WO2004089939A1 - Derives de furan condense utilises en tant qu'antagonistes d'adenosine - Google Patents

Derives de furan condense utilises en tant qu'antagonistes d'adenosine Download PDF

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WO2004089939A1
WO2004089939A1 PCT/JP2004/003435 JP2004003435W WO2004089939A1 WO 2004089939 A1 WO2004089939 A1 WO 2004089939A1 JP 2004003435 W JP2004003435 W JP 2004003435W WO 2004089939 A1 WO2004089939 A1 WO 2004089939A1
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Prior art keywords
compound
salt
pharmaceutically acceptable
hydrogen
phenyl
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PCT/JP2004/003435
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English (en)
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Satoshi Yonishi
Hiromichi Itani
Yoshinari Sato
Hideo Tsutsumi
Atsushi Akahane
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Fujisawa Pharmaceutical Co., Ltd.
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Publication of WO2004089939A1 publication Critical patent/WO2004089939A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel compound and a salt thereof, which are useful as medicaments.
  • the present invention relates to a novel compound and a pharmaceutically acceptable salt thereof, which are useful as medicaments; processes for the preparation of said compound and a salt thereof; a pharmaceutical composition comprising, as an active ingredient, said compound or a pharmaceutically acceptable salt thereof; a use of said compound or a pharmaceutically acceptable salt thereof as a medicament; and amethod for using said compound or a pharmaceutically acceptable salt thereof for therapeutic purposes, which comprises administering said compound or a pharmaceutically acceptable salt thereof to a human being or an animal.
  • the said compound and a salt thereof are adenosine antagonists (especially, Ai receptor and A 2 (particularly A 2a ) receptor dual antagonists) and possess various pharmacological actions such as anticatalepsy action, cognitive enhancing action, analgesic action, locomotor action, antidepressant action, diuretic action, cardioprotective action, cardiotonic action, vasodilating action (e.g.
  • cognitive enhancer useful as cognitive enhancer, antianxiety drug, antidementia drug, psychostimulant, analgesic, cardioprotective agent, antidepressant, ameliorants of cerebral circulation, tranquilizer, drug for heart failure, cardiotonic agent, antihypertensive agent, drug for renal failure ' (renal insufficiency), drug for renal toxicity, renal protective agent, drug for improvement of renal function, diuretic, drug for edema, antiobesity, antiasthmatic, bronchodilator, drug for apnea, drug for gout, drug for hyperuricemia, drug for sudden infant death syndrome (SIDS), ameliorants of immunosuppressive action of adenosine, antidiabetic agent, drug for ulcer, drug for pancreatitis, drug for Meniere's syndrome, drug for anemia, drug for thrombosis, drug for myocardial infarction, drug for obstruction, drug for arteriosclerosis obliterans, drug for thrombophle
  • ischemia/reperfusion injury e.g. myocardial ischemia/reperfusion injury, cerebral ischemia/reperfusion injury, peripheral ischemia/reperfusion injury, etc.
  • shock e.g. myocardial ischemia/reperfusion injury, cerebral ischemia/reperfusion injury, peripheral ischemia/reperfusion injury, etc.
  • nephrosis nephritis
  • edema e.g. cardiac edema, nephritic edema, hepatic edema, idiopathic edema, drug edema, acute angioneurotic edema, hereditary angioneurotic edema, carcinomatous ascites, gestational edema, etc.
  • obesity bronchial asthma, gout, hyperuricemia, sudden infant death syndrome, immunosuppression, diabetes, ulcer such as peptic ulcer (e.g.
  • ischemic bowel disease e.g. mechanical ileus, adynamic ileus, etc.
  • myocardial infarction thrombosis (e.g. arterial thrombosis, cerebral thrombosis, etc.), obstruction, arteriosclerosis obliterans, thrombophlebitis, cerebral infarction, transient ischemic attack, angina pectoris, or the like, in which the preferred onemaybe Parkinson' s disease and symptoms associating therewith, depression, dementia' (e.g. Alzheimer's disease, cerebrovascular dementia, dementia accompanying Parkinson's disease, etc.), anxiety, pain, cerebrovascular disease (e.g. stroke, etc.), Meniere's syndrome or cerebral infarction.
  • dementia' e.g. Alzheimer's disease, cerebrovascular dementia, dementia accompanying Parkinson's disease, etc.
  • anxiety pain
  • cerebrovascular disease e.g. stroke, etc.
  • Meniere's syndrome or cerebral infarction e.g. Alzheimer's disease, cerebro
  • novel compound of the present invention can be shown by the following formula (I):
  • Z is a phenyl or pyridyl which condenses to a furan ring;
  • X is CH or N;
  • R is hydrogen or optionally substituted lower alkyl; R is hydrogen, halogen, or lower alkoxy; and R is hydrogen, hydroxy, lower alkyl, lower alkoxy or halogen, or a salt thereof.
  • the object compound (I) and a salt thereof of the present invention can be prepared by the following processes.
  • Y is a leaving group
  • R is lower alkyl
  • Hal is a halogen atom; and is a phenyl or pyridyl . ]
  • the object compound (I) and a salt thereof can be prepared, for example, according to the procedures as illustrated in Examples in the present specification or in a manner similar thereto.
  • the starting compounds can be prepared, for example, according to the procedures as illustrated in Preparations in the present specification or in a manner similar thereto.
  • the object compound (I) and a salt thereof can be prepared according to the methods as shown in a Preparation or Examples, or in a manner similar thereto.
  • Suitable salts of the object compounds (I) are pharmaceutically acceptable conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, etc. ) , an organic acid salt (e.g.
  • a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, etc. )
  • an organic acid salt e.g.
  • acetate maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.
  • an inorganic acid salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • a salt with an amino acid e.g. arginine, aspartic acid, glutamic acid, etc.
  • Suitable "low alkyl” may include straight or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, or the like, in which the preferred one may be (C1-C4) alkyl and the more preferred one may be methyl, ethyl, propyl, or isopropyl.
  • Suitable "lower alkoxy” may include straight or branched ones such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, or the like, in which the preferred one may be (C1-C4) alkoxy and the more preferred one may be methoxy.
  • halogen means fluoro, chloro, bromo, and iodo.
  • Suitable “optionally substituted lower alkyl” may include lower alkyl and lower, alkyl substituted by a suitable substituent (s) such as aryl, halogen, nitro, cyano, amino, substituted amino, acyl, and the like.
  • a suitable substituent such as aryl, halogen, nitro, cyano, amino, substituted amino, acyl, and the like.
  • Suitable example of aforesaid "aryl” may include phenyl, naphthyl, indenyl and indanyl.
  • Suitable example of aforesaid "substituted amino” may include amino substitutedby suitable substituent (s) suchas lower alkyl, acyl, and the like.
  • acyl may include lower alkanoyl (e . g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, etc.), carboxy, protected carboxy, and the like .
  • lower alkanoyl e . g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, etc.
  • Suitable examples of aforesaid "protected carboxy” may be i) esterified carboxy, in which suitable esterified carboxy may include lower alkoxycarbonyl, aryl (lower) alkoxycarbonyl, and the like; ii) amida'ted carboxy, in which suitable amidated carboxy may include carbamoyl, N- (lower) alkylcarbamoyl, N, -di (lower) alkylcarbamoyl (e.g.
  • Z is phenyl
  • R is hydrogen, lower alkyl, benzyl or phenethyl
  • p is phenyl
  • R is hydrogen or lower alkoxy
  • R is hydrogen, hydroxy, lower alkoxy, lower alkyl or halogen.
  • R is hydrogen, lower alkyl, benzyl or phenethyl
  • R is hydrogen, halogen or lower alkoxy
  • R 3 i is hydrogen, hydroxy, lower alkoxy, lower alkyl or halogen.
  • R is hydrogen or lower alkyl
  • R 2 is hydrogen
  • R is hydrogen, hydroxy or lower alkoxy.
  • R is hydrogen or halogen
  • R 3 i is hydrogen or lower alkoxy.
  • R 2 is hydrogen or halogen; R is hydrogen,
  • the compound (I) or a salt thereof can be prepared by reacting the compound (la) or a salt thereof with the compound (II) or a salt thereof.
  • Suitable salt of the compound (II) can be referred ones as exemplified for the compound (I) .
  • This reaction is carried out in a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chlolide, formamide, N, N-dimethylformamide, methanol, ethanol, sec-butanol, amyl alcohol, diethyl ether, dioxane, tetrahydrofuran, dimethyl sulfoxide, or any other organic solvent which does not adversely affect the reaction, preferably in ones having strong polarities .
  • a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chlolide, formamide, N, N-dimethylformamide, methanol, ethanol, sec-butanol, amyl alcohol, diethyl ether, dioxane, tetrahydrofuran, dimethyl sulfoxide, or any other
  • the reaction is preferably conducted in the presence of a base, for example, inorganic base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, alkali metal hydride (e.g. sodium hydride, etc.), or organicbase suchas trialkylamine (e.g. triethylamine, etc. ) , or basic resin, and the like.
  • a base for example, inorganic base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, alkali metal hydride (e.g. sodium hydride, etc.), or organicbase suchas trialkylamine (e.g. triethylamine, etc. ) , or basic resin, and the like.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or heating.
  • the present reaction is preferably carried out in the presence of alkali metal halide (e.g. sodium iodide, potassium iodide, etc.), alkali metal thiocyanate (e.g. sodium thiocyanate, potassium thiocyanate, etc.), or the like.
  • alkali metal halide e.g. sodium iodide, potassium iodide, etc.
  • alkali metal thiocyanate e.g. sodium thiocyanate, potassium thiocyanate, etc.
  • the compound (lb) or a salt thereof can be prepared by subjecting the compound (III) or a salt thereof to hydrolysis.
  • Suitable salt of the compound (III) can be referred to an acid addition salt as exemplified for the compound (I).
  • This reaction is carried out in accordance with a conventional method.
  • the hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
  • Suitable base includes an inorganic base and an organic base such as an alkali metal (e.g. sodium, potassium, etc.), an alkaline earth metal (e.g. magnesium, calcium, etc.), the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine (e.g. triethylamine, trimethylamine, etc.), hydrazine, pyridine compound (e.g. pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.), 1, 5-diazabicyclo [4.3.0] non- 5-ene, 1, 4-diazabicyclo [2.2.2] octane,
  • an alkali metal e.g. sodium, potassium, etc.
  • an alkaline earth metal e.g. magnesium, calcium, etc.
  • trialkylamine e.g. triethylamine, trimethylamine, etc.
  • hydrazine pyridine compound (e.g. pyridine, lutidine, picoline
  • Suitable acid includes anorganic acid (e.g. formicacid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc. ) .
  • anorganic acid e.g. formicacid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.
  • an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.
  • BX 3 [e.g. boron trihal.ide (e.g. boron trichloride, etc . ) , etc . ] ,
  • A1X 3 [e.g. aluminumhalide (e.g. aluminumchloride, etc. ) , etc. ] , or the like is preferably carried out in the presence of cation trapping agents (e.g. anisole, phenol, etc.).
  • cation trapping agents e.g. anisole, phenol, etc.
  • the reaction is usually carried out in a solvent such as water, an alcohol (e.g. methanol, ethanol, isopropyl alcohol, etc.), acetic acid, tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene chloride, chloroform, N, N-dimethylformamide, N, N-dimethylacetamide, or other organic solvents which do not adversely affect the reaction, or a mixture thereof.
  • a solvent such as water, an alcohol (e.g. methanol, ethanol, isopropyl alcohol, etc.), acetic acid, tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene chloride, chloroform, N, N-dimethylformamide, N, N-dimethylacetamide, or other organic solvents which do not adversely affect the reaction, or a mixture thereof.
  • an alcohol e.g. methanol, ethanol, isoprop
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the object compound (Ic) or a salt thereof can be prepared by subjecting the compound (IVa) or a salt thereof to pyridazinone ring-forming reaction.
  • Suitable salt of the compound (IVa) can be referred to acid addition salts as exemplified for the compound (I).
  • This ring-forming reaction of this process can be carried out, for example, by reacting the compound (IVa) or a salt thereof with glyoxylic acid or its reactive derivative or a salt thereof and hydrazine or a salt thereof.
  • Suitable salt of glyoxylic acid can be referred to a salt with a base as exemplified for the compound (I) .
  • Suitable salt of hydrazine can be referred to an acid addition salt as exemplified for the compound (I) .
  • Suitable reactive derivative of glyoxylic acid may be the ones conventionally used in this field of the art such as an activated ester thereof.
  • the reaction can be carried out in the presence or absence of a solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under warming to heating.
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (Va) or a salt thereof with the compound (Via) or a salt thereof.
  • Suitable salt of the compound (Va) and (Via) can be referred to ones as exemplified for the compound (I).
  • This reaction is preferably carried out in a conventional solvent such as water, an alcohol (e.g. methanol, ethanol, etc. ) , acetone, tetrahydrofuran, dioxane, acetonitrile, methylene, chloride, ethylene chloride, chloroform, N, N-dimethylformamide, ethyl acetate, pyridine or other organic solvents which do not adversely affect the reaction, or a mixture thereof.
  • a conventional solvent such as water, an alcohol (e.g. methanol, ethanol, etc. ) , acetone, tetrahydrofuran, dioxane, acetonitrile, methylene, chloride, ethylene chloride, chloroform, N, N-dimethylformamide, ethyl acetate, pyridine or other organic solvent
  • the present reaction is preferably carried out in the presence of an organic or inorganic base such as an alkali metal hydroxide (e.g. sodiumhydroxide, potassiumhydroxide, etc. ) , alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydride (e.g. sodium hydride, etc.), alkali metal alkoxide (e.g. sodium ethoxide, potassium tert-butoxide, etc.), trialkylamine (e.g. triethylamine, trimethylamine, etc.), pyridine compound (e.g. pyridine, picoline, lutidine, etc.), and the like.
  • an organic or inorganic base such as an alkali metal hydroxide (e.g. sodiumhydroxide, potassiumhydroxide, etc. ) , alkali metal carbonate (e.g. sodium carbon
  • reaction temperature is not critical and the reaction is usually carried out at ambient temperature, under warming or heating.
  • the compound (IVb) or a salt thereof can be prepared by subjecting the compound (VIb) or a salt thereof to condensing reaction with the compound (VII) or a salt thereof, successively to hydrolysis and decarboxylation.
  • the condensing reaction can be carried out in the similar manner as in the aforementioned Process 4 or the similarmanners thereto, and therefore the reagents to be used and the reaction conditions
  • Process B The compound (IVb) or a salt thereof can be prepared by reacting the compound (Vic) or a salt thereof with the compound (VIII) or a salt thereof.
  • the compound (III) or a salt thereof can be prepared by reacting the compound (IVc) or a salt thereof with the compound (IX) or a salt thereof. This reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, 1, 2-dimethoxyethane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate,
  • the present reaction is preferably carried out in the presence of an organic or inorganic base such as an alkali metal (e.g. sodium, potassium, etc. ) , an alkaline earthmetal (e.g. magnesium, calcium, etc . ) , the hydride or hydroxide or alkoxide or carbonate or hydrogencarbonate or alkanoic acid thereof, trialkylamine (e.g. triethylamine, trimethylamine, etc.), hydrazine, pyridine compound (e.g. pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.), quinoline, lithium diisopropylamide, alkali metal thiocyanate (e.g.
  • an organic or inorganic base such as an alkali metal (e.g. sodium, potassium, etc. ) , an alkaline earthmetal (e.g. magnesium, calcium, etc . ) , the hydride or hydroxide or alkoxide or carbonate or
  • di (lower) alkyl azodicarboxylate e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.
  • di (lower) alkyl azodicarboxylate e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N' -dicyclohexylcarbodiimide, trialkyl phosphite, phosphorous oxychloride, N-ethyl-N'-
  • a conventional condensing agent such as N,N' -dicyclohexylcarbodiimide, trialkyl phosphite, phosphorous oxychloride, N-ethyl-N'-
  • reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or heating.
  • the compound (Xe) can be synthesized by functional trans formation of carbonyl group, which is obvious to the person skilled in the organic chemistry from the compound (Xa) exemplified by Step 1, 3 and 4 of this process.
  • Step 2 of this process can be carried out in the similar manner as in the aforementioned Process 1 or the similar manners thereto, and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of Process 1.
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (Vb) can be prepared from the benzylating reaction of the compound (Xe) with a kind of benzylbromide (exemplified by Step 5) by the methods disclosed in Preparation 28 mentioned later or the similar manner thereto.
  • the object compound (Va) can be prepared by subjecting the compound (Vb) to the halogenating reaction (exemplified by Step 6) that disclosed in Preparation 29 mentioned later or the similar manners thereto.
  • Process G
  • the compound (Vc) can be prepared from the benzylating reaction of the compound (Xc) with a kind of phenylacetonitrile (exemplified by Step 1) by the methods disclosed in Preparation 24 mentioned later or the similar manner thereto.
  • the object compound (Vb) can be prepared by subjecting the compound (Vc) to the decyanating reaction (exemplified by Step 2) that disclosed in Preparation 25 mentioned later or the similar manners thereto.
  • the compounds of above processes can be converted to salts according to a conventional method.
  • the compound (I) of the present invention is an adenosine antagonist and possesses the various pharmacological actions as stated before.
  • Test 1 Adenosine antagonistic activity
  • the adenosine antagonistic activity [Ki (nM) ] of the test compound was examined by radioligand binding techniques using 8-cyclopentyl-l, 3-dipropylxanthine, [dipropyl-2 f 3- 3 H(N) ] ([ 3 H]DPCPX, 4.5 nM) for human A x receptor and [ 3 H]CGS 21680 (20 nM) for human A 2a receptor.
  • Test 2 Anticatalepsy activity in Mouse
  • Test compound l-Isopropyl-5- (2-phenylfuro [3, 2-c] pyridin-3-yl) -2 (1H) - pyridine (Example 27)
  • Test compound Manifestation rate of catalepsy (Example No.) (number of mouse)
  • the compound (I) and a salt thereof of this invention are useful as adenosine antagonists (especially, Ai receptor and A 2 (particularly A 2a receptor dual antagonists) and for the prevention and/or the treatment of depression, dementia (e.g. Alzheimer's disease, cerebrovascular dementia, dementia accompanying Parkinson' s disease, etc.), Parkinson' s disease, anxiety, pain, cerebrovascular disease, heart failure, hypertension, circulatory insufficiency, post-resuscitation asystole, bradyarrhythmia, electro-mechanical dissociation, hemodynamic collapse, SIRS (systemic inflammatory response syndrome) , multiple organ failure, renal failure (renal insufficiency) , renal toxicity, nephrosis, nephritis, edema, obesity, bronchial asthma, gout, hyperuricemia, sudden infant death syndrome, immunosuppression, diabetes, ulcer, pancreatitis, Meniere's syndrome, anemia, dialysis-induced hypotension, constipation,
  • the pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in a solid, semisolid or liquid form, which contains the compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation) , nasal ocular, external (topical) , oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.
  • an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation) , nasal ocular, external (topical) , oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use.
  • auxiliary, stabilizing agents, thickening agents, coloring agents and perfumes may be used where necessary.
  • the compound (I) or a pharmaceutically acceptable salt thereof is included in a pharmaceutical composition in an amount sufficient to produce the desired aforesaid pharmaceutical effect upon the process or condition of diseases.
  • the composition For applying the composition to a human being or an animal, it is preferable to apply it by intravenous, intramuscular, pulmonary or oral administration, or insufflation. While the dosage of therapeutically effective amount of the compound (I) varies depending on the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 100 mg of the compound (I) per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.1 - 100 mg of the compound (I) per kg weight of a human being or an animal is generally given for the prevention and/or treatment of the aforesaid diseases .
  • 2-Phenyl-l-benzofuran (720 mg) was dissolved in carbon disulfide (5 ml) and cooled at -10°C. To the solution was added bromine (593 mg) dropwise at -10°C. The reaction mixture was stirred at ambient temperature for 2 hours, and portioned to EtOAc and aq. NaHC0 3 solution. The organic layer was separated, washed with brine, and dried over MgS0 4 .
  • tetrakis (triphenylphosphine) palladium(O) (69.3 mg) was suspended in DME (2.5 ml). To the suspension were added 3-bromo-2-phenyl-l-benzofuran (546 mg) , 6-methoxy-3-pyridylboronic acid (337 mg) , EtOH (0.6 ml) andaq. sodium carbonate solution (424 mg in water 1.5 ml) successively. The mixture was stirred at 100°C for 15 hours. The mixture was cooled to room temperature, and portioned to EtOAc and water. The organic layer was separated, and washed with water and brine.
  • Methyl 6-oxo-l, 6-dihydro-3-pyridazinecarboxylate (10.71 g) was added in a suspension of sodium hydride (60% dispersion in mineral oil) (2.92 g) in DMF (100 ml) under ice cooling. The mixture was heated at 55-60°C for 30 minutes .2-Iodopropane (7.29 ml) was added to the mixture, and the mixture was heated at the same temperature for 4 hours.
  • the reaction mixture was poured into ice water, and adjusted pH to 5.0 with 6N-HC1 aqueous solution .
  • the mixture was extracted with EtOAc twice, and washed with water and brine. After drying over MgS0 4 , the solvent was removed in vacuo to give blue oil (6.10 g) , which was subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (1 : 1) to afford red oil.
  • the oil crystallized by allowing to stand, and the solid was triturated with IPE.
  • Example 7 l-Isopropyl-5- (2-phenyl-l-benzofuran-3-yl) -2 (IH) -pyridone (25 mg) was prepared from 5- (2-phenyl-l-benzofuran-3-yl) - 2 (IH) -pyridone (28.7 mg) and x PrI (85 mg) in a similar manner to that of Example 4.
  • Example 12 l-Isopropyl-5- (5-methoxy-2-phenyl-l-benzofuran-3-yl) - 2 (IH) -pyridone (16mg) was prepared from 5- (5-methoxy-2-phenyl- l-benzofuran-3-yl) -2 (IH) -pyridone (31.7 mg) and x PrI (85 mg) in a similar manner to that of Example 4.
  • the reaction mixture was portioned to EtOAc and water.

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Abstract

L'invention concerne un nouveau composé représenté par la formule suivante (I). Dans cette formule, Z représente un phényle ou un pyridyle qui se condense au niveau d'un cycle furan, X représente CH ou N; R1 représente un hydrogène ou éventuellement un alkyle inférieur substitué; R2 représente un hydrogène, un halogène ou un alcoxy inférieur; et R3 représente un hydrogène, un hydroxy, un alkyle inférieur, un alcoxy ou un halogène inférieur, ou un sel de ceux-ci. Le composé (I) et son sel sont des antagonistes d'adénosine et sont utiles dans la prévention et/ou le traitement de la dépression, de la démence (par exemple la maladie d'Alzheimer, la démence cérébrovasculaire, la maladie de Parkinson accompagnée de démence, etc.), la maladie de Parkinson, l'anxiété, la douleur, les maladies cérébrovasculaires (par exemple l'accident vasculaire cérébral, etc.), l'insuffisance cardiaque et analogue.
PCT/JP2004/003435 2003-04-04 2004-03-15 Derives de furan condense utilises en tant qu'antagonistes d'adenosine WO2004089939A1 (fr)

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AU2003901647A AU2003901647A0 (en) 2003-04-04 2003-04-04 Novel Condensed Furan Compounds and Pharmaceutical Use Thereof
AU2003901647 2003-04-04

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007530434A (ja) * 2004-04-01 2007-11-01 アステラス製薬株式会社 ピラジン誘導体およびその医薬的使用
US20110112142A1 (en) * 2008-04-11 2011-05-12 Noeteberg Daniel Novel estrogen receptor ligands
WO2014017803A1 (fr) * 2012-07-23 2014-01-30 주식회사 유한양행 Composé à cycles fusionnés contenant du furane ou un sel de celui-ci et composition pharmaceutique comprenant celui-ci
US9586891B2 (en) 2011-08-04 2017-03-07 Karo Pharma Ab Estrogen receptor ligands
CN113939295A (zh) * 2019-03-20 2022-01-14 金翅雀生物公司 哒嗪酮及其使用方法

Citations (2)

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WO1998003507A1 (fr) * 1996-07-18 1998-01-29 Fujisawa Pharmaceutical Co., Ltd. Compose de pyrazolopyridine et son utilisation pharmaceutique
WO2000024742A1 (fr) * 1998-10-23 2000-05-04 Fujisawa Pharmaceutical Co., Ltd. Composes de pyrazolopyridine utiles en tant qu'antagonistes d'adenosine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998003507A1 (fr) * 1996-07-18 1998-01-29 Fujisawa Pharmaceutical Co., Ltd. Compose de pyrazolopyridine et son utilisation pharmaceutique
WO2000024742A1 (fr) * 1998-10-23 2000-05-04 Fujisawa Pharmaceutical Co., Ltd. Composes de pyrazolopyridine utiles en tant qu'antagonistes d'adenosine

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007530434A (ja) * 2004-04-01 2007-11-01 アステラス製薬株式会社 ピラジン誘導体およびその医薬的使用
US20110112142A1 (en) * 2008-04-11 2011-05-12 Noeteberg Daniel Novel estrogen receptor ligands
US9586891B2 (en) 2011-08-04 2017-03-07 Karo Pharma Ab Estrogen receptor ligands
WO2014017803A1 (fr) * 2012-07-23 2014-01-30 주식회사 유한양행 Composé à cycles fusionnés contenant du furane ou un sel de celui-ci et composition pharmaceutique comprenant celui-ci
KR20140018795A (ko) * 2012-07-23 2014-02-13 주식회사유한양행 퓨란-함유 융합 고리 화합물 또는 그의 염 및 이를 포함하는 약학 조성물
US9493478B2 (en) 2012-07-23 2016-11-15 Yuhan Corporation Fused ring compound containing furan or salt thereof and pharmaceutical composition comprising same
KR101684955B1 (ko) * 2012-07-23 2016-12-12 주식회사유한양행 퓨란-함유 융합 고리 화합물 또는 그의 염 및 이를 포함하는 약학 조성물
CN113939295A (zh) * 2019-03-20 2022-01-14 金翅雀生物公司 哒嗪酮及其使用方法

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