0 radium, no, .radiodium charcoal, colloidal palladium, no, .radiodium / sulphate
  • Platinum catalysts for example, reduced nickel, nickel oxide, Rane-122
  • cobalt catalysts for example, radium barium carbonate.
  • reduced cobalt, Ranekobalt, etc. iron catalysts (eg, reduced iron, Raney iron, etc.), copper catalysts (eg, reduced copper, Raney copper, Ullman copper, etc.) It is a common practice.
  • Reduction is usually carried out with water, alcohol (for example, methanol, ethanol, etc.), N, N-dimethylthionoremamine.
  • the reaction is carried out in a conventional solvent such as tetrahydrofuran, a mixture thereof, or any other solvent that does not adversely influence the reaction.
  • a hydrophilic solvent may be used by mixing with water.
  • the reaction temperature for this reduction is not particularly limited, but usually the reaction is carried out without cooling or heating.
  • Compound (IXa) or a salt thereof can be produced by reacting compound (V) or a salt thereof with compound (X) or a salt thereof.
  • This reaction can be carried out by the method disclosed in Production Example 7 or a method analogous thereto.
  • the compound (XII) or a salt thereof can be produced by reacting the compound (IXb) or a salt thereof with the compound (XI) or a salt thereof.
  • This reaction can be carried out by the method disclosed in Production Example 8 or a method analogous thereto.
  • Compound (XIII) or a salt thereof can be produced by subjecting compound (XII) or a salt thereof to a reduction reaction.
  • Compound (XVI) or a salt thereof can be produced by reacting compound (XIV) or a salt thereof with compound (XV) or a salt thereof.
  • This reaction can be carried out by the method disclosed in Production Example 11 or a method analogous thereto.
  • Compound (XVI) or a salt thereof can be produced by subjecting compound (XVI) or a salt thereof to a reduction reaction.
  • This reaction can be carried out by the method disclosed in Production Example 12 or a method analogous thereto.
  • the compound (VIII) or a salt thereof can be produced by reacting the compound (XVII) or a salt thereof with the compound (XIX) or a salt thereof.
  • This reaction can be carried out by the method disclosed in Production Example 17 or a method analogous thereto.
  • the compound (VIII) or a salt thereof can be produced by reacting the compound (XXIII) or a salt thereof with the compound (XX) or a salt thereof.
  • This reaction can be carried out by the method disclosed in Production Example 19 or a method analogous thereto.
  • Compound (VIIIa) or a salt thereof is compound (II) It can be produced by reacting Ia) or a salt thereof with compound (XXI).
  • This reaction can be carried out by the method disclosed in Production Example 20 or a method analogous thereto.
  • Suitable salts of the target compound and the starting compound in the methods (1) to (6) and (I) to (I) include those exemplified for the compound (I).
  • Preferred specific examples of the target compound (I) are as follows.
  • R 1 is hydrogen; lower alkyl; contains 1 to 4 nitrogen atoms, and is selected from the group consisting of lower alkyl, lower alkoxy, nitro, and halogen
  • R 1 is hydrogen; lower alkyl; contains 1 to 4 nitrogen atoms, and is selected from the group consisting of lower alkyl, lower alkoxy, nitro, and halogen
  • pyridyl or lower alkyltetrahydropyridyl ; or lower alkyl, lower alkoxy, acylamino, lower alkylthio, halogenogen, etc. 1 to 3 (more preferably 1 or 2) substituents selected from the group consisting of Preference is given to phenyl, lower alkylphenol, mono (or di) lower phenolic phenyl, halophenyl. Two-way, two-way phenyl, lower phenol, lower phenol, or lower alkanoinorea phenyl).
  • R 2 is hydrogen; lower alkyl; contains 1 to 4 nitrogen atoms, and is selected from ⁇ consisting of lower alkyl, lower alkoxy, nitro and halogen.
  • 3 to 8 (more preferably 5 or 6 members) which may have 1 to 3 (more preferably 1 or 2) substituents Heterocyclic groups [preferably pyridyl or lower phenol] or lower alkyl, lower alkyl, lower alkoxy, acylamino, halo
  • a phenyl which may have from 1 to 3 (more preferably 1 or 2) substituents selected from the group consisting of gen and ditoxin [ Or more preferably phenyl, ditrophenyl, or lower alkoxyphenyl) or
  • R 1 and R 2 combine with each other to form
  • Z represents S or 0, respectively) or a group represented by
  • W is a bond, lower alkylene or lower alkylene
  • Y is lower alkylene
  • R is hydrogen or lower alkyl, or a group of the formula:
  • R ' is a hydroxy or protected hydroxy [more preferably an acyloxy, particularly preferably a lower alkanoinoleoxy].
  • A is a bond or lower alkylene
  • R 8 is a lower alkyl group
  • R 9 is an al (lower) alkyl group [more preferably, a lower alkyl group, particularly preferably a lower alkyl group].
  • R 8 is a lower alkyl group
  • R 9 is an al (lower) alkyl group [more preferably, a lower alkyl group, particularly preferably a lower alkyl group].
  • R 8 is a lower alkyl group
  • R 9 is an al (lower) alkyl group [more preferably, a lower alkyl group, particularly preferably a lower alkyl group].
  • R 4 is lower alkyl, or an optionally substituted alkyl (lower) alkyl [preferably lower alkyl, lower alkoxy, lower alkylthio, 1-3 selected from the group consisting of halogen and nitro
  • the target compound (I) of the present invention and a pharmaceutically acceptable salt thereof have strong acetylethylcholinesterase inhibitory activity, but almost no inhibitory activity against butyrinolecholinesterase. Not shown. That is, the target compound of the present invention
  • (I) and its pharmaceutically acceptable salts are selective inhibitors of acetylcholinesterase and are therefore amnestic, dementia (eg Alzheimer's senile) dementia, It is useful for the treatment of central nervous system diseases such as vascular dementia and cerebrovascular disease.
  • the pharmacological test data of the compound (I) are shown below to show the usefulness of the compound (I).
  • Example 2 — (1) means the compound produced in Example 2 — (1).
  • the acetylcholinesterase inhibitory effect was measured by the method (enzyme analysis method) described in C 1 inica Chimica Acta, 115 (1 1981) 163-170. .
  • the acetylcholinesterase used in this study was obtained from rat striatum.
  • the target compound (I) or a pharmaceutically acceptable salt thereof is generally used in mammals including humans in conventional pharmaceutical preparations, for example, capsules, microcapsules, tablets, granules, and powders. It is administered in the form of, for example, troches, syrups, aerosols, inhalants, solutions, injections, emollients, and emulsions.
  • the pharmaceutical composition of the present invention is commonly used for pharmaceutical use.
  • Various organic or inorganic carriers such as excipients (eg, sucrose, starch, mannitol, sonoleitol, lactose, glucose, cellulose) , Tanolek, phosphoric acid phosphate, calcium carbonate, etc.), binders (for example, cellulose, methyl phenol resin, hydroxypropyl phenol resin, poly lipase) Lopinole pyrrolidone, gelatin, arabia rubber, polyethylene glycol, sucrose, starch, etc.), disintegrants (for example, sucrose, canoleboxime tylsenorreose, cal Calcium salt of boxymethyl cellulose, hydroxypropyl mouth pinorestat, sodium glycol starch, sodium bicarbonate, potassium phosphate, Calcium citrate ), Lubricants (for example, magnesium stearate, tanolek, sodium laurenole sulfate), and flavoring agents (
  • preservatives eg sodium benzoate, sodium bisulfite, methylparaben, propylparaben
  • Stabilizing agents for example, citric acid, sodium citrate, drunkic acid, etc.
  • emollients for example, methylcellulose, polyvinylpyrrole
  • aqueous diluents eg,
  • a single dose of 0.0 lmg / kg to 10 mg / kg of active ingredient should be administered 1 to 4 times a day, but the age, weight, condition or administration of the patient Depending on the method The amount may be increased or decreased.
  • Production Example 6 Production Example 11 The following compounds are obtained in the same manner as in (1) and (5). 2 — ethoxycarbone 4 1 (3,4-methoxin) 1 5 — methinoretia
  • N, N-dimensions of (2—bromopropioninole) benzene (8.1 g) and 2,2—di (methoxy) thioacetamide (10.28 g) Heat the mixture in Chinole Honoremamide (25 ml) at 50 ° C for 30 minutes. Then the mixture is poured into water, extracted with ethyl acetate and concentrated under reduced pressure. The residue is dissolved in a mixture of concentrated sulfuric acid (0.5 ml) and acetate (50 ml). After stirring this solution for 30 minutes, it is subjected to an evaporation operation under reduced pressure, and is extracted with ethyl acetate.
  • Phenolinole 5 Methinorethia sonole (0.7 g) and palladium hydroxide (II) (0.15 g)
  • the mixture in tetrahydrofuran (15 ml) is hydrogenated at normal pressure for 8 hours.
  • the palladium hydroxide (II) is removed, and the solution is concentrated under reduced pressure.
  • the obtained precipitate is washed with ether to obtain 2- (2-canolepoxytinole) -141-phen-2-ole-5-methinoretia-zinole (0.7 g).
  • Example 3 (1) 2 — Ethanol Cane Boninole 5 — Methinole 14 1 Fe 2 Norethia Sonole (0.5 g) and 1 Benzinole 4 1 ( A mixture of 2-aminopropyl) pyridine (0.53 g) is stirred and heated at 100 ° C for 1 hour. After cooling, the mixture was subjected to column chromatography on alumina, eluted with chloroform, and then eluted with 4-chlorophenol and 5-methylethylene.
  • Example 6 The following compounds were obtained in the same manner as in Example 3 (1).
  • Example 7 (1) 2 — [(1 — Penzinole biperidine-1 4 — ⁇ ⁇ ) Nole] ⁇ 5 — Methanol 4 Dissolve the sodium fermentation (0.4 g) and maleic acid (0.12 g) in warm ethanol (10 ml). I do. After allowing to stand at room temperature for 4 hours, the formed precipitate is collected, washed with ether, and used to remove 2-((1-benzinole-pyridine-1-4-inole) carbyl)
  • Example 4 and Example 7 The following compounds are obtained in the same manner as in (1).
  • Penzinole biperidine (0.38 g) is added at room temperature. After 1 hour, the mixture is added to sodium borohydride (0.06 g) and stirred at room temperature for 1 hour. Then the mixture is poured into water and extracted with ethyl acetate. The extract is washed with water and brine sequentially, dried over magnesium sulfate, and concentrated. The residue is treated with a solution of hydrogen chloride in ethanol, the solvent is distilled off under reduced pressure, and the residue is pulverized with ether to give 2 — [ ⁇ 2- (1-pentylene biperidine). 14-amino) hydroquinone] -15-methyl-4-phenylisoazole.2 hydrochloride (0.30 g) is obtained.
  • Example 12 The following compounds are obtained in the same manner as in Examples 11 and 7 — (1).
  • Example 16 The following compound is obtained in the same manner as in Examples 2_ (1) and 10- (1).
  • Example 3 The following compounds are obtained in the same manner as in (1).
  • (1) 2 t [2 — ⁇ 1-(4-phenolic mouth benzene) porridge 1-porcelain ⁇ echinore] kanoreha * moinore] one 4 one (4 (1) Trofene 2) 1-5 — Methynorethiazonole, fumarate

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Abstract

Composé utile comme médicament, représenté par la formule générale M-W-Y-A-Q, sel pharmaceutiquement acceptable de ce composé et composition médicinale renfermant cette substance et présentant une activité inhibitrice de l'acétylcholinestérase. Dans cette formule M-W-Y-A-Q, M correspond à un groupe représenté par la formule générale (a) (dans laquelle R1 et R2 représentent l'un et l'autre l'hydrogène, etc., et Z représente S ou O), etc.; W représente une liaison, un alkylène inférieur, etc.; Y représente un alkylène inférieur, -NH-, -C(=O)-, etc.; A représente une liaison ou un alkylène inférieur; et Q correspond à un groupe représenté par la formule générale (b) (dans laquelle R4 représente un alkyle inférieur, etc.), etc.
PCT/JP1993/001233 1993-03-02 1993-09-01 Nouveau compose heterocyclique WO1994020476A1 (fr)

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JP4081393A JPH05345772A (ja) 1992-03-06 1993-03-02 新規複素環化合物
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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005028456A1 (fr) * 2003-09-19 2005-03-31 Solvay Pharmaceuticals B.V. Utilisation de derives du thiazole comme modulateurs des recepteurs cannabinoides
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
WO2008104580A1 (fr) 2007-03-01 2008-09-04 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011100373A1 (fr) 2010-02-09 2011-08-18 The Johns Hopkins University Procédés et compositions pour améliorer la fonction cognitive
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
WO2014144801A1 (fr) 2013-03-15 2014-09-18 Agenebio Inc. Procédés et compositions pour améliorer la fonction cognitive
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10159648B2 (en) 2015-05-22 2018-12-25 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase
US10806717B2 (en) 2013-03-15 2020-10-20 The Johns Hopkins University Methods and compositions for improving cognitive function

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JPS62129282A (ja) * 1985-04-15 1987-06-11 ジヤンセン・フア−マシユ−チカ・ナ−ムロ−ゼ・フエンノ−トシヤツプ 置換ｎ−〔（４−ピペリジニル）アルキル〕二環式縮合オキサゾ−ル−及びチアゾ−ル−アミン類
JPS63243080A (ja) * 1987-03-12 1988-10-07 サノフイ コリン作用系に作用する新規チアゾール誘導体、製造方法および医薬組成物
JPH02289556A (ja) * 1989-02-08 1990-11-29 Takeda Chem Ind Ltd オキサゾール化合物
JPH04210975A (ja) * 1990-02-01 1992-08-03 Takeda Chem Ind Ltd オキサゾール化合物

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JPS62129282A (ja) * 1985-04-15 1987-06-11 ジヤンセン・フア−マシユ−チカ・ナ−ムロ−ゼ・フエンノ−トシヤツプ 置換ｎ−〔（４−ピペリジニル）アルキル〕二環式縮合オキサゾ−ル−及びチアゾ−ル−アミン類
JPS63243080A (ja) * 1987-03-12 1988-10-07 サノフイ コリン作用系に作用する新規チアゾール誘導体、製造方法および医薬組成物
JPH02289556A (ja) * 1989-02-08 1990-11-29 Takeda Chem Ind Ltd オキサゾール化合物
JPH04210975A (ja) * 1990-02-01 1992-08-03 Takeda Chem Ind Ltd オキサゾール化合物

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005028456A1 (fr) * 2003-09-19 2005-03-31 Solvay Pharmaceuticals B.V. Utilisation de derives du thiazole comme modulateurs des recepteurs cannabinoides
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
WO2008104580A1 (fr) 2007-03-01 2008-09-04 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
EP2481408A2 (fr) 2007-03-01 2012-08-01 Probiodrug AG Nouvelle utilisation d'inhibiteurs glutaminyle cyclase
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011100373A1 (fr) 2010-02-09 2011-08-18 The Johns Hopkins University Procédés et compositions pour améliorer la fonction cognitive
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10624875B2 (en) 2012-11-14 2020-04-21 The Johns Hopkins University Methods and compositions for treating schizophrenia
WO2014144801A1 (fr) 2013-03-15 2014-09-18 Agenebio Inc. Procédés et compositions pour améliorer la fonction cognitive
US10806717B2 (en) 2013-03-15 2020-10-20 The Johns Hopkins University Methods and compositions for improving cognitive function
US11160785B2 (en) 2013-03-15 2021-11-02 Agenebio Inc. Methods and compositions for improving cognitive function
US10159648B2 (en) 2015-05-22 2018-12-25 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
US10925834B2 (en) 2015-05-22 2021-02-23 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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