EP1244669A1 - Pyrazolopyrazines et leur utilisation comme antagonistes vis-a-vis de l'adenosine - Google Patents

Pyrazolopyrazines et leur utilisation comme antagonistes vis-a-vis de l'adenosine

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Publication number
EP1244669A1
EP1244669A1 EP00974973A EP00974973A EP1244669A1 EP 1244669 A1 EP1244669 A1 EP 1244669A1 EP 00974973 A EP00974973 A EP 00974973A EP 00974973 A EP00974973 A EP 00974973A EP 1244669 A1 EP1244669 A1 EP 1244669A1
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EP
European Patent Office
Prior art keywords
compound
alkyl
salt
cyclo
pyrazine
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00974973A
Other languages
German (de)
English (en)
Inventor
Atsushi Fujisawa Pharmaceutical Co. Ltd. AKAHANE
Satoru Fujisawa Pharmaceutical Co. Ltd. KURODA
Hiromichi Fujisawa Pharmaceutical Co. Ltd. ITANI
Seiichiro Fujisawa Pharmaceu. Co. Ltd. TABUCHI
Yoshiniro Fujisawa Pharmaceutical Co. Ltd. SATO
Nobuya Fujisawa Pharmaceutical Co. Ltd. MATSUOKA
Miho Fujisawa Pharmaceutical Co. Ltd. TADA
Hideaki Fujisawa Pharmaceu. Co. Ltd. MATSUOKA
Takuma Fujisawa Pharmaceutical Co. Ltd. OKU
Akira Fujisawa Pharmaceutical Co. Ltd. TANAKA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
Original Assignee
Fujisawa Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Publication of EP1244669A1 publication Critical patent/EP1244669A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a novel compound and 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.).
  • pyrazolopyrazine compounds are novel, so there has been no knowledge about these compounds.
  • the present invention relates to a novel pyrazolopyrazine compound and a pharmaceutically acceptable salt thereof, which are useful as medicaments; processes for the preparation of said pyrazolopyrazine compound and a salt thereof; a pharmaceutical composition comprising, as an active ingredient, said pyrazolopyrazine compound or a pharmaceutically acceptable salt thereof; a use of said pyrazolopyrazine compound or a pharmaceutically acceptable salt thereof as a medicament; and a method for using said pyrazolopyrazine compound or a pharmaceutically acceptable salt thereof for therapeutic purposes, which comprises administering said pyrazolopyrazine compound or a pharmaceutically acceptable salt thereof to a human being or an animal.
  • the pyrazolopyrazine compound and a salt thereof are adenosine antagonists (especially, A ! 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, 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 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
  • ischemia/reperfusion injury e.g. myocardial ischemia/reperfusion injury, cerebral ischemia/reperfusion injury, peripheral ischemia/re
  • SIRS systemic inflammatory response syndrome
  • multiple organ failure e.g. 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. cyclosporin A) or the like; 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 pyrazolopyrazine compound of the present invention can be shown by the following formula (I) .
  • R is aryl which may have one or more suitable substituent (s) , and
  • R is hydrogen; lower alkyl; lower alkenyl; cyclo (lower) alkyl; heteromonocyclic group; or lower alkyl substituted with one or more substituent (s) selected from the group consisting of cyclo (lower) alkyl, halogen, cyano, aryl and heteromonocyclic group, or a salt thereof.
  • the object compound (I) or a salt thereof of the present invention can be prepared by the following processes.
  • Process 1
  • R 1 is as defined above
  • R is arylsulfonyl which may have one or more suitable substituent (s) ; di (lower) alkylamino; lower alkoxy; lower alkylthio; or acyloxy,
  • R a is lower alkyl; cyclo (lower) alkyl; lower alkyl substituted with cyclo (lower ) alkyl; lower alkyl substituted with aryl; heteromonocyclic group; or lower alkyl substituted with heteromonocyclic group,
  • R 4 and R 5 are each lower alkyl
  • X is a leaving group
  • the starting compound (II) or a salt thereof is novel and can be prepared, for example, by the following reaction schemes.
  • Tf 2 0 is trifluoromethanesulfonic anhydride.
  • 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. trimethylamine 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. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt , N, N ' -d
  • an inorganic acid salt e.g. hydrochloride, hydrobromide, hydriodide, sulfate, phosphate, etc.
  • a salt with an amino acid e.g. argimne, aspartic acid, glutamic acid, etc.
  • Suitable "lower 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 methyl, isopropyl or pentyl.
  • Suitable "lower alkenyl” may include straight or branched ones such as vinyl, allyl, lsopropenyl or the like, in which the preferred one may be vinyl.
  • Suitable "lower alkyl substituted with halogen” may include, for example, fluoromethyl, chloromethyl, bromomethyl, lodomethyl, fluoroethyl, chloroethyl, bromoethyl, lodoethyl, fluoropropyl, chloropropyl, bromopropyl, lodopropyl, difluoromethyl, dichloromethyl, dibromomethyl, dnodomethyl, difluoroethyl, dichloroethyl, dibromoethyl, dnodoethyl, difluoropropyl, dichloropropyl, dibromopropyl, dnodopropyl, trifluoromethyl, t ⁇ chloromethyl, t ⁇ bromomethyl, trnodomethyl, trifluoroethyl, trichloroethyl, tribromoethyl, trii
  • Suitable "aryl” may include phenyl, naphthyl, mdenyl, anthryl, and the like, in which the preferred one may be (C6- CIO) aryl, and the more preferred one may be phenyl.
  • the "aryl” mentioned above may have one or more (preferably 1 to 3) suitable substituent (s) selected from the group consisting of halogen (e.g. fluoro, chloro, bromo, lodo) , lower alkyl as mentioned above, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc. ) , hydroxy, and the like.
  • suitable substituent selected from the group consisting of halogen (e.g. fluoro, chloro, bromo, lodo) , lower alkyl as mentioned above, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc. ) , hydroxy, and the like.
  • 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 (C5-C6) alkyl such as cyclopentyl or cyclohexyl.
  • Suitable "heteromonocyclic group” may include saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 hetero atom(s) selected from among oxygen, sulfur and nitrogen in its ring, in which the preferred one may be saturated 5 to 6-memberd heteromonocyclic group containing 1 to 2 oxygen atom(s) in its ring such as tetrahydrofuranyl or tetrahydropyranyl; or unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 hetero atom(s) selected from among oxygen, sulfur and nitrogen in its ring, in which the preferred one may be unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 hetero atom(s) selected from among oxygen, sulfur and nitrogen in its ring such as pyridyl, furanyl, thienyl and thiazolyl.
  • Suitable “a leaving group” may include halogen (e.g. fluoro, chloro, bromo and iodo) , hydroxy, acyloxy such as alkanoyloxy (e.g. acetoxy, propionyloxy, etc.), sulfonyloxy (e.g. mesyloxy, tosyloxy, etc.), and the like.
  • halogen e.g. fluoro, chloro, bromo and iodo
  • hydroxy acyloxy such as alkanoyloxy (e.g. acetoxy, propionyloxy, etc.), sulfonyloxy (e.g. mesyloxy, tosyloxy, etc.), and the like.
  • Suitable “anion” may be formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, chloride, bromide, iodide, sulfate, phosphate, or the like.
  • the compound (la) or a salt thereof can be prepared by subjecting the compound (II) or a salt thereof to hydrolysis.
  • Suitable salt of the compound (II) 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, 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] undec-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-
  • 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 such as trihaloacetic acid (e.g. trichloroacetic acid, trifluoroacetic acid, 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.), 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 solvent such as water, an alcohol (e.g. methanol, ethanol, isopropy
  • 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.
  • Suitable salt of the compound (la) can be referred to an acid addition salt as exemplified for the compound (I).
  • Suitable salt of the compound (III) 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.
  • 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, alkali metal carbonate, alkali metal bicarbonate, alkali metal hydride, organic base such as trialkylamine, and the like.
  • a base for example, inorganic base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, alkali metal hydride, 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 is -OH
  • the compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to elimination reaction of alkyl group.
  • Suitable salts of the compound (Ic) and (Id) 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 earth metal (e.g. magnesium, calcium, etc.), hydroxide or carbonate or bicarbonate thereof, trialkylamine (e.g. trimethylamme, t ⁇ ethylamine, etc.), hydrazine, picolme, 1, 5-d ⁇ azab ⁇ cyclo [4.3.0] non-5-ene, 1, 4-d ⁇ azab ⁇ cyclo [2.2.2] octane,
  • an alkali metal e.g. sodium, potassium, etc.
  • an alkaline earth metal e.g. magnesium, calcium, etc.
  • hydroxide or carbonate or bicarbonate thereof e.g. trimethylamme, t ⁇ ethylamine, etc.
  • trialkylamine e.g. trimethylamme, t ⁇ ethylamine, etc.
  • hydrazine picolme, 1, 5-d ⁇ azab ⁇
  • 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, titanium trichloride, tin tetrachlo ⁇ de, 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 can be 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 (IV) or a salt thereof.
  • Suitable salt of the compound (Ie), (IV) and (If) can be referred to the ones as exemplified for the compound (I) .
  • Step 3 The compound (II) or a salt thereof can be prepared by reacting the compound (VII) or a salt thereof with the compound (VIII). Suitable salts of the compounds (II) and (VII) can be referred to acid addition salts as exemplified for the compound (I).
  • 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.
  • the reaction can be carried out in the presence of a base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), ar (low.er) alkyltri (lower) alkylammonium halide (e.g. benzyltrimethylammonium chloride, etc.) or the like.
  • a base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), ar (low.er) 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 room temperature or under warming .
  • the object compound (I) of the present invention is an adenosine antagonist and possesses the various pharmacological actions as stated before.
  • the pharmacological test result of the representative compound of the present invention is shown in the following .
  • 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, 4.5n ) for human A*, receptor and [ 3 H] CGS 21680 (20nM) for human A 2a receptor.
  • Test compound Manifestation rate of catalepsy (Example No. ) (number of mouse) 1/7 0/7
  • the pyrazolopyrazine compound (I) and a salt thereof of this invention are useful as adenosine antagonists (especially, A L 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 pyrazolopyrazine 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 pyrazolopyrazine 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 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 pyrazolopyrazine 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 pyrazolopyrazine 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 pyrazolopyrazine 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 pyrazolopyrazine 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 pyrazolopyrazine 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.
  • Trifluoromethanesulfonic acid 6-benzene-sulfonylpyridazin-3-yl ester (200 g) was obtained by filtration.
  • Example 1 3- [2- (2-Thenyl) -3-OXO-2, 3-dihydropyridazin-6-yl] -2- phenylpyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Example 3.
  • NMR (DMSO-d6, ⁇ ): 5.55(2H,s), 6.96 ( IH, d, J 9.7Hz) , 7.01-
  • Example 15 3- [2- (4-Tetrahydropyranyl) -3-oxo-2, 3-dihydropyridazin-6- yl] -2-phenylpyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 3. mp: 217-218°C (AcOEt-hexane)
  • Example 28 3- (2-Isopropyl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- (4- chlorophenyl) pyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 167-169°C (EtOH)
  • N, N-dimethylformamide (6 ml) was added 60%-sodium hydroxide (74 mg) at ambient temperature. After stirring for 1 h, isopropyl iodide (0.25 ml) was added to the mixture which was stirred 16 hours . The mixture was partitioned between water and ethyl acetate .
  • Example 31 3- (2-Methyl-3-oxo-2, 3-dihydropyridazin-6-yl ) -2- (3- chlorophenyl) pyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 239-241°C (AcOEt)
  • Example 33 3- [2- (4-Tetrahydropyranyl) -3-oxo-2, 3-dihydropyridazin-6- yl] -2- (3-chlorophenyl ) pyrazolo [ 1 , 5-a] pyrazine was obtained in a similar manner to that of Example 3. mp: 153-155°C (EtOH)
  • Example 36 3- (3-Oxo-2 , 3-dihydropyridazin-6-yl) -2- (2-fluorophenyl ) pyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Example 1. mp: >250°C (CHC1 3 , MeOH)
  • 6-yl) -2- (3-fluorophenyl) pyrazolo [1, 5-a] pyrazine 400 mg
  • N, N-dimethylformamide 5 ml
  • 60%-sodium hydroxide 78 mg
  • isopropyl iodide (0.26 ml) was added to the mixture which was stirred 16 hours .
  • the mixture was partitioned between water and ethyl acetate .
  • N,N-dimethylformamide 200 ml was added 60%-sodium hydroxide (2.93 g) at ambient temperature. After stirring for 1 h, isopropyl iodide ( 9.7 ml ) was added to the mixture which was stirred 16 hours .
  • Example 62 3- [2- (3, 3, 3-Trifluoropropyl) -3-oxo-2, 3-dihydropyridazin- 6-yl] -2-phenylpyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Example 61.
  • Example 74 3- (2-Isopropyl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- (3-fluoro- 4-hydroxyphenyl) pyrazolo [1, 5-a] pyrazine can be obtained in a similar manner to that of Example 22.

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Abstract

L'invention concerne un composé de pyrazolopyrazine représenté par la formule (I), dans laquelle R1 est aryle pouvant avoir un ou plusieurs substituants appropriés; et R2 est hydrogène; alkyle inférieur; alcényle inférieur; cycloalkyle inférieur; un groupe hétéromonocyclique; alkyle inférieur substitué par un ou plusieurs substituants pouvant être cycloalkyle inférieur, halogène, cyano, aryle et un groupe hétéromonocyclique, ou un sel correspondant. Le composé de pyrazolopyrazine de formule (I), ou un sel correspondant, est un antagoniste vis-à-vis de l'adénosine, utile pour la prévention et/ou le traitement de la dépression, de la démence (par exemple, maladie d'Alzheimer, démence par accident vasculaire cérébral, démence accompagnant la maladie de Parkinson, etc.), de la maladie de Parkinson, de l'anxiété, de la douleur, des accidents vasculaires cérébraux (par exemple, attaques, etc.), de l'insuffisance cardiaque et autres affections.
EP00974973A 1999-12-02 2000-11-13 Pyrazolopyrazines et leur utilisation comme antagonistes vis-a-vis de l'adenosine Withdrawn EP1244669A1 (fr)

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AUPQ441499 1999-12-02
AUPQ4414A AUPQ441499A0 (en) 1999-12-02 1999-12-02 Novel compound
PCT/JP2000/008008 WO2001040230A1 (fr) 1999-12-02 2000-11-13 Pyrazolopyrazines et leur utilisation comme antagonistes vis-a-vis de l'adenosine

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US20020115635A1 (en) * 2001-02-21 2002-08-22 Pnina Fishman Modulation of GSK-3beta activity and its different uses
AUPR548601A0 (en) 2001-06-06 2001-06-28 Fujisawa Pharmaceutical Co., Ltd. Pyrazolopyrazinecompound and pharmaceutical use thereof
AUPR606401A0 (en) * 2001-07-02 2001-07-26 Fujisawa Pharmaceutical Co., Ltd. Pyrazolopyridine compound and pharmaceutical use thereof
JP2005510508A (ja) * 2001-11-08 2005-04-21 藤沢薬品工業株式会社 アデノシンアンタゴニストとしてのチアゾールピリダジノン類
EP2942082B1 (fr) 2002-01-28 2019-03-06 Kyowa Hakko Kogyo Co., Ltd Antagonistes des récepteurs a2a pour utilisation dans le traitement des troubles du mouvement
GB0419192D0 (en) 2004-08-27 2004-09-29 Merck Sharp & Dohme Therapeutic agents
WO2006038734A1 (fr) * 2004-10-08 2006-04-13 Astellas Pharma Inc. Dérivés de la pyridazinone inhibiteurs de cytokines
CA2620740A1 (fr) * 2005-09-01 2007-03-08 Astellas Pharma Inc. Nouveaux composes
CA2623813A1 (fr) 2005-10-03 2007-04-12 Ono Pharmaceutical Co., Ltd. Compose heterocyclique azote et application pharmaceutique de celui-ci
ES2273599B1 (es) 2005-10-14 2008-06-01 Universidad De Barcelona Compuestos para el tratamiento de la fibrilacion auricular.
ES2544869B2 (es) * 2014-03-04 2016-01-18 Universidade De Vigo Derivados de piridazin-3(2H)-ona inhibidores selectivos de la isoforma B de la monoaminooxidasa
CA3132580A1 (fr) * 2019-03-20 2020-09-24 Goldfinch Bio, Inc. Pyridazinones et leurs procedes d'utilisation
JP2022533570A (ja) 2019-05-13 2022-07-25 リレー セラピューティクス， インコーポレイテッド Ｆｇｆｒ阻害剤およびそれらの使用
CA3159791A1 (fr) * 2019-10-31 2021-05-06 Holosmedic Derives d'hexahydro-2h-pyrazino[1,2-a]pyrazine-6,9-dione et compositionspharmaceutiques comprenant les derives pour la prevention ou le traitement du cancer

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GB8901423D0 (en) * 1989-01-23 1989-03-15 Fujisawa Pharmaceutical Co Pyrazolopyridine compound and processes for preparation thereof
GB9015764D0 (en) * 1990-07-18 1990-09-05 Fujisawa Pharmaceutical Co Pyrazolopyridine compound and processes for preparation thereof
HUT76280A (en) * 1993-12-29 1997-07-28 Fujisawa Pharmaceutical Co Pyrazolopyridine derivatives, pharmaceutical compositions containing them, process for proiducing them and their use

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