WO2003045950A1 - Dérivés de pyrazolopyridine et leur utilisation pharmaceutique - Google Patents

Dérivés de pyrazolopyridine et leur utilisation pharmaceutique Download PDF

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Publication number
WO2003045950A1
WO2003045950A1 PCT/JP2002/012381 JP0212381W WO03045950A1 WO 2003045950 A1 WO2003045950 A1 WO 2003045950A1 JP 0212381 W JP0212381 W JP 0212381W WO 03045950 A1 WO03045950 A1 WO 03045950A1
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Prior art keywords
salt
compound
hydrogen
alkyl
formula
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PCT/JP2002/012381
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English (en)
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Akira Tanaka
Masatoshi Minagawa
Atsushi Akahane
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Fujisawa Pharmaceutical Co., Ltd.
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Priority to AU2002347633A priority Critical patent/AU2002347633A1/en
Publication of WO2003045950A1 publication Critical patent/WO2003045950A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a novel pyrazolopyridine compound a'nd a salt thereof, which are useful as medicaments.
  • pyrazolopyridine compounds to be useful as psychostimulant, remedy for renal failure, or the like are known(e.g. EP-0299209, EP-0379979, EP-0467248, EP-0516941, etc.) .
  • the present invention relates to a novel pyrazolopyridine compound and a pharmaceutically acceptable salt thereof, which are useful as medicaments; processes for the preparation of said pyrazolopyridine compound and a salt thereof; a pharmaceutical composition comprising, as an active ingredient, said pyrazolopyridine compound or a pharmaceutically acceptable salt thereof; a use of said pyrazolopyridine compound or a pharmaceutically acceptable salt thereof as a medicament; and a method for using said pyrazolopyridine compound or a pharmaceutically acceptable salt thereof for therapeutic purposes, which comprises administering said pyrazolopyridine compound or a pharmaceutically acceptable salt thereof to a human being or an animal.
  • the pyrazolopyridine compound and a salt thereof are adenosine antagonists (especially, ireceptor andA 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, antianxietry 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 i munosuppressive action of adenosine, antidiabetic agent, drug for ulcer, drug for pancreatitis, drug for Meniere's syndrome, drug for anemia; drug for thrombosis, drug for yocardial infarction, drug for obstruction, drug for arteriosclerosis obliterans, drug
  • ischemia/reperfusion injury e.g. myocardial ischemia/reperfusion injury, cerebral ischemia/reperfusion injury, peripheral ischemia/reper
  • SIRS systemic inflammatory response syndrome
  • multiple organ failure renal failure (renal insufficiency) (e.g. acute renal failure, etc.), renal toxicity [e.g. renal toxicity induced by a drug such as cisplatins, gentamicin, FR-900506 (disclosed in EP-0184162) , cyclosporin (e.g. cyclosporinA) orthelike; glycerol, etc.], nephrosis, nephritis, edema (e.g.
  • cardiac edema cardiac edema, nephrotic 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. gastric ulcer, duodenal ulcer, etc.), pancreatitis, Meniere's syndrome, anemia, dialysis-induced hypotension, constipation, ischemic bowel disease, ileus (e.g.
  • thrombosis e.g. arterial thrombosis, cerebral thrombosis, etc.
  • obstruction arteriosclerosis obliterans, thrombophlebitis, cerebral infarction, transient ischemic attack, angina pectoris, or the like.
  • novel pyrazolopyridine compound of the present invention can be shown by the following formula (I) .
  • R 1 is hydrogen, optionally substituted lower alkyl or cyclo (lower) alkyl
  • R 2 is hydrogen, optionally substituted hydroxy, acyl or optionally substituted amino
  • R 3 is hydrogen or halogen, and at least one of R 1 , R 2 and R 3 are not hydrogen, or a salt thereof.
  • the preferred embodiments of the pyrazolopyridine compound of the present invention represented by the general formula (I) are as follows. (1) The pyrazolopyridine compound of the general formula (I) wherein
  • R 1 is hydrogen or lower alkyl
  • R 2 is hydrogen, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di (lower) alkylcarbamoyl, amino, protected amino, lower alkylamino, di (lower) alkylamino or -0-R 21 in which
  • R 21 is hydrogen, optionally substituted lower alkyl, acyl, optionally substituted heterocyclic group or optionally substituted sulfino
  • R 3 is hydrogen, and at least one of R 1 and R 2 are not hydrogen, or a salt thereof.
  • R 2 is hydrogen, carboxy, lower alkoxycarbonyl, lower alkylcarbamoyl, di (lower) alkylcarbamoyl, amino, protected amino, lower alkylamino, di (lower) alkylamino or -O-R 21 in which
  • R 21 is hydrogen, lower alkyl, morpholinyl (lower) alkyl, tetrahydro-2H-pyranyl (lower) alkyl, optionally substituted pyridyl, optionally substituted piperidyl or halo (lower) alkylsulfonyl, lower alkoxy (lower) alkyl, carboxy (lower) alkyl, lower alkoxycarbonyl (lower) alkyl, lower alkylcarbamoyl (lower) alkyl, di (lower) alkylcarbamoyl (lower) alkyl, amino (lower) alkyl, lower alkylamino (lower) alkyl, di (lower) alkylamino (lower) alkyl, protected amino (lower) alkyl or N-protected-N- (lower) alkylamino (lower) alkyl, or a salt thereof.
  • R 1 is hydrogen, methyl, ethyl, propyl or isopropyl
  • R 2 is hydrogen, carboxy, methoxycarbonyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, amino, tert-butoxycarbonylamino or -O-R 21 in which
  • R 21 is hydrogen, methyl , morpholinylethyl , tetrahydro-2H-pyranylmethyl , methoxyethyl, carboxymethyl, ethoxycarbonylmethyl, nitropyridyl , aminopyridyl, piperidyl, 1-tert-butoxycarbonylpiperidyl, trif luoromethylsulf onyl , (CH 2 ) 2 -N(R 22 ) (R 23 ) in which
  • R ,22 is hydrogen or methyl
  • R ,23 is hydrogen, methyl or tert-butoxycarbonyl, or
  • R 24 is hydrogen or methyl
  • R 25 is hydrogen, methyl or ethyl, or a salt thereof.
  • the object compound (I) and a salt thereof of the present invention can be prepared by the following processes.
  • R 1 is hydrogen, optionally substituted lower alkyl or cyclo (lower) alkyl
  • R 3 is hydrogen or halogen
  • R la is optionally substituted lower alkyl or cyclo (lower) alkyl
  • R 2a is hydrogen, optionally substituted hydroxy, acyl or optionally substituted amino
  • R 3a is hydrogen or halogen, at least one of R 2a and R 3a are not hydrogen, R 4 is lower alkyl,
  • R 21a is lower alkyl
  • R 21 is optionally substituted lower alkyl, acyl, optionally substitutedheterocyclic group or optionally substituted sulfino,
  • R 26 and R 26a are lower alkyl
  • R 27 and R 28 are each independently hydrogen or lower alkyl
  • R 29 is hydrogen or lower alkyl
  • A is direct bond or -CH 2 -0-, or a salt thereof
  • X and X 2 are leaving groups
  • Tf means trifluoromethylsulfonyl
  • Boc means tert-butoxycarbonyl
  • the starting compound (II) or a salt thereof is novel and can be prepared, for example, by the following reaction schemes.
  • R 2b is hydrogen, optionally substituted hydroxy, acyl or optionally substituted amino
  • R 3b is hydrogen or halogen, both of R 2b and R 3b may be hydrogen,
  • R 4 is as defined above
  • R 5 is arylsulfonyl which may have one or more suitable substituent (s) or lower alkylsulfonyl;
  • Y is halogen
  • Z ⁇ is an anion
  • 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 Preparations or Examples, or in a manner similar thereto.
  • the object compound (I) may include the geometrical isomer(s) due to the double bond(s) and/or the stereo isomer(s) due to the asymmetric carbon atom(s) .
  • one isomer can be converted to another according to a conventional method in this field of the art.
  • Suitable salts of the object compound (I) are conventional pharmaceutically acceptable ones 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. trimethyla ine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N' -dibenzylethylenediamine 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. trimethyla ine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N' -di
  • an inorganic acid salt e.g. hydrochloride, hydrobromide, hydriodide, sulfate, phosphate, etc.
  • a salt with an amino acid e.g. arginine, aspartic acid, glutamic acid, etc.
  • Suitable examples of "lower alkyl” and “lower alkyl” moiety in the terms “lower alkylcarbamoyl”, “di (lower) alkylcarbamoyl”, “lower alkylamino” and”di (lower) alkylamino” 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 "cyclo (lower) alkyl” may be cyclo (C3-C8) -alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or the like, in which the preferred one may be cyclo (C3-C7 ) alkyl such as cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl .
  • Suitable "lower alkoxy” and “lower alkoxy” moiety in the terms “lower alkoxycarbonyl” and “lower alkoxy (lower) alkyl” 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, ethoxy and tert-butoxy.
  • Suitable "acyl” mayinclude lower alkanoyl, carboxy, protected carboxy, and the like.
  • Suitable examples of aforesaid "lower alkanoyl” maybe formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, or the like, in which the preferred one may be (C1-C4) alkanoyl and the more preferred one may be formyl and acetyl.
  • Suitable examples of aforesaid "protected carboxy” may be (1) esterified carboxy, in which suitable esterified carboxy may include lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), aryl (lower) alkoxycarbonyl (e.g.
  • amidated carboxy in which suitable a idated carboxy may include carbamoyl, N- (lower) alkylcarbamoyl (e.g.
  • N-lower alkyl-N-ar (lower) alkylcarbamoyl e.g. N-methyl-N-benzylcarbamoyl, etc, and the like.
  • heterocyclic group is saturated or unsaturated, monocyclic or condensed heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms.
  • heterocyclic group Preferable examples of the heterocyclic group are described in the following.
  • (1) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1, 2, 4-triazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, etc. ) , tetrazolyl (e.g. , lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
  • saturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g., morpholinyl, etc.
  • unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms for example, thiazolyl, thiadiazolyl (e.g., 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, etc. ) , etc.
  • unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms e.g., benzofuryl, benzodioxolyl, etc.
  • unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g., benzoxazolyl, benzoxadiazolyl, phenoxazinyl, etc.
  • unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., benzothiazolyl, benzisothiazolyl, phenothiazinyl, etc.
  • heterocyclic group is unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms such as pyridyl, or saturated 5- or 6-membered heteromonocyclic group containing 1 to 4 heteroatom(s) selected from nitrogen and oxygen such as piperidyl, morpholinyl and tetrahydro-2H-pyranyl .
  • Suitable “amino protective group” and “amino protective group” moiety in the terms “protected amino”, “protected amino (lower) - alkyl” and “N-protected-N- (lower) alkylamino (lower) alkyl” may include acyl such as lower alkanoyl (e.g. , formyl, acetyl, etc.
  • Suitable "halogen” may be fluoro, chloro, bromo and iodo.
  • Suitable "a leaving group” may include halogen as mentioned above, hydroxy, acyloxy such as alkanoyloxy (e.g. acetoxy, propionyloxy, etc. ) , sulfonyloxy (e.g.
  • Suitable "anion” may be formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, chloride, bromide, iodide, sulfate, phosphate, or the like.
  • Suitable examples of the substituent of "optionally substituted lower alkyl” may include cyclo (lower) alkyl, lower alkoxy, acyl, optionally substituted amino, optionally substituted heterocyclic group, aryl, halo, or the like.
  • Suitable examples of the substituent of "optionally substituted hydroxy” may include optionally substituted lower alkyl, cyclo (lower) alkyl, acyl, optionally substituted amino, optionally substituted heterocyclic group, aryl, optionally substituted sulfino or the like.
  • Suitable examples of the substituent of "optionally substituted amino” may include lower alkyl, amino protective group or the like.
  • Suitable examples of the substituent of "optionally substituted heterocyclic group” may include optionally substituted amino, nitro, lower alkyl, lower alkoxy, or the like.
  • Suitable examples of "aryl” may include phenyl, naphthyl or the like, which is optionally substituted by suitable substituent (s) such as lower alkyl, lower alkoxy, hydroxy, halo or the like.
  • suitable substituent (s) such as lower alkyl, lower alkoxy, hydroxy, halo or the like.
  • Suitable examples of “optionally substituted sulfino” may include arylsulfonyl, lower alkylsulfonyl, halo (lower) alkylsulfonyl or the like.
  • Suitable "arylsulfonyl” may include phenylsulfonyl, tolylsulfonyl, naphthylsulfonyl and the like, in which the preferred one may be phenylsulfonyl, and said "arylsulfonyl” may have one or more (preferably 1 to 3) suitable substituent (s) such as lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.), aforesaid halogen, or the like.
  • suitable substituent (s) such as lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.), aforesaid halogen, or the like.
  • Suitable "lower alkylsulfonyl” may include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, tert-butylsulfonyl and the like, in which the preferred one may be methylsulfonyl.
  • Suitable "halo (lower) alkylsulfonyl” may include chloromethylsulfonyl, bromomethylsulfonyl, fluoromethylsulfonyl, 2-chloroethylsulfonyl,
  • the compound (la) or a salt thereof can be preparedby subjecting the compound (Ila) or a salt thereof to hydrolysis.
  • 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, trialkylamide (e.g. trimethylamine, triethylamine, etc.), hydrazine, picoline, 1, 5-diazabicyclo [4.3.0] non-5-ene, 1, 4-diazabicyclo [2.2.2] octane, 1, 8-diazabicyclo [5.4.0] ndec-7-ene, or the like.
  • an alkali metal e.g. sodium, potassium, etc.
  • an alkaline earth metal e.g. magnesium, calcium, etc.
  • trialkylamide e.g. trimethylamine, triethylamine, etc.
  • hydrazine picoline, 1, 5-diazabicyclo [4.3.0] non-5-ene, 1, 4-d
  • Suitable acid includes an organic acid (e.g. formic acid, 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.).
  • organic acid e.g. formic acid, 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.
  • the elimination using Lewis acid such as BBr 3 , BC1 3 , BF 3 , A1C1 3 , TiCl 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.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, or any 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.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
  • 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 compound (lb) or a salt thereof can be prepared by reacting the compound (la) or a salt thereof with the compound (III) or a salt thereof.
  • the present reaction may be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, 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 chloride, formamide, N,N-dimethylformamide, methanol, ethanol, sec-butanol, amyl alcohol, diethyl ether, dioxane, tetrahydrofuran, dimethyl sulfoxide, or any other organic solvent which does not
  • the reaction is preferably conducted in the presence of a base, for example, inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate, alkali metal bicarbonate, alkali metal hydride (e.g. sodium hydride) , alkali metal alkoxide (e.g. EtONa, t-BuOK, etc.) organic base such as trialkylamine, and the like.
  • a base for example, inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate, alkali metal bicarbonate, alkali metal hydride (e.g. sodium hydride) , alkali metal alkoxide (e.g. EtONa, t-BuOK, etc.) organic base such as trialkylamine, and the like.
  • a base for example, inorganic base such as alkali metal hydroxide
  • the present reaction is preferably carried out in the presence of alkali metal halide (e.g. sodium iodide, potassium iodide, lithium bromide, etc.), alkali metal thiocyanate (e.g. sodium thiocyanate, potassium thiocyanate, etc.), di (lower) alkyl azodicarboxylate (e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.) or the like.
  • alkali metal halide e.g. sodium iodide, potassium iodide, lithium bromide, etc.
  • alkali metal thiocyanate e.g. sodium thiocyanate, potassium thiocyanate, etc.
  • di (lower) alkyl azodicarboxylate e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.
  • X is -
  • the compound (Ic) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (III) or a salt thereof.
  • reaction of this process can be carried out in the manner similar to that of Process 2.
  • Process 4 The compound (Ie) or a salt thereof canbe preparedby subjecting the compound (Id) or a salt thereof to elimination reaction of alkyl group.
  • Suitable salts of the compound (Id) and (Ie) can be referred to the ones as exemplified for the compound (I) .
  • This reaction is carried out in accordance with a conventional method such as hydrolysis.
  • 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 earthmetal (e. g. magnesium, calcium, etc.), hydroxide or carbonate or bicarbonate thereof, trialkylamine (e.g. trimethylamine, triethylamine, etc. ) , hydrazine, picoline, 1, 5-diazabicyclo [4.3.0] non-5-ene, 1, 4-diazabicyclo [2.2.2] octane,
  • alkali metal e.g. sodium, potassium, etc.
  • an alkaline earthmetal e. g. magnesium, calcium, etc.
  • hydroxide or carbonate or bicarbonate thereof e.g. trimethylamine, triethylamine, etc.
  • trialkylamine e.g. trimethylamine, triethylamine, etc.
  • Suitable acid includes an organic acid (e.g. formic acid, 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.).
  • organic acid e.g. formic acid, 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.
  • Lewis acid e.g. aluminium chloride, boron tribromide, boron trichloride, titanium trichloride, tin tetrachloride, etc.
  • cation trapping agents e.g. anisole, phenol, etc.
  • the reaction is usually carried out in a solvent such as water, alcohol (e.g. methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
  • a liquid base or acid can be also used as the solvent.
  • reaction of this process canbe also carried out according to a conventional reduction method employed in this field of the art (e.g. chemical reduction, catalytic reduction, etc.).
  • a conventional reduction method employed in this field of the art (e.g. chemical reduction, catalytic reduction, etc.).
  • reaction temperature is not critical and the reaction is usually carried out at ambient temperature, under warming or under heating.
  • the compound (If) or a salt thereof can be prepared by reacting the compound (Ie) or a salt thereof with the compound (X) or a salt thereof.
  • Suitable salt of the compound (Ie) can be referred to an acid addition salt as exemplified for the compound (I) .
  • Suitable salt of the compound (X) can be referred to the ones as exemplified for the compound (I),.
  • the present reaction may be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, 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 .
  • hydrophilic solvents may be used in a mixture with water.
  • the compound (X) When the compound (X) is in liquid, it can also be used as a solvent.
  • the reaction is preferably conducted in the presence of a base, for example, inorganic base such as alkali metal hydroxide, alkalimetal carbonate, alkalimetal bicarbonate, alkali metal hydride (e.g. sodium hydride, etc.), organic base such as trialkylamine, and the like.
  • a base for example, inorganic base such as alkali metal hydroxide, alkalimetal carbonate, alkalimetal bicarbonate, alkali metal hydride (e.g. sodium hydride, etc.), organic base such as trialkylamine, and the like.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under 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.), di (lower) alkyl azodicarboxylate (e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.) or the like.
  • alkali metal halide e.g. sodium iodide, potassium iodide, etc.
  • alkali metal thiocyanate e.g. sodium thiocyanate, potassium thiocyanate, etc.
  • di (lower) alkyl azodicarboxylate e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.
  • X 2 is -OH
  • the compound (Ih) or a salt thereof canbe preparedby subjecting the compound (Ig) or a salt thereof to elimination reaction of alkyl group.
  • Suitable method of this elimination reaction includes conventional one such as hydrolysis.
  • the hydrolysis can be carried out in the same manner as in the aforementioned Process 4, and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of Process 4.
  • Process 7 the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of Process 4.
  • the compound (Ii) or a salt thereof can be prepared by reacting the compound (Ih) or its reactive derivative at the carboxy group, or a salt thereof with the compound (XI) or its reactive derivative or a salt thereof.
  • Suitable reactive derivative of the compound (XI) may include Schiff's base type imino or its tauto eric enamine type isomer formedby the reaction of the compound (XI) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (XI) with a silyl compound such as N,0-bis (trimethylsilyl) acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (XI) with phosphorus trichloride or phosgene, and the like.
  • Suitable reactive derivative of the compound (Ih) may include an acid halide, an acid anhydride, an activated ester, and the like.
  • the suitable example may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.
  • dialkylphosphorous acid e.g., sulfurous acid, thiosulfuric acid, alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc. ) ; aromatic carboxylic acid (e.g. , benzoic acid, etc.
  • alkanesulfonic acid e.g., methanesulfonic acid, ethanesulfonic acid, etc.
  • sulfuric acid alkylcarbonic acid
  • aliphatic carboxylic acid e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc
  • N-hydroxybenzotriazole HOBt
  • N-hydroxyphthalimide N-hydroxyphthalimide
  • l-hydroxy-6-chloro-lH-benzotriazole etc.
  • reactivederivatives canoptionallybe selectedfromthemaccording to the kind of the compound (Ih) to be used.
  • the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide (DMF), pyridine or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
  • a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide (DMF), pyridine or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction is preferable carried out in the presence of a conventional condensing agent such as N, ' -dicyclohexylcarbodiimide; N-cyclohexyl-N ' -morpholinoethylcarbodiimide; N-cyclohexyl-N' - (4-diethylaminocyclohexyl) carbodiimide; N,N' -diisopropylcarbodiimide; N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide (EDAC) ; N,N-carbonyl-bis (2-methylimidazole) ; pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l-chloroethylene; trialkyl
  • the compound (Io) or a salt thereof can be preparedby subjecting the compound (In) or a salt thereof to elimination reaction of the amino protective group.
  • Step 2 The reaction of this step can be carried out by the method disclosed in Preparation 3 or 9 mentioned later or the similar manners thereto. Step 2
  • the compound (IX) or a salt thereof can be prepared by reacting the compound (VII) or a salt thereof with the compound (VIII) or a salt thereof.
  • the reaction is usually carried out in a solvent such as water, methylene chloride, ethylene chloride, N,N-dimethylformamide or any other solvent which does not adversely influence the reaction or a mixture thereof.
  • a base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate, alkali metal hydride (e.g. sodium hydride) , alkali metal alkoxide (e.g.
  • EtONa, t-BuOK, etc. organic base such as trialkylamine, ar (lower) alkyltri (lower) alkylammonium halide (e.g. benzyltrimethylammonium chloride, etc.) or the like.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling, at ambient temperature or under warming.
  • reaction of this step can be carried out by the method disclosed in Preparation 5 mentioned later or the similar manners thereto.
  • the compound (IV) or a salt thereof canbe preparedby subjecting the compound (lib) or a salt thereof to hydrolysis.
  • the reaction of this process can be carried out in the manner similar to that of Process 1.
  • Suitable salts of the starting compounds in Process 1 to 3, Step 1 to 3 in Process A, and Process B can be referred to the one as exemplified for the compound (I) .
  • the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.
  • the object 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, 3- 3 H (N) ] ([ 3 H]DPCPX, 4.5nM) for human x receptor and [ 3 H]CGS 21680 (20nM) for human A 2a receptor.
  • Example 4 0/7
  • Example 8 0/7
  • Example 9 0/7
  • the pyrazolopyridine 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.
  • 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 pyrazolopyridine 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.
  • a pharmaceutical preparation for example, in a solid, semisolid or liquid form, which contains the pyrazolopyridine 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.
  • the active ingredient maybe 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 pyrazolopyridine 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 oftherapeutically effective amount of the pyrazolopyridine compound (I) varies depending on the age and condition of each individual patient to be treated, in the case of intravenous administration, adailydose of 0.01 - 100 mg of the pyrazolopyridine 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 pyrazolopyridine compound (I) per kg weight of a human being or an animal, and in case of oral administration, a daily dose of 0.5 - 100 mg of the pyrazolopyridine 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 .
  • Example 10 To the solution of boron tribromide (1.74 g) in CH 2 C1 2 (5 ml) was added a solutipn of l-isopropyl-5- (5-methoxy-2-phenylpyrazolo [1, 5-a] pyridin- 3-yl)-2 (lH)-pyridinone (1.74 g) in CH 2 C1 2 (2 ml) below 30°C for 15 minutes, and the mixture was stirred below 30 °C for 3 hours.
  • the reaction mixture was poured into water (300 ml) and the mixture was extracted with AcOEt (200 ml x 2) , and the combined organic layer was washed with water (200 ml x 2) , aqueous 1 N-HC1 (200 ml), water (200 ml), aqueous saturated NaHC0 3 (200 ml), water (200 ml) and brine (200 ml), dried over MgS0 4 , filtered and evaporated.
  • N-Ethyl-2- ⁇ [3- (l-isopropyl-6-oxo-l, 6-dihydro-3- pyridinyl) -2-phenylpyrazolo [1, 5-a] pyridin-5-yl] oxy ⁇ acetamide was prepared in a similar manner to that of Example 13.
  • Example 17 l-Isopropyl-5- ⁇ 5- [2- (4-morpholinyl) ethoxy] -2- phenylpyrazolo [1, 5-a]pyridin-3-yl ⁇ -2 (IH) -pyridinone was prepared in a similar manner to that of Example 11.
  • Example 18 l-Isopropyl-5- [2-phenyl-5- (2-pyridinyloxy) pyrazolo [1,5- a]pyridin-3-yl] -2 (IH) -pyridinone was prepared in a similarmanner to that of Example 11.
  • Example 19 l-Isopropyl-5- [5- (2-methoxyethoxy) -2-phenylpyrazolo [1,5- a]pyridin-3-yl] -2 (IH) -pyridinone was prepared in a similarmanner to that of Example 11.
  • reaction mixture was stirred with N 2 bubbling at ambient temperature for 2 hours.
  • the reaction mixture was diluted with AcOEt (500 ml) and washed with H 2 0 (500 ml) , aqueous 1 N-HCl (200 ml) , saturated aqueous
  • N-Ethyl-3- (l-isopropyl-6-oxo-l, 6-dihydro-3-pyridinyl) -2- phenylpyrazolo [1, 5-a] pyridine-5-carboxamide was prepared in a similar manner to that of Example 13.

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Abstract

La présente invention concerne un composé de pyrazolopyridine de la formule (1) suivante, dans laquelle R1 est hydrogène, alkyle inférieur ou cycloalkyle inférieur facultativement substitué, R2 est hydrogène, hydroxy facultativement substitué, acyle, ou amino facultativement substitué, R3 est hydrogène ou halogène, et au moins l'un de R1, R2 et R3 n'est pas hydrogène, ou un sel de ce dernier. Le composé pyrazolopyridine (I) et sel de ce dernier de l'invention sont des antagonistes de l'adénosine et sont utilisés dans la prévention et/ou le traitement de la dépression, de la démence (par exemple, la maladie d'Alzheimer, la démence cérébrovasculaire, la démence qui accompagne la maladie de Parkinson, etc), la maladie de Parkinson, l'anxiété, la douleur, la maladie cérébrovasculaire (par exemple, l'accident vasculaire cérébral, etc.), l'insuffisance cardiaque et analogue.
PCT/JP2002/012381 2001-11-29 2002-11-27 Dérivés de pyrazolopyridine et leur utilisation pharmaceutique WO2003045950A1 (fr)

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Cited By (6)

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WO2007146087A2 (fr) * 2006-06-06 2007-12-21 Avigen, Inc. COMPOSÉS DE PYRAZOLO-[1,5-a]PYRIDINE SUBSTITUÉE ET LEURS PROCÉDÉS D'UTILISATION
WO2009095454A2 (fr) * 2008-02-01 2009-08-06 Brahms Aktiengesellschaft Procédé d'identification de patients présentant de légers troubles cognitifs, nécessitant un traitement, et traitement de ces patients
WO2011074658A1 (fr) * 2009-12-18 2011-06-23 田辺三菱製薬株式会社 Nouvel agent antiplaquettaire
US8835441B2 (en) 2005-05-20 2014-09-16 Amgen Inc. Heterobicyclic metalloprotease inhibitors
US8871754B2 (en) 2012-11-19 2014-10-28 Irm Llc Compounds and compositions for the treatment of parasitic diseases
US9556169B2 (en) 2012-11-19 2017-01-31 Novartis Ag Compounds and compositions for the treatment of parasitic diseases

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EP0379979A1 (fr) * 1989-01-23 1990-08-01 Fujisawa Pharmaceutical Co., Ltd. Composés pyrazolopyridiniques et procédés pour sa préparation

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
EP0379979A1 (fr) * 1989-01-23 1990-08-01 Fujisawa Pharmaceutical Co., Ltd. Composés pyrazolopyridiniques et procédés pour sa préparation

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8835441B2 (en) 2005-05-20 2014-09-16 Amgen Inc. Heterobicyclic metalloprotease inhibitors
JP2013189479A (ja) * 2006-06-06 2013-09-26 Medicinova Inc 置換ピラゾロ［１，５−ａ］ピリジン化合物およびその使用方法
WO2007146087A3 (fr) * 2006-06-06 2008-03-20 Avigen Inc COMPOSÉS DE PYRAZOLO-[1,5-a]PYRIDINE SUBSTITUÉE ET LEURS PROCÉDÉS D'UTILISATION
US7585875B2 (en) 2006-06-06 2009-09-08 Avigen, Inc. Substituted pyrazolo[1,5-a]pyridine compounds and their methods of use
JP2009539851A (ja) * 2006-06-06 2009-11-19 アビジェン， インコーポレイテッド 置換ピラゾロ［１，５−ａ］ピリジン化合物およびその使用方法
AU2007258567B2 (en) * 2006-06-06 2012-04-19 Medicinova, Inc. Substituted pyrazolo (1,5-alpha) pyridine compounds and their methods of use
WO2007146087A2 (fr) * 2006-06-06 2007-12-21 Avigen, Inc. COMPOSÉS DE PYRAZOLO-[1,5-a]PYRIDINE SUBSTITUÉE ET LEURS PROCÉDÉS D'UTILISATION
WO2009095454A2 (fr) * 2008-02-01 2009-08-06 Brahms Aktiengesellschaft Procédé d'identification de patients présentant de légers troubles cognitifs, nécessitant un traitement, et traitement de ces patients
WO2009095454A3 (fr) * 2008-02-01 2009-10-01 Brahms Aktiengesellschaft Procédé d'identification de patients présentant de légers troubles cognitifs, nécessitant un traitement, et traitement de ces patients
JPWO2011074658A1 (ja) * 2009-12-18 2013-05-02 田辺三菱製薬株式会社 新規抗血小板薬
US8703760B2 (en) 2009-12-18 2014-04-22 Mitsubishi Tanabe Pharma Corporation Antiplatelet agent
JP5543980B2 (ja) * 2009-12-18 2014-07-09 田辺三菱製薬株式会社 新規抗血小板薬
AU2010331175B2 (en) * 2009-12-18 2014-08-28 Mitsubishi Tanabe Pharma Corporation Novel antiplatelet agent
WO2011074658A1 (fr) * 2009-12-18 2011-06-23 田辺三菱製薬株式会社 Nouvel agent antiplaquettaire
US9533983B2 (en) 2009-12-18 2017-01-03 Mitsubishi Tanabe Pharma Corporation Antiplatelet agent
US8871754B2 (en) 2012-11-19 2014-10-28 Irm Llc Compounds and compositions for the treatment of parasitic diseases
US9556169B2 (en) 2012-11-19 2017-01-31 Novartis Ag Compounds and compositions for the treatment of parasitic diseases
US9926314B2 (en) 2012-11-19 2018-03-27 Novartis Ag Compounds and compositions for the treatment of parasitic diseases

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