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WO1994020475A1 - Derive d'isoxazole - Google Patents

Derive d'isoxazole Download PDF

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Publication number
WO1994020475A1
WO1994020475A1 PCT/JP1994/000308 JP9400308W WO9420475A1 WO 1994020475 A1 WO1994020475 A1 WO 1994020475A1 JP 9400308 W JP9400308 W JP 9400308W WO 9420475 A1 WO9420475 A1 WO 9420475A1
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WO
WIPO (PCT)
Prior art keywords
formula
salt
alkyl
compound
group
Prior art date
Application number
PCT/JP1994/000308
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English (en)
Japanese (ja)
Inventor
Hisashi Takasugi
Atsushi Kuno
Mitsuru Ohkubo
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
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
Priority claimed from JP4081393A external-priority patent/JPH05345772A/ja
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU61157/94A priority Critical patent/AU6115794A/en
Publication of WO1994020475A1 publication Critical patent/WO1994020475A1/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 isoxoxazole derivative having an acetylcholinesterase inhibitory action and a strong affinity for a musculin 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 isoxazole derivative and a pharmaceutically acceptable salt thereof.
  • the present invention relates to an acetylcholinesterase inhibitor, which is useful for treating amnesia, dementia (for example, Alzheimer-type senile dementia, vascular dementia).
  • the present invention also relates to a novel isoxazole derivative which is useful for the prevention and treatment of diseases of the central nervous system such as cerebrovascular disorders and pharmaceutically acceptable salts thereof.
  • the isoxazole derivatives to which the present invention is directed are new and represented by the following general formula (I): M-W-Y-A-Q (I)
  • R 2 represents hydrogen, lower alkyl, a heterocyclic group which may have a suitable substituent, or phenyl which may have a suitable substituent;
  • R 1 and R 2 are bonded to each other to form the formula:
  • W represents a bond, lower alkylene or lower alkylene
  • Y is lower alkylene, Formula: One CO— N—
  • R 3 represents hydrogen or lower alkyl.
  • R 7 represents a hydroxy or a protected hydroxy
  • A represents a bond or lower alkylene
  • R 8 represents lower alkyl and R 9 represents al (lower) alkyl.
  • R 4 represents lower alkyl or a lower alkyl which may have a suitable substituent, Represents a single bond or a double bond. ).
  • the target compound (I) of the present invention can be produced by the following various methods.
  • R 3 * is lower alkyl
  • X 1 represents an acid residue
  • W 1 is a bond, - C 5 alkylene-les-down or is C 2 ⁇
  • R 7 a represents a protected human mud key sheet.
  • the starting compounds or their salts can be prepared by the following methods. Manufacturing method (A)
  • R 1 , R 2 , M and W are each as defined above,
  • R 5 is a carboxy sheet protected was carboxy sheet or, W 2 is a bond, - C 4 A Ruki les down or represents C 2 ⁇ C 4 A Rukeni les down.
  • Suitable pharmaceutically acceptable salts of the target 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 Salts, for example, organic base salts (for example, triethylenamine salts, pyridin salts, picolin salts, earth ethanol salts, triethanol amine salts, etc.) , Dicyclohexylaminate, N, N'-dibenzyldiethylenediamine, etc.); inorganic acid addition salts (eg, hydrochloride, hydrobromide, sulfate) , Phosphates, etc.); organic
  • lower is used to mean a group having 1 to 6, preferably 1 to 4, carbon atoms, unless otherwise specified.
  • lower alkyl moieties in the term "lower alkyl” and “alkyl (lower) alkyl” include methynole, ethyl, propynole, isoprone. C1-C6 linear or branched, such as pinole, butynole, isobutyl, secondary butyl, tertiary butyl, pentyl, tertiary pentyl, hexyl, etc. Examples of the chain include those having a chain shape, and preferred are those having 1 to 4 carbon atoms.
  • Suitable “lower grades” include methoxy, ethoxy, proboxy, isoproboxy, butoxy, isobutoxy, secondary butoxy. Linear or branched chain having 1 to 6 carbon atoms, such as tertiary butoxy, pentoxy, tertiary pentoxy, hexyloxy, etc. Some examples are:
  • heterocyclic groups are saturated or unsaturated monocyclic or polycyclic rings containing at least one heteroatom such as an oxygen atom, a sulfur atom or a nitrogen atom. It means a formula heterocyclic group.
  • heterocyclic groups include the following heterocyclic groups: 3- to 8-membered unsaturated heterocyclic groups containing 14 nitrogen atoms.
  • heterocyclic groups 3- to 8-membered unsaturated heterocyclic groups containing 14 nitrogen atoms.
  • 3- to 8-membered saturated heterocyclic group containing 1 to 4 nitrogen atoms such as azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinole, virazolidininole, pipera Dinyl, etc .;
  • a fused unsaturated heterocyclic group containing 1 to 5 nitrogen atoms for example, indolinole, isoindolinole, indolinyl, benzoimidazolinole, Quinolinole, Isoquinolinole, Indazolinole, Benzotriazolinole, Tetrazolopyridinole, Tetrazolopyridinole (for example, Tetra Zolo [1,5—b] pyridinyl), dihydrotriazolo pyridinyl, etc .;
  • 3- to 8-membered unsaturated heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms for example, oxazolyl, isoxoxazolyl, oxazodiazo Linole (for example, 1,2,4) 2, 5 — oxaziazolinole etc.);
  • 3- to 8-membered unsaturated heterocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms for example 1,3-thiazolinole, 1,2-thiazoline Linole, thiazolinole, thiadiazolinole (for example, 1,2,4—thiadiazolinole, 1,3,4—thiadiazolinole, 1,2,5— Thia diazolinole, 1, 2, 3-thiadiazolinole);
  • a 3- to 8-membered saturated heterocyclic group such as thiazolidinyl; a 3- to 8-membered unsaturated heterocyclic group containing one sulfur atom, such as chenyl;
  • Condensed unsaturated heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as benzothiazolyl and benzothiadiazolyl;
  • lower alkylenes include methylene, ethylene, trimethylene, tetramethylene, pentamethylen, hexamethylene. More preferred are straight-chain or branched-chain ones having 1 to 6 carbon atoms, such as styrene, methinolethylene, ethynolethylene, and propylene. A good example is C! ⁇ C ⁇ alkylene.
  • Suitable "lower alkenylene” include vinylene, plorenylene, 1- 1 (or 2-) butenylene, 1-1 (or 2-or 3-) —) Pentenelen, 1-11 (or 2 — or 3 —) hexenylene, methylenobilene, etilbinylene, 1- (or 2 — Or 3 —) methylpropenylene, 1 (or 2 — or 3 —) chillidopenylene, 1 1 (or 2 — or 3 — or 4 1) straight-chain or branched-chain ones having 2 to 6 carbon atoms, such as methyl-111 (or 2-) butenylene, and more.
  • a preferred example is C 2 -C anolekenylene.
  • 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 carboxyls and the like.
  • ester moiety of the esterified carboxy examples include lower alkyl esters (for example, methyl tertenol, ethinoles tenore, propinores tenore, isopropinores tenore, butinorees tenore, a Sobutinoester, tertiary butinoester, pentinoester, hexylester, etc.), lower alkyl esters having at least one suitable substituent, such as lower alka No-lokish lower alkyl esters [for example, acetonitrile chillo-stenilia, propioninoleoxyl chitinol-estenol, butyrinindi ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ Ter, 1 (or 2 —)
  • Suitable "acid residues” include halogen (eg, chlorine, bromine, iodine or fluorine); alkanoyloxy (eg, acetoxy, etc.). ), And low-alkane sulphones (for example, methance norehoniloxy), and the like, and the preferred is halogen.
  • Suitable "protected hydroxy” are acyloxy; phenyl-lower alkyl optionally having one or more suitable substituents (e.g. And hydroxy-substituted with conventional 10-protected groups such as benzyl, 4-methoxybenzyl, etc.) and tetrahydroviranyl.
  • acyl moieties in the expression “asyloxy” include carbamoyl, an aliphatic acyl group, and an aromatic or heterocyclic ring And an acyl group.
  • Preferable examples of the acyl include lower-grade alkanol (for example, honole minore, acetinole, propionolone, butyrinole, isotino).
  • Suitable "Ci-C5 phenol” includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene. And linear or branched ones such as methionolemethylene, ethynoleethylene, and propylene.
  • Suitable “C i -c phenol” includes methylene, ethylene, trimethylene, tetramethylene, ethynoleethylene, and propylene. Examples thereof include linear or branched ones such as pyrene.
  • Suitable “C 2 -C 5 alkenylene” includes vinylene, p-phenylene, 1 — (or 2-) butenylene, 1-1 (or 2 — or Or 3 —) Pentylene, methylvinylene, ethylvinylene, 11 (or 2 — or 3 —) methylpropenylene, 1 ( Or 2 — or 3 —) ethyl propylene, 11 (or 2 — or 3 — or 4 1) methinoure 11 (or 2 —) buteni Examples include straight or branched ones such as ren.
  • Suitable “C 2 -C 4 alkenylene” includes vinylene, propenylene, 11- (or 2-) butenylene, Linear or branched ones such as chinolevinilene, ethinovinylene, and 11 (or 2— or 3—) methylprobelene Is mentioned.
  • Preferred "substituents" in the expression “optionally substituted aryl” include lower alkyl (for example, methyl, ethyl, Propyl, isopropyl, butyryl, isobutyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl, hexyl, etc.), lower alkoxy For example, methoxy, ethoxy, pro box, isopropoxy, isobutoxy, tertiary butoxy, pentiloki, neopentillo, tertiary Grade pentinoleoxy, hexyloxy, etc.), lower alkenyl (for example, butyl, 1-propylinole, arinole, 1-methylinole, 1- or 2-- or 3 — Buteninole, 1 or 2 — or 3 — or 4-Pentenil, 1 1 or 2 — or 3 — or 4 1 or 5 ⁇ x
  • Halo low-ranking quinole for example, quinole olomethinole, diphnole olomethinole, trifnoleolomechinore, chloromethinole, dichloromethyl, Tri-Chrome Mole, Brom Memo, Jib Mouth Mole, Tri-Brom Memo, 1- or 2--Fnole Mole 1 or 2 — Bromo ⁇ chinore, 1 or 2 — Krolo ⁇ chinore, 1,1 ⁇ 1 ⁇ 2 ⁇ 2 ⁇ 2 ⁇ 2 ⁇ 2 , Etc.), halogens (eg, chlorine
  • aryl for example, vinyl, naphthyl, etc.
  • phenolic low-grade quinole eg, -benzinole, fenenchinole
  • Lower alkenyl (lower) alkyls lower alkyl moieties such as those mentioned above
  • Carboxy (lower) anoalkyl lower alkyl moiety is exemplified above.
  • protected carboxyl moieties may be those cited above), nitro, amino, protected amino, di-lower alkylamino ( For example, dimethylamino, diethanolamine, diisopropylamino, ethylmethylamino, isopropylmethylinorea, ethylinopropylamine, etc.
  • lower alkylsulfinyl for example,-methinoles finoleno, eschinoles enole
  • Fininore Fininore
  • 'Propinoresnofinino Isopropinolesnorennojenole
  • Butinolessurfinyl Butinolessurfinyl, etc.
  • Suitable "protected aminos” include asilamino (For example, the cited examples are cited as examples of the acylation part.)
  • a preferred “substituent” in the expression “heterocyclic group optionally having substituent (s)” is a lower alkyl (for example, methyl, ethyl, propyl).
  • a suitable “substituent” in the expression “Alkyl (lower alkyl) which may have a suitable substituent” is lower alkyl (eg, methylol, ethyl, Propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl, hexyl, etc., lower phenolic (eg, methacrylate) Kishi, ethoxy, propoxy, isopro box, isobutoki, tertiary butoxy, pentizoleoki, neopentillo, tertiary pentyl Kishi, Hekisilo Kishi, etc.), lower alkenyl (for example, 'bininole, 1-propinolone, alinole, 1-methinole allyl, 1-in-1 or 2—or Or 3 — butenyl, 1 1 or 2 — or
  • Compound (Ia) or a salt thereof is converted to compound (IIa) or a reactive derivative at the carboxyl group or a salt thereof to compound (II) or a salt thereof. It can be produced by reacting with a reactive derivative or a salt thereof.
  • a Schiff base type formed by the reaction of the compound (III) with a phenolic compound such as an phenol or ketone is exemplified.
  • a phenolic compound such as an phenol or ketone
  • Min or its enamine type tautomer compound (III), bis (trimethinolene) acetoamide, mono (trimethinolene) Reaction with silyl compounds such as acetate amide [for example, N- (trimethylsilyl) acetamide], bis (trimethylsilole) and urea
  • silyl compounds such as acetate amide [for example, N- (trimethylsilyl) acetamide], bis (trimethylsilole) and urea
  • Suitable reactive derivatives at the carboxyl group of the compound ( ⁇ a) include, for example, acid halides, acid anhydrides, active amides and active esters.
  • Preferred examples of such reactive derivatives include acid chlorides; acid azides; substituted phosphoric acids (eg, dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzic acid).
  • acetic acid, propionic acid, severe acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanic acid, 2-ethylbutyric acid, trichloroacetic acid for example, acetic acid, propionic acid, severe acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanic acid, 2-ethylbutyric acid, trichloroacetic acid.
  • These reactive derivatives may be appropriately selected according to the type of the compound (IIa) to be used.
  • the reaction is usually carried out in a conventional solvent, for example, water, alcohol (for example, methanol, ethanol, etc.), acetate, dioxane, acetone. Tonitrinole, black mouth film, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylforma
  • a solvent for example, water, alcohol (for example, methanol, ethanol, etc.), acetate, dioxane, acetone. Tonitrinole, black mouth film, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylforma
  • the reaction should be performed in an organic solvent that does not adversely affect mid, pyridin, or other reactions. These solvents for concern may be used as a mixture with water.
  • the compound (IIa) when used in the form of a free acid or a salt thereof, the compound (IIa) may be added to the N, N, one-dimensional mouth.
  • No. N'-I (3-methylaminopropyl) force No., N, N, No. Boninolevis (2-No.
  • the starting compound When the starting compound is in a liquid state, it can be used as a solvent.
  • the reaction can be carried out by alkaline metal bicarbonate, tri- (lower) alkylamine, pyridin, N-lower acrekyl phenol olefin, N, N—di (lower) alkyl benzylamine. It can also be performed in the presence of any inorganic or organic base.
  • the reaction temperature is not particularly limited, but the reaction is usually performed without cooling or heating.
  • 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.), chlorophorol, air Perform in ter, tetrahydrofuran, benzene, N, N—dimethyl honolem amide, or any other organic solvent that does not adversely affect the reaction.
  • a conventional solvent for example, alcohol (for example, methanol, ethanol, ethylene glycol, etc.), chlorophorol, air Perform in ter, tetrahydrofuran, benzene, N, N—dimethyl honolem 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, an alkali metal bicarbonate, an alkali metal carbonate, an alkali metal acetate, a tri (lower) alkylamine, Lucari metal hydride, pyridin, norethidin, picolin, dimethinorea minopyridine, N—lower phenolic, N, N—di (lower ) Performed in the presence of inorganic or organic bases such as benzoylbenzylamine, N, N-di (lower) alkylanilinine. When the base and / or the starting compound are in liquid form, they can be used as a solvent.
  • Compound (Ie) or a salt thereof is obtained by reacting compound (K) or a salt thereof with compound (Ilia) or a salt thereof, and subjecting the resulting compound to a reduction reaction. This enables production.
  • This reduction is carried out by a conventional method, including chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used in chemical reduction are hydrides (eg, hydrogen iodide, hydrogen sulfide, aluminum hydride, sodium borohydride, sodium hydride).
  • boron such as sodium
  • metal for example, tin, zinc, iron, etc.
  • metal compound for example, chromium chloride, chromium acetate, etc.
  • Organic or inorganic acids for example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesnolephonic acid, hydrochloric acid, hydrobromic acid, etc. It is a combination of and.
  • Suitable catalysts to be used for catalytic reduction are platinum catalysts (for example, platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (for example sponge Jono, 0 La di cormorant-time, Roh, 0 La Ji-time black, oxide Roh,. La-di-um, Roh,. La di ⁇ -time charcoal, co-b A de-like para-di-c-time, Nono Radium sulphate barium, no., Radium carbonate, etc.), nickel catalyst
  • cobalt catalysts for example, reduced cobalt, Raney cobalt, etc.
  • iron Conventional materials such as catalysts (eg, reduced iron, Raney iron, etc.) and copper catalysts (eg, reduced copper, Raney copper, Urman copper, etc.).
  • the reaction is usually carried out in water, alcohol (for example, methanol, ethanol), N, N-dimethylaminophenol, tetrahydrofuran,
  • alcohol for example, methanol, ethanol
  • N, N-dimethylaminophenol for example, tetrahydrofuran
  • the reaction is performed in a solvent such as a mixture thereof or any other solvent that does not adversely influence the reaction.
  • the acids to be used in the above-mentioned chemical reduction are liquid, they can be used as a solvent.
  • the reaction temperature is not particularly limited, but the reaction is usually carried out without cooling or heating.
  • Compound (Ig) or a salt thereof can be produced by subjecting compound (If) or a salt thereof to an elimination reaction of a hydroxy protecting group.
  • Suitable methods for this elimination reaction include hydrolysis and reduction. Examples of the common law include:
  • the hydrolysis is preferably performed in the presence of a base or an acid, including Lewis acid.
  • Suitable bases include alkaline metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, magnesium, calcium, etc.). ), These hydroxides, carbonates or bicarbonates, tri (alkyl) amines (for example, trimethylaminoamine, tris).
  • alkaline metals eg, sodium, potassium, etc.
  • alkaline earth metals eg, magnesium, calcium, etc.
  • Inorganic and organic bases such as ethynoleamine, picolin, 1,5—diazabicyclo [4.3.0] non-5—ene Is mentioned.
  • Suitable acids include organic acids (eg, formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid) and inorganic acids (eg, hydrochloric acid) , Hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.).
  • organic acids eg, formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid
  • inorganic acids eg, hydrochloric acid
  • Hydrobromic acid sulfuric acid, hydrogen chloride, hydrogen bromide, etc.
  • Isolation using a trihaloacetic acid for example, trichloroacetic acid, trifluoric acid, etc.
  • a cation trapping agent for example, aniani
  • It is preferable to carry out the program in the presence of a source such as a software or a phenol.
  • the reaction is usually carried out with water, alcohol (for example, methanol, ethanol, isopropinorea, etc.), tetrahydrofuran, diethanol, etc.
  • alcohol for example, methanol, ethanol, isopropinorea, etc.
  • a conventional solvent The reaction is performed in any 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 usually the reaction is carried out without cooling or heating.
  • the reduction is carried out by standard methods including chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used in chemical reduction are metals (for example, tin, zinc, iron, etc.) or metal compounds (for example, chromium chloride, chromium acetate, etc.) and organic acids. Or a combination with an inorganic acid (for example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, P-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.). .
  • metals for example, tin, zinc, iron, etc.
  • metal compounds for example, chromium chloride, chromium acetate, etc.
  • organic acids for example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, P-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.
  • Suitable catalysts to be used for catalytic reduction include platinum catalysts (for example, platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (for example, For example, spongy-like, 0- radium, no., Radium black, oxidized palladium, no., Radium charcoal, colloidal palladium, no., .Radium / Barium sulfate, palladium barium carbonate, etc.), nickel catalysts (for example, reduced nickel, nickel oxide, rankel, etc.), cobalt Catalysts (for example, reduced cobalt, Raney cobalt), copper catalysts (for example, reduced copper, Raney copper, uranium copper), iron catalysts (for example, Reduced iron, la Such as iron, uraman, etc.).
  • platinum catalysts for example, platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalysts for example,
  • This reduction is usually carried out with water, methanol, ethanol, prononor, N, N-dimethylaminophenol, dimethyl ether, diol.
  • the reaction is performed in a conventional solvent such as san, tetrahydrofuran, or a mixture thereof that does not adversely influence the reaction.
  • the acids to be used in the above-mentioned 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.
  • Suitable oxidizing agents include dimethinolethrenofoxide and N, N'-dicyclohexynolecalpodiimide, lower alkanoic anhydride (eg, Anhydrous acetic acid, etc.), sulfur pentoxide, sulfur trioxide-pyridinine, N-nitrosuccinimide (for example, ⁇ -chlorosuccinimide) ), Oxalyl chloride and the like.
  • the reaction is carried out in the presence of an acid.
  • Suitable acids include organic acids (eg, formic acid, acetic acid, propionic acid, trichloroacetic acid, trichloroacetic acid, etc.) and inorganic acids (eg, Hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.).
  • the reaction may be carried out on an alkali metal (for example, sodium or potassium), an alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide).
  • Alkali metal bicarbonate eg, sodium bicarbonate, potassium bicarbonate
  • Alkali metal carbonate eg, sodium carbonate, carbonate
  • Tri-lower alkylamines for example, trimethylamine, triethylamine, diisopropizoleamine, etc.
  • alkali metal hydrides E.g., sodium hydride
  • Alkali metal lower alcohols e.g., sodium methoxide, sodium ethoxide, etc.
  • Pyridines eg, pyridin, noretidine, C, dimethylaminopyridine, etc.
  • N—lower alkanol, hololin N, N—lower alkanol benzoylamine, N, N—lower alk It may be carried out in the presence of an inorganic or organic base such as chiranilin.
  • the base, acid, or starting compound When the base, acid, or starting compound is in liquid form, it can be used as a solvent.
  • This reaction is usually carried out in water, phenolic (eg, methanol, ethanol), benzene, N, N—dimethylformamide, Solvents such as lahydrofuran, tonolene, methylene chloride, methylene dichloride, ethylene dichloride, chlorophonolem, dioxane, and getyl ether, and other reactions Perform in any solvent that does not adversely affect it.
  • solvents may be used by mixing with water.
  • the reaction temperature is not particularly limited, but is usually not cooled or Perform reaction under heating 0
  • Compound (XII) or a salt thereof can be produced by reacting compound (Kb) or a salt thereof with compound (XI) or a salt thereof.
  • the reaction is usually alcohol (for example, methanol, ethanol, ethyl alcohol, etc.), chro-honolem, ether,
  • alcohol for example, methanol, ethanol, ethyl alcohol, etc.
  • chro-honolem ether
  • the reaction is carried out in a conventional solvent such as transhydran, benzene, or 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 alkaline metal hydroxides, alkaline metal carbonates, alkaline metal carbonates, alkaline metal acetates, tri (lower) alkylamines, pyridines, Noretidine, picolin, dimethinoreaminopyridine, N-lower acetyl morpholine, N, N-di-lower alkyl benzyl benzylamine, N, N-di-lower This can be done in the presence of an inorganic base such as alkylaniline or an organic base. When the base and the starting compound are in liquid form, they can be used as a solvent. Manufacturing method (A) —2
  • Compound (XII) or a salt thereof can be produced by subjecting compound (XII) or a salt thereof to a reduction reaction.
  • This reaction can be carried out in the same manner as in the above-mentioned production method (3). Therefore, the reagents to be used and, for example, the solvent and reaction temperature For the reaction conditions such as the above, the description of the production method (3) may be referred to.
  • Compound ((b) 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, phenolic alcohol (for example, methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, etc. , Dioxane, chlorofonolem, methylene chloride, dimethylinoreacetamide, N, N—dimethinole honolem, and other conventional solvents, and other reactions Perform in any organic solvent that does not adversely affect the performance.
  • phenolic alcohol for example, methanol, ethanol, isopropyl alcohol, etc.
  • tetrahydrofuran etc.
  • Dioxane chlorofonolem
  • methylene chloride dimethylinoreacetamide
  • N N—dimethinole honolem
  • other conventional solvents and other reactions Perform in any organic solvent that does not adversely affect the performance.
  • the reaction is preferably performed in the presence of an acid.
  • Suitable acids include organic acids (eg, formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and inorganic acids (eg, Hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, etc.).
  • organic acids eg, formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.
  • inorganic acids eg, Hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, etc.
  • the reaction temperature is not particularly limited, but the reaction is usually carried out without heating or under heating.
  • Compound (W) or a salt thereof can be produced by subjecting compound (IIc) or a salt thereof to a reduction reaction. 'This reaction can be carried out by the method disclosed in Production Example 3 or by a method similar thereto. Manufacturing method (C) ⁇ 2
  • Compound (Kb) or a salt thereof can be produced by subjecting compound (VII) or a salt thereof to a formylation reaction.
  • This reaction can be carried out by the method disclosed in Production Example 5 or a method similar thereto.
  • Suitable salts of the target compound and the starting compound in the methods (1) to (5) and (A) to (C) are those exemplified for the compound (I). Can be mentioned.
  • 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.
  • Unsaturated 3 to 8 members (more preferably 5 or 6 members) which may have 1 to 3 (more preferably 1 or 2) substituents Heterocyclic group
  • pyridyl or lower alkyltetrahydropyridyl or lower alkyl, lower alkoxy, acylamino, acyl, lower acrequino Halo (lower) alkyl, cyano, lower alkinorecho, halogen and nitrite
  • a funnel which may have 1 to 3 (more preferably 1 or 2) substituents selected from the group consisting of the mouth [more preferred Or phenyl, lower alkyl phenyl, mono (or di) lower alkoxy phenyl, halo phenyl, nitro phenyl, lower phenol, lower phenol, lower alkynole Snorre honole phenolic, low-grade phenolic phenolic phenol, trino, mouth (lower) phenolic phenol, cyanophenyl, or lower alkanoyl Norea Minophenyl]
  • R 2 is hydrogen; lower alkyl; has 1 to 4 nitrogen atoms, and is a substituent selected from the group consisting of lower alkyl, lower alkoxy, nitro and halogen.
  • Unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heterocyclic group which may have 1 to 3 (more preferably 1 or 2) [Preferably pyridyl, or lower alkyltetrahydropyridyl]; or lower alkyl, lower alkoxy, asilamino, halogen, and It may have from 1 to 3 (more preferably 1 or 2) substituents selected from the group consisting of nitro and phenyl [more preferably Or phenyl, dinitrophenyl, or lower alkoxyphenyl) or
  • R 1 and R 2 are bonded to each other to form the formula:
  • W is a bond, lower alkylene or lower alkylene
  • Y is a low-level anorekiren
  • R 3 is hydrogen or lower alkyl, or a group of formula:
  • R 7 is a hydroxy or protected hydroxy group [more preferably an axyloxene, particularly preferably a lower alcanoinoyloxy] ).
  • A is a bond or a lower alkylene [preferably C 4 alkylene; particularly preferably ethylene]
  • R 8 is lower alkyl
  • R 9 is al (lower) alkyl [more preferably phenyl (lower) alkyl, particularly preferably benzyl. Jill]) or a formula:
  • R 4 is lower alkyl or 1 to 3 (more preferably 1 or 2; particularly preferably 1) substituents.
  • Good phenyl (lower) alkyl [more preferably a group consisting of lower alkyl, lower alkoxy, lower alkylthio, halogen, cyano and nitro
  • One to three (more preferably one or two; particularly preferably one) selected substituents which may have one or more substituents
  • Objective compound (I) of the present invention and a pharmaceutically acceptable salt thereof show a strong acetylcholinesterase inhibitory action, but have an effect on butyrinolecholinesterase. On the other hand, it shows almost no inhibitory effect. That is, the target compound (I) of the present invention and a pharmaceutically acceptable salt thereof are selective inhibitors of acetylcholinesterase, and thus have amnesia and dementia. For example, it is useful for the treatment of central nervous system diseases such as Alzheimer-type senile dementia, vascular dementia, and cerebrovascular disorders.
  • Example 1 means the compound produced in Example 1.
  • Test results were obtained from rat linear bodies.
  • Test compounds ⁇ C 50
  • M Example 1 2 0 X 1 0 - 8
  • the target compound (I) or a pharmaceutically acceptable salt thereof is generally used in mammals including humans in conventional pharmaceutical preparations such as capsules, microcapsules, tablets, and granules. It is administered in the form of powders, powders, troches, syrups, aerosols, inhalants, liquids, injections, clouding agents, emulsions, etc.
  • various organic or inorganic carriers commonly used for pharmaceutical applications for example, excipients (for example, sucrose, starch, mannitol) , Sonorebitone, lactose, gnorecose, senorose, talc, canola phosphate, canecarbonate, etc.
  • excipients for example, sucrose, starch, mannitol
  • Sonorebitone for example, lactose, gnorecose, senorose, talc, canola phosphate, canecarbonate, etc.
  • a single dose of 0.1 mg Olmg / kg to 100 mgZ kg of the active ingredient should be administered 1 to 4 times a day, but it depends on the age, body weight, condition and administration method of the patient. The above dose may be increased or decreased.
  • Etinole 4- (12-tropininole) -12,4-dioxobutanoate (1.65 g) and hydroxylamine hydrochloride (1.73 g)
  • ethanol solution 20 ml
  • hydroxylamine hydrochloride 1.73 g
  • a mixture of the above ethanol solution (20 ml) was refluxed with stirring. After 3 hours, the mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure. Obtain (0.72 g).
  • Ethanol Cane Boninole 5 (412 Trofenyl) Isoxazole (0.5 g) and 2 — (1 Benzyl Pigment 1 4 1 Heat the N, N-dimethylhonolem amide (lml) solution of a mixture of ethylamylamine (0.7g) to 120 ° C while stirring for 1 hour. . After cooling to room temperature, the mixture is dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure.
  • 6-Tetrahedro-Pyridine 1 4 1 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇

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Abstract

Composé utile comme médicament et représenté par la formule générale: M-W-Y-A-Q, (dans laquelle M correspond à un groupe de la fomule générale (I), dans laquelle R1 et R2 représentent l'un et l'autre l'hydrogène 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 de la formule générale (II) etc., dans laquelle R4 représente un alkyle inférieur, etc.; et le symbole.^_.^_.^_.^_.^_.^_ représente soit une liaison unique soit une liaison double), sel pharmaceutiquement acceptable de cette substance et composition pharmaceutique renfermant le composé sus-visé et présentant une activité inhibitrice de l'acétylcholine estérase.
PCT/JP1994/000308 1993-03-02 1994-02-23 Derive d'isoxazole WO1994020475A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU61157/94A AU6115794A (en) 1993-03-02 1994-02-23 Isoxazole derivative

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP4081393A JPH05345772A (ja) 1992-03-06 1993-03-02 新規複素環化合物
JP5/40813 1993-03-02
JP5/216275 1993-08-31
JP21627593 1993-08-31

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WO1994020475A1 true WO1994020475A1 (fr) 1994-09-15

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5633272A (en) * 1995-02-13 1997-05-27 Talley; John J. Substituted isoxazoles for the treatment of inflammation
US5859257A (en) * 1995-02-13 1999-01-12 G. D. Searle & Co. Isoxazole compounds as cyclooxygenase inhibitors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0395166A (ja) * 1989-09-07 1991-04-19 Takeda Chem Ind Ltd イソキサゾロン誘導体含有脳機能改善剤
JPH03173864A (ja) * 1988-10-31 1991-07-29 Takeda Chem Ind Ltd Ｔａｎ―９５０類及び脳機能改善剤
JPH04235145A (ja) * 1990-03-13 1992-08-24 Hoechst Roussel Pharmaceut Inc １−アルキル−、１−アルケニル−および１−アルキニルアリール−２−アミノ−１，３−プロパンジオールおよび関連した化合物
JPH04234857A (ja) * 1990-04-12 1992-08-24 Hoechst Ag ３，５−ジ置換２−イソキサゾリンおよびイソキサゾール、それらの製法およびそれらを含有する薬学的組成物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03173864A (ja) * 1988-10-31 1991-07-29 Takeda Chem Ind Ltd Ｔａｎ―９５０類及び脳機能改善剤
JPH0395166A (ja) * 1989-09-07 1991-04-19 Takeda Chem Ind Ltd イソキサゾロン誘導体含有脳機能改善剤
JPH04235145A (ja) * 1990-03-13 1992-08-24 Hoechst Roussel Pharmaceut Inc １−アルキル−、１−アルケニル−および１−アルキニルアリール−２−アミノ−１，３−プロパンジオールおよび関連した化合物
JPH04234857A (ja) * 1990-04-12 1992-08-24 Hoechst Ag ３，５−ジ置換２−イソキサゾリンおよびイソキサゾール、それらの製法およびそれらを含有する薬学的組成物

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5633272A (en) * 1995-02-13 1997-05-27 Talley; John J. Substituted isoxazoles for the treatment of inflammation
US5859257A (en) * 1995-02-13 1999-01-12 G. D. Searle & Co. Isoxazole compounds as cyclooxygenase inhibitors
US5985902A (en) * 1995-02-13 1999-11-16 G.D. Searle & Co. Substituted isoxazole for the treatment of inflammation

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