WO2001040230A1 - Pyrazolopyrazines and their use as adenosine antagonists - Google Patents

Pyrazolopyrazines and their use as adenosine antagonists Download PDF

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Publication number
WO2001040230A1
WO2001040230A1 PCT/JP2000/008008 JP0008008W WO0140230A1 WO 2001040230 A1 WO2001040230 A1 WO 2001040230A1 JP 0008008 W JP0008008 W JP 0008008W WO 0140230 A1 WO0140230 A1 WO 0140230A1
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Prior art keywords
compound
alkyl
salt
cyclo
pyrazine
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PCT/JP2000/008008
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French (fr)
Inventor
Atsushi Akahane
Satoru Kuroda
Hiromichi Itani
Seiichiro Tabuchi
Yoshiniro Sato
Nobuya Matsuoka
Miho Tada
Hideaki Matsuoka
Takuma Oku
Akira Tanaka
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Fujisawa Pharmaceutical Co., Ltd.
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Priority to EP00974973A priority Critical patent/EP1244669A1/en
Priority to JP2001540985A priority patent/JP2003515537A/en
Priority to AU13093/01A priority patent/AU1309301A/en
Publication of WO2001040230A1 publication Critical patent/WO2001040230A1/en

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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
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    • 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
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    • A—HUMAN NECESSITIES
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    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • 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.

Abstract

A pyrazolopyrazine compound of formula (I): wherein R1 is aryl which may have one or more suitable substituent(s); and R2 is hydrogen; lower alkyl; lower alkenyl; cyclo(lower)alkyl; heteromonocyclic group; 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 pyrazolopyrazine compound (I) and salt thereof of the present invention are adenosine antagonists and are useful for the prevention and/or treatment of depression, dementia (e.g. Alhzheimer's disease, cerebrovascular dementia, dementia accompanying Parkinson's disease, etc.), Parkinson's disease, anxiety, pain, cerebrovascular disease (e.g. stroke, etc.), heart failure and the like.

Description

ESCRIPTI ON
PYRAZOLOPYRAZINES AND THEIR USE AS ADENOSINE ANTAGONISTS
TECHNICAL FIELD The present invention relates to a novel compound and a salt thereof, which are useful as medicaments. BACKGROUND ART
Some 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.). However, pyrazolopyrazine compounds are novel, so there has been no knowledge about these compounds.
DISCLOSURE OF INVENTION 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 A2 (particularly A2a) 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. cerebral vasodilating action, etc.), the action of increasing the renal blood flow, renal protective action, improvement action of renal function, enhancing action of lipolysis, inhibition action of anaphylactic bronchoconstriction, acceleration action of the insulin release, the action of increasing the production of erythropoietin, inhibiting action of platelet aggregation, or the like.
They are 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 thrombophlebitis, drug for cerebral infarction, drug for transient ischemic attack, drug for angina pectoris, or the like; and useful for the prevention and/or treatment of depression, dementia (e.g. Alzheimer's disease, cerebrovascular dementia, dementia accompanying Parkinson's disease, etc.), Parkinson's disease, anxiety, pain, cerebrovascular disease (e.g. stroke, etc. ) , heart failure; hypertension (e.g. essential hypertension, nephrogenous hypertension, etc.); circulatory insufficiency (acute circulatory insufficiency) cuased by, for example, ischemia/reperfusion injury (e.g. myocardial ischemia/reperfusion injury, cerebral ischemia/reperfusion injury, peripheral ischemia/reperfusion injury, etc.), shock (e.g. endotoxin shock, hemorrhagic shock, etc.), surgical procedure, or the like; post-resuscitation asystole; bradyarrhythmia ; electro-mechanical dissociation; hemodynamic collapse;
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. cyclosporin A) or the like; glycerol, etc.], nephrosis, nephritis, edema (e.g. 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. mechanical ileus, adynamic ileus, etc.); and myocardial infarction, thrombosis (e.g. arterial thrombosis, cerebral thrombosis, etc.), obstruction, arteriosclerosis obliterans, thrombophlebitis, cerebral infarction, transient ischemic attack, angina pectoris, or the like.
The novel pyrazolopyrazine compound of the present invention can be shown by the following formula (I) .
Figure imgf000004_0001
wherein R is aryl which may have one or more suitable substituent (s) , and
2
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
hydrolysis
Figure imgf000005_0001
Figure imgf000005_0002
(ID la' or a salt thereof or a salt thereof Process 2
Figure imgf000005_0003
ereof
Figure imgf000005_0004
(la) (lb) or a salt thereof or a salt thereof Process 3
elimination
Figure imgf000006_0002
reaction of
Figure imgf000006_0001
: ic ) lower alkyl group (Id) or a salt thereof or a salt thereof
Process 4
Figure imgf000006_0003
(Ie) or a salt thereof (If) or a salt thereof or a salt thereof
wherein R1 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,
R4 and R5 are each lower alkyl, and
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. Process A
H
Figure imgf000007_0001
(IV) or a salt thereof
Figure imgf000007_0002
Step 1 (VI)
(V) or its reactive de :rivative or a salt thereof or a salt . thereof
Figure imgf000007_0003
(VII) :vιιι;
Figure imgf000007_0004
(II) or a salt thiereof wherein R1 and R3 is as defined above,
7b is an anion,
Tf20 is trifluoromethanesulfonic anhydride.
In addition to the processes as mentioned above, 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.
It is to be noted that 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) . In this regard, one isomer can be converted to another according to a conventional method in this field of the art.
It is also to be noted that the solvating form of the compound (I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I) are included within the scope of the present invention.
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. acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), 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.), and the like.
Suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof and which appear in the above and following description in the present specification are explained in detail as follows.
The term "lower" is intended to mean 1 to 6 carbon atom(s) unless otherwise indicated.
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, tπchloromethyl, tπbromomethyl, trnodomethyl, trifluoroethyl, trichloroethyl, tribromoethyl, triiodoethyl, trifluoropropyl, trichloropropyl, tribromopropyl, trnodopropyl, in which the preferred one may be fluoroethyl, fluoropropyl, trifluoroethyl or trifluoropropyl .
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 "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.
Suitable "anion" may be formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, chloride, bromide, iodide, sulfate, phosphate, or the like.
The processes for preparing the object compound (I) are explained in detail in the following. Process 1
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.
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.).
The elimination using 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.).
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 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. Process 2
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. Among the solvents, hydrophilic solvents may be used in a mixture with water. When the compound (III) 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, 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 . When X is -OH, activation of OH with triphenylphosphine and the like may be necessary. Process 3
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, tπethylamine, etc.), hydrazine, picolme, 1, 5-dιazabιcyclo [4.3.0] non-5-ene, 1, 4-dιazabιcyclo [2.2.2] octane,
1, 8-dιazabιcyclo [5.4.0] undec-7-ene, or the like.
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.).
The elimination using Lewis acid (e.g. aluminium chloride, titanium trichloride, tin tetrachloπde, etc.) or the like is preferably carried out in the presence of 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.
The 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.).
The reaction temperature is not critical and the reaction is usually carried out at ambient temperature, under warming or under heating. Process 4
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) .
The reaction of this process can be carried out in the manner similar to that of Process 2. Process A Step 1 and 2
The reaction of this steps can be carried out by the methods disclosed in Preparation 1 and Preparation 2 mentioned later or the similar manners thereto. 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.
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. In order to show the usefulness of the compound (I) of the present invention, the pharmacological test result of the representative compound of the present invention is shown in the following .
Test 1 : Adenosine antagonistic activity
[I] Test method
The adenosine antagonistic activity [Ki(nM)] of the test compound was examined by radioligand binding techniques using 8-cyclopentyl-l, 3-dipropylxanthine, [dipropyl-2, 3-3H (N) ] ([3H]DPCPX, 4.5n ) for human A*, receptor and [3H] CGS 21680 (20nM) for human A2a receptor.
[II] Test compound
3- [2- ( Pyridin-3-ylmethyl) -3-oxo-2, 3-dihydropyridazin-6-yl] -2- phenylpyrazolo [ 1 , 5-a] pyrazine (Example 3) 3- (2-Ethyl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- phenylpyrazolo [1, 5-a] pyrazine (Example 5)
3- (2-Cyclopentyl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- phenylpyrazolo [ 1 , 5-a] pyrazine (Example 8)
3- (2-Furfuryl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- phenylpyrazolo [ 1, 5-a] pyrazine (Example 12)
3- [2- (2-Thenyl) -3-oxo-2, 3-dihydropyridazin-6-yl] -2- phenylpyrazolo [1, 5-a] pyrazine (Example 14)
3- [2- ( 4-Tetrahydropyranyl ) -3-oxo-2, 3-dihydropyridazin-6-yl] -
2-phenylpyrazolo [ 1, 5-a] pyrazine (Example 15) [III] Test result
Table 1
Adenosine receptor binding Test compound (Example No.) (Kι:nM)
A-, A 2a
3 0.10 2. ,79 5 0.16 1. .91 0.10 0. 84
12 0.07 1. .42 14 0.06 2. .35 15 0.10 3. .17
Test 2 : Anti catalepsy activity in Mouse
[I] Test method
The test compound (3.2mg/kg) was administered orally with ddY mιce(n=7). Then, halopeπdol (0.32mg/kg) was injected mtraperitoneally 30 mm. after the administration of the compound. Thirty mm. after the injection, the cataleptic responses of mice were measured. The forelimbs of each mouse were placed on a 3 cm high, 3 mm wide horizontal bar, and the duration of cataleptic posture was measured for up to 30 sec.
[II] Test compound 3- (2-Ethyl-3-oxo-2, 3-dιhydropyπdazm-6-yl) -2- phenylpyrazolo [ 1, 5-a] pyrazine (Example 5) 3- (2-Cyclopentyl-3-oxo-2, 3-dιhydropyπdazm-6-yl ) -2- phenylpyrazolo [ 1, 5-a] pyrazine (Example 8) 3- (2-Furf uryl-3-oxo-2 , 3-dιhydropyπdazm-6-yl) -2- phenylpyrazolo [1, 5-a] pyrazine (Example 12)
3- [2- (2-Thenyl) -3-oxo-2, 3-dιhydropyπdazιn-6-yl] -2- phenylpyrazolo [ 1, 5-a] pyrazine (Example 14) [ I I I ] Test result
Table 2
Test compound Manifestation rate of catalepsy (Example No. ) (number of mouse) 1/7 0/7
12 0/7 14 2/7
The pyrazolopyrazine compound (I) and a salt thereof of this invention are useful as adenosine antagonists (especially, AL receptor and A2 (particularly A2a) 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, hyperuπcemia, sudden infant death syndrome, lmmunosuppression, diabetes, ulcer, pancreatitis, Meniere's syndrome, anemia, dialysis-induced hypotension, constipation, ischemic bowel disease, ileus, myocardial infarction, thrombosis, obstruction, arteriosclerosis obliterans, thrombophlebitis, cerebral infarction, transient ischemic attack, angina pectoris, and the like.
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. 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. In addition, 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.
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.
The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail. Preparation 1
A mixture of 6-benzenesulfonyl-2H-pyridazin-3-one (150 g) , triethylamine (115 ml) in dichloromethane (1.21) was stirred at -8°C. Trifluoromethanesulfonic anhydride (117 ml) was added dropwise to the above solution over 1 hour, and the whole was stirred under same conditions for 1 hour. The reaction mixture was stirred at room temperature for 2 hours. IN-Hydrochloric acid was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with IN-hydrochloric acid twice, saturated aqueous sodium hydrogen-carbonate and brine, and dried over magnesium sulfate. The solvent was removed in vacuo to afford a powder, which was triturated with diisopropyl ether. Trifluoromethanesulfonic acid 6-benzene-sulfonylpyridazin-3-yl ester (200 g) was obtained by filtration.
NMR (CDC13, 6) : 7.5-7.8 ( 4H, m) , 8.1-8.2 (2H, m) , 8.52 (lH,d, J=9.0Hz) APCI/MS: 369[M+H]+ . Preparation 2 A mixture of trifluoromethanesulfonic acid 6-benzenesulfonylpyridin-3-yl ester (400 g) , dichlorobis (triphenylphosphine) palladium (7.8 g) , cuprous iodide (2.12 g) , phenylacetylene (158 ml) and triethylamine (310 ml) in N,N- dimethylformamide (3.0 1) was stirred at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (20 1) to afford a brown powder, which was triturated with diisopropyl ether (1000 ml) and ethanol (400 ml) . A crude was obtained by filtration. The crude was subjected to column chromatography on silica gel eluting with chloroform to afford 3-benzenesulfonyl-6-phenylethynyl- pyridazine ( 160 g) as a pale yellow powder.
NMR (CDC13, 5) : 7.3-7. 5 ( 3H, m) , 7.5-7.75 ( 5H, m) , 7.75-7.85 (2H,m) , 8.25 (lH,d, J=8.8Hz) , 7.81 ( IH, d, J=8.7Hz) APCI/MS: 321[M+H]+ . Preparation 3
To a stirred mixture of 1-aminopyrazinium iodide (25.6 g) and 3-benzenesulfonyl-6-phenylethynylpyridazine (9 g) in N,N- dimethylformamide ( 150 ml) was added powder potassium carbonate (23 g) at ambient temperature. After stirring for 3 hours, the mixture was poured into water. The resultant precipitate was collected by filteration to give 3- ( 6-benzenesulfonyl- pyridazin-3-yl) -2-phenylpyrazolo [ 1 , 5-a] pyrazine (11.4 g) mp: 208-210°C (CHC13-IPE)
NMR (DMSO-d6, δ) : 7.51-7.83 ( 9H, m) , 8.03-8.19 ( 3H, m) , 8.33-
8.38(lH,m), 8.99 ( IH, dd, J=l .3, 4.6Hz), 8.99 ( IH, d, J=l .3Hz)
IR (nujol) : 1562, 1506 cm"1
APCI/MS: 414[M+H]+ Anal. Calcd for C22H15N502S • 0.26H20:
C, 63.20; H,3.74; N,16.75
Found: C, 63.19; H,3.55; N,16.69.
Preparation 4
3-Benzenesulfonyl-6- (2-methoxyphenylethynyl) pyridazine was obtained in a similar manner to that of Preparation 2.
NMR (CDC13, δ): 3.90(3H, s), 6.85-7.0(2H, m) , 7.3-7.75(5H, m) ,
7.82(1H, d, J=8.7Hz), 8.05-8.2(2H, m) , 8.22(1H, d, J=8.7Hz)
APCI/MS: 351 [M+H]+ .
Preparation 5 3- ( 6-Benzenesulfonylpyridazin-3-yl) -2- (2-methoxyphenyl ) pyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Preparation 3. mp: >250°C (CHC13, MeOH)
NMR (DMSO-d6, δ): 3.33(3H, s), 7.05-7.2(2H, m) , 7.45-7.85 ( 6H, m) , 8.0-8.M2H, m) , 8.16(1H, d, J=4.7Hz), 8.41(1H, d, J=8.9Hz),
8.97(1H, dd, J=1.3Hz and 4.7Hz), 9.69(1H, d, J=1.3Hz)
IR (KBr, cm"1) : 1652, 1608 APCI/MS: 444 [M+H]+ .
Prepara ion 6
3-Benzenesulfonyl-6- (3-methoxyphenylethynyl) pyridazine was obtained in a similar manner to that of Preparation 2. NMR (CDC13, δ): 3.83(3H, s), 6.9-7.85(9H, m) , 8.1-8.35(2H, m)
APCI/MS: 351 [M+H]+ .
Preparation 7
3- (6-Benzenesulfonylpyridazin-3-yl ) -2- (3-methoxyphenyl) pyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Preparation 3. mp: 231-233°C
NMR (DMSO-d6, δ): 3.72(3H, s), 7.0-8.15 ( 10H, m) , 8.18(1H, d,
J=4.7Hz), 8.37(1H, d, J=9.0Hz), 8.99(1H, dd, J=l .3Hz and 4.7Hz) ,
9.61(1H, d, J=1.2Hz) IR (KBr, cm"1) : 1650, 1592
APCI/MS: 444 [M+H]+ .
Preparation 8
3-Benzenesulfonyl-6- (3-methoxyphenylethynyl ) pyridazine was obtained in a similar manner to that of Preparation 2. NMR (CDC13, δ): 3.83(3H, s), 6.9-7.85(9H, m) , 8.1-8.35(2H, m)
APCI/MS: 351 [M+H]+ .
Preparation 9
3- ( 6-Benzenesulfonylpyridazin-3-yl ) -2- (4-methoxyphenyl ) pyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Preparation 3. mp: 230-232°C (CHC13, MeOH)
NMR (DMSO-d6, δ): 3.72(3H, s), 7.0-8.4(12H, m) , 8.95-9.05 ( IH, m) , 9.60-9.65(1H, m)
IR (KBr, cm"1) : 1650, 1592 APCI/MS: 444 [M+H]+ .
Preparation 10
3-Benzenesulfonyl-6-(4-tolylethynyl) pyridazine was obtained in a similar manner to that of Preparation 2. mp: 208-211°C (CHC13)
NMR (CDC13, δ): 2.37(3H, s), 7.32(2H, d, J=8.0Hz) , 7.60(2H, d,
J=8.0Hz), 7.65-7.85 (3H, m) , 8.08(1H, dd, J=l .6Hz and 7.0Hz), 8.25(1H, d, J=8.8Hz), 8.49(1H, d, J=8.8Hz)
IR (KBr, cm"1) : 2217
APCI/MS: 335 [M+H]+ .
Preparation 11
3-Benzenesulfonyl-6- (2-chlorophenylethynyl) pyridazine was obtained in a similar manner to that of Preparation 2.
NMR (CDC13, δ): 7.5-7.65(2H, m) , 7.65-7.9(5H, m) , 8.0-8.15 (2H, m) , 8.29(1H, d, J=8.8Hz), 8.52 (IH, d, J=8.8Hz)
IR (KBr, cm"1) : 2217
APCI/MS: 355 [M+H]+ . Preparation 12
3-Benzenesulfonyl-6- (3-chlorophenylethynyl) pyridazine was obtained in a similar manner to that of Preparation 2. mp: 149-151°C (CHC13)
NMR (CDC13, δ): 7.25-7.75 (7H, m) , 7.82(1H, d, J=8.7Hz), 8.1- 8.2(2H, m) , 8.27(1H, d, J=8.7Hz)
IR (KBr, cm"1) : 2225, 1589
APCI/MS: 355 [M+H]+ .
Preparation 1
3- ( 6-Benzenesulfonylpyridazin-3-yl) -2- (3-chlorophenyl) pyrazolo [ 1 , 5-a] pyrazine was obtained in a similar manner to that of Preparation 3. mp: 239-241°C (CHC13, MeOH)
NMR (DMS0-d6, δ): 7.0-9.8(14H, m)
IR (KBr, cm"1) : 1594, 1565 APCI/MS: 448 [M+H]+ .
Preparation 14
3-Benzenesulfonyl-6- (2-chlorophenylethynyl) pyridazine was obtained in a similar manner to that of Preparation 2. mp: 177-179°C (CHC13)
NMR (CDC13, δ ) : 7.2-7.75 (7H, m) , 7.86(1H, d, J=8.8Hz) , 8.1-8.2 (2H, m) , 8.27(1H, d, J=8.8Hz) IR (KBr, cm"1) : 2223
APCI/MS: 355 [M+H]+ .
Preparation 15
3-Benzenesulfonyl-6- (2-fluorophenylethynyl) pyridazine was obtained in a similar manner to that of Preparation 2. mp: 192-194°C (CHC13)
NMR (CDC13, δ): 7.3-7.5(2H, m) , 7.55-7.9(5H, m) , 8.05-8.15 (2H, m) , 8.30(1H, d, J=8.8Hz), 8.53(1H, d, J=8.8Hz)
IR (KBr, cm"1) : 2225
APCI/MS: 339 [M+H]+ . Preparation 16
3- ( 6-Benzenesulfonylpyridazin-3-yl ) -2- (2-fluorophenyl) pyrazolo [ 1 , 5-a] pyrazine was obtained in a similar manner to that of Preparation 3. mp: 228-230°C (CHC13, MeOH) NMR (DMSO-d6, δ ) : 7.25-7.5 (2H, m) , 7.55-7.9 ( 6H, m) , 8.05-8.15 (2H, m) , 8.21(1H, d, J=4.7Hz), 8.40(1H, d, J=9.0Hz), 9.02(1H, dd,
J=1.4Hz and 4 . 1Hz ) , 9.68(1H, d, J=1.4Hz )
IR (KBr, cm"1) : 1616, 1565
APCI/MS: 432 [M+H]+ . Preparation 17
3-Benzenesulfonyl-6- ( 3-fluorophenylethynyl) pyridazine was obtained in a similar manner to that of Preparation 2. mp: 150-152°C (CHC13)
NMR (CDC13, δ ) : 7.0-7.75 (7H, m) , 7.83(1H, d, J=8.7Hz) , 8.0-8.2 (2H, m) , 8.27(1H, d, J=8.7Hz)
IR (KBr, cm"1) : 2219 APCI/MS: 339 [M+H]+ .
Preparation 18
3- (6-Benzenesulfonylpyridazin-3-yl) -2- (3-fluorophenyl ) pyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Preparation 3. mp: 226-228°C (CHC13)
NMR (DMS0-d6, δ ) : 7.2-8.8 (12H, m) , 8.99(1H, dd, J=l.lHz and 4.7Hz) ,
9.61(1H, d, J=l.lHz)
IR (KBr, cm"1) : 1565 ESI/MS: 434 [M+Na]+ .
Preparation 19
3-Benzenesulfonyl-6- ( 4-fluorophenylethynyl) pyridazine was obtained in a similar manner to that of Preparation 2. mp: 189-191°C (CHC13) NMR (CDC13, δ): 7.0-7.2(2H, m) , 7.5-7.75(5H, m) , 7.80(1H, d,
J=8.7Hz), 8.1-8.2(2H, m) , 8.25(1H, d, J=8.7Hz)
IR (KBr, cm"1) : 2221
APCI/MS: 339 [M+H]+ .
Preparation 20 3- ( 6-Benzenesulfonylpyridazin-3-yl) -2- (4-fluorophenyl) pyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Preparation 3. mp: 218-220°C (CHC13, MeOH)
NMR (DMSO-d6, δ ) : 7.3-7.45(lH, m) , 7.6-7.9(7H, m) , 8.0-8.2(3H, m) , 8.3-8.4(lH, m) , 8.98(1H, dd, J=1.4Hz and 4.7Hz), 9.60-(lH, d, J=1.4Hz)
IR (KBr, cm"1) : 1677, 1606
APCI/MS: 432 [M+H]+ .
Preparation 21 3-Benzenesulfonyl-6- ( 4-pentyl-phenylethynyl) pyridazine was obtained in a similar manner to that of Preparation 2. mp: 164-166°C (CHC13) NMR (CDC13, δ ) : 0.8-1.0(3H, m) , 1.25-1.45 (4H, m) , 1.5-1.75(2H, m) , 2.55-2.75(2H, m) , 7.1-7.3(2H, m) , 7.45-7.75 (5H, m) , 7.78(1H, d, J=8.7Hz), 8.1-8.2(2H, m) , 8.23(1H, d, J=8.7Hz)
IR (KBr, cm"1) : 2217 APCI/MS: 391 [M+H]+ .
Preparation 22
3-Benzenesulfonyl-6- (3, -difluorophenylethynyl ) pyridazine was obtained in a similar manner to that of Preparation
2. mp: 170-172°C (CHC13)
NMR (CDC13, δ): 7.5-8.0(6H, m) , 8.0-8.2(2H, m) , 8.29(1H, d,
J=8.8Hz), 8.55(1H, d, J=8.8Hz)
IR (KBr, cm"1) : 2221
APCI/MS: 357 [M+H]+ . Preparation 23
3- ( 6-Benzenesulfonylpyridazin-3-yl) -2- (3, 4- difluorophenyl ) pyrazolo [ 1 , 5-a] pyrazine was obtained in a similar manner to that of Preparation 3. mp: 230-232°C (CHC13, MeOH) NMR (DMSO-d6, δ ) : 7.4-8.4 (11H, m) , 8.99(1H, dd, J=1.4Hz and 4.7Hz) ,
9.61(1H, d, J=1.4Hz)
IR (KBr, cm"1) : 1606, 1565
APCI/MS: 450 [M+H]+ .
Preparation 24 3-Benzenesulfonyl-6- (2, 4-difluorophenylethynyl ) pyridazine was obtained in a similar manner to that of Preparation
2. mp: 192-195°C (CHC13)
NMR (CDC13, δ): 7.2-7.35(lH, m) , 7.45-7.6(lH, m) , 7.65-7.95 ( 4H, m) , 8.0-8.2(2H, m) , 8.29(1H, d, J=8.8Hz), 8.53(1H, d, J=8.8Hz)
IR (KBr, cm"1) : 2223
APCI/MS: 357 [M+H]+ . Preparation 25
3- ( 6-Benzenesulfonylpyridazin-3-yl ) -2- (2, 4- difluorophenyl ) pyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Preparation 3. mp: 202-204°C (CHC13, MeOH)
NMR (DMSO-d6, δ ) ; 7.2-7.55 (2H, m) , 7.65-7.9(4H, m) , 8.0-8.15 (2H, m) , 8.2K1H, d, J=4.7Hz). 8.3-8.5(lH, m) , 9.02(1H, dd, J=1.4Hz and 4.7Hz), 9.67(1H, d, J=1.4Hz)
IR (KBr, cm"1) : 1617, 1596 APCI/MS: 450 [M+H]+ .
Preparation 26
To a mixture of 3- (2-cyanomethyl-3-oxo-2, 3- dihydropyridazin-6-yl) -2-phenylpyrazolo [ 1 , 5-a] pyrazine ( 4g) and triethylamine (20ml) in pyridine (40ml) was introduced hydrogen sulfide at 60°C for 35 minutes. The mixture was poured into water. The resulting solid was collected by filtration and washed with acetone to give 3- (2-thiocarbamoylmethyl-3-oxo-
2, 3-dihydropyridazin-6-yl) -2-phenylpyrazolo [ 1, 5-a] pyrazine
(3.3g) . mp: 236-237°C (acetone)
NMR (DMSO,δ) : 5.08(2H,S), 6.95 ( IH, d, J=9.7Hz) ,
7.13 (lH,d, J=9.7Hz) , 7.50-7.5 ( 3H, m) , 7.67-7.73 (2H, m) ,
8.08 (lH,d, J=4.7Hz) , 8.90 ( IH, d, J=l .3, 4.7Hz ) , 9.45 ( IH, d, J=l .3Hz) ,
9.47(1H,S), 9.92(1H,S) IR(nujol): 3241, 3100, 1670, 1592, 1531, 1500 cm"1
ESI/MS: 385[M+Na]+
Anal. Calcd for C18H12N60 :
C,59.66; H,3.89; N,23.19.
Found: C, 59.74; H,3.84; N,22.85. Preparation 27
3- [2- ( l-tert-Butoxycarbonylpiperidin-4-yl) -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: 165-166°C (AcOEt-hexane)
NMR(DMSO, 5): 1. 0 ( 9H, S) , 1.62-1.87 ( 4H, m) , 2.80-3.10 (2H,m) ,
3.90-4.15(2H,m) , 3.90-4.15 (2H,m) , 4.97-5.10 ( lH,m) , 6.96(lH,d, J=9.6Hz) , 7.28 ( IH, d, J=9.6Hz) , 7.48-7.64 (5H,m) ,
8.09(lH,d, J=4.7Hz) , 8.92 ( IH, dd, J=l .3, 4.7Hz) ,
9.30(lH,d, J=1.3Hz)
IR(nujol): 1704, 1687, 1662, 1589, 1517 cm"1
APCI/MS: 473[M+H]+ Anal. Calcd for C26H28N603 • 0.3H20:
C65.34; H,6.03; N,17.58.
Found: C, 65.35; H,5.93; N,17.63.
Preparation 28
3-Benzenesulfonyl-6- (5-fluolo-2-methoxyphenylethynyl) pyridazine can be obtained in a similar manner to that of
Preparation 2.
Preparation 29
3- ( 6-Benzenesulfonylpyridazin-3-yl ) -2- (5-fluoro-2- methoxyphenyl) pyrazolo [1, 5-a] pyrazine can be obtained in a similar manner to that of Preparation 3.
Preparation 30
3-Benzenesulfonyl-6- (3-fluolo-5-methoxyphenylethynyl) pyridazine can be obtained in a similar manner to that of
Preparation 2. Preparation 31
3- ( 6-Benzenesulfonylpyridazin-3-yl ) -2- (3-fluoro-5- methoxyphenyl ) pyrazolo [1, 5-a] pyrazine can be obtained in a similar manner to that of Preparation 3.
Preparation 32 3-Benzenesulfonyl-6- (3-fluolo-4-methoxyphenylethynyl) pyridazine can be obtained in a similar manner to that of
Preparation 2. Preparation 33
3- ( 6-Benzenesulfonylpyridazin-3-yl) -2-(3-fluoro-4- methoxyphenyl) pyrazolo [ 1, 5-a] pyrazine can be obtained in a similar manner to that of Preparation 3. Example 1
A mixture of 3- ( 6-benzenesulfonylpyridazin-3-yl) -2- phenylpyrazolo [ 1, 5-a] pyrazine (0.61 g) , sodium hydroxide (0.25 g) , water (2.5 ml ) and dioxane ( 6 ml ) was refluxed for 0.5 hours . After evaporating the solvent, the residue was dissolved in water and then the solution was acidified with IN-hydrochloric acid. The mixture was partitioned between an aqueous sodium bicarbonate and chloroform. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of chloroform and diisopropyl ether to give 3-(3-oxo- 2, 3-dihydropyridazin-6-yl ) -2-phenylpyrazolo [1, 5-a] pyrazine (0.41 g) as a solid, mp: >250°C
NMR (DMS0-d6,δ): 6.88 ( IH, d, J=9.9Hz) , 7.20 ( IH, d, J=9.9Hz) , 7.48-7.64 (5H,m) , 8.07 ( IH, d, J=4.8Hz) , 8.91 ( IH, d, J=4.8Hz) , 9.29(lH,s), 13.28(lH,s)
IR ( nuj ol ) : 1673 , 1658 , 1592 , 1550 , 1527 cm"1
APCI /MS : 290 [M+H ] +
Anal . Calcd f or C16H N50 - 0 . 36H20 :
C , 64 . 97 ; H , 3 . 99 ; N , 23 . 88 Found: C, 64.86; H,3.69; N,23.63. Example 2
To a stirred solution of 3- (3-oxo-2, 3-dihydropyridazin- 6-yl) -2-phenylpyrazolo [1, 5-a] pyrazine (0.19 g) in N,N- dimethylformamide (12 ml) was added 60%-sodium hydride (40 mg) at ambient temperature. After stirring for 15 minutes, isopropyl iodide (0.097 ml) was added to the mixture which was stirred for 16 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 3- (2-isopropyl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- phenylpyrazolo [ 1 , 5-a] pyrazine (0.135 g) as a solid. mp: 173-175°C
NMR (DMS0-d6,δ): 1.31 ( 6H, d, J=6.6Hz ) , 5.14-5.28 (IH, m) , 6.29(lH,d, J=9.6Hz) , 7.25 ( IH, d, J=9.6Hz) , 7.48-7.63 (5H, m) , 8.09(lH,d, J=4.7Hz) , 8.92 ( IH, dd, J=l .2, 4.7Hz), 9.33 (lH,d, J=1.2Hz) IR (nujol) : 1662, 1589, 1523 cm"1 APCI/MS: 332[M+H]+
Anal. Calcd for C19H17N50: C, 68.87; H,5.17; N,21.13 Found: C, 68.69; H,5.11; N,21.08. Example 3 To a stirred mixture of 3- ( 3-oxo-2, 3-dihydropyridazin-6- yl) -2-phenylpyrazolo [1, 5-a] pyrazine (0.19 g) , 3- pyridinemethanol (0.11 ml) and triphenylphosphine ( 0.38 g) in tetrahydrofuran ( 10 ml) was added diethyl azodicarboxylate (0.23 ml) under ice-cooling. After stirring for 16 hours at ambient temperature, the solution was evaporated in vacuo. The residue was chromatographed on silica-gel ( 150 ml) using a mixture of methanol and ethyl acetate ( 1 : 100) . The desired fractions were collected and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 3- [2- (pyridin-3-ylmethyl ) -3-oxo-2, 3-dihydropyridazin-6-yl] -2- phenylpyrazolo [ 1, 5-a] pyrazine (0.145 g) as a solid, mp: 158-159°C
NMR (DMSO-d6,δ): 5.43(2H,s), 6.99 ( IH, d, J=9.7Hz ) , 7.20 (lH,d, J=9.7Hz) , 7.38-7.80 (7H, m) , 8.08 (IH, d, J=4.7Hz) , 8.53-8.65 (2H,m) , 8.90 (IH, dd, J=l .2, 4.7Hz), 9.21 ( IH, d, J=l .2Hz ) IR (nujol) : 1664, 1590, 1531 cm"1 APCI/MS: 381[M+H]+ Anal. Calcd for C:2H16N60- 0.2H:0: C, 68.81; H,4.30; N, 21.88 Found: C,69.03; H,4.28; N,21.59
Example 4
3- (2-Methyl-3-oxo-2, 3-dihydropyridazin-6-yl ) -2- phenylpyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 196-197°C (AcOEt-Hexane)
NMR (DMSO-d6,δ) : 3.78(3H,s), 6.92 ( IH, d, J=9.7Hz) ,
7.14 (lH,d, J=9.7Hz) , 7.49-7.66 (5H,m) , 8.09 ( IH, d, J=4.7Hz) ,
8.91 (lH,d, J=4.7Hz) , 9.43(lH,s) IR (nujol) : 1666, 1592, 1527, 1502 cm"1
APCI/MS: 304[M+H]+
Anal. Calcd for C17H13N50- 0.12H20:
C66.84; H,4.37; N,22.93
Found: C, 66.84; H,4.26; N,22.90. Example 5
3- (2-Ethyl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- phenylpyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 160-163°C (AcOEt-Et20) NMR (DMSO-d6,δ) : 1.33 ( 3H, t , J=7.1Hz ) , 4.20 (2H, q, J=7.1Hz ) ,
6.93(lH,d, J=9.6Hz) , 7.20 (IH, d, J=9.6Hz) , 7.49-7.65 (5H,m) ,
8.09(lH,d, J=4.5Hz) , 8.90-8.93 ( IH, m) , 9.39(lH,s)
IR (nujol) : 1664, 1589, 1519, 1506 cm"1
APCI/MS: 318[M+H]+ Anal. Calcd for C18H15N50- 0.58H20:
C,65.98; H,4.97; N,21.36
Found: C, 66.25; H,4.71; N,20.90.
Exampl 6
3- (2-Propyl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- phenylpyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 110-115°C (Et20-Hexane) NMR (DMSO-d6,δ) : 0.93 (3H, t , J=7.4Hz) , 1.73-1.85 (2H,m) ,
4.13(2H,t, J=7.1Hz) , 6.93 ( IH, d, J=9.6Hz) , 7.19 (IH, d, J=9.6Hz) ,
7.49-7.64 (5H,m) , 8.09 ( IH, d, J=4.7Hz) , 8.92 (IH, d, J=4.7Hz) ,
9.36(lH,s) IR (nujol) : 1666, 1664, 1589, 1519, 1506 cm"1
APCI/MS: 332[M+H]+ .
Example 7
3- (2-Butyl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- phenylpyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 145-147°C (AcOEt-Et20)
NMR (DMSO-d6,δ): 0.92 ( 3H, t, J=7.2Hz ) , 1.29-1.41 (2H,m) , 1.70-
1.79(2H,m), 4.16 (2H, t , J=7.2Hz ) , 6.93 ( IH, d, J=9.6Hz ) ,
7.20 (lH,d, J=9.6Hz) , 7.49-7.64 (5H,m) , 8.09 (IH, d, J=4.4Hz) , 8.90-8.93 (lH,m) , 9.36(lH,s)
IR (nujol): 1662, 1592, 1533, 1500 cm"1
APCI/MS: 346[M+H]+
Anal. Calcd for C20H19N5O- 0.35H20:
C,68.30; H,5.65; N,19.91 Found: C, 68.30; H,5.57; N,19.64.
Example 8
3- (2-Cyclopentyl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- phenylpyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 163-166°C (AcOEt-Et20)
NMR (DMSO-d6,δ) : 1.15-2.15 ( 8H,m) , 5.30-5.50 ( IH, m) ,
6.91 (lH,d, J=9.6Hz) , 7.27 ( IH, d, J=9.6Hz) , 7.48-7.62 (5H,m) ,
8.08 (lH,d, J=4.6Hz) , 8.92 ( IH, d, J=4.6Hz ) , 9.30(lH,s)
IR (nujol) : 1660, 1590, 1525, 1500 cm"1 APCI/MS: 358[M+H]+
Anal. Calcd for C21H19N50- 0.3H20:
C,69.52; H,5.44; N, 19.30 Found: C,69.49; H,5.26; N, 19.26.
Example 9
3- (2-Cyclohexylmethyl-3-oxo-2, 3-dihydropyridazin-6-yl) -
2-phenylpyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 140-145°C (AcOEt-Et20)
NMR (DMS0-d6,δ): 0.90-2.10 ( 11H, m) , 4.00 (2H, d, J=7.3Hz) ,
6.93(lH,d, J=9.6Hz) , 7.21 ( IH, d, J=9.6Hz) , 7.49-7.64 (5H,m) ,
8.09(lH,d, J=4.7Hz) , 8.92 ( IH, d, J=4.7Hz) , 9.34(lH,s) IR (nujol): 1664, 1590, 1529, 1504 cm"1
APCI/MS: 386[M+H]+
Anal. Calcd for C23H23N50- 0.34H,0:
C70.55; H,6.09; N,17.88
Found: C,70.54; H,5.92 N, 17.68. Exampl 10
3- (2-Benzyl-3-oxo-2 , 3-dihydropyridazin-6-yl) -2- phenylpyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 144-151°C (AcOEt-Et20) NMR (DMSO-d6,δ) : 5.39(2H,s), 6.98 ( IH, d, J=9.7Hz) ,
7.18 (lH,d, J=9.7Hz) , 7.20-7.65 ( 10H, m) , 8.05 ( IH, d, J=4.7Hz) ,
8.90 (lH,d, J=4.7Hz) , 9.15(lH,s)
IR (nujol) : 1664, 1592, 1527 cm"1
APCI/MS: 380[M+H]+ . Example 11
3- (2-Cyclohexyl-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: 192-193°C (AcOEt-hexane) NMR (DMSO-d6,δ) : 1.05-1.83 ( 11H, m) , 4.75-4.87 ( IH, m) ,
6.93 (lH,d, J=9.7Hz) , 7.25 ( IH, d, J=9.7Hz) , 7.48-7.64 ( 5H,m) ,
8.09(lH,d, J=4.7Hz) , 8.91 ( IH, dd, J=l .1 , 4.7Hz), 9.32 (lH,d, J=l.lHz) IR (nujol) : 1658, 1587, 1521 cm"1 APCI/MS: 372[M+H]+ Anal. Calcd for C22H21N50- 0.16H20: C,70.59; H,5.71; N, 18.71
Found: C,70.58; H,5.64 N, 18.67. Example 12
3-(2-Furfuryl-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: 197-201°C (AcOEt-hexane)
NMR (DMSO-d6,δ) : 5.40(2H,s), 6.49-6.50 (2H,m) ,
6.95 (lH,d, J=9.7Hz) , 7.12 ( IH, d, J=9.7Hz) , 7.49-7.68 ( 6H,m) ,
8.08 (lH,d, J=4.7Hz) , 8.90 ( IH, dd, J=l .2 , 4.7Hz), 9.23(lH,s) IR (nujol) : 1664, 1592, 1527 cm"1
APCI/MS: 370[M+H]+
Anal. Calcd for C21H15N502- 0.37H20:
C, 67.07; H,4.22; N, 18.62
Found: C, 67.06; H,4.01 N, 18.58. Example 13
3- (2-Furan-3-ylmethyl-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: 157-158°C (AcOEt-hexane) NMR (DMSO-d6,δ): 5.22(2H,s), 6.50(lH,s), 6.96 ( IH, d, J=9.7Hz) ,
7.17 (lH,d, J=9.7Hz) , 7.48-7.75 ( 7H, m) , 8.08 (IH, d, J=4.7Hz) ,
8.90 (lH,d, J=4.7Hz) , 9.27(lH,s)
IR (nujol) : 1660, 1589, 1531 cm"1
APCI/MS: 370[M+H]+ Anal. Calcd for C21H15N502 • 0.25H20:
C,67.46; H,4.18; N, 18.73
Found: C, 67.45; H,4.05 N, 18.57.
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. mp: 188-189°C (AcOEt-hexane) NMR (DMSO-d6,δ): 5.55(2H,s), 6.96 ( IH, d, J=9.7Hz) , 7.01-
7.06(lH,m), 7.14 (lH,d, J=9.7Hz) , 7.20-7.21 (IH, m) , 7.48-
7.64(6H,m), 8.09(lH,d, J=4.7Hz), 8.91 (IH, dd, J=l .2, 4.7Hz) ,
9.34 (lH,d, J=1.2Hz)
IR (nujol) : 1660, 1590, 1529 cm"1 APCI/MS: 386[M+H]+
Anal. Calcd for C21H15N5OS • 0.65H20:
C63.51; H,4.14; N,17.63
Found: C, 63.23; H,3.76 N, 17.44.
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)
NMR (DMSO-d6,δ): 1.82-1.99 ( 4H, m) , 3.43-3.56 (2H,m) , 3.95- 4.01(2H,m), 5.03-5.14 (IH, m) , 6.96 ( IH, d, J=9.7Hz) ,
7.25 (lH,d, J=9.7Hz) , 7.49-7.65 ( 5H, m) , 8.10 ( IH, d, J=4.7Hz) ,
8.93(lH,dd, J=1.2, 4.7Hz), 9.34 ( IH, d, J=l .2Hz)
IR (nujol) : 1662, 1589, 1521 cm"1
APCI/MS: 374[M+H]+ Anal. Calcd for C21H19N502- 0.27H20:
C,66.68; H,5.21; N, 18.51
Found: C, 66.67; H,5.06 N, 18.44.
Example 16
3- (3-Oxo-2, 3-dihydropyridazin-6-yl) -2- (2-methoxyphenyl ) pyrazolo [l,5-a]pyrazine was obtained in a similar manner to that of Example 1. mp: >250°C (CHC13, MeOH) NMR (DMSO-d6, δ ) ; 3.55(3H, s), 6.75-6.9(lH, m) , 7.0-7.2(2H, m) ,
7.4-7.7(3H, m) , 7.95-8.1(lH, m) , 8.8-8.95(lH, m) , 9.40(1H, d,
J=1.3Hz) , 13.1(1H, br)
IR (KBr, cm"1) : 1679, 1660, 1589 APCI/MS: 320 [M+H]+ .
Example 17
3- (2-Isopropyl-3-oxo-2, 3-dihydropyridazin-6-yl ) -2- (2- methoxyphenyl) pyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 146.0-148.2°C (EtOH)
NMR (DMSO-d6, δ ) : 1.28(6H, d, J=6.6Hz), 3.50(3H, s), 5.1-5.3(1H, m) , 6.88(1H, d, J=9.6Hz), 7.05-7.2(3H, m) , 7.45-7.60 (2H, m) ,
8.06(1H, d, J=4.7Hz), 8.89(1H, dd, J=l .3Hz and 4.7Hz ) , 9.41(1H, d, J=1.2Hz) IR (KBr, cm"1): 1658, 1589
APCI/MS: 362 [M+H]+
Anal C20H19N5O2 • 0.1H20 calcd C:66.14, H.-5.33, N:19.28 found C-66.12, H:5.21, N:19.23. Example 18
3- (3-Oxo-2, 3-dihydropyridazin-6-yl) -2- (3-methoxyphenyl) pyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Example 1. mp: 229-230°C (CHC13, MeOH) NMR (DMSO-d6, δ): 3.78(3H, s) , 6.85-7.7(6H, m) , 8.07(1H, d,
J=4.7Hz) , 8.91 (IH, dd, J=1.3Hz and 4.7Hz) , 9.29 (IH, d, J=1.2Hz) ,
13.3(1H, br)
IR (KBr, cm"1) : 1677, 1650, 1589
APCI/MS: 320 [M+H]+ . Example 19
3- (2-Isopropyl-3-oxo-2, 3-dihydropyridazin-6-yl ) -2- (3- methoxyphenyl) pyrazolo [ 1 , 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 165.0-167.1°C (EtOH) NMR (DMSO-d6, 8 ) : 1.32 (6H, d, J=6.6Hz) , 3.77(3H, s), 5.1-5.35 (IH, m) , 6.93(1H, d, J=9.6Hz), 7.0-7.5(5H, m) , 8.09(1H, d, J=4.7Hz), 8.92(1H, dd, J=1.3Hz and 4.7Hz), 9.34(1H, d, J=1.3Hz)
IR (KBr, cm"1): 1656, 1610, 1587
APCI/MS: 362 [M+H]+
Anal C20H19N5O2 • 0.3H20 calcd C:65.49, H:5.39, N:19.09 found C:65.53, H:5.25, N:19.00.
Example 20
3- (3-Oxo-2, 3-dihydropyridazin-6-yl) -2- (4-methoxyphenyl ) pyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 1. NMR (DMS0-d6, δ ) : 3.78(3H, s), 6.85-7.8(6H, m) , 8.0-8.2(lH, m) ,
8.9-9.0(lH, m) , 9.3-9.4(lH, m) , 13.1-13.3 ( IH, br)
APCI/MS: 320 [M+H]+ .
Example 21
3- (2-Isopropyl-3-oxo-2, 3-dihydropyridazin-6-yl ) -2- (4- methoxyphenyl) pyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 150.2-153.0°C (EtOH)
NMR (DMS0-d6, δ ) : 1.32(6H, d, J=6.6Hz), 3.78(3H, s), 5.1-5.3(1H, m) , 6.93(1H, d, J=9.6Hz), 7.0-7.6(5H, m) , 8.09(1H, d, J=4.8Hz), 8.92(1H, dd, J=1.3Hz and 4.7Hz), 9.34(1H, d, J=1.3Hz)
IR (KBr, cm"1) : 1656, 1610, 1587
APCI/MS: 362 [M+H]+
Anal C20H19N5O2 • 0.4H2O calcd C:65.17, H:5.41, N:19.00 found C:65.58, H.5.21, N:18.61.
Example 22
To a solution of 3- (2-isopropyl-3-oxo-2, 3- dihydropyridazin-6-yl) -2- ( -methoxyphenyl ) pyrazolo [1,5- a] pyrazine (350mg) in dichloromethane (3.0ml) was added a IN solutoin of boran tribromode in dichloromethane under nitrogen at cooling with a ice-bath. After lh, the reaction mixture was stirred at ambient temperature for 2h. Water and ethyl acetate were added to the reaction mixture. The separated organic layer was washed with brine and dried over magnesium sulfate. Removal of the solvent in vacuo afforded a 3- (2-isopropyl-3-oxo-2, 3- dihydropyridazin-6-yl) -2- ( 4-hydroxyphenyl) pyrazolo [1,5- a]pyrazine (152mg)as a pale yellow powder. mp: 257-260°C (EtOH)
NMR (DMSO-d6, δ ) : 1.33(6H, d, J=6.6Hz), 5.1-5.35(1H, m) , 6.8-
7.1(3H, m) , 7.1-7.35(2H, m) , 7.4-7.5(lH, m) , 8.0-8.1(lH, m) ,
8.9-9.0(lH, m) , 9.3-9.4(lH, m) IR (KBr, cm"1): 3127, 1654, 1587
APCI/MS: 348 [M+H]+
Anal C20H19N5O2 ' 0.4H2O calcd C:65.17, H:5.41, N:19.00 found C: 65.58, H:5.21, N:18.61. Example 23
3- (2-Isopropyl-3-oxo-2, 3-dihydropyridazin-6-yl ) -2- (4- isopropoxyphenyl ) pyrazolo [ 1 , 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 108-111°C (diisopropylether) NMR (DMSO-d6, δ ) : 1.35(6H, d, J=6.1Hz), 1.50(6H, d, J=6.6Hz),
4.4-4.65(lH, m) , 5.3-5.55(lH, m) , 6.79(1H, d, J=9.6Hz), 6.95-
7.45(5H, m) , 8.02 (IH, d, J=4.7Hz) , 8.43 (IH, dd, J=1.4Hz and 4.7Hz) ,
9.48(1H, d, J=1.4Hz)
IR ( KBr , cm"1 ) : 1664 , 1594 APCI /MS : 390 [M+H T
Anal C22H23N502 calcd C : 67 . 85 , H : 5 . 95 , N : 17 . 98 found C:67.65, H:6.07, N:17.81.
Example 24
To a stirred mixture of 1-aminopyrazium sulfonate (6.6g) and
3-benzenesulfonyl-6- (4-tolylethynyl ) pyridazine (3.67g) in N,N, -dimethylformamide (37 ml) was added powder potassium carbonate (7.64 g) at ambient temperature. After stirring 20h, the mixture was poured into water. The resultant precipitate was collected by filtration to give brown powder (4.75 g) . A mixture of the obtained powder (4.75 g) , sodium hydroxide (2.1 g) , water (24 ml) and dioxane (48 ml) was refluxed for 2h. The mixture was acidified with IN hydrochloric acid. Chloroform was added to the reaction mixture . The separated organic layer was washed with 0.1
N aqueous hydrochloric acid and brine, successively, and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was subjected to column chromatography on silica gel eluting with a mixture of chloroform and methanol (50 : 1) to give
3- (3-oxo-2, 3-dihydropyridazin-6-yl) -2- (4-tolyl) pyrazolo [1,5- a]pyrazine as a powder (1.0 g)
NMR (DMSO-d6, δ ) : 2.38(3H, s), 6.89(1H, d, J=9.8Hz), 7.20(1H, d, J=9.8Hz), 7.25-7.40 (2H, m) , 7.45-7.60 (2H, m) , 8.05(1H, d,
J=4.7Hz) , 8.89 (IH, dd, J=1.3Hz and 4.7Hz) , 9.28 (IH, d, J=1.3Hz) ,
13.28 (IH, br)
APCI/MS: 304 [M+H]+ .
Exampl 25 3- (2-Isopropyl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- (4- tolyl ) pyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 112-115°C (diisopropylether) NMR (DMS0-d6, δ ) : 1.34 (6H, d, J=6.6Hz) , 2.38 (3H, s) , 5.1-5.3(1H, m) , 6.92(1H, d, J=9.6Hz), 7.21(1H, d, J=9.6Hz), 7.32(2H, d,
J=8.0Hz), 7.52(2H, d, J=8.0Hz), 8.07(1H, d, J=4.7Hz), 8.90(1H, dd, J=1.4Hz and 4.7Hz), 9.32(1H, d, J=1.3Hz) IR ( KBr , cm"1 ) : 1 664 , 1590
APCI/MS: 346 [M+H]+
Anal C20H19N5O • 0.3H20 calcd C:68.48, H:5.36, N:19.96 found C:68.29, H:5.45, N:19.69.
Example 26
3- (2-Methyl-3-oxo-2, 3-dihydropyridazin-6-yl ) -2- (4- tolyl ) pyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 207-210°C (EtOH)
NMR (DMSO-d6, δ ) ; 2.38 (3H, s) , 3.79(3H, s) , 6.92(1H, d, J=9.6Hz) ,
7.14(1H, d, J=9.6Hz), 7.32(2H, d, J=8.0Hz), 7.53(2H, d, J=8.0Hz),
8.07(1H, d, J=4.7Hz), 8.89(1H, dd, J=l .3Hz and 4.7Hz) , 9.42(1H, d, J=1.3Hz) IR (KBr, cm"1) : 1664, 1587
APCI/MS: 318 [M+H]+
Anal C18H15N50 • 0.9H20 calcd C:64.81, H:5.08, N:21.00 found C:65.02, H:4.76, N:20.58. Example 27
3- (3-Oxo-2, 3-dihydropyridazin-6-yl) -2- (4-chlorophenyl ) pyrazolo[l,5-a] pyrazine was obtained in a similar manner to that of Example 24.
NMR (DMS0-d6, δ ) : 6.92(1H, d, J=9.8Hz), 7.28(1H, d, J=9.8Hz), 7.5-7.7(4H, m) , 8.08(1H, d, J=4.7Hz), 8.90(1H, dd, J=1.3Hz and
4.7Hz), 9.29(1H, d, J=1.3Hz), 13.29(1H, br)
IR (KBr, cm"1) : 1671, 1648, 1596
APCI/MS: 324 [M+H]+ .
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)
NMR (DMSO-d6, δ ) : 1.30 (6H, d, J=6.6Hz) , 5.1-5.3(1H, m) , 6.95 (IH, d, J=9.6Hz), 7.33(1H, d, J=9.6Hz), 7.5-7.7(4H, m) , 8.10(1H, d,
J=4.7Hz), 8.92(1H, dd, J=1.4Hz and 4.7Hz), 9.33(1H, d, J=1.4Hz) IR (KBr, cm"1) : 1668, 1594
APCI/MS: 366 [M+H]+
Anal C20H19N5O2 • 0.4H2O calcd C:62.38, H.4.41, N:19.14 found C:62.32, H:4.33, N:19.07. Example 29
3- (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 1. mp: >250°C (CHC13, MeOH) NMR (DMS0-d6, δ ) : 6.93(1H, d, J=9.8Hz), 7.30(1H, d, J=9.8Hz),
7.5-7.75 (4H, m) , 8.0-8.2 (IH, m) , 8.8-8.95 ( IH, m) , 9.2-9.4 ( IH, m) ,
13.32(1H, br)
IR (KBr, cm"1): 1675, 1648, 1596
APCI/MS: 324 [M+H]+ . Example 30
To a stirred solution of 3- (3-oxo-2, 3-dihydropyridazin-
6-yl) -2- (3-chlorophenyl ) pyrazolo [1, 5-a] pyrazine (400 mg) in
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 .
The organic layer was washed with water and brine, dried over magnesium sulfate and evaporater in vacuo. The residue was recrystallized from a ethyl acetate to give 3- (2-isopropyl-3- oxo-2 , 3-dihydropyridazin-6-yl) -2- ( 3-chlorophenyl ) pyrazolo
[ 1, 5-a] pyrazine (330 mg) as a pale yellow solid. mp: 195-197°C (AcOEt) NMR (DMSO-d6, δ ) : 1.27 (6H, d, J=6.6Hz) , 5.1-5.25 (IH, m) , 6.97 (IH, d, J=9.6Hz), 7.41(1H, d, J=9.6Hz) , 7.45-7.7(4H, m) , 8.11(1H, d,
J=4.7Hz) , 8.93(1H, dd, J=l .3Hz and 4.7Hz) , 9.34(1H, d, J=1.3Hz)
IR (KBr, cm"1) : 1673, 1670, 1664, 1650, 1600, 1594 APCI/MS: 366 [M+H]+
Anal C19H16N50 • 0.2H2O calcd C:61.77, H:4.47, N:18.96 found C:61.69, H:4.27, N:18.94.
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)
NMR (DMSO-d6, δ ) : 3.78(3H, s), 6.95(1H, d, J=9.6Hz), 7.24(1H, d, J=9.6Hz), 7.5-7.65(3H, m) , 7.7-7.8(lH, m) , 8.11(1H, d,
J=4.7Hz), 8.92(1H, dd, J=1.4Hz and 4.7Hz), 9.44(1H, d, J=1.4Hz)
IR (KBr, cm"1) : 1658, 1587
APCI/MS: 338 [M+H]+
Anal C17H12C1N50 calcd C:60.45, H:3.58, N:20.73 found C:60.21, H:3.58, N:20.66.
Example 32
3- [2- ( 3-Tetrahydrofuranyl ) -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: 190-192°C (EtOH) NMR (DMSO-d6, δ ) : 2.0-2.6(2H, m) , 3.7-4.1(4H, m) , 5.5-5.7(lH, m) , 6.97(1H, d, J=9.6Hz), 7.34(1H, d, J=9.6Hz), 7.5-7.6(3H, m) ,
7.65-7.75 (IH, m) , 8.11 (IH, d, J=4.7Hz) , 8.92 (IH, dd, J=1.3Hz and 4.7Hz), 9.39(1H, d, J=l.lHz)
IR (KBr, cm"1) : 1662, 1587
APCI/MS: 394 [M+H]+ Anal C20H16ClN5O2 • 0.1H2O calcd C:60.72, H:4.13, N:17.70 found C:60.56, H:3.96, N:17.67.
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)
NMR (DMSO-d6, δ ) : 1.7-1.9(4H, m) , 3.4-3.6(2H, m) , 3.85-4.0(2H, m) , 4.95-5.2(lH, m) , 7.00(1H, d, J=9.6Hz), 7.41(1H, d, J=9.6Hz),
7.45-7.6(3H, m) , 7.65-7.70 (IH, m) , 8.12(1H, d, J=4.7Hz), 8.9-
9.0 (IH, m) , 9.3-9.4 (IH, m)
IR (KBr, cm"1): 1664, 1662, 1592
APCI/MS: 408 [M+H]+ Anal C21H18C1N502 • 0.5H20 calcd C:60.57, H:4.59, N:16.80 found C:60.71, H:4.55, N:16.42.
Example 34
3- (3-Oxo-2, 3-dihydropyridazin-6-yl) -2- (2-chlorophenyl ) pyrazolo [ 1 , 5-a] pyrazine was obtained in a similar manner to that of Example 24. mp: >250°C (CHC13, MeOH)
NMR (DMS0-d6,δ): 6.86(1H, d, J=9.9Hz), 7.04 (IH, d, J=9.9Hz),
7.45-7.75 (4H, m) , 8.12 (IH, d, J=4.7Hz) , 8.93 (IH, dd, J=1.3Hz and 4.7Hz), 9.47(1H, m) , 13.23(1H, br)
IR (KBr, cm"1): 1685, 1662, 1592
APCI/MS: 324 [M+H]+ .
Example 35
3- (2-Isopropyl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- (2- chlorophenyl) pyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 142-144°C (EtOH) NMR (DMSO-d6, δ ) : 1.12 (6H, d, J=6.6Hz) , 5.0-5.2 (IH, m) , 6.96(1H, d, J=9.6Hz), 7.36(1H, d, J=9.6Hz), 7.45-7.7(4H, m) , 8.13(1H, d,
J=4.7Hz), 8.94(1H, d, J= 4.3Hz), 9.50(1H, s)
IR (KBr, cm"1) : 1660, 1590 APCI/MS: 366 [M+H]+
Anal C19H16C1N50 • 0.3H20 calcd C:61.47, H:4.51, N:18.87 found C:61.54, H:4.33, N:18.76.
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 (CHC13, MeOH)
NMR (DMS0-d6, δ ) : 6.90(1H, d, J=9.8Hz), 7.25(1H, d, J=9.8Hz), 7.3-7.45(2H, m) , 7.5-7.75(2H, m) , 8.11(1H, d, J=4.7Hz), 8.93(1H, dd, J=1.4Hz and 4.7Hz), 9.39(1H, d, J=1.4Hz), 13.2(1H, br)
IR (KBr, cm"1) : 1689, 1668, 1592
APCI/MS: 308 [M+H]+ .
Example 37 To a stirred solution of 3- (3-oxo-2, 3-dihydropyridazin-
6-yl) -2- (2-fluorophenyl) pyrazolo [ 1, 5-a] pyrazine (20.1 g) in
N, N-dimethylformamide (180 ml) was added 60%-sodium hydroxide
(3.92 g) at ambient temperature. After stirring for 1 hour, isopropyl iodide (13.0 ml) was added to the mixture which was stirred 16 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporater in vacuo. The residue was recrystallized from a ethanol to give 3- (2-isopropyl-3- oxo-2, 3-dihydropyridazin-6-yl ) -2- (2-fluorophenyl ) pyrazolo [ 1, 5-a] pyrazine (18.1 g) as a pale yellow solid. mp: 180-181°C (EtOH)
NMR (DMSO-d6, δ ) : 1.17 (6H, d, J=6.6Hz) , 5.0-5.25 (IH, m) , 6.95 (IH, d, J=9.6Hz), 7.2-7.8(5H, m) , 8.12(1H, d, J=4.7Hz), 8.94(1H, dd,
J= 1.4Hz and 4.7Hz), 9.43(1H, d, J=1.4Hz)
IR (KBr, cm"1) : 1662, 1590
APCI /MS : 350 [ M+H ] + Anal C19H16FN50 calcd C:65.32, H:4.62, N:20.05 found C:65.15, H:4.51, N:20.01.
Example 38
3- (3-Oxo-2, 3-dihydropyridazin-6-yl) -2- (3-fluorophenyl ) pyrazolo [l,5-a]pyrazine was obtained in a similar manner to that of Example 1. mp: >250°C (CHC13, MeOH)
NMR (DMS0-d6, δ ) : 6.91(1H, d, J=9.8Hz), 7.2-7.7(5H, m) , 8.0-
8.15(1H, m) , 8.8-8.95(lH, m) , 9.2-9.4(lH, m),13.3(lH, br) IR (KBr, cm"1) : 1685, 1652, 1598
APCI/MS: 308 [M+H]+ .
Example 39
To a stirred solution of 3- (3-oxo-2, 3-dihydropyridazin-
6-yl) -2- (3-fluorophenyl) pyrazolo [1, 5-a] pyrazine (400 mg) in N, N-dimethylformamide ( 5 ml ) was added 60%-sodium hydroxide (78 mg) at ambient temperature. After stirring for 1 h, isopropyl iodide (0.26 ml) was added to the mixture which was stirred 16 hours . The mixture was partitioned between water and ethyl acetate .
The organic layer was washed with water and brine, dried over magnesium sulfate and evaporater in vacuo. The residue was recrystallized from a ethanol to give 3- (2-isopropyl-3-oxo-
2, 3-dihydropyridazin-6-yl) -2- ( 3-fluorophenyl ) pyrazolo [1,5- a]pyrazine (250 mg) as a pale yellow solid. mp: 155-157°C (EtOH) NMR (DMSO-d6, δ): 1.28 (6H, d, J=6.6Hz) , 5.1-5.3 (IH, m) , 6.96(1H, d, J=9.6Hz), 7.37(1H, d, J=9.6Hz), 7.3-7.65(4H, m) , 8.11(1H, d,
J=4.7Hz) , 8.93 (IH, dd, J= 1.4Hz and 4.7Hz) , 9.3 (IH, d, J=1.4Hz ) IR (KBr, cm,-"ι1 ■): 1664, 1658, 1612, 1590
APCI/MS: 350 [M+H]+
Anal C19H16FN50 calcd C:65.32, H:4.62, N:20.05 found C:65.38, H:4.65, N:19.97.
Example 40
3- (3-0xo-2, 3-dihydropyridazin-6-yl) -2- (4-fluorophenyl) pyrazolo [ 1 , 5-a] pyrazine was obtained in a similar manner to that of Example 1. mp: >250°C (CHC13, MeOH)
NMR (DMSO-d6, δ ) : 6.91 (IH, d, J=9.8Hz), 7.25(1H, d, J=9.8Hz),
7.2-7.45(2H, m) , 7.6-7.75(2H, m) , 8.07(1H, d, J=4.7Hz), 8.90(1H, dd, J=1.4Hz and 4.7Hz), 9.29(1H, d, J=1.4Hz), 13.29(1H, br)
IR (KBr, cm"1) : 1675, 1650, 1598 APCI/MS: 308 [M+H]+ .
Example 41
To a stirred solution of 3- (3-oxo-2, 3-dihydropyridazin-
6-yl ) -2- ( 4-fluorophenyl ) pyrazolo [1, 5-a] pyrazine (15.0 g) in
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 .
The mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporater in vacuo. The residue was recrystallized from a ethanol to give 3- (2-isopropyl-3-oxo-
2, 3-dihydropyridazin-6-yl) -2- (4-fluorophenyl ) pyrazolo [1,5- a]pyrazine (13.6 g) as a pale yellow solid. mp: 196-197°C (EtOH)
NMR (DMSO-d6, δ): 1.29 (6H, d, J=6.6Hz) , 5.1-5.3 (IH, m) , 6.94 (IH, d, J=9.6Hz), 7.25-7.45(3H, m) , 7.6-7.8(2H, m) , 8.09(1H, d,
J=4.7Hz), 8.9K1H, dd, J= 1.4Hz and 4.7Hz), 9.33(1H, d, J=1.4Hz )
IR (KBr, cm"1) : 1671, 1662, 1600, 1594 APCI/MS: 350 [M+H]+
Anal C19H16FN50 calcd C:65.32, H:4.62, N:20.05 found C:65.48, H:4.60, N:20.10. Example 42
3- (2-Methyl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- (4- fluorophenyl) pyrazolo [ 1 , 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 235-237°C (EtOH) NMR (DMS0-d6, δ ) :3.78 (3H, s), 6.94(1H, d, J=9.6Hz), 7.18(1H, d,
J=9.6Hz) , 7.25-7.45 (2H, m) , 7.6-7.75 (2H, m) , 8.09 (IH, d, J=4.7Hz) ,
8.90(1H, dd, J= 1.3Hz and 4.7Hz), 9.43(1H, d, J=1.3Hz)
IR (KBr, cm"1) : 1679, 1608, 1590
APCI/MS: 322 [M+H]+ Anal C17H12FN50 • 0.1H20 calcd C:63.19, H:3.81, N:21.67 found C:63.11, H:3.68, N:21.64.
Example 43
3- (2-Methyl-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: 236-238°C (EtOH)
NMR (DMS0-d6, δ ) : 3.78(3H, s), 6.95(1H, d, J=9.6Hz), 7.21(1H, d,
J=9.6Hz), 7.57(2H, d, J=8.5Hz), 7.68(2H, d, J=8.5Hz), 8.10(1H, d, J=4.7Hz), 8.88-8.20 (IH, m) , 9.43(1H, br)
IR (KBr, cm"1) : 1677, 1589
APCI/MS: 338 [M+H]+
Anal C17H12C1N50 calcd C:60.45, H:3.58, N:20.73 found C:60.19, H:3.50, N:20.64.
Example 44
3- (3-Oxo-2, 3-dihydropyridazin-6-yl) -2- ( 4-pentylphenyl ) pyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Example 24. mp: 231-234°C (CHC13, MeOH)
NMR (DMSO-d6, δ): 0.8-0.95(3H, m) , 1.2-1.45(4H, m) , 1.5-1.7(2H, m) , 2.55-2.75(2H, m) , 6.89(1H, d, J=9.8Hz), 7.21(1H, d, J=9.8Hz),
7.31(2H, d, J=8.1Hz), 7.53(2H, d, J=8.1Hz), 8.05(1H, d, J=4.7Hz),
8.88(1H, dd, J=1.4Hz and 4.7Hz), 9.27(1H, m) , 13.27(1H, br)
IR (KBr, cm"1) : 1675, 1656, 1592
APCI/MS: 360 [M+H]+ . Example 45
3- (2-Isopropyl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- (4- pentylphenyl ) pyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 127-128°C (diisopropylether) NMR (DMSO-d6, δ): 0.80-0.93 (3H, m) , 1.2-1.45 ( 10H, m) , 1.5-
1.7(2H, m) , 2.55-2.70(2H, m) , 5.1-5.3(1H, m) , 6.92(1H, d,
J=9.6Hz), 7.27(1H, d, J=9.6Hz), 7.29-7.4(2H, m) , 7.52(1H, d,
J=8.1Hz), 8.07(1H, d, J=4.7Hz), 8.90(1H, dd, J=l .3Hz and 4.7Hz) ,
9.31(1H, d, J=l.lHz) IR (KBr, cm"1) : 1664, 1590
APCI/MS: 402 [M+H]+
Anal C24H27N50 • 0.2H2O calcd C:71.16, H:6.82, N:17.29 found C:71.49, H:6.85, N:16.99. Example 46
3- (2-Methyl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- (4- pentylphenyl) pyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 150-152°C (diisopropylether) NMR (DMSO-d6, δ ) : 0.8-0.95 ( 3H, m) , 1.25-1.4 ( 4H, m) , 1.5-1.7 (2H, m) , 2.55-2.7(2H, m),3.79(3H, s), 6.92(1H, d, J=9.6Hz), 7.15(1H, d, J=9.6Hz), 7.32(2H, d, J=8.1Hz), 7.54(2H, d, J=8.1Hz), 8.07(1H, d, J=4.7Hz) , 8.88 (IH, dd, J=1.3Hz and 4.7Hz) , 9.41 (IH, d, J=1.3Hz)
IR (KBr, cm"1) : 1662, 1617, 1589
APCI/MS: 374 [M+H]+
Anal C22H23N50 • 0.2H2O calcd C:70.08, H:6.25, N:18.57 found C:70.08, H:6.17, N:18.51.
Example 47
3- (2-Methyl-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 2. mp: 185-187°C (EtOH)
NMR (DMSO-d6, δ ) : 3.74(3H, s), 6.93(1H, d, J=9.6Hz), 7.15(1H, d,
J=9.6Hz) , 7.3-7.45 (2H, m) , 7.5-7.75 (2H, m) , 8.13(1H, d, J=4.7Hz) ,
8.94(1H, dd, J=1.4Hz and 4.7Hz), 9.54(1H, d, J=1.4Hz) IR (KBr, cm"1): 1679, 1670, 1594, 1590
APCI/MS: 322 [M+H]+ .
Example 48
3- (2-Methyl-3-oxo-2, 3-dihydropyridazin-6-yl ) -2- ( 3- fluorophenyl) pyrazolo [ 1 , 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 194-195°C (EtOH)
NMR (DMSO-d6, δ ) : 3.88(3H, s), 6.96(1H, d, J=9.6Hz), 7.21(1H, d, J=9.6Hz), 7.25-7.65 (4H, m) , 8.10(1H, d, J=4.7Hz), 8.91(1H, dd,
J=1.4Hz and 4.7Hz), 9.44(1H, d, J=1.4Hz) IR (KBr, cm"1) : 1673, 1616, 1587
APCI/MS: 322 [M+H]+ .
Exampl 49
3- (3-Oxo-2, 3-dihydropyridazin-6-yl) -2- (3,4- difluorophenyl ) pyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 1. mp: >250°C (CHC13, MeOH)
NMR (DMSO-d6, δ): 6.92(1H, d, J=9.8Hz), 7.32(1H, d, J=9.8Hz), 7.4-7.8(4H, m) , 8.11(1H, d, J=4.8Hz) , 8.94(1H, dd, J+1.4Hz and
4.8Hz), 9.33(1H, d, J=1.4Hz), 13.2-13.5 (IH, br)
IR (KBr, cm"1) : 1671, 1648, 1594
APCI/MS: 326 [M+H]+ . Example 50
3- (2-Isopropyl-3-oxo-2, 3-dihydropyridazin-6-yl) -2- (3, 4- difluorophenyl) pyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 175-176°C (EtOH) NMR (DMSO-d6, δ ) : 1.28 (6H, d, J=6.6Hz) , 5.05-5.3 (IH, m) , 6.96(1H, d, J=9.6Hz), 7.40(1H, d, J=9.6Hz), 7.4-7.8(3H, m) , 8.11(1H, d,
J=4.7Hz), 8.92(1H, dd, J= 1.4Hz and 4.7Hz), 9.34(1H, d, J=1.4Hz)
IR (KBr, cm"1) : 1662, 1590
APCI/MS: 368 [M+H]+ Anal C19H16F2N50 calcd C:61.82, H:4.15, N:18.97 found C:61.77, H:4.10, N:18.84.
Example 51
3- (3-Oxo-2, 3-dihydropyridazin-6-yl) -2- (2,4- difluorophenyl) pyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 1. mp: >250°C (CHC13, MeOH)
NMR (DMS0-d6, δ ) :6.91 (IH, d, J=9.8Hz), 7.2-7.8(4H, ) , 8.11(1H, d, J=4.8Hz) , 8.93 (IH, dd, J=1.4Hz and 4.7Hz) , 9.39(1H, d, J=1.4Hz ) , 13.22(1H, br)
IR (KBr, cm"1) : 1691, 1670, 1621, 1592
APCI/MS: 326 [M+H]+ .
Example 52
To a stirred solution of 3- (3-oxo-2, 3-dihydropyridazin- 6-yl) -2- (2, 4-difluorophenyl) pyrazolo [1, 5-a] pyrazine (460 mg) in N, N-dimethylformamide (5 ml) was added 60%-sodium hydroxide
(85 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 .
The organic layer was washed with water and brine, dried over magnesium sulfate and evaporater in vacuo. The residue was recrystallized from a ethanol to give 3- (2-isopropyl-3-oxo-
2, 3-dihydropyridazin-6-yl) -2- (2, 4-difluorophenyl) pyrazolo
[ 1, 5-a] pyrazine (195 mg) as a pale yellow solid. mp: 165-166°C (EtOH)
NMR (DMSO-d6, δ ) : 1.17 (6H, d, J=6.6Hz) , 5.0-5.3(lH, ) , 6.97 (IH, d, J=9.6Hz), 7.2-7.55(3H, m) , 7.65-7.85 ( IH, m) , 8.12(1H, d,
J=4.7Hz), 8.94(1H, dd, J= 1.4Hz and 4.7Hz), 9.43(1H, d, J=1.4Hz )
IR (KBr, cm"1) : 1666, 1619, 1592
APCI/MS: 368 [M+H]+
Anal C19H15F2N50 • 0.1H20 calcd C:61.82, H:4.15, N:18.97 found C:61.71, H:4.05, N:18.85.
Example 53.
3- [ 2- (3-Tetrahydrofuranyl) -3-oxo-2, 3-dihydropyridazin-6- yl] -2- (4-fluorophenyl) pyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 3. mp: 202.1-203.5°C (EtOH)
NMR (DMSO-d6, δ ) : 2.0-2.5(2H, m) , 3.7-4.1 (4H, m) , 5.5-5.7 (IH, m) ,
6.95(1H, d, J=9.6Hz), 7.26(1H, d, J=9.6Hz), 7.3-7.5(2H, m) ,
7.6-7.8(2H, m) , 8.09(1H, d, J=4.7Hz), 8.90(1H, dd, J=1.4Hz and 4.7Hz), 9.38(1H, d, J=1.4Hz)
IR (KBr, cm"1) : 1658, 1585
APCI/MS: 378 [M+H]+
Anal C20H16FN5O2 • 0.1H2O calcd C: 63.35, H:4.31, N:18.47 found C:63.29, H:4.18, N:18.46.
Example 54
3- [2- (4-Tetrahydropyranyl) -3-oxo-2, 3-dihydropyridazin-6- yl] -2- (4-fluorophenyl) pyrazolo [ 1 , 5-a] pyrazine was obtained in a similar manner to that of Example 3. mp: 209-211°C (EtOH)
NMR (DMSO-d6, δ ) : 1.7-2.0 (4H, m) , 3.35-3.6 (2H, m) , 3.85-4.05 (2H, m) , 4.95-5.2(lH, m) , 6.97(1H, d, J=9.6Hz), 7.29(1H, d, J=9.6Hz),
7.25-7.45 (2H, m) , 7.6-7.75 (2H, m) , 8.05-8.15 (IH, m) , 8.92(1H, dd,
J=1.4Hz and 4.7Hz), 9.32(1H, d, J=1.4Hz)
IR (KBr, cm"1) : 1670, 1596
APCI/MS: 392 [M+H]+ Anal C21H18FN502 • 0.3H20 calcd C:63.56, H:4.72, N:17.65 found C:63.45, H:4.68, N:17.62.
Example 55
3- (2-Cyanomethyl-3-oxo-2, 3-dihydropyridazin-6-yl ) -2- phenylpyrazolo [ 1, 5-a] pyrazine_was obtained in a similar manner to that of Example 2. mp:195-200°C (AcOEt-Hexane)
NMR(DMSO, δ): 5.41(2H,S), 7.03 ( IH, d, J=9.7Hz ) ,
7.18 (lH,d, J=9.7Hz) , 7.51-7.70 ( 5H,m) , 8.13 ( IH, d, J=4.7Hz ) , 8.94 (lH,d,J=l.3, 4.7Hz) , 9.55 ( IH, d, J=l .3Hz )
IR(nujol) :1677, 1600, 1527 cm"1
ESI/MS: 351 [M+Na]+
Anal. Calcd for C18H12N60 • 0.17AcOEt :
C, 65.35; H,3.92; N,24.48. Found: C, 65.09; H, 3.67; N, 24.74.
Example 56
A mixture of 3- (2-thiocarbamoylmethyl-3-oxo-2, 3- dihydropyridazin-6-yl) -2-phenylpyrazolo [1, 5-a] pyrazine (lg) and bromoacetaldehyde dimethyl acetal (0.85ml ) in dimethoxyethane (20ml) was refluxed for one day. After evaporating the solvent, the residue was partitioned between chloroform and an aquous sodium bicarbonate. The separated organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (150ml) using ethyl acetate. The desired fractions were collected and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 3- [2- ( 1 , 3-thiazol-2-ylmethyl ) -3-oxo-2, 3- dihydropyridazin-6-yl] -2-phenylpyrazolo [ 1, 5-a] pyrazine (0.49g) . mp: 196-198°C (EtOAc)
NMR(DMSO, δ): 5.72(2H,S), 7.01 ( IH, d, J=9.7Hz ) , 7.18 (lH,d, J=9.7Hz) , 7.49-7.53 ( 3H,m) 7.62-7.67 (2H,m) ,
7.76(lH,d, J=3.3Hz) , 7.83 (IH, d, J=3.3Hz) , 8.09 ( IH, d, J=9.7Hz) , 8.92 (lH,dd, J=1.3,4.7Hz) , 9.33 ( IH, d, J=l .3Hz) IR(nujol): 1662, 1590, 1527, 1500 cm"1 APCI/MS: 387 [M+H]+ Anal. Calcd for C18H12N60 • 0.2H20: C, 61.59; H,3.72; N,21.55. Found: C, 61.78; H, 3.54; N, 21.50. Example 57
To a solution of 3- [2- (1-tert-butoxycarbonylpiperidin- 4-yl) -3-oxo-2, 3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5- a] pyrazine (2.2g) in ethyl acetate (50ml) was added 4N-hydrogen chloride in ethyl acetate ( 17ml ) at ambient temperature. After stirring for lδhours, the solvent were evaporated in vacuo. The residue was partitioned between water sodium bicarbonate and ethyl acetate. The separated water layer was made basic with an aqueous sodium bicarbonate and extracted with chloroform. The separated organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 3- (2-piperidin-4-yl-3- oxo-2, 3-dihydropyridazin-6-yl) -2-phenylpyrazolo [1,5- a]pyrazine (1.67g) as a yellow solid, mp: 210-212°C (EtOAc) NMR(DMSO, δ ) : 1.70-1.85(4H,m) , 2.50-2.67 (2H,m) , 3.02-3.10 (2H,m) ,
4.80-5.00 (lH,m) , .97-5.10 ( lH,m) , 6.93 ( IH, d, J=9.7Hz) ,
7.20(lH,d, J=9.7Hz) , 7.50-7.65 (5H,m) , 8.09 ( IH, d, J=4.7Hz) ,
8.92 (lH,dd,J=l.3, 4.7Hz) , 9.34 ( IH, d, J=l .3Hz) . APCI/MS: 373 [M+H]+
IR(nujol): 3529, 3293, 1668, 1589, 1521 cm"1 Anal. Calcd for C21H20N6 • 1H20 • 0.2AcOEt :
C, 64.17; H,5.83; N,20.59.
Found: C,64.00; H,5.61; N,20.63. Example 58
3- (2-Tetrahydrofuran-3-yl-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: 175-176°C (EtOAc-Hexane) NMR(DMSO, δ): 2.16-2.24 (2H,m) , 3.72-4.05 (4H,m) , 5.57-
5.64(lH,m), 6.93 (IH, d, =9.6Hz) , 7.21 (lH,d, J=9.6Hz) , 7.49-
7.66(5H,m), 8.09 ( IH, d, J=4.7Hz) , 8.91 ( IH, dd, J=l .2, 4.7Hz) ,
9.39(lH,d, J=1.2Hz)
IR(nujol): 1662, 1590, 1517 cm"1 APCI/MS: 360 [M+H]+
Anal. Calcd for C20H17N5O2 • 0.3H20:
C, 65.85; H,4.86; N, 19.20.
Found: C, 65.82; H,4.62; N, 19.00.
Example 59 (R) -3- [2- (3R) -Tetrahydrofuran-3-yl-3-oxo-2, 3- dihydropyridazin-6-yl] -2-phenylpyrazolo [ 1, 5-a] pyrazine was obtained in a similar manner to that of Example 2. mp: 180-182°C (EtOH)
[α]D=86.4° (C=0.25, EtOH, 22°C) IR(nujol) : 1662, 1589, 1517 cm"1
Anal. Calcd for C20H17N5O2:
C, 66.84; H,4.77; N, 19.49. Found: C,66.73; H,4.65; N, 19.43.
Example 60
(S) -3- [2-(3S)-Tetrahydrofuran-3-yl-3-oxo-2,3- dihydropyridazin-6-yl ] -2-phenylpyrazolo [ 1 , 5-a] pyrazine was obtained in a similar manner to that carried out in the preparation of Example 2. mp: 180-181°C (AtOAc) [α]D=82.4° (C=0.25, EtOH, 28°C) IR(nujol): 1662, 1590, 1519 cm"1 Anal. Calcd for C20H17N5O2: C, 66.84; H,4.77; N,19.49. Found: C,66.59; H,4.65; N, 19.34. Example 61
To a suspension of 3- (3-oxo-2, 3-dihydropyridazin-6-yl) - 2-phenylpyrazolo [ 1, 5-a] pyrazine (200 mg) in dimethylformamide (4 ml) was added sodium hydride (60% oil suspension, 41.5 mg) and stirred at room temperature for 10 min. To the mixture was added l-bromo-3-fluoropropane (0.095 ml) and stirred at room temperature for 16 hours. The reaction mixture was poured into ice water, extracted with EtOAc, washed with water and brine, dried over sodium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give 3- [2- (3-fluoropropyl ) -3-oxo-2, 3-dihydropyridazin-6-yl] -2- phenylpyrazolo [ 1 , 5-a] pyrazine (139.5 mg) as a solid. mp: 154-155°C (EtOAc-hexane)
IH NMR (CDC13, δ ) : 2.20-2.50 (2H,m) , 4.40-4.80 (4H, m) , 6.81 (IH, d, J = 9.7 Hz) , 7.06 (IH, d, J = 9.7 Hz) , 7.45-7.70 (5H, m) , 8.04 (IH, d, J = 4.7 Hz), 8.44 (IH, dd, J = 4.7, 1.4 Hz), 9.47 (IH, d, J = 1.4 Hz) IR (KBr): 3026, 2970, 1662, 1587, 1504, 1311 cm"1 APCI/MS: 350 [M+H]+ . 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. mp: 156-157°C (Et20-hexane) IH NMR (CDC13, δ ) : 2.65-2.93 (2H,m), 4.55 (2H, t, J = 7.0 Hz), 6.82 (IH, d, J = 9.7 Hz), 7.07 (IH, d, J = 9.7 Hz), 7.43-7.68 (5H, m) , 8.05 (IH, d, J = 4.7 Hz) , 8.44 (IH, dd, J = 4.7, 1.4 Hz) , 9.43 (IH, d, J = 1.4 Hz) IR (KBr): 3087, 3024, 2960, 1668, 1591, 1522, 1502, 1460 cm"1 APCI/MS: 386 [M+H]+ . Example 63
To a suspension of 3- (3-oxo-2, 3-dihydropyridazin-6-yl ) - 2-phenylpyrazolo [1, 5-a] pyrazine (200 mg) in dimethylformamide (4 ml) was added sodium hydride (60% oil suspension, 41.5 mg) and stirred at room temperature for 10 minutes. To the mixture was added 2-iodo-l, 1, 1-trifluoroethane (0.682 ml) and stirred at 60°C for 15 hours. To the mixture was added another 2-iodo-l , 1, 1- trifluoroethane (0.682 ml) and stirred at 60 °C for 24 hours. After cooling to room temperature, the reaction mixture was poured into ice water, extracted with EtOAc, washed with water and brine, dried over sodium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2-MeOH, 30:1) to give 3- [2- (2, 2, 2-trifluoroethyl) -3-oxo-2, 3- dihydropyridazin-6-yl] -2-phenylpyrazolo [1, 5-a] pyrazine (138.3 mg) as a solid. mp: 208-209°C (Et20-hexane)
IH NMR (CDC13, δ): 4.92 (2H, q, J = 8.4 Hz), 6.84 (IH, d, J= 9.8 Hz), 7.07 (IH, d, J = 9.8 Hz), 7.43-7.67 (5H, m) , 8.06 (IH, d, J= 4.7 Hz), 8.44 (IH, dd, J = 4.7, 1.3 Hz), 9.46 (IH, d, J = 1.3 Hz)
IR (KBr) : 3072, 3028, 1676, 1599, 1525, 1508, 1460 cm"1 APCI/MS: 372 [M+H]+ . Example 64
3- (2-Isobutyl-3-oxo-2 , 3-dihydropyridazin-6-yl) -2- phenylpyrazolo [1, 5-a] pyrazine was obtained in a similar manner to that of Example 61. mp: 150-151°C (EtOAc-hexane)
IH NMR (CDC13, δ): 1.04 (6H, d, J = 6.7 Hz), 2.27-2.55 (IH, m), 4.12 (2H, d, J = 7.5 Hz), 6.80 (IH, d, J = 9.7 Hz), 7.03 (IH, d, J = 9.7 Hz), 7.38-7.68 (5H, m) , 8.02 (IH, d, J = 4.7 Hz), 8.43 (IH, dd, J = 4.7, 1.4 Hz), 9.46 (IH, d, J = 1.4 Hz) IR (KBr): 3068, 3026, 2960, 2868, 1670, 1592, 1527, 1504, 1460 cm
APCI/MS: 346 [M+H]+ . Example 65
The following compounds were obtained in a similar manner to that of Example 61.
1) 3- [2- (2-Fluoroethyl) -3-OXO-2, 3-dihydropyridazin-6-yl] -2- phenylpyrazolo [1, 5-a] pyrazine mp: 167-168°C (EtOAc-hexane)
IH NMR (CDC13, δ): 4.50-5.08 (4H,m), 6.83 (IH, d, J = 9.7 Hz), 7.08 (IH, d, J = 9.7 Hz), 7.43-7.68 (5H, m), 8.03 (IH, d, J = 4.7 Hz), 8.43 (IH, dd, J = 4.7, 1.4 Hz), 9.48 (IH, d, J = 1-4 Hz) IR (KBr): 3095, 3028, 2954, 1668, 1591, 1522, 1504, 1456 cm"1 APCI/MS: 336 [M+H]+
2) 3- (2-Vinyl-3-oxo-2 , 3-dihydropyridazin-6-yl ) -2- phenylpyrazolo [ 1, 5-a] pyrazine mp: 191-193°C (EtOAc-hexane)
IH NMR (CDC13, δ): 5.11 (IH, d, J= 8.8 Hz), 5.91 (IH, d, J = 15.5 Hz), 6.83 (IH, d, J= 9.8 Hz), 7.04 (IH, d, J= 9.8 Hz), 7.43-7.70 (5H, m) , 7.86 (IH, dd, J = 15.5, 8.8 Hz), 8.06 (IH, d, J = 4.7 Hz), 8.45 (IH, dd, J = 4.7, 1.4 Hz), 9.54 (IH, d, J = 1.4 Hz) IR (KBr) : 3089, 1660, 1637, 1527, 1462 cm"1 APCI/MS: 316 [M+H]+ . Example 66
3- (3-Oxo-2 , 3-dιhydropyrιdazm-6-yl ) -2- (5-fluoro-2- methoxyphenyl ) pyrazolo [ 1, 5-a] pyrazine can be obtained in a similar manner to that of Example 1. Example 67
3- (2-Isopropyl-3-oxo-2 , 3-dιhydropyrιdazm-6-yl) -2- (5-fluoro-
2-methoxyphenyl ) pyrazolo [ 1, 5-a] pyrazine can be obtained in a similar manner to that of Example 2.
Example 68 3- (2-Isopropyl-3-oxo-2, 3-dιhydropyπdazm-6-yl) -2- (5-fluoro-
2-hydroxyphenyl ) pyrazolo [ 1, 5-a] pyrazine can be obtained in a similar manner to that of Example 22.
Example 69
3- (3-Oxo-2, 3-dιhydropyrιdazm-6-yl) -2- (3-fluoro-5- methoxyphenyl ) pyrazolo [ 1 , 5-a] pyrazine can be obtained in a similar manner to that of Example 1.
Example 70
3- (2-Isopropyl-3-oxo-2, 3-dιhydropyrιdazm-6-yl) -2- (3-fluoro-
5-methoxyphenyl ) pyrazolo [ 1, 5-a] pyrazine can be obtained in a similar manner to that of Example 2.
Example 71
3- (2-Isopropyl-3-oxo-2, 3-dιhydropyπdazm-6-yl) -2- (3-fluoro-
5-hydroxyphenyl ) pyrazolo [1, 5-a] pyrazine can be obtained in a similar manner to that of Example 22. Example 72
3- (3-Oxo-2, 3-dιhydropyπdazm-6-yl) -2- (3-fluoro-4- methoxyphenyl) pyrazolo [ 1, 5-a] pyrazine can be obtained in a similar manner to that of Example 1.
Example 73 3- (2-Isopropyl-3-oxo-2 , 3-dιhydropyπdazιn-6-yl) -2- (3-fluoro-
4-methoxyphenyl) pyrazolo [ 1, 5-a] pyrazine can be obtained in a similar manner to that of Example 2.
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.

Claims

CLAIMS 1. A pyrazolopyrazine compound of the following formula (I):
Figure imgf000059_0001
wherein R is aryl which may have one or more suitable substituent (s) ; and
2
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.
2. A compound of claim 1, wherein
R is phenyl which may have one or more substituent ( s) selected from the group consisting of lower alkyl, lower alkoxy, hydroxy and halogen; and
2
R is hydrogen; lower alkyl; lower alkenyl; mono- or di- or trihalo (lower) alkyl; cyclo (C3-C8) alkyl; 3 to 8-membered heteromonocyclic group; or lower alkyl substituted with a substituent selected from the group consisting of cyclo (C3-C8 ) alkyl, cyano, phenyl and 3 to 8- membered heteromonocyclic group.
3. A compound of claim 2, wherein
R is phenyl which may have 1 to 3 substituent (s) selected from the group consisting of lower alkyl, lower alkoxy, hydroxy and halogen; and
2 R is hydrogen; lower alkyl; lower alkenyl; mono- or di- or trihalo ( lower) alkyl; cyclo (C3-C8) alkyl; 3 to 8-membered heteromonocyclic group containing 1 to 4 hetero atom(s) selected from among oxygen, sulfur and nitrogen in its ring; or lower alkyl substituted with a substituent selected from the group consisting of cyclo (C3-C8 ) alkyl, cyano, phenyl and 3 to 8- membered heteromonocyclic group containing 1 to 4 hetero atom(s) selected from among oxygen, sulfur and nitrogen in its ring.
4. A compound of claim 3, wherein
2 R is hydrogen; lower alkyl; lower alkenyl; mono- or di- or trihalo (lower) alkyl ; cyclo (C3-C8) alkyl; saturated 5 to 6-memberd heteromonocyclic group containing 1 to
2 oxygen atom(s) in its ring; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 hetero atom(s) selected from among oxygen, sulfur and nitrogen in its ring; or lower alkyl substituted with a substituent selected from the group consisting of cyclo (C3-C8 ) alkyl, cyano, phenyl, saturated 5 to 6-memberd heteromonocyclic group containing 1 to 2 oxygen atom(s) in its ring and unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 hetero atom(s) selected from among oxygen, sulfur and nitrogen in its ring.
5. A compound of claim 4, wherein
2
R is hydrogen; lower alkyl; lower alkenyl; fluoro (lower ) alkyl; trifluoro (lower) alkyl; cyclo (C3-C8) alkyl; heteromonocyclic group selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, pyridyl, furanyl, thienyl and thiazolyl; or lower alkyl substituted with a substituent selected from the group consisting of cyclo (C3-C8 ) alkyl, cyano, phenyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, furanyl, thienyl and thiazolyl.
6. A process for the preparation of the pyrazolopyrazine compound of claim 1 or a salt thereof, which comprises, (1) hydrolyzin mula (II) :
Figure imgf000061_0001
wherein R1 is aryl which may have one or more suitable substituent ( s) ;
R3 is arylsulfonyl which may have one or more suitable substituent (s) ; di (lower ) alkylamino; lower alkoxy; lower alkylthio; or acyloxy, or a salt thereof, to give a compound of the formula (la) :
Figure imgf000062_0001
wherein R1 is as defined above or a salt thereof,
(2) reacting a compound of the formula (la) or a salt thereof, with a compound of the formula (III): R2a-X (III) wherein R2a 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, and
X is a leaving group, or a salt thereof to give a compound of the formula (lb) :
Figure imgf000063_0001
wherein R1, R2a are as defined above, or a salt thereof,
(3) eliminating of alkyl group of a compound of the formula (Ic)
Figure imgf000063_0002
wherein R is hydrogen; 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 is lower alkyl, or a salt thereof, to give a compound of a formula (Id) :
Figure imgf000063_0003
wherein R is as defined above, or a salt thereof, or (4) reacting a compound of the formula (Ie):
Figure imgf000064_0001
wherein R is as defined above or a salt thereof, with a compound of the formula (IV) :
R5-X (IV) wherein R5 is lower alkyl, and X is a leaving group, or a salt thereof, to give a compound of the formula (If):
Figure imgf000064_0002
wherein R a and R are as defined above or a salt thereof.
7. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.
8. A method for preventing or treating a disease selected from the group consisting of depression, dementia, 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, ischemic bowel disease, ileus, myocardial infarction, thrombosis, obstruction, arteriosclerosis obliterans, thrombophlebitis, cerebral infarction, transient ischemic attack and angina pectoris, which comprises administering the compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal .
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament.
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof for use as an adenosine antagonist.
11. The compound of claim 1 or a pharmaceutically acceptable salt thereof for use as an A1 receptor and A2 receptor dual antagonist.
12. A process for preparing a pharmaceutical composition which comprises admixing the compound of claim 1 or a pharmaceutically acceptable sat thereof with a pharmaceutically acceptable carrier .
13. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the production of a pharmaceutical composition for the therapy of diseases on which an adenosine antagonist is therapeutically effective.
14. A method for evaluation of adenosine antagonim which comprises use of compound of claim 1 or a pharmaceutically acceptable sat thereof .
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