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WO2005095384A1 - Pyrazine derivatives and pharmaceutical use thereof as adenosine antagonists - Google Patents

Pyrazine derivatives and pharmaceutical use thereof as adenosine antagonists Download PDF

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Publication number
WO2005095384A1
WO2005095384A1 PCT/JP2005/005663 JP2005005663W WO2005095384A1 WO 2005095384 A1 WO2005095384 A1 WO 2005095384A1 JP 2005005663 W JP2005005663 W JP 2005005663W WO 2005095384 A1 WO2005095384 A1 WO 2005095384A1
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Prior art keywords
amino
phenyl
isopropyl
salt
pyridazinone
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PCT/JP2005/005663
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French (fr)
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WO2005095384A8 (en
Inventor
Hideo Tsutsumi
Seiichiro Tabuchi
Masatoshi Minagawa
Atsushi Akahane
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Astellas Pharma Inc.
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Priority claimed from AU2004901772A external-priority patent/AU2004901772A0/en
Application filed by Astellas Pharma Inc. filed Critical Astellas Pharma Inc.
Priority to EP05721590A priority Critical patent/EP1737841A1/en
Priority to JP2006529402A priority patent/JP4978192B2/en
Priority to CA002562126A priority patent/CA2562126A1/en
Publication of WO2005095384A1 publication Critical patent/WO2005095384A1/en
Publication of WO2005095384A8 publication Critical patent/WO2005095384A8/en

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Definitions

  • the present invention relates to a novel pyrazine derivative and a salt thereof, iwhich are useful as medicaments.
  • Adenosine is a ubiquitous biochemical messenger. Adenosine binds to and activates seven-transmembrane spanning G-protein coupled receptors, eliciting a variety of physiological responses. Adenosine receptors are divided into four known subtypes (i.e., Ai, A 2a , A 2b , and A 3 ) . These receptor subtypes mediate different, and sometimes opposing, effects. Activation of the adenosine Ai receptor, for example, elicits an increase in renal vascular resistance, while activation of the adenosine A 2a receptor elicits a decrease in renal vascular resistance. Accordingly, adenosine antagonists are useful in the prevention and/or treatment of numerous diseases, including cardiac and circulatory disorders, degenerative disorders of the central nervous system, respiratory disorders, and many diseases for which diuretic treatment is suitable.
  • 2-aminopyridine compounds to exhibit adenosine receptor antagonism are known (WO 02/14282, WO 01/25210, etc. )
  • 2-aminopyrimidine compounds are also known (WO 03/035639, US 2001/0027196, etc.).
  • Ar and Ar' are independently same or different aryl ;
  • R, R' and M are independently hydrogen or suitable substituent; is reported (e.g. ( 1 ) J. Org . Chem. , 40, 2341 (1975), (2) J. Heterocyclic Chem. , 15, 665 (1978), (3) J. Chem. Soc.
  • the present invention relates to a novel pyrazine derivative and a pharmaceutically acceptable salt thereof, which are useful as medicaments; processes for preparing the preparation of pyrazine derivative and a salt thereof; a pharmaceutical composition comprising, as an active ingredient, said pyrazine derivative or a pharmaceutically acceptable salt thereof; a use of said pyrazine derivative or a pharmaceutically acceptable salt thereof as a medicament; and a method for using said pyrazine derivative or a pharmaceutically acceptable salt thereof for therapeutic purposes, which comprises administering said pyrazine derivative or a pharmaceutically acceptable salt thereof to a human being or an animal.
  • the pyrazine derivatives and a salt thereof are adenosine antagonists (especially, A 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.
  • 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-90O506 (disclosed in EP-0184162) , cyclosporine (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.
  • 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.
  • thrombosis e.g. arterial thrombosis, cerebral thrombosis, etc.
  • obstruction arteriosclerosis obliterans
  • thrombophlebitis thrombophlebitis
  • cerebral infarction transient ischemic attack
  • angina pectoris or the like.
  • novel pyrazine derivative or a salt thereof of the present invention can be shown by the following formula (I) :
  • R 1 is hydrogen or optionally substituted lower alkyl
  • X is hydrogen, halogen, hydroxy, mercapto, cyano or, acyl; oi ⁇ lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, cyclo (lower ) alkoxy, lower alkylthio, aryloxy, arylthio, amino, aryl, heterocyclic group or heterocyclyloxy, each ,of which is optionally substituted; Y is hydrogen, halogen, hydroxy, mercapto, cyano or acyl; or lower alkyl, lower alkoxy, lower alkylthio, amino, aryl or heteroaryl, each of which is optionally substituted; and Z is aryl or heteroaryl, each of which is optionally substituted; or a salt thereof.
  • R 1 is hydrogen or lower alkyl
  • Y is hydrogen, hydroxy, lower alkoxy, cyano, acyl or optionally substituted amino; or a salt thereof.
  • Y is hydrogen, amino or dimethylsulfanylideneamino; and Z is phenyl, pyridyl or thienyl, each of which is optionally substituted; or a salt thereof.
  • X is hydrogen, halogen, hydroxy, cyano, carboxy, lower alkyl carbonyl, lower alkoxy carbonyl, lower alkyl sulfinyl, lower alkyl sulfonyl; or a salt thereof.
  • X is lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, cyclo (lower) alkoxy, lower alkylthio, carbamoyl, thiocarbamoyl , aryloxy, arylthio, amino, aryl, heterocyclic group or heterocyclyloxy, each of which is optionally substituted; or a salt thereof.
  • (5) The pyrazine compound of (2) wherein
  • Y is hydrogen or amino
  • Z is phenyl or thienyl which is optionally substituted; or a salt thereof.
  • X is hydrogen, chloro, bromo, hydroxy, cyano, methylcarbonyl, methylthio, carbamoyl, furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, phenoxy, fluorophenoxy, pyrrolidinyloxy, benzylpyrrolidinyloxy, thiazolyl, methylthiazolyl or phenylthiazolyl; or a salt thereof.
  • (7) The pyrazine compound of (5) wherein
  • X is amino, vinyl, ethynyl or lower alkoxy, each of which is optionally substituted; or a salt thereof.
  • R 1 is methyl, ethyl or isopropyl
  • X is hydrogen, chloro, bromo, hydroxy, cyano, methylcarbonyl, carbamoyl, pyrazolyl, triazolyl, methylthiazolyl, pyridylmethylamino, methoxyethylamino, furylmethylamino, cyclohexylethynyl, trifluoromethylmethoxy or butoxy
  • Y is amino
  • Z is phenyl or fluorophenyl; or a salt thereof.
  • the object compound (I) and a salt thereof of the present invention can be prepared by the following processes.
  • R 2 is hydrogen or lower alkyl
  • R 3 is lower alkyl
  • R 4 is lower alkozxy
  • X 1 is aryl or heteroaryl, each of which is optionally substituted;
  • X 2 is lower alkenyl, lower alkynyl, lower alkoxy, cyclo (lower ) alkoxy, lower alkylthio, aryloxy, arylthio, NR 5 R 6 (wherein R 5 and R 6 are each hydrogen, lower alkyl, cyclo (lower-) alkyl, aryl, heterocyclic group, or R 5 , R 6 and nitrogen atom to which they are attached form a N-containing heterocyclic group) or heterocyclyloxy, each of wh-Lch is optionally substituted, or hydroxy;
  • Hal is a halogen atom
  • L is a leaving group
  • BW 2 is a constituent of boronic acid such as B(OH) 2 , tetramethyl-1, 3, 2-dioxaborolan-2-yl, B (CHCH 3 CH (CH 3 ) 2 ) 2, or 9-borab ⁇ cyclo [3.3.1] nonanyl . ]
  • the starting compounds or a salt thereof is novel and can be prepared, for example, by the following reaction schemes .
  • the object compound (I) and a salt thereof can be prepared, for example, according to the procedures as ⁇ llustrated 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.
  • 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 s alt triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N' -dibenzylethylenediamine salt, etc.
  • anorganic 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. arginine, aspartic acid, glutamic acid, etc.
  • lower is intended to mean 1 to 6 carbon atom(s) unless otherwise indicated.
  • Suitable “lower alkyl” and “lower alkyl” moiety in the term of “lower alkylthio” and " mono- or di- (lowerr) alkylamino” may include straight or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, he ⁇ -yl or the like, in which the preferred one may be methyl, ethyl or isopropyl.
  • Suitable "optionally substituted lower aLkyl” may include lower alkyl which is optionally substituted by suitable substituent (s) such as halogen, lower alkenyl, -lower alkoxy, hydroxy, cyclo (lower ) alkyl, optionally substituted amino, acylamino, aryl, heterocyclic group, acyl or the -Like, in which the preferred one may be hydroxymethyl, hydrox ⁇ ethyl, aminoethyl, benzyl or pyridylmethyl .
  • suitable substituent such as halogen, lower alkenyl, -lower alkoxy, hydroxy, cyclo (lower ) alkyl, optionally substituted amino, acylamino, aryl, heterocyclic group, acyl or the -Like, in which the preferred one may be hydroxymethyl, hydrox ⁇ ethyl, aminoethyl, benzyl or pyridylmethyl .
  • Suitable "lower alkenyl” may include straig-ht or branched ones such as vinyl, propenyl, allyl, isopropen;yl, butenyl, pentenyl, hexenyl or the like, in which the preferred one may be vinyl.
  • Suitable “optionally substituted lower alkenyl” may include lower alkenyl which is optionally substituted by suitable substituent (s) such as lower alkoxy, tiydroxy, cyclo (lower) alkyl, amino, aryl, heterocyclic group, acyl or the like.
  • suitable substituent such as lower alkoxy, tiydroxy, cyclo (lower) alkyl, amino, aryl, heterocyclic group, acyl or the like.
  • Suitable “lower alkynyl” may include straig t or branched ones such as ethynyl, propynyl, butynyl, pentynyl, hexynyl or the like, in which the preferred one may be ettnynyl .
  • Suitable “optionally substituted lower al-kynyl” may include lower alkynyl which is optionally substituted by suitable substituent (s) such as lower alkoxy, hydroxy, cyclo (lower) alkyl, amino, aryl, heterocyclic groi p, acyl or the like .
  • Suitable "lower alkoxy” may include straighat or branched ones such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-buto y, pentyloxy, hexyloxy or the like, ⁇ n which the preferred one may be (C ⁇ C 4 ) alkoxy and the more preferred one may be methoxy or ethoxy.
  • Suitable "optionally substituted lower alkoxy” may include lower alkoxy which is optionally substituted by suitable substituent (s) such as hydroxy, halogen, cyclo (lower) alkyl, lower alkoxy, optionally substituted amino, optionally substituted aryl, heterocyclic group, acyl or the like.
  • Suitable "cyclo (lower) alkyl” may be cyclo (C 3 —C 8 ) alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyciohexyl, cycloheptyl, cyclooctyl or the like, in which the preferred one may be cyciohexyl.
  • Suitable "aryl” and “aryl” moiety in the terms of “aryloxy” and “arylthio” may include phenyl, naphthyl , indenyl, anthryl, or the like, in which the preferred one may be (C 6 -C ⁇ 0 ) aryl, and the more preferred one may be phenyl.
  • Suitable “optionally substituted aryl” may include aryl which is optionally substituted by suitable substi tuent (s) , preferably 1 to 3 substituent (s) , such as lower alkzyl, lower alkoxy, hydroxy, halogen, etc.
  • suitable examples of optionally substituted aryl include lower alkylphenyl, lower alk-oxyphenyl and halophenyl, in which more preferred one is meth-oxyphenyl or fluorophenyl.
  • Suitable “heterocyclic group” may be saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one heteroatom selected from among oxygen, sulfur and nitrogen.
  • the particularly preferred example of said heterocyclic group may include
  • 3- through 8-membered unsaturated heteromonocyclic groups containing 1 through 4 nitrogen atom(s) such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-l,2,4-triazolyl, 1H-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, etc.), tetrazolyl (e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g. 4, 5-dihydro-l, 2, 4-triazinyl, 2, 5-dihydro-l, 2, 4-triazinyl, etc.), etc.;
  • 3- through 8-membered unsaturated heteromonocyclic groups containing 1 or 2 oxygen atoms and 1 through 3 nitrogen atom(s) such as oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, etc . ) , etc. ;
  • 3- through 8-membered saturated heteromonocyclic groups containing 1 or 2 oxygen atom(s) and 1 through 3 nitrogen atoms such as morpholinyl, oxazolidinyl (e.g. 1, 3-oxazolidinyl etc . ) , etc.; unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atom(s) and 1 through 3 nitrogen atom(s), such as benzoxazolyl, benzoxadiazolyl, etc.; saturated condensed heterocyclic groups containing 1 or 2 oxygen atom(s) and 1 through 3 nitrogen atom(s), such as 8-oxa-3-azabicyclo [3.2.1] octyl, etc. ;
  • 1 or 2 oxygen atom(s) such as oxolanyl, tetrahydropyranyl (e.g. tetrahydro-2H-pyran-2-yl etc.), dioxolanyl, etc.
  • unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atom(s) such as isobenzo
  • Suitable “optionally substituted heterocyclic group” may include heterocyclic group which is optionally substituted by suitable substituent (s) , preferably 1 to 3 substituent (s) , such as lower alkyl, lower alkoxy, hydroxy, oxo, halogen, benzyl, optionally substituted amino, aryl, or the like.
  • Suitable "heteroaryl” and “heteroaryl” moiety in the term of “heteroaryl (lower) alkyl” may be aforesaid "heterocyclic group", in which those categorized as an aromatic heterocyclic group, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, dihydrotriazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl, dihydrotriazolopyridazinyl, oxazolyl, isoxazolyl, ox
  • Suitable “acyl” may include lower alkanoyl, aroyl, carboxy, protected carboxy, and the like.
  • Suitable examples of aforesaid "lower alkanoyl” may be formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, lower (alkyl) sulfinyl (e.g. , ethylsulfinyl, etc.), or the like, in which the preferred one may be (C ⁇ C 4 ) alkanoyl .
  • Suitable examples of aforesaid "aroyl” may be benzoyl, toluoyl, or the like.
  • Suitable examples of aforesaid "protected carboxy” may be i) esterified carboxy, in which suitable esterified carboxy may include lower alkoxycarbonyl (e.g. metho.xycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), aryl (lower) alkoxycarbonyl (e.g.
  • amidated carboxy in which suitable amidated carboxy may include carbamoyl, N- (lower) alkylcarbamoyl (e.g.
  • Suitable "halogen” may be fluoro, chloro, bromo and iodo.
  • Suitable "a leaving group” may include halogen, hydroxy, acyloxy such as alkanoyloxy (e.g. acetoxy, propionyloxy, etc.) or sulfonyloxy (e.g. mesyloxy, tosyloxy, etc.), or the like.
  • Suitable "optionally substituted amino” may include amino, mono- or di- (lower) alkylamino (e.g. methylamine, dimethylamino, methylethylamino, etc.), optionally substituted lower alkyl amino (e.g.
  • acylamino e.g. formylamino, lower alkoxycarbonylamino (e.g. methoxycarbonylamino, ethoxycarbonylamino, etc.), sulf onylamino (e.g. mesylamino, etc.), ureido, etc.), methyleneamino, (dimethyl amino) me thyleneamino, dimethylsulf anylideneamino, or the like.
  • the compound (la) or a salt thereof can be prepared by subjecting the compound (II) or a salt thereof to re-ring- conformation with ammonium acetate following the ring-opening reaction with an acid.
  • This reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, 1,2-dimethoxyethane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, N, N-dimethylf ormamide, methanol, ethanol, dimethyl sulfoxide, diethyl ether, ethyl acetate, a mixture thereof or any other organic solvent which does not adversely affect the reaction.
  • a conventional solvent such as water, acetone, dioxane, acetonitrile, 1,2-dimethoxyethane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, N, N-dimethylf ormamide, methanol, ethanol, dimethyl sulfoxide, diethyl ether, ethyl acetate, a mixture thereof or any other organic solvent which does not adversely affect the reaction.
  • reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or heating.
  • the compound (lb) or a salt thereof can be prepared by subjecting the compound (III) or a salt thereof to ring- conformation with ammonium acetate.
  • the reaction may be carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene dichloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely affect the reaction.
  • a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene dichloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely affect the reaction.
  • alcohol e.g. methanol, ethanol, etc.
  • acetone e.g. acetone
  • dioxane aceton
  • reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating.
  • the compound (Ic) or a salt thereof can be prepared by one pot reaction consisting of in situ rearrangement-amination following the alkylation of hydroxyl-oxygen atom of the compound (la) or a salt thereof with iodoacetamide .
  • the present reaction may be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene dichloride, formamide, N, -dimethylformamide, methanol, ethanol, sec-butanol, amyl alcohol, diethyl ether, dioxane, tetrahydrof ran, 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 dichloride, formamide, N, -dimethylformamide, methanol, ethanol, sec-butanol, amyl alcohol, diethyl ether, dioxane, tetrahydrof ran, dimethyl sulfoxide, or any other organic solvent, which
  • the reaction is preferably conducted in the presence of base, for example, inorganic base such as alkali metal hydroxide, alkalimetal carbonate, alkalimetal bicarbonate, alkali metal hydride (e.g. sodium hydride, etc.), organic base such as trialkylamine, and the like.
  • inorganic base such as alkali metal hydroxide, alkalimetal carbonate, alkalimetal bicarbonate, alkali metal hydride (e.g. sodium hydride, etc.), organic base such as trialkylamine, and the like.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating.
  • the present reaction is preferably carried out in the presence of alkali metal halide (e.g. sodium iodide, potassium iodide, etc.), alkali metal thiocyanate (e.g. sodium thiocyanate, potassium thiocyanate, etc.), di (lower) alkyl azodicarboxylate (e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.) or the like.
  • alkali metal halide e.g. sodium iodide, potassium iodide, etc.
  • alkali metal thiocyanate e.g. sodium thiocyanate, potassium thiocyanate, etc.
  • di (lower) alkyl azodicarboxylate e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.
  • the compound (Ie) or a salt thereof can be prepared by reacting the compound (Id) or a salt thereof with the compound (IV) or a salt thereof.
  • the compound (If) or a salt thereof can be prepared by subjecting the compound (V) or a salt thereof to pyrazine ring- formation with 2 , 3-diamino-2-butenedinitrile .
  • the reactions may be carried out in a conventional solvent such as water, alcohol (e . g . methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene dichloride, tetrahydrofuran, ethyl acetate, toluene, N, N-dimethylformamide, dimethyl sulfoxide, pyridine or any other organic solvent which does not adversely affect the reaction.
  • a conventional solvent such as water, alcohol (e . g . methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene dichloride, tetrahydrofuran,
  • Suitable base includes an inorganic base and 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 bicarbonate or hydride or alkoxide thereof, trialkylamine (e.g. trimethylamine, triethylamine, etc.), hydrazine, picoline, or the like.
  • alkali metal e.g. sodium, potassium, etc.
  • an alkaline earth metal e.g. magnesium, calcium, etc.
  • trialkylamine e.g. trimethylamine, triethylamine, etc.
  • hydrazine picoline, or the like.
  • Suitable acid includes an inorganic acid and organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, or the like.
  • reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating. This reaction can be carried out by ' the method disclosed in Example 4, etc. mentioned later or the similar manners thereto.
  • the compound (Ic) or a salt thereof can be prepared by subjecting the compound (Ig) to substitution with aqueous ammonia .
  • the reactions may be carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, N, N-dimethylformamide, tetrahydrofuran, acetonitrile, dioxane, or any other solvent which is easy to mix with water and does not adversely affect the reaction.
  • a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, N, N-dimethylformamide, tetrahydrofuran, acetonitrile, dioxane, or any other solvent which is easy to mix with water and does not adversely affect the reaction.
  • reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating. This reaction can be carried out by the method disclosed in Example 21 mentioned later or the similar manners thereto.
  • the compound (lh) or a salt thereof can be prepared by subjecting the compound (Ig) or a salt thereof to nucleophilic substitution with an amine such as the compound (VI) or a salt thereof.
  • the reactions may be carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetamide, dimethyl acetamide, N, N-dimethylformamide, tetrahydrofuran, acetonitrile, dioxane, or any other solvent which does not adversely affect the reaction.
  • a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetamide, dimethyl acetamide, N, N-dimethylformamide, tetrahydrofuran, acetonitrile, dioxane, or any other solvent which does not adversely affect the reaction.
  • a liquid amine can be also used as the solvent.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating.
  • the compound (Ic) or a salt thereof can be prepared by subjecting the compound (lh) or a salt thereof to deprotection of amino using 2, 3-dichloro-5, 6-dicyano-l , 4-benzoquinone.
  • 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,NT-dimethylformamide, N,N-dimethylacetamide, or any other organic solvent which does 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,NT-dimethylformamide, N,N-dimethylacetamide, or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (Ii) or a salt thereof can be prepared by subjecting the compound (VII) or a salt thereof coupling reaction with the organoboron compound (VIII) or a salt thereof .
  • the present reaction is preferably carried out by the method disclosed in Example 200 and 201 mentioned later or the similar manner thereto.
  • Process 10
  • the compound (Ic) or a salt thereof can be prepared from the compound (Ii) by 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 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 bicarbonate thereof, trialkylamine (e.g. trimethylamine, triethylamine, etc.), hydrazine, picoline, 1, 5-diazabicyclo [4.3.0]non- 5-ene, 4, 4-diazabicyclo [2.2.2] octane,
  • alkali metal e.g. sodium, potassium, etc.
  • an alkaline earth metal e.g. magnesium, calcium, etc.
  • trialkylamine e.g. trimethylamine, triethylamine, etc.
  • hydrazine picoline, 1, 5-diazabicyclo [4.3.0]non- 5-ene, 4, 4-diazabicyclo [2.2.2] octane,
  • Suitable acid includes an 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.) and Lewis acid (e.g. boron tribromide, boron trichloride, boron trifluoride, aluminum chloride, titanium trichloride, 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. boron tribromide, boron trichloride, boron trifluoride, aluminum chloride, titanium trich
  • 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,
  • 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,
  • 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 (Ij) or a salt thereof can be prepared by subjecting the compound (If) or a salt thereof coupling reaction with the organoboron compound (IX) or a salt thereof.
  • the present reaction is preferably carried out Joy the method disclosed in Example 78 mentioned later or the similar manner thereto.
  • the compound (Im) or a salt thereof can be prepared by subjecting the compound (Ik) or a salt thereof coupling reaction with the compound (X) or a salt thereof.
  • the present reaction is preferably carried out by the method disclos ed in Examination
  • the compound (XII) or a salt thereof can be prepared by subjecting the compound (XI) to the oxime-formation reaction (exemplified by Step 1) by the methods disclosed in Preparation 1 and 2 mentioned later or the similar manners thereto.
  • the compound (XV) can be synthesized by functional trans-formation reaction of the oxime, which is the method disclosed in Preparation 3, 4, 5 and 6 mentioned later or the similar manners thereto that is obvious to the person skilled in the organic chemistry, from the compound (XII) .
  • Step 5 of this process can be carried out by the method disclosed in Preparation 7 mentioned later or the similar manners thereto.
  • the object compound (Ila) or a salt thereof can be prepared by subjecting the compound (XVI) or a salt thereof to the alkylation (exemplified by Step 6) . This reaction is carried out in the method disclosed in Preparation 8 and 9 mentioned later or the similar manners thereto.
  • the another object compound (lib) can be prepared by subjecting the compound (Ila) to the hydrolysis (exemplified by Step 7) that is disclosed in Preparation 10 mentioned later or the similar manners thereto.
  • the compound (XVIII) or a salt thereof can be prepared by subjecting the compound (XVII) or a salt thereof to the alkylation (exemplified by Step 1) . This reaction is carried out in the method disclosed in Preparation 12 and 14 mentioned later or the similar manners thereto.
  • the object compound (V) or a salt thereof can be prepared by subjecting the compound (XVIII) to oxidation (exemplified by Step 2) , which is disclosed in Preparation 11, for example, mentioned later or the similar manners thereto.
  • Step 2 oxidation
  • the compound (III) or a salt thereof can be prepared by reacting the compound (XIX) or a salt thereof with the compound (XX) or a salt thereof. This reaction can be carried out by the method disclosed in Preparation 17 mentioned later or the similar manners thereto.
  • the compound (XXII) can be prepared by subjecting the compound (XXI) to the oxime-formation reaction (exemplified by Step 1) that disclosed in Preparation 20 mentioned later or the similar manners thereto.
  • the compound (XXIII) or a salt thereof can be prepared by reacting the compound (XXII) or a salt thereof with aminomalonitrile .
  • the present reaction is preferably, carried out by the method disclosed in Preparation 21 mentioned later or the similar mariner thereto.
  • the object compound (VII) or a salt thereof can be carried out by reacting the compound (XXIII) or a salt thereof with phosphorus oxychloride. This reaction can be carried out by the method disclosed in Preparation 22 mentioned later or the similar manner thereto.
  • all starting materials and product compounds may be salts.
  • the compounds of above processes can be converted to salts according to a conventional method.
  • 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 [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- 3 H (N) ] ([ 3 H]DPCPX, 4.5nM) for human A x receptor and [ 3 H] CGS 21680 (20nM) for human A 2a receptor
  • Test compound (Ki:nM) (Example No.) Ai A, ;
  • Test 2 Anticatalepsy activity in Mouse [I] Test method
  • 3S were placed on a 3 cm high, 3 mm w ⁇ de horizontal bar, and the duration of cataleptic posture was measured for up to 30 sec.
  • Test compound Manifestation rate of Catalepsy (Example No. ) (number of mouse)
  • the pyrazine compound (I) and a salt thereof of this invention are useful as adenosine antagonists (especially, Ai receptor and A 2 (particularly A 2a ) receptor dual antagonists) and for the prevention and/or the treatment of depression, dementia (e.g.
  • Alzheimer' s disease cerebrovascular dementia, dementia accompanying Parkinson ' s disease, etc.
  • Parkinson's disease anxiety, pain, cerebrovas cular disease, heart failure, hypertension, circulatory insuffi ciency, 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, immunosuppressior., 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 ische
  • Adenosine antagonists can Doe useful for Parkinson' s disease by co-administrating with L-3, 4-dihidroxy- phenylalanine (L-DOPA) , which is the most popular drug for Parkinson' s disease (R.Grondin et _ al, Neurology, 52, 1673-1677 (1999)). So the combination use of the pyrazine compound (I) and a salt thereof of this invention with L-DOPA may be also useful for treatment and/or prevention of Parkinson's disease with decreasing or reducing the side effect such as the onset of dyskinesia eliciting by the long-team application of L-DOPA, and so on.
  • L-DOPA 4-dihidroxy- phenylalanine
  • 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 pyrazine 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 pyrazine 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 pyrazine 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 pyrazine 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 pyrazine compound (I) per kg weight of a human being or an animal, and in case of oralL administration, a daily dose of 0.1 - 100 mg of the pyrazine 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.
  • Zinc dust (1.57 g) was added in portions to a suspension of 1- (l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) - 2-phenyl-l, 2-ethanedione 1-oxime (856 mg) in a mixture acetic anhydride (1.7 ml) and AcOH (10 ml) under ambient temperature and the mixture was stirred at the same temperature for 4 hours. An insoluble material was filtered off and a filtrate was concentrated under reduced pressure to give a residue. The residue was dissolved in EtOAc, washed with sat. aq .
  • 6- (phenylethynyl) -3 (2if) - pyridazinone (15.54 g) was added to a suspension of NaH (60% in oil suspension) (3.33 g) in DMF (90 ml) and the mixture was stirred at 50-55°C for 30 minutes. Under ice-cooling, iodoethane (6.97 ml) was added to the mixture and the mixture was stirred at 50-55°C for 3 hours. After addition of water, the reaction mixture was extracted with EtOAc, dried over MgS0 4 and concentrated under reduced pressure to give a residue.
  • Example 3 Potassium carbonate (77 mg) was added to a solution of 6- (5-hydroxy-6-methyl-3-phenyl-2-pyrazinyl) -2-isopropyl- 3 (2f) -pyridazinone (150 mg) and iodoacetamide (95 mg) in DMA (1 ml) and the mixture was stirred at 20-25°C for 2 hours. To the reaction mixture, potassium carbonate (235 rag) was added and heated at 150-155°C for 2 hours. After addition of water, the mixture was extracted with CHCI 3 , washed with brine, dried over MgS0 4 and concentrated under reduced pressure to give a residue.
  • the precipitate was purified by column chromatography on silica gel (EtOAc only) to give a solid.
  • the solid was crystallized from a mixture of n-hexane and CHCI 3 to give 3- [bis (4- methoxybenzyl) amino] -6- (l-isopropyl-6-oxo-l , 6-dihydro- 3-pyridazinyl) -5-phenyl-2-pyrazinecarbonitrile (16.58 g) . m.p.
  • Example 53 N-bromosuccinimide (875 mg) was added to a solution of 6- (5-amino-3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2Jf) — pyridazinone (1.51 g) in DMF (15 ml). The mixture w s stirred at 50-55°C for one hour and poured into water (150 ml) . The precipitate was collected by filtration, dissolved in CHCI3, dried over MgS0 4 and concentrated under reduced pressure to give a solid.
  • m-chloroperbenzoic acid 70-75% purity (530 mg) was added to a mixture of 6-[5-amino- 6- (methylsulfinyl) -3-phenyl-2-pyrazinyl] -2-isopropyl-3 (2ff) - pyridazinone (750 mg) in CH 2 C1 2 (7.5 ml). The mixture was stirred at 25-30°C for 5 hours, washed with saturated aq. sodium thiosulfate, saturated aq. NaHC0 3 and brine, dried over MgS0 4 and concentrated under reduced pressure to give a residue.
  • Example 55 The title compounds were obtained in a similar manner to that of Example 55.
  • Example 64 A solution of 6- [5-amino-6- (methylsulfonyl) -3-phenyl- 2-pyrazinyl] -2-isopropyl-3 (2ff) -pyridazinone (200 mg) in a mixture of IN aq. ⁇ aOH (1 ml) and dioxane (2 ml) was refluxed for 6 hours. After cooling, the mixture was adjusted to pH 4 with 1NHC1 to give a precipitate.
  • Example 72 The following 2 compounds were obtained in a similar manner to that of Example 71.
  • Example 72 The following 2 compounds were obtained in a similar manner to that of Example 71.
  • Example 72 The following 2 compounds were obtained in a similar manner to that of Example 71.
  • Example 72 The following 2 compounds were obtained in a similar manner to that of Example 71.
  • Example 72 The following 2 compounds were obtained in a similar manner to that of Example 71.
  • Example 72 Example 72
  • triethylamine (0.0596 ml) was dropwise added to a mixture of 6- ( 5-amino-6-bromo-3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2if) - pyridazinone (150 mg) and 5-ethynyl—l-methyl-lff-imidazole (45.4 mg) in THF (1.5 ml) at 50°C. The mixture was refluxed for 2 hours. Water was added to the reaction mixture to give a solid.
  • the solid was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40:60 v/v) to give a solid.
  • the solid was suspended in acetone to give 6- [ 5-amino-3-phenyl-6- (phenylethynyl) -2-pyrazinyl] - 2-methyl-3 (2if) -pyridazinone (96 mg) . m.p. : 234-236°C
  • Example 90 Under nitrogen atmosphere, a solution of sodium carbonate (330 mg) in water (2.4 ml) was added to a suspension of 6- (5-amino-6-bromo-3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2if) - pyridazinone (300 mg) , tert-butyl 4- ⁇ 4 , 4 , 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl) -lif-pyrazole—1-carboxylate (573 mg) and tetrakis (triphenylphosphine) palladium (27 mg) in dioxane (6 ml) and the mixture was stirred at 100-105°C for 4 hours.
  • 6- [5-ami-no-3-phenyl- 6- (lif-pyrazol-4-yl) -2-pyrazinyl] -2-isopropyl-3 (2if) - pyridazinone 120 mg was added to a suspen-sion of NaH (60% in oil) (14.2 mg) and the mixture was stirrecd at 25-30°C for 30 minutes. The mixture was cooled in an ice bath and iodomethane
  • 2-imidazolidinone (0.3 ml) was heated at 120-125°C for 50 hours . After addition of water (3 ml) , a precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give a solid. The solid was suspended in acetone to give
  • Example 101 A mixture of 6- (5-amino-6-bromo-3-phenyl-2-pyrazinyl) - 2-isopropyl-3 (2if) -pyridazinone (150 mg) and allylamine (0.0881 ml) in 1, 3-dimethyl-2-imidazolidinone (0.3 ml) was heated at 120-125°C for 50 hours. After addition of water (3 ml), an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHC1 3 , dried over MgS0 4 and concentrated under reduced pressure to give syrup.
  • Example 102 The following 30 compounds were obtained in a similar manner to that of Example 101.
  • Example 102 The following 30 compounds were obtained in a similar manner to that of Example 101.
  • Example 102 The following 30 compounds were obtained in a similar manner to that of Example 101.
  • Example 102 The following 30 compounds were obtained in a similar manner to that of Example 101.
  • Example 102 The following 30 compounds were obtained in a similar manner to that of Example 101.
  • Example 102 Example 102
  • 2-imiciazolidinone (0.3 ml) was heated at 120-125°C for 50 hours. After addition of water (3 ml), the mixture was extracted with CHCI 3 , dried over MgS0 4 , concentrated under reduced pressure and pmrified by column chromatography on silica gel [Chromatorex® NH] eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a syrup.

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Abstract

A pyrazine derivative of the following formula (I): wherein is hydrogen or optionally substituted lower alkyl; X,is hydrogen, halogen, hydroxy, cyano, acyl, or amino, aryl, heterocyclic group or the like; Y is hydrogen, halogen, hydroxy, acyl, amino, or the like; Z is aryl. or heteroaryl, each of which is optionallysubstituted; or a salt thereof. The pyrazine compound (I) and a salt thereof of the present invention are adenosine antagonists and are 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 and the like.

Description

DESCRIPTION
PYRAZINE DERIVATIVES AND PHARMACEUTICAL US THEREOF AS ADENOSINE ANTAGONISTS
TECHNICAL FIELD The present invention relates to a novel pyrazine derivative and a salt thereof, iwhich are useful as medicaments.
BACKGROUND ART Adenosine is a ubiquitous biochemical messenger. Adenosine binds to and activates seven-transmembrane spanning G-protein coupled receptors, eliciting a variety of physiological responses. Adenosine receptors are divided into four known subtypes (i.e., Ai, A2a, A2b, and A3) . These receptor subtypes mediate different, and sometimes opposing, effects. Activation of the adenosine Ai receptor, for example, elicits an increase in renal vascular resistance, while activation of the adenosine A2a receptor elicits a decrease in renal vascular resistance. Accordingly, adenosine antagonists are useful in the prevention and/or treatment of numerous diseases, including cardiac and circulatory disorders, degenerative disorders of the central nervous system, respiratory disorders, and many diseases for which diuretic treatment is suitable.
Some 2-aminopyridine compounds to exhibit adenosine receptor antagonism are known (WO 02/14282, WO 01/25210, etc. ) , and some 2-aminopyrimidine compounds are also known (WO 03/035639, US 2001/0027196, etc.).
However, it is generally difficult to produce a pyrazine which is substituted by four different substituents, and for example the synthesis of a pyrazine compound of the formula A :
Figure imgf000003_0001
wherein Ar and Ar' are independently same or different aryl ; and
R, R' and M are independently hydrogen or suitable substituent; is reported (e.g. ( 1 ) J. Org . Chem. , 40, 2341 (1975), (2) J. Heterocyclic Chem. , 15, 665 (1978), (3) J. Chem. Soc. Perkin Trans.1, 1994, 885, ( 4 ) Synthesis, 1994, 931, (5) O-02/088084 , etc.), however practically, the Ar and Ar' thereof are same, and the selective synthesis of a pyrazine compound A wherein Ar and Ar' are different is not shown as far as we know, and 6-aryl-5- ( 6-oxo-l, 6-dihydro-pyridazin-3-yl) -pyrazine compounds and derivatives thereof are novel, so there has been no knowledge about these compounds, so far. In addition, any pyrazine derivatives having both of adenosine Ai and A2a inhibitory activities are not known. DISCLOSURE OF INVENTION The present invention relates to a novel pyrazine derivative and a pharmaceutically acceptable salt thereof, which are useful as medicaments; processes for preparing the preparation of pyrazine derivative and a salt thereof; a pharmaceutical composition comprising, as an active ingredient, said pyrazine derivative or a pharmaceutically acceptable salt thereof; a use of said pyrazine derivative or a pharmaceutically acceptable salt thereof as a medicament; and a method for using said pyrazine derivative or a pharmaceutically acceptable salt thereof for therapeutic purposes, which comprises administering said pyrazine derivative or a pharmaceutically acceptable salt thereof to a human being or an animal.
The pyrazine derivatives and a salt thereof are adenosine antagonists (especially, Aa 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, a eliorants 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) caused 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-90O506 (disclosed in EP-0184162) , cyclosporine (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 pyrazine derivative or a salt thereof of the present invention can be shown by the following formula (I) :
Figure imgf000007_0001
wherein
R1 is hydrogen or optionally substituted lower alkyl; X is hydrogen, halogen, hydroxy, mercapto, cyano or, acyl; oi¬ lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, cyclo (lower ) alkoxy, lower alkylthio, aryloxy, arylthio, amino, aryl, heterocyclic group or heterocyclyloxy, each ,of which is optionally substituted; Y is hydrogen, halogen, hydroxy, mercapto, cyano or acyl; or lower alkyl, lower alkoxy, lower alkylthio, amino, aryl or heteroaryl, each of which is optionally substituted; and Z is aryl or heteroaryl, each of which is optionally substituted; or a salt thereof.
The preferred embodiments of the pyrazine compound of the present invention are as follows.
(1) The pyrazine compound of the general formula (I) wherein
R1 is hydrogen or lower alkyl; and Y is hydrogen, hydroxy, lower alkoxy, cyano, acyl or optionally substituted amino; or a salt thereof.
(2) The pyrazine compound of (1) wherein R1 is lower alkyl;
Y is hydrogen, amino or dimethylsulfanylideneamino; and Z is phenyl, pyridyl or thienyl, each of which is optionally substituted; or a salt thereof. (3) The pyrazine compound of (2) wherein
X is hydrogen, halogen, hydroxy, cyano, carboxy, lower alkyl carbonyl, lower alkoxy carbonyl, lower alkyl sulfinyl, lower alkyl sulfonyl; or a salt thereof. (4) The pyrazine compound of (2) wherein
X is lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, cyclo (lower) alkoxy, lower alkylthio, carbamoyl, thiocarbamoyl , aryloxy, arylthio, amino, aryl, heterocyclic group or heterocyclyloxy, each of which is optionally substituted; or a salt thereof. (5) The pyrazine compound of (2) wherein
Y is hydrogen or amino; and
Z is phenyl or thienyl which is optionally substituted; or a salt thereof. (6) The pyrazine compound of (5) wherein X is hydrogen, chloro, bromo, hydroxy, cyano, methylcarbonyl, methylthio, carbamoyl, furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, phenoxy, fluorophenoxy, pyrrolidinyloxy, benzylpyrrolidinyloxy, thiazolyl, methylthiazolyl or phenylthiazolyl; or a salt thereof. (7) The pyrazine compound of (5) wherein
X is amino, vinyl, ethynyl or lower alkoxy, each of which is optionally substituted; or a salt thereof. (8) The pyrazine compound of (1) wherein
R1 is methyl, ethyl or isopropyl; X is hydrogen, chloro, bromo, hydroxy, cyano, methylcarbonyl, carbamoyl, pyrazolyl, triazolyl, methylthiazolyl, pyridylmethylamino, methoxyethylamino, furylmethylamino, cyclohexylethynyl, trifluoromethylmethoxy or butoxy; Y is amino; and Z is phenyl or fluorophenyl; or a salt thereof.
The object compound (I) and a salt thereof of the present invention can be prepared by the following processes.
Figure imgf000010_0001
ιι: (la) or a salt thereof or a salt thereof Process 2
Figure imgf000011_0001
(III) (lb) or a salt thereof or a salt thereof
Proces s 3
Figure imgf000011_0002
(la) Ic) or a salt thereof or a salt thereof
Process 4
Figure imgf000011_0003
or a salt thereof (IV) or a salt thereof or a salt thereof
Proces s 5
Figure imgf000011_0004
(V) (If) or a salt thereof or a salt thereof Process 6
Figure imgf000012_0001
(ig) (Ic) or a salt thereof or a salt thereof Process 7
Figure imgf000012_0002
or a salt thereof (VI) or a salt thereof or a salt thereof
Process 8
Figure imgf000012_0003
(lh) (Ic) or a salt thereof or a salt thereof
Process 9
Figure imgf000012_0004
(VII) (VIII) (Ii) or a salt thereof or a salt thereof or a salt thereof Process 10
Figure imgf000013_0001
: ii ) (Ic)
Figure imgf000013_0002
or a salt ther eof or a salt thereof or a salt thereof Process 12
Figure imgf000013_0003
(Ik) (X) (Im) or a salt thereof or a salt thereof or a salt thereof
[wherein R1, X, Y and Z are defined above,
R2 is hydrogen or lower alkyl;
R3 is lower alkyl;
R4 is lower alkozxy;
X1 is aryl or heteroaryl, each of which is optionally substituted;
X2 is lower alkenyl, lower alkynyl, lower alkoxy, cyclo (lower ) alkoxy, lower alkylthio, aryloxy, arylthio, NR5R6 (wherein R5 and R6 are each hydrogen, lower alkyl, cyclo (lower-) alkyl, aryl, heterocyclic group, or R5, R6 and nitrogen atom to which they are attached form a N-containing heterocyclic group) or heterocyclyloxy, each of wh-Lch is optionally substituted, or hydroxy;
Hal is a halogen atom;
L is a leaving group; and
BW2 is a constituent of boronic acid such as B(OH)2, tetramethyl-1, 3, 2-dioxaborolan-2-yl, B (CHCH3CH (CH3) 2) 2, or 9-borab±cyclo [3.3.1] nonanyl . ]
The starting compounds or a salt thereof is novel and can be prepared, for example, by the following reaction schemes .
Process A
Figure imgf000014_0001
(XI) (XIII) or a salt thereof (XII) or a salt thereof or a salt thereof
Figure imgf000015_0001
(XIV) (XV) or a salt thereof or a salt thereof
Figure imgf000015_0002
(XVI) (Ha) or a salt thereof or a salt thereof
Figure imgf000015_0003
(lib) or a salt thereof
Process B
Figure imgf000015_0004
(XVII) (V) or a salt thereof (XV'III) or a salt thereof or a salt thereof Process C
Figure imgf000016_0001
(XIX) (III) or a salt thereof (XX) or a- salt thereof or a salt thereof
Process D
Figure imgf000016_0002
(XXI) (XXIII) or a salt thereof (XXII) or a salt thereof or a salt thereof
Figure imgf000016_0003
(VII) or a salt thereof
[wherein R1, R3, Z and Hal are defined above; and R2a and R5 are each lower alkyl.] 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 ±llustrated 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 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 . It is also to be noted that rad iolabelled derivatives of compound (I) , which are suitable for -biological studies, 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 s alt , triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N' -dibenzylethylenediamine salt, etc.), anorganic 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. arginine, aspartic acid, glutamic acid, etc.), and the like.
Suitable examples and illustrations of t e 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" and "lower alkyl" moiety in the term of "lower alkylthio" and " mono- or di- (lowerr) alkylamino" may include straight or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, heχ-yl or the like, in which the preferred one may be methyl, ethyl or isopropyl. Suitable "optionally substituted lower aLkyl" may include lower alkyl which is optionally substituted by suitable substituent (s) such as halogen, lower alkenyl, -lower alkoxy, hydroxy, cyclo (lower ) alkyl, optionally substituted amino, acylamino, aryl, heterocyclic group, acyl or the -Like, in which the preferred one may be hydroxymethyl, hydrox^ethyl, aminoethyl, benzyl or pyridylmethyl .
Suitable "lower alkenyl" may include straig-ht or branched ones such as vinyl, propenyl, allyl, isopropen;yl, butenyl, pentenyl, hexenyl or the like, in which the preferred one may be vinyl.
Suitable "optionally substituted lower alkenyl" may include lower alkenyl which is optionally substituted by suitable substituent (s) such as lower alkoxy, tiydroxy, cyclo (lower) alkyl, amino, aryl, heterocyclic group, acyl or the like.
Suitable "lower alkynyl" may include straig t or branched ones such as ethynyl, propynyl, butynyl, pentynyl, hexynyl or the like, in which the preferred one may be ettnynyl . Suitable "optionally substituted lower al-kynyl" may include lower alkynyl which is optionally substituted by suitable substituent (s) such as lower alkoxy, hydroxy, cyclo (lower) alkyl, amino, aryl, heterocyclic groi p, acyl or the like . Suitable "lower alkoxy" may include straighat or branched ones such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-buto y, pentyloxy, hexyloxy or the like, ±n which the preferred one may be (Cι~C4) alkoxy and the more preferred one may be methoxy or ethoxy. Suitable "optionally substituted lower alkoxy" may include lower alkoxy which is optionally substituted by suitable substituent (s) such as hydroxy, halogen, cyclo (lower) alkyl, lower alkoxy, optionally substituted amino, optionally substituted aryl, heterocyclic group, acyl or the like.
Suitable "cyclo (lower) alkyl" may be cyclo (C3—C8) alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyciohexyl, cycloheptyl, cyclooctyl or the like, in which the preferred one may be cyciohexyl.
Suitable "aryl" and "aryl" moiety in the terms of "aryloxy" and "arylthio" may include phenyl, naphthyl , indenyl, anthryl, or the like, in which the preferred one may be (C6-Cι0) aryl, and the more preferred one may be phenyl. Suitable "optionally substituted aryl" may include aryl which is optionally substituted by suitable substi tuent (s) , preferably 1 to 3 substituent (s) , such as lower alkzyl, lower alkoxy, hydroxy, halogen, etc. Suitable examples of optionally substituted aryl include lower alkylphenyl, lower alk-oxyphenyl and halophenyl, in which more preferred one is meth-oxyphenyl or fluorophenyl.
Suitable "heterocyclic group" may be saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one heteroatom selected from among oxygen, sulfur and nitrogen.
The particularly preferred example of said heterocyclic group may include
3- through 8-membered unsaturated heteromonocyclic groups containing 1 through 4 nitrogen atom(s) , such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-l,2,4-triazolyl, 1H-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, etc.), tetrazolyl (e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g. 4, 5-dihydro-l, 2, 4-triazinyl, 2, 5-dihydro-l, 2, 4-triazinyl, etc.), etc.;
3- through 8-membered saturated heteromonocyclic groups containing 1 through 4 nitrogen atom(s), such as azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl (e.g. piperidino, etc.), piperazinyl, etc.; unsaturated condensed heterocyclic groups containing 1 through 5 nitrogen atom(s), such as indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g. tetrazolo [1, 5-b] pyridazinyl etc. ) , dihydrotriazolopyridazinyl, etc. ; saturated condensed heterocyclic groups containing 1 through 5 nitrogen atom(s) , such as hexahydropyrrolopyrazinyl, etc. ;
3- through 8-membered unsaturated heteromonocyclic groups containing 1 or 2 oxygen atoms and 1 through 3 nitrogen atom(s) , such as oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, etc . ) , etc. ;
3- through 8-membered saturated heteromonocyclic groups containing 1 or 2 oxygen atom(s) and 1 through 3 nitrogen atoms, such as morpholinyl, oxazolidinyl (e.g. 1, 3-oxazolidinyl etc . ) , etc.; unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atom(s) and 1 through 3 nitrogen atom(s), such as benzoxazolyl, benzoxadiazolyl, etc.; saturated condensed heterocyclic groups containing 1 or 2 oxygen atom(s) and 1 through 3 nitrogen atom(s), such as 8-oxa-3-azabicyclo [3.2.1] octyl, etc. ;
3- through 8-membered unsaturated heteromonocyclic groups containing 1 or 2 sulfur atom(s) and 1 through 3 nitrogen atom(s), such as thiazolyl, isothiazolyl, thiazolinyl, thiadiazolyl (e.g. 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 2, 3-thiadiazolyl) , etc.;
3- through 8-membered saturated heteromonocyclic groups containing 1 or 2 sulfur atom(s) and 1 through 3 nitrogen atom(s) , such as thiazolidinyl etc.; 3- through 8-membered unsaturated heteromonocyclic groups containing 1 sulfur atom, such as thienyl etc.; unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atoms and 1 through 3 nitrogen atom(s), such as benzothiazolyl, benzothiadiazolyl, etc.;
3- through 8-membered unsaturated heteromonocyclic groups containing 1 or 2 oxygen atom(s) , such as furyl, pyranyl, dioxolyl, etc. ;
3- through 8-membered saturated heteromonocyclic groups containing 1 or 2 oxygen atom(s), such as oxolanyl, tetrahydropyranyl (e.g. tetrahydro-2H-pyran-2-yl etc.), dioxolanyl, etc.; and unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atom(s), such as isobenzofuranyl, chromenyl (e.g. 2H-chromen-3-yl etc.), dihydrochromenyl (e.g. 3, 4-dihydro-2H-chromen-4-yl etc.), etc.
Suitable "optionally substituted heterocyclic group" may include heterocyclic group which is optionally substituted by suitable substituent (s) , preferably 1 to 3 substituent (s) , such as lower alkyl, lower alkoxy, hydroxy, oxo, halogen, benzyl, optionally substituted amino, aryl, or the like.
Suitable "heteroaryl" and "heteroaryl" moiety in the term of "heteroaryl (lower) alkyl" may be aforesaid "heterocyclic group", in which those categorized as an aromatic heterocyclic group, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, dihydrotriazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl, dihydrotriazolopyridazinyl, oxazolyl, isoxazolyl, oxadiazolyl, ben∑oxazolyl, benzoxadiazolyl, thiazolyl, isothiazolyl, thiazolinyl, thiadiazolyl, thienyl, benzothiazolyl, benzothiadiazolyl, furyl, pyranyl, dioxolyl, isobenzofuranyl, chromenyl, dihydrochromenyl, etc.
Suitable "acyl" may include lower alkanoyl, aroyl, carboxy, protected carboxy, and the like.
Suitable examples of aforesaid "lower alkanoyl" may be formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, lower (alkyl) sulfinyl (e.g. , ethylsulfinyl, etc.), or the like, in which the preferred one may be (Cι~C4) alkanoyl .
Suitable examples of aforesaid "aroyl" may be benzoyl, toluoyl, or the like.
Suitable examples of aforesaid "protected carboxy" may be i) esterified carboxy, in which suitable esterified carboxy may include lower alkoxycarbonyl (e.g. metho.xycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), aryl (lower) alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, 2-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl, 4-phenylpentyloxycarbonyl, 1, 3-diphenylhexyloxycarbonyl, etc. ) , lower (alkyl) sulfonyl (e. g . methylsulfonyl, etc.), and the like; ii) amidated carboxy, in which suitable amidated carboxy may include carbamoyl, N- (lower) alkylcarbamoyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-pentylcarbamoyl, N-hexylcarbamoyl, etc.), N,N-di (lower) alkylcarbamoyl [e.g. N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N,N-dipropylcarbamoyl, N, -di (t-butyl) carbamoyl, N-pentyl- N-hexylcarbamoyl, etc.], N-lower alkyl-N-ar (lower ) alkyl- carbamoyl (e.g. N-methyl-N-benzylcarbamoyl, etc), thiocarbamoyl, and the like.
Suitable "halogen" may be fluoro, chloro, bromo and iodo. Suitable "a leaving group" may include halogen, hydroxy, acyloxy such as alkanoyloxy (e.g. acetoxy, propionyloxy, etc.) or sulfonyloxy (e.g. mesyloxy, tosyloxy, etc.), or the like. Suitable "optionally substituted amino" may include amino, mono- or di- (lower) alkylamino (e.g. methylamine, dimethylamino, methylethylamino, etc.), optionally substituted lower alkyl amino (e.g. methoxyethylamino, dimethylaminoethylamino, benzylamino, morphorinoethylamino, pyridylmethylamino, furylmethylamino, etc.) acylamino (e.g. formylamino, lower alkoxycarbonylamino (e.g. methoxycarbonylamino, ethoxycarbonylamino, etc.), sulf onylamino (e.g. mesylamino, etc.), ureido, etc.), methyleneamino, (dimethyl amino) me thyleneamino, dimethylsulf anylideneamino, or the like.
The processes for preparing the object pyrazine 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 re-ring- conformation with ammonium acetate following the ring-opening reaction with an acid.
This reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, 1,2-dimethoxyethane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, N, N-dimethylf ormamide, methanol, ethanol, dimethyl sulfoxide, diethyl ether, ethyl acetate, a mixture thereof or any other organic solvent which does not adversely affect the reaction.
The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or heating. Process 2
The compound (lb) or a salt thereof can be prepared by subjecting the compound (III) or a salt thereof to ring- conformation with ammonium acetate.
The reaction may be carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene dichloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely affect the reaction. These conventional solvents may also be used in a mixture with water.
The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating. Process 3
The compound (Ic) or a salt thereof can be prepared by one pot reaction consisting of in situ rearrangement-amination following the alkylation of hydroxyl-oxygen atom of the compound (la) or a salt thereof with iodoacetamide .
The present reaction may be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene dichloride, formamide, N, -dimethylformamide, methanol, ethanol, sec-butanol, amyl alcohol, diethyl ether, dioxane, tetrahydrof ran, 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 used in a mixture with water. The reaction is preferably conducted in the presence of base, for example, inorganic base such as alkali metal hydroxide, alkalimetal carbonate, alkalimetal bicarbonate, alkali metal hydride (e.g. sodium hydride, etc.), organic base such as trialkylamine, and the like.
The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating.
The present reaction is preferably carried out in the presence of alkali metal halide (e.g. sodium iodide, potassium iodide, etc.), alkali metal thiocyanate (e.g. sodium thiocyanate, potassium thiocyanate, etc.), di (lower) alkyl azodicarboxylate (e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.) or the like. This reaction can be carried out by the method disclosed in Example 3 and 31, etc. mentioned later or the similar manners thereto . Process 4
The compound (Ie) or a salt thereof can be prepared by reacting the compound (Id) or a salt thereof with the compound (IV) or a salt thereof.
This reaction can be carried out by the method disclosed in Example 32, etc. mentioned later or the similar manners thereto. Process 5
The compound (If) or a salt thereof can be prepared by subjecting the compound (V) or a salt thereof to pyrazine ring- formation with 2 , 3-diamino-2-butenedinitrile . The reactions may be carried out in a conventional solvent such as water, alcohol (e . g . methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene dichloride, tetrahydrofuran, ethyl acetate, toluene, N, N-dimethylformamide, dimethyl sulfoxide, pyridine or any other organic solvent which does not adversely affect the reaction. These conventional solvents may also be used in a mixture with water.
The reaction is preferably conducted in the presence of a base or an acid. Suitable base includes an inorganic base and 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 bicarbonate or hydride or alkoxide thereof, trialkylamine (e.g. trimethylamine, triethylamine, etc.), hydrazine, picoline, or the like.
Suitable acid includes an inorganic acid and organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, or the like.
The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating. This reaction can be carried out by'the method disclosed in Example 4, etc. mentioned later or the similar manners thereto. Process 6
The compound (Ic) or a salt thereof can be prepared by subjecting the compound (Ig) to substitution with aqueous ammonia .
The reactions may be carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, N, N-dimethylformamide, tetrahydrofuran, acetonitrile, dioxane, or any other solvent which is easy to mix with water and does not adversely affect the reaction.
The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating. This reaction can be carried out by the method disclosed in Example 21 mentioned later or the similar manners thereto. Process 7
The compound (lh) or a salt thereof can be prepared by subjecting the compound (Ig) or a salt thereof to nucleophilic substitution with an amine such as the compound (VI) or a salt thereof.
The reactions may be carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetamide, dimethyl acetamide, N, N-dimethylformamide, tetrahydrofuran, acetonitrile, dioxane, or any other solvent which does not adversely affect the reaction.
A liquid amine can be also used as the solvent.
The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating.
This reaction can be carried out by the method disclosed in Example 5 mentioned later or the similar manners thereto. Process 8 The compound (Ic) or a salt thereof can be prepared by subjecting the compound (lh) or a salt thereof to deprotection of amino using 2, 3-dichloro-5, 6-dicyano-l , 4-benzoquinone.
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,NT-dimethylformamide, N,N-dimethylacetamide, or any other organic solvent which does not adversely affect the reaction, or a mixture thereof. The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
This reaction can be carried out by the method disclosed in Example 6 mentioned later or the similar manners thereto. Process 9 The compound (Ii) or a salt thereof can be prepared by subjecting the compound (VII) or a salt thereof coupling reaction with the organoboron compound (VIII) or a salt thereof . The present reaction is preferably carried out by the method disclosed in Example 200 and 201 mentioned later or the similar manner thereto. Process 10
The compound (Ic) or a salt thereof can be prepared from the compound (Ii) by 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 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 bicarbonate thereof, trialkylamine (e.g. trimethylamine, triethylamine, etc.), hydrazine, picoline, 1, 5-diazabicyclo [4.3.0]non- 5-ene, 4, 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.), an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.) and Lewis acid (e.g. boron tribromide, boron trichloride, boron trifluoride, aluminum chloride, titanium trichloride, 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 solvent which does 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.
This reaction can be carried out by the method disclosed in Example 41 mentioned later or the similar manners thereto. Process 11
The compound (Ij) or a salt thereof can be prepared by subjecting the compound (If) or a salt thereof coupling reaction with the organoboron compound (IX) or a salt thereof. The present reaction is preferably carried out Joy the method disclosed in Example 78 mentioned later or the similar manner thereto. Process 12
The compound (Im) or a salt thereof can be prepared by subjecting the compound (Ik) or a salt thereof coupling reaction with the compound (X) or a salt thereof. The present reaction is preferably carried out by the method disclos ed in Examination
69 mentioned later or the similar manner thereto.
Process A
The compound (XII) or a salt thereof can be prepared by subjecting the compound (XI) to the oxime-formation reaction (exemplified by Step 1) by the methods disclosed in Preparation 1 and 2 mentioned later or the similar manners thereto.
Then the compound (XV) can be synthesized by functional trans-formation reaction of the oxime, which is the method disclosed in Preparation 3, 4, 5 and 6 mentioned later or the similar manners thereto that is obvious to the person skilled in the organic chemistry, from the compound (XII) .
And then the ring-formation reaction exemplified by Step 5 of this process can be carried out by the method disclosed in Preparation 7 mentioned later or the similar manners thereto. The object compound (Ila) or a salt thereof can be prepared by subjecting the compound (XVI) or a salt thereof to the alkylation (exemplified by Step 6) . This reaction is carried out in the method disclosed in Preparation 8 and 9 mentioned later or the similar manners thereto.
And the another object compound (lib) can be prepared by subjecting the compound (Ila) to the hydrolysis (exemplified by Step 7) that is disclosed in Preparation 10 mentioned later or the similar manners thereto. Process B
The compound (XVIII) or a salt thereof can be prepared by subjecting the compound (XVII) or a salt thereof to the alkylation (exemplified by Step 1) . This reaction is carried out in the method disclosed in Preparation 12 and 14 mentioned later or the similar manners thereto.
And the object compound (V) or a salt thereof can be prepared by subjecting the compound (XVIII) to oxidation (exemplified by Step 2) , which is disclosed in Preparation 11, for example, mentioned later or the similar manners thereto. Process C
The compound (III) or a salt thereof can be prepared by reacting the compound (XIX) or a salt thereof with the compound (XX) or a salt thereof. This reaction can be carried out by the method disclosed in Preparation 17 mentioned later or the similar manners thereto. Process D
The compound (XXII) can be prepared by subjecting the compound (XXI) to the oxime-formation reaction (exemplified by Step 1) that disclosed in Preparation 20 mentioned later or the similar manners thereto.
And the compound (XXIII) or a salt thereof can be prepared by reacting the compound (XXII) or a salt thereof with aminomalonitrile . The present reaction is preferably, carried out by the method disclosed in Preparation 21 mentioned later or the similar mariner thereto.
The object compound (VII) or a salt thereof can be carried out by reacting the compound (XXIII) or a salt thereof with phosphorus oxychloride. This reaction can be carried out by the method disclosed in Preparation 22 mentioned later or the similar manner thereto.
Above processes, all starting materials and product compounds may be salts. The compounds of above processes can be converted to salts according to a conventional method.
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 Compounds]
3 -amino- 6- ( l-methyl-6-oxo-l , 6-dihydro-3-pyridazinyl ) - 5-phenyl-2-pyrazinecarbonitrile (Example 17)
6- [5-amino-3- (4-f luorophenyl) -2-pyrazinyl] - 2-isopropyl-3 (2H) -pyridaz inone (Example 36)
6- [5-amino-6-chloro-3- (4-f luorophenyl ) -2-pyrazinyl] - 2-isopropyl-3 (2H) -pyridaz inone (Example 37)
6- { 6-bromo-5- [ (dimethyl-lambda~4~- sulf anylidene) amino] -3-phenyl-2-pyrazinyl } -2-isopropyl- 3 (2H) -pyridazinone (Example 66)
6- [5-amino-3-phenyl-6- (phenylethynyl) -2-pyra∑inyl] - 2-isopropyl-3 (2H) -pyridaz. inone (Example 70)
6- { 5 -amino- 6- [ ( 1 -methyl- lH-imidazol -5 -yl) ethynyl] - 3-phenyl-2-pyrazinyl } -2-i sopropyl-3 (2H) -pyridazinone (Example 75)
6- { 5-amino-6- [ (2-f urylmethyl) amino] -3-phenyl- 2-pyrazinyl } -2-isopropyl — 3 (2H) -pyridazinone (Example 134)
6- [5-amino-3-phenyl-6- (IF-pyrazol-l-yl) -2-pyrazinyl] — 2-methyl-3 (2H) -pyridazinone (Example 153) 6- [5-amino-3-phenyl-6- (2-pyridylmethoxy) -2-pyrazinyl] - 2-isopropyl-3 (2H) -pyridazinone (Example 163)
6- (5-amino-6-butoxy-3-phenyl-2-pyrazinyl) -2-methyl- 3 (2H) -pyridazinone (Example 179) 6- [5-amino-6- (2-f urylmethoxy) -3-phenyl-2-pyrazinyl] -
2-methyl-3 (2H) -pyridaz inone (Example 184)
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, 4.5nM) for human Ax receptor and [3H] CGS 21680 (20nM) for human A2a receptor
[II] Test result
Table H
Adenos ine receptor binding
Test compound (Ki:nM) (Example No.) Ai A,;
17 11.23 1.7:
36 23.0-1 6.89
37 15.88 2.65
66 16.0-1 6.79
70 0.88 0.29
75 0.72 0.25
134 6.66 2.60
153 18.88 4.95
163 1.35 0.42
179 16.36 1.57
184 13.22 1.49
Test 2 : Anticatalepsy activity in Mouse [I] Test method
The test compound (3.2mg/kg) was administered orally with ddY mice(n=7). Then, haloperidol (0.32mg/kg) was injected intraperitoneally 30 min. after the administration of the compound. Thirty min. after the injection, the cataleptic responses of mice were measured. The forelimbs of each mouse
3S were placed on a 3 cm high, 3 mm w±de horizontal bar, and the duration of cataleptic posture was measured for up to 30 sec.
[II] Test result
Table 2
Test compound Manifestation rate of Catalepsy (Example No. ) (number of mouse)
17 0/7
36 0/7
37 0/7
66 1/7
70 0/7
75 0/7
134 1/7
153 2/7
163 2/7
179 1/7
184 2/7
The pyrazine compound (I) and a salt thereof of this invention are useful as adenosine antagonists (especially, Ai 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, cerebrovas cular disease, heart failure, hypertension, circulatory insuffi ciency, 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, immunosuppressior., 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.
Adenosine antagonists can Doe useful for Parkinson' s disease by co-administrating with L-3, 4-dihidroxy- phenylalanine (L-DOPA) , which is the most popular drug for Parkinson' s disease (R.Grondin et _ al, Neurology, 52, 1673-1677 (1999)). So the combination use of the pyrazine compound (I) and a salt thereof of this invention with L-DOPA may be also useful for treatment and/or prevention of Parkinson's disease with decreasing or reducing the side effect such as the onset of dyskinesia eliciting by the long-team application of L-DOPA, and so on.
Further, in view of the field using these compounds for as a medicament, these compounds should be durable to some degree. And the duration time of the p^yrazine compound (I) or a salt thereof of this invention are expected to be long-lasting. 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 pyrazine 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 pyrazine 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 pyrazine 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 pyrazine 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 pyrazine compound (I) per kg weight of a human being or an animal, and in case of oralL administration, a daily dose of 0.1 - 100 mg of the pyrazine 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 Preparation and Examples are given for the purpose of illustrating the present invention i_n more detail.
The abbreviations, symbols and terms used in the Preparations and Examples have the following meanings.
AcOH acetic acid
CHC13 chloroform
CDC13 chloroform-d
CH2C12 dichloromethane
DMA N, N-dimethylacetamide
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
EtOAc ethyl acetate
EtOH ethanol
IPE diisopropyl ether
MeOH methanol
THF tetrahydrofuran
HCl hydrochloric acid
MgS04 magnesium sulfate
Na2C03 sodium carbonate
NaH sodium hydride
NaHC03 sodium hydrogen carbonate
NaOH sodium hydroxide
Na2S04 sodium sulfate aq. aqueous cone. concentrated sat. saturated Preparation 1
Under nitrogen atmosphere, 2-isopropyl-6- (2 —oxo- 2-phenylethyl) -3 ( 2E) -pyridazinone (513 mg) was ad-ded to a suspension of NaH (60% dispersion in mineral oil) (84 mg) in THF (5 ml) and the mixture was stirred at 45-50°C for 30 minutes . After addition of isoamyl nitrite (0.27 ml), the mixture was stirred at the same temperature for 8 hours. The mixture was dissolved in EtOAc, washed with IN HCl and brine and dried over MgS04. The mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to gd-ve 1- (l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -2-phenyl- 1, 2-ethanedione 1-oxime as a solid (185 mg) . m.p. : 173-175°C (IPE)
IR (KBr) : 3153, 3024, 2854, 1691, 1647, 1576 cm-1 Mass (ESI) : 593 (2M+Na)+, 308 (M+Na)+
1R NMR (CDC13, δ) : 1.01 (6H, d, J=6.60 Hz), 5.13 ( IH, 7-plet, J=6.60 Hz), 7.01 (IH, d, J=9.62 Hz), 7.45-7.63 (3H, m) , 7.81 (IH, d, J=9.62 Hz), 7.87-7.93 (2H, m) , 9.03 (IH, s) Preparation 2
A solution of sodium nitrite (1.725 g) of water (5.42 ml) was added in portions to a solution of 2-isopropyl- 6- (2-oxo-2-phenylethyl) -3 (2H) -pyridazinone (2.57 g) in a mixture of AcOH (2ml) and EtOAc (8 ml) at 20-25°C and the mixture was stirred at the same temperature for 8 hours. EtOAc w s added to the mixture, washed with sat. aq. NaHC03 solution and brine, dried over MgS04 and concentrated under reduced pressure to give a solid. The solid was triturated with IPE and collected by filtration to give 1- (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -2-phenyl-l, 2-ethanedione 1-oxime as a solid (1.71 g) , which was identical to the authentic sample (the product of Preparation 1) by melting point and IR, MS and NMR spectra. Preparation 3
Zinc dust (1.57 g) was added in portions to a suspension of 1- (l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) - 2-phenyl-l, 2-ethanedione 1-oxime (856 mg) in a mixture acetic anhydride (1.7 ml) and AcOH (10 ml) under ambient temperature and the mixture was stirred at the same temperature for 4 hours. An insoluble material was filtered off and a filtrate was concentrated under reduced pressure to give a residue. The residue was dissolved in EtOAc, washed with sat. aq . NaHC03 solution, dried over MgS04 and subjected to column chromatography on silica gel eluting with a mixture of MeOH and EtOAc (2:98 v/v) to give N- [1- (l-isopropyl-6-oxo-l, 6- dihydro- 3-pyridazinyl) -2-oxo-2-phenylethyl] acetamide as a solid (724 mg) . m.p. : 65-66°C (acetone - IPE) IR (KBr) : 3494, 3303, 1657, 1583, 1514 cm"1 Mass (ESI) : 336 (2M+Na)+ XH NMR (CDC13, δ) : 0.96 (3H, d, J=6.60 Hz), 1.16 (3H, d, J=6.60 Hz), 2.16 (3H, s) , 5.11 (IH, 7-plet, J-6.60 Hz), 6.56 (IH, d, J=7.02 Hz), 6.86 (IH, d, J=9.54 Hz), 7.10 (IH, d, J=7.02 Hz), 7.39-7.59 (4H, m) , 7.94-8.01 (2H, ) Preparation 4 A solution of N- [1- (l-isopropyl-6-oxo-l, 6-dihydro-
3-pyridazinyl) -2-oxo-2-phenylethyl] acetamide (1.00 g) in 10% hydrogen chloride solution of MeOH (10 ml) was refluxed for 24 hours. After cooling, a precipitate was collected by filtration to give 6- ( l-amino-2-oxo-2-phenylethyl) -2-isopropyl- 3 ( 2H) -pyridazinone hydrochloride as a solid (534 mg) . A filtrate was concentrated under reduced pressure, triturated with IPE and collected by filtration to give the same compound as a solid (333 mg) . m.p. : 145°C (dec.) (MeOH) IR (KBr) : 3425, 3037-2939, 1697, 1664, 1576 cm-1 Mass (ESI) : 294 (M+Na)+, 272 (M+H)+ αH NMR (DMSO-d6, δ) : 0.79 (3H, d, J=6.60 Hz) , 1.11 (3H, d, J=6.60 Hz), 4.94 (IH, 7-plet, J=6.60 Hz), 6.45 (IH, s) , 7.04 (IH, d, J=9.64 Hz), 7.49-7.71 (3H, m) , 7.80 (IH, d, J=9.64 Hz), 7.97-8.02 (2H, m) , 9.11 (3H, brs) Preparation 5
Under ice-cooling, triethylamine (2.79 ml) was added dropwise to a suspension of 6- (l-amino-2-oxo-2-phenylethyl) - 2-isopropyl-3 (2f) -pyridazinone hydrochloride (3.08 g) and dimethyl dicarbonate (2.01 g) in CH2C12 (30 ml) and stirred at the same temperature for 40 minutes . The mixture was w ashed with IN HCl and sat. aq. NaHC03 solution, dried over MgjS04 and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (30:70 v/v) to give methyl [1- (l-isopropyl-6-oxo-l, 6-dihydro-3-pyrida zinyl ) - 2-oxo-2-phenylethyl] carbamate as a syrup (2.96 g) . IR (Neat) : 6329, 1734-1651, 1595 cm"1 Mass (ESI) : 681 (2M+Na)+, 352 (M+Na)+, 330 (M+H)"1"
XH NMR (CDC13, δ) : 1.06 (3H, d, J=6.60Hz), 1.19 (3H, d, J=6.60 Hz), 3.73 (3H, s) , 5.14 (IH, 7-plet, J=6.60Hz), 6.33 (2H, brs), 6.86 (IH, d, J=9.56Hz), 7.31-7.62 (4H, m) , 7.98-8.03 (2H, m) Preparation 6 Under ice-cooling, a solution of triethylamine (16.8 ml) of CH2CI2 (30 ml) was added dropwise to a suspension of 6- (l-amino-2-oxo-2-phenylethyl) -2-isopropyl-3 (2f) - pyridazinone hydrochloride (15.42 g) and methyl chloroformate (4.65 ml) in CH2C12 (155 ml) and stirred at the same temperature for 30 minutes. The mixture was washed with water, IN HCl ancd sat. aq. NaHC03 solution, dried over MgS04 and concentrated- under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (30:70 v/v) to give methyl [1- (l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -2-oxo- 2-phenylethyl] carbamate as a syrup (15.78 g) , which was identical to the authentic sample (the product of Preparation 5) by IR, MS and NMR spectra. Preparation 7
A solution of methyl [1- (l-isopropyl-6-oxo-l, 6-dihydro-
3-pyridazinyl) -2-oxo-2-phenylethyl] carbamate (2.46 g) in DKIF
(10 ml) was added to a suspension of NaH (60% dispersion in mineral oil) (314 mg) in DMF (15 ml) and the mixture was heated at 70-75°C for 3 hours. A mixture of AcOH (0.5 ml) and water (75 ml) was added to the mixture to give a precipitate. Trie precipitate was collected by filtration and dried under reduced pressure to give 2-isopropyl-6- (2-oxo-5-phenyl-2, 3-dihydrσ- oxazol-4-yl) -3 (2if) -pyridazinone as a solid (1.56 g) . m.p. : 238-239.5°C (acetone - n-hexane) IR (KBr) : 1753, 1664, 1591 cm"1 Mass (ESI) : 617 (2M+Na)+, 320 (M+Na)+, 298 (M+H)+ λH NMR (CDC13, δ) : 1.43 (6H, d, J=6.60 Hz), 5.36 (IH, 7-plet, J=6.60 Hz), 6.83 (IH, d, J=9.60 Hz), 7.27 (IH, d, J=9.60 Hz> , 7 . 45-7 . 59 ( 5H, m) , 9 . 25 ( IH, brs )
Preparation 8
Under nitrogen atmosphere, 2-isopropyl-6- (2-oxo-
5-phenyl-2, 3-dihydro-oxazol-4-yl) -3 ( 2H) -pyridazinone (100 mg) was added to a suspension of NaH (60% dispersion in mineral oil) (14 mg) in DMF (0.3 ml) at 20-25°C and the mixture was stirred at the same temperature for 30 minutes. Methyl bromoacetate (0.0035 ml) was added to the mixture and stirred at 70-75°C for 7 hours. After an addition of water (5 ml), an aqueous solution was removed by decantation to give a residue.
The residue was dissolved in CHC13, dried over MgS04, concentrated under reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40:60 v/v) to give methyl [ 4- (l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -2-oxo-5-phenyl-oxazol-3 (2f) -yl] - acetate as a solid (64 mg) . m.p. : 109.5-111QC (acetone - n-hexane)
IR (KBr) : 1765, 1670, 1593 cm"1
Mass (ESI) : 392 (M+Na)+ 2H NMR (CDC13, δ) : 1.38 (6H, d, J=6.65 Hz), 3.70 (3H, s), 4.73
(2H, s), 5.37 (IH, 7-plet, J=6.65Hz), 6.82 (IH, d, J=9.63Hz),
7.10 (IH, d, J=9.63 Hz), 7.37-7.47 (5H, m)
Preparation 9
Ethyl 2- [ 4- ( 1 -isopropyl- 6-oxo-l, 6-dihydro- 3 -pyridazinyl ) - 2-oxo-5-phenyl-oxazol-3 (2f) -yl] propanoate
The title compound was obtained in a similar manner to that of Preparation 8. IR (Neat) : 1770, 1670, 1589 cm"1 Mass (ESI) : 420 (M+Na)+
XH NMR (CDC13, δ) : 1.25 (3H, t, J=7.10 Hz), 1.40 (6H, d, J=6.66 Hz), 1.77 (3H, d, J=7.25Hz), 4.19 (2H, q, J=7.10Hz), 4.89 (IH, q, J=7.25Hz), 5.38 (IH, 7-plet, J=6.66Hz), 6.87 (IH, d, J=9.66 Hz), 7.11 (IH, d, J=9.66 Hz), 7.36-7.41 (5H, m) Preparation 10
A solution of ethyl 2- [4- (l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -2-oxo-5-phenyl-oxazol-3 (2ff) -yl] - propanoate (3.32 g) in a mixture of IN aq. ΝaOH (25 ml) and THF (25 ml) was heated at 50-55°C for 2 hours. After removal of THF, the mixture was acidified with li aq. HCl, extracted with EtOAc, dried over MgS04 and concentrated under reduced pressure to give a residue . The residue was recrystallized from a mixture of CHC13 and n-hexane to give 2- [4- (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -2-oxo-5-phenyl-oxazol-3 (2ff) -yl] propanoic acid as a solid (2.53 g) . m.p. : 173-175°C (CHC13 - n-hexane) IR (KBr) : 2989, 1765-1747, 1630, 1568 cm"1 Mass (ESI, Νeg) : 368 (M-H)"
XH ΝMR (CDCI3, δ) : 1.42 (6H, d, J=6.61 Hz), 1.78 (3H, d, J=7.20 Hz), 4.99 (IH, q, J=7.20Hz), 5.34 (IH, 7-plet, J=6.61Hz), 7.01 (IH, d, J=9.58 Hz), 7.13 (IH, d, J=9.58 Hz), 7.34 (5H, s) Preparation 11
In the presence of palladium chloride (3.72 g), a solution of 2-isopropyl-6- (phenylethynyl) -3 (2if) -pyridazinone (50.13 g) in DMSO (125 ml) was heated at 140-145°C for 3 hours. After cooling, water (500 ml) was added and the mixture was extracted with EtOAc. An organic solution was dried over MgS04, concentrated under reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (20:80 v/v) to give 1- (l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -2-phenyl-l, 2-ethanedione as a solid (44.98 g) . m.p. : 71-73°C (IPE - n-hexane) IR (KBr) : 1682, 1666 cm"1
Mass (ESI) : 271 (M+Na)+, 293 (M+H)+
XH NMR (CDC13, δ) : 1.13 (6H, d, J=6.58 Hz), 5.21 (IH, 7-plet, J=6.58 Hz), 7.00 (IH, d, J=9.58 Hz), 7.26-7.57 (2H, m) , 7.62-7.71 (IH, m) , 7.86-7.95 (3H, m) Preparation 12
Under nitrogen atmosphere, 6- (phenylethynyl) -3 (2if) - pyridazinone (15.54 g) was added to a suspension of NaH (60% in oil suspension) (3.33 g) in DMF (90 ml) and the mixture was stirred at 50-55°C for 30 minutes. Under ice-cooling, iodoethane (6.97 ml) was added to the mixture and the mixture was stirred at 50-55°C for 3 hours. After addition of water, the reaction mixture was extracted with EtOAc, dried over MgS04 and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (70:30 v/v) to give 2-ethyl-6- (phenylethynyl) -3 (2if) -pyridazinone as a solid (14.06 g) . m.p. : 74-75°C (acetone - n-hexane) IR (KBr) : 2214, 1674, 1587 cm"1
Mass (ESI) : 471 (2M+Na)+, 247 (M+Na)+, 225 (M+H) + H NMR (CDC13, δ) : 1.41 (3H, t, J=7.21 Hz), 4.25 (2H, q, J=7.21
Hz), 6.90 (IH, d, J=9.54Hz), 7.33 (IH, d, J=9.5 Hz), 7.36-7.43 (3H, m) , 7.53-7.60 (2H, m) Preparation 13
1- (l-Ethyl-6-oxo-l, 6-dihydro-3-pyridazinyl ) -2-phenyl-
1 , 2-ethanedione
The title compound was obtained in a similar manner to that of Preparation 11. IR (Neat) : 1697-1662, 1595 cm"1
Mass (ESI) : 279 (M+Na)+, 257 (M+H)+ H NMR (CDCI3, δ) : 1.23 (3H, t, J=7.22 Hz), 4.14 (2H, q, J=7.22
Hz), 7.02 (IH, d, J=9.64 Hz), 7.48-7.57 (2H, m) , 7.63-7.72 (IH, m) , 7.87-7.98 (3H, m) Preparation 14
2-Methyl-6- (phenylethynyl) -3 (2if) -pyridazinone
The title compound was obtained in a similar manner to that of Preparation 12. m.p. : 118-120°C (acetone - n-hexane)
IR (KBr) : 2214, 1668, 1583 cm"1
Mass (ESI) : 443 (2M+Na)+, 233 (M+Na)+, 211 (M+H)+
1H NMR (CDC13, δ) : 3.83 (3H, s), 6.92 (IH, d, J=9.60 Hz),
7.32-7.43 (4H, m) , 7.53-7.59 (2H, m) Preparation 15
1- (l-Methyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -2-phenyl-
1 , 2-ethanedione
The title compound was obtained in a similar manner to that of Preparation 11. m.p. : 89-92°C (acetone - n-hexane)
IR (KBr) : 1685, 1676, 1664, 1599 cm"1
Mass (ESI) : 265 (M+Na)+, 243 (M+H) +
:H NMR (CDCI3, δ) : 3.74 (3H, s), 7.04 (IH, d, J=9.84 Hz),
7.49-7.58 (2H, m) , 7.65-7.71 (IH, m) , 7.88-8.01 (3H, m) Preparation 16
A mixture of 2-isopropyl-6- (2-oxo-2-phenylethyl) -
3 (2if) -pyridazinone (100 g) and sulfurylchloride (32.9 ml) in
CH2CI2 (200 ml) was refluxed with stirring for 5 hours. Water and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgS04. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain 6-(l-chloro- 2-oxo-2-phenylethyl) -2-isopropyl-3 (2if) -pyridazinone (100 g) as white powder.
1R NMR (CDC13, δ) : 1.2-1.4 (6H, m) , 5.26 (IH, 7-plet, J=6.6 Hz), 6.25 (IH, s), 6.94 (IH, d, J=9.6 Hz), 7.4-7.7 (4H, m) , 8.0-8.15 (2H, m) Mass (ESI) : 291 (M+H)+, 313 (M+Na) + Preparation 17
A mixture of 6- (l-chloro-2-oxo-2-phenylethyl) - 2-isopropyl-3 (2H) -pyridazinone (500 mg) , glysine ethyl ester (264 mg) and pottasium carbonate (523 mg) in DMF(5 ml) was stirred at room temperature for 2 hours, then at 50°C for 1.5 hours. To the mixture was added water (30 ml) and the mixture was extracted with EtOAc (20 mlx2) , then the combined organic layers was washed with water (30 mlx2) and brine (20 ml) , dried over MgS04, filtered and evaporated. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain ethyl { [1- (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -2-oxo-2-phenylethyl] amino}acetate (437.7 mg) as white powder. XH NMR (CDCI3, δ) : 1.1-1.4 (9H, m) , 3.46 (2H, s) , 4.0-4.3 (2H, ) , 5.22 (IH, 7-plet, J=6.6Hz), 5.39 (IH, s) , 6.83 (IH, d, J=9.5 Hz), 7.2-7.7 (4H, m) , 7.9-8.1 (2H, ) Mass (ESI) : 380 (M+Na)+ Preparation 18
6- [l-Chloro-2- (4-f luorophenyl) -2-oxoethyl] -2-isopropyl- 3 (2if) -pyridazinone
The title compound was obtained in a similar manner to that of Preparation 16. λ NMR (DMSO-d6, δ) : 1.2-1.4 (6H, m) , 5.26 (IH, 7-plet, J=6.6
Hz), 6.18 (IH, s), 6.95 (IH, d, J=9.6Hz), 7.1-7.3 (2H, m) , 7.50 (IH, d, J=9.6Hz), 8.0-8.2 (2H, m)
Mass (ESI) : 309 (M+H)+, 331 (M+Na)+
Preparation 19 Ethyl ( [2— (4-f luorophenyl) -1- (l-isopropyl-6-oxo-
1, 6-dihydro- 3 -pyridazinyl ) -2-oxoethyl] amino} acetate
The title compound was obtained in a similar manner to that of Preparation 17. aH NMR (CDCI3, δ) : 1.1-1.4 (9H, m) , 3.45 (2H, s) , 4.0-4.3 (2H, m) , 5.23 (IH, 7-plet, J=6.6 Hz) , 5.35 (IH, s) , 6.84 (IH, d, J=9.6
Hz), 7.0-7.2 (4H, m) , 7.2-7.4 (IH, m) , 7.9-8.15 (2H, m)
Mass (ESI) : 376 (M+H)\ 398 (M+Na) +
Preparation 20
A mixture of 6-acetyl-2-isopropyl-3 (2ff) -pyridazinone (74.0 g) and t-butyl nitrite (73.3 l) in THF (740 ml) was stirred at 0°C. Pottasium t-butoxide (55.3 g) was added to the reaction mixture. Then the reaction mixture was stirred at 25°C for 1 hour. Water, I N HCl and EtOAc were added to the reaction mixture. The organic layer was washed with IN HCl, aq. ΝaHC0 and brine. The organic layer was separated, and dried over MgS04. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain (1-isopropyl- β-oxo-1, 6-dihydro-3-pyridazinyl) (oxo)- acetaldehyde oxime (15.0 g) as white powder.
1H NMR (DMSO-d6, δ) : 1.44 (6H, d, J=6.6 Hz), 5.37 (IH, 7-plet, J=6.6Hz), 7.02 (IH, d, J=9.6Hz), 7.93 (IH, d, J=9.6Hz), 8.82 (IH, s), 9.7-10.5 (IH, br) Mass (ESI) : 210 (M+H)+, 232 (M+Na)+ Preparation 21
A mixture of (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl ) (oxo) acetaldehyde oxime (11.16 g) , aminomalononitrile (13.6 g) and p-toluenesulfonic acid (10.2 g) in 2-propanol (200 ml) was stirred at 50°C for 3 hours. Water, aq. NaHC03 and EtOAc were added to the reaction mixture to give a pale yellow precipitate. The precipitate was collected by filtration to obtain 3-amino-6- ( l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -2-pyrazinecarbonitrile 4-oxide (3.84 g) as white powder. λH NMR (DMSO-ds, δ) : 1.36 (6H, d, J=6.6 Hz), 5.18 (IH, 7-plet,
J=6.6Hz), 7.03 (IH, d, J=9.6Hz), 8.02 (IH, d, J=9.6Hz), 8.33
(2H, br) , 8.94 (IH, s) Mass (ESI) : 273 (M+H)+, 295 (M+Na)+
Preparation 22
A solution of 3-amino-6- (l-isopropyl-6-oxo-
1, 6-dihydro-3-pyridazinyl) -2-pyrazinecarbonitrile 4-oxide (1.54 g) in DMF (30 ml) was stirred at 0°C. Phosphorous oxychloride (1.58ml) was dropped to the solution and the reaction mixture was stirred under same condition for 3 hours.
Water was added to the reaction mixture. The reaction mixture was stirred at 20°C for 20 hours to give a yellow precipitate.
The precipitate was collected by filtration to obtain yellow powder. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain N ' - [6-chloro-
3-cyano-5- ( l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -
2-pyrazinyl] -N, N-dimethylimidoformamide (1.0 g) as white powder.
XH NMR (DMSO-d6, δ) : 1.42 (6H, d, J=6.6 Hz), 3.26 (3H, s), 3.27 (3H, s), 5.40 (IH, 7-plet, J=6.6 Hz), 6.99 (IH, d, J=9.6 Hz),
7.86 (IH, d, J=9.6 Hz), 8.68 (IH, s)
Mass (ESI) : 346 (M+H)+, 368 (M+Na)+ Preparation 23
Under ice-cooling, to a suspension of 6- (l-amino-2-oxo- 2-phenylethyl) -2-isopropyl-3 (2if) -pyridazinone hydrochloride (1.00 g) and tert-butyl { 2- [ (2, 5-dioxo-l-pyrrolidinyl) oxy] - 2-oxoethyl } carbamate (973 mg) in CHCI2 (10 ml) was added ethyl (diisopropyl) amine (0.651 ml) and stirred at the same temperature for 2 hours and at 20-25°C for 18 hours. The mixture was washed with water, dried over MgS0 and concentrated under reduced pressure to give syrup. The syrup was purified by column chromatography on silica gel (EtOAc only) to give tert-butyl (2-{ [1- (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -2-oxo-2-phenylethyl] amino} - 2-oxoethyl ) carbamate as an amorphous solid (1.13 g) . IR (KBr) : 3370-3290, 2978, 1714-1649, 1589, 1516 cm"1 Mass (ESI) : 879 (2M+Na)+, 451 (M+Na)+, 429 (M+H)+
1R NMR (CDCI3, δ) : 1.00 (3H, d, J=6.60 Hz), 1.16 (3H, d, J=6.60 Hz), 1.47 (9H, s) , 3.88-3.93 (2H, m) , 5.03-5.21 (2H, m) , 6.54 (IH, d, J=6.98 Hz) , 6.87 (IH, d, J=9.56 Hz) , 7.35-7.69 (5H, m) , 7.95-8.01 (2H, m) Preparation 24
In a sealed tube, iodomethane (0.6 ml) was added to a solution of 6- [5-amino-3-phenyl-6- (4-pyridyl) -2-pyrazinyl] - 2-isopropyl-3 (2if) -pyridazinone (120 mg) in THF (3 ml) and the mixture was stirred at 25-35°C for 18 hours. A precipitate was collected by filtration to give 4- [3-amino-6- (1-isopropyl-
6-oxo-l, β-dihydro-3-pyridazinyl) -5-phenyl-2-pyrazinyl] -
1-methylpyridinium iodide (152 mg) . m.p. : 166-168°C IR (KBr) : 3495-3338, 3207, 1643, 1576, 1530 cm-1
Mass (ESI) : 399 (M-I)+
XH NMR (DMS0-d6, δ) : 0.74 (6H, d, J=6.60 Hz), 4.39 (3H, s) ,
4.90 (IH, 7-plet, J=6.60Hz), 7.02 (IH, d, J=9.56Hz), 7.38-7.48
(7H, m) , 7.97 (IH, d, J=9.56 Hz) , 8.56 (2H, d, J=6.80 Hz) , 9.01 (2H, d, J=6.80 Hz)
Preparation 25
3- [3-amino-6- (l-isopropyl-6-oxo-l , 6-dihydro-3-pyridazinyl) -
5-phenyl-2-pyrazinyl] -1-methylpyridinium iodide
The title compound was obtained in a similar manner to that of Preparation 26. m.p. : 250-253°C
IR (KBr) : 3495-3323, 3190, 1643, 1581, 1541, 1504 cm"1
Mass (ESI) : 399 (M-I)+ αH NMR (DMSO-de, δ) : 0.74 ( 6H r d, J=6.60 Hz), 4.43 (3H, s) , 4.90 (IH, 7-plet, J=6.60 Hz) , 7.01 (IH, d, J=9.60 Hz) , 7.23 (2H, brs) , 7.38-7.45 (5H, m) , 7.92 (IH, d, J=9.60 Hz) , 8.25 (IH, dd,
J=6.08, 8.12 Hz), 8.93 (IH, d, J=8.12 Hz), 9.02 (IH, d, J=6.08
Hz), 9.43 (IH, s)
Preparation 26 A suspension of 3-amino-6- (l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -2-pyrazinecarbonitrile 4-oxide (500 mg) in 25% hydrogen bromide in AcOH (3 ml) was stirred at 20-25°C for 4 hours. After addition of dioxane (9 ml), a precipitate was collected by filtration. The precipitate was added in water (3 ml) and adjusted to pH 8 with IN aq. ΝaOH solution. The solid was collected by filtration and dried under reduced pressure to give 3-amino-6- ( l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -2-pyrazinecarboxamide 4-oxide (366 mg) . m.p. : >250°C
IR (KBr) : 3533-3386, 2233, 1651, 1641, 1587 cm"1
Mass (ESI) : 603
Figure imgf000061_0001
313 (M+Na)+, 291 (M+H) + αH NMR (DMSO-d6, δ) : 1.34 (6H, d, J=6.60Hz), 5.19 (IH, 7-plet, J=6.60 Hz), 7.05 (IH, d, J=9.65 Hz)^ 7.93 (IH, brs), 7.9-8.6 (2H, br) , 8.63 (IH, brs), 8.66 (IH, d, J=9.65 Hz), 8.89 (IH, s) Preparation 27
To a suspension 3-amino-6- (l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -2-pyrazinecarboxamide 4-oxide
(1.65 g) in DMF (33 ml), phosphorous oxychloride (1.59 ml) was added below -30°C and the mixture was stirred at 0-5°C for one hour. The reaction mixture was poured into ice-water (132 ml) , stirred at 40-50°C for 2 hours, adjusted to pH 8 with 30 % aq. NaOH solution under ice-cooling and a precipitate was collected by filtration. The precipitate was purified by column chromatography on silica gel eluting with a mixture of MeOH and EtOAc (2:98 v/v) to give 3-amino-5-chloro-6- (1-isopropyl- 6-oxo-l, 6-dihydro-3-pyridazinyl) -2-pyrazinecarboxamide as a solid (682 mg) . m.p. : >250°C
IR (KBr) : 3458, 3400, 3278, 3145, 1684, 1664, 1616, 1593, 1523, 1514 cm"1 Mass (ESI) : 641 and 639 (2M+Na)+, 333 and 331 (M+Na)+, 311 and 309 (M+H)+ H NMR (DMSO-de, δ) : 1.33 (6H, d, J=6.62 Hz), 5.23 (IH, 7-plet, J=6.62 Hz), 6.99 (IH, d, J=9.67 Hz), 7.79 (IH, brs), 8.0-8.3 (4H, m) Example 1
A solution of methyl [4- (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl ) -2-oxo-5-phenyloxazol-3 (2ff)-yl]acetate (100 mg) in a mixture of cone. HCl (1.5 ml) and AcOH (3.5 ml) was heated at 95-100°C for 10 hours. The reaction mixture was concentrated under reduced pressure, dissolved in 5% hydrogen chloride solution of MeOH (5 ml) and heated under reflux for 5 hours. After concentration, the residue was dissolved in DMSO (0.5 ml). Ammonium acetate (209 mg) was added to the mixture and heated at 120-125°C for 10 hours. The reaction mixture was suspended in CHC13, washed with water, dried over MgS04 and concentrated under reduced pressure to give a residue. The residue was purified by preparative thin layer chromatography on silica gel (EtOAc) to give 6- (5-hydroxy-3-phenyl- 2-pyrazinyl) -2-isopropyl-3 (2f) -pyridazinone as a solid (14 mg) . m.p. : 225-227°C (acetone) IR (KBr:) : 1649, 1589 cm"1 Mass (ESI) : 331 (M+Na) + XH NMR (CDC13, δ) : 0.80 (6H, d, J=6.60 Hz), 5.05 (IH, 7-plet,
J=6.60 Hz), 6.94 (IH, d, J=9.60 Hz), 7.32-7.50 (5H, m) , 7.73
(IH, d , J=9.60 Hz), 8.19 (IH, s)
Example 2
6- (5-Hγdroxy-6-methyl-3-phenyl-2-pyrazinyl) -2-isopropyl- 3 (2f) -pyridazinone
The title compound was obtained in a similar manner to that of Example 1. m.p. : >250°C (acetone - n-hexane)
IR (KBx) : 3087-2917, 1678, 1651, 1575 cm"1 Mass (ESI) : 667 (2M+Na)+, 345 (M+Na)+, 323 (M+H) +
XH NMR (CDCI3, δ) : 0.80 (6H, d, J=6.62 Hz), 2.50 (3H, s), 5.04
(IH, 7-plet, J=6.62 Hz) , 6.94 (IH, d, J=9.58 Hz) , 7.28-7.47 (5H, m) , 7.77 (IH, s) , 10.7 (IH, brs)
Example 3 Potassium carbonate (77 mg) was added to a solution of 6- (5-hydroxy-6-methyl-3-phenyl-2-pyrazinyl) -2-isopropyl- 3 (2f) -pyridazinone (150 mg) and iodoacetamide (95 mg) in DMA (1 ml) and the mixture was stirred at 20-25°C for 2 hours. To the reaction mixture, potassium carbonate (235 rag) was added and heated at 150-155°C for 2 hours. After addition of water, the mixture was extracted with CHCI3, washed with brine, dried over MgS04 and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (20:80 v/v) to give 6- ( 5-amino-6-methyl-3-phenyl-2-pyrazinyl) - 2-isopropyl-3 (2if) -pyridazinone as a solid (97 mg) . m.p. : 208-209.5°C (MeOH) IR (KBr) : 3284, 3155, 1657, 1616, 1585 cm"1 Mass (ESI) : 665 (2M+Na)+, 344 (M+Na)+, 322 (M+H) +
XH NMR (CDCI3, δ) : 0.84 (6H, d, J=6.60 Hz), 2.50 (3H, s), 4.78 (2H, brs), 5.07 (IH, 7-plet, J=6.60 Hz), 6.94 (IH, d, J=9.55 Hz), 7.26-7.38 (5H, m) , 7.76 (IH, d, J=9.55 Hz) Example 4 A mixture of 1- (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -2-phenyl-l, 2-ethanedione (1.15 g) and 2, 3-diamino-2-butenedinitrile (0.46 g) in acetonitrile (6 ml) was heated at 70-75°C for 3 hours. A reaction mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 5- ( l-isopropyl-6-oxo-l, 6 — dihydro-3-pyridazi yl) -6-phenyl-2, 3-pyrazinedicarbonitxile as a solid (1.30 g ) . m.p. : 201-202°C (acetone - n-hexane) IR (KBr) : 2247, 1660, 1593, 1518 cm"1 Mass (ESI) : 365 (M+Na) +
1H NMR (CDC13, δ) : 0.8-1 (6H, d, J=6.60 Hz), 5.07 (IH, 7-plet, J=6.60 Hz), 7.06 ( IH, d, J=9.80 Hz), 7.42-7.57 (5H, m) , 7.99 (IH, d, J=9.80 Hz)
1tt NMR (DMSO-de, δ) : 0.73 (6H, d, J=6.60 Hz), 4.90 (IH, 7-plet, J=6.60 Hz), 7.11 ( IH, d, J=9.85 Hz), 7.47-7.63 (5H, m) , 8.03 (IH, d, J=9.85 Hz) Example 5 A mixture of: 5- ( l-isopropyl-6-oxo-l, 6-dihydro-
3-pyridazinyl) -6-phenyl-2, 3-pyrazinedicarbonitrile (343 mg) and (4-methoxybenz:yl) amine (0.137 ml) in DMA (1 ml) was heated at 80-85°C for 25 hours. After addition of water, a precipitate was collected by filtration, dissolved in CHC13, dried over MgS04 and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel eluting with a. mixture of n-hexane and EtOAc (60:40 v/v) to give 6- (l-isop:ropyl-6-oxo-l, 6-dihydro-3-pyridazinyl ) - 3- [ ( 4-methoxybenzyl) amino] -5-phenyl-2-pyrazinecarbonitrile as an amorphous solid (227 mg) .
IR (KBr) : 2220, 1655, 1562, 1510 cm"1
Mass (ESI) : 927 (2M+Na)+, 475 (M+Na) +
1 NMR (CDC13, δ) : 0.82 (6H, d, J=6.60 Hz), 3.82 (3H, s) , 4.72 (2H, d, J=5.42 Hz), 5.06 (IH, 7-plet, J=6.60 Hz), 5.70 (IH, t,
J=5.42 Hz) , 6.89-7.00 (3H, m) , 7.26-7.43 (7H, m) , 7.76 (IH, d,
J=9.70 Hz)
Example 6
To a solution of 6- ( l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -3- [ ( 4-methoxybenzyl) amino] -5-phenyl-
2-pyrazinecarbonit-rile (590 mg) in a mixture of water (1.5 ml) and CHCI3 (30 ml) was added 4 , 5-dichloro-3, 6-dioxo-
1, 4-cyclohexadiene—1, 2-dicarbonitrile (888 mg) . The reaction. mixture was stirred at 25-30°C for 10 hours, washed with IN aq . ΝaOH solution, dried over MgS04 and concentrated under reduced pressure to give a rresidue. The residue was subjected to column chromatography on s ilica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 3-amino-6- (l-isopropyl-6-oxo—
1, 6-dihydro-3-pyri dazinyl) -5-phenyl-2-pyrazinecarbonitrile as a solid (335 mg ) . m.p. : 231-233°C (acetone - n-hexane)
IR (KBr) : 3410, 3325, 3305, 2227, 1639, 1583, 1543, 1525 cm"1
Mass (ESI) : 355 (M+Νa)+
Η NMR (CDCI3, δ) : 0.81 (6H, d, J=6.60 Hz), 5.06 (IH, 7-pletΛ J=6.60 Hz), 5.46 (2H, brs), 6.98 (IH, d, J=9.58 Hz), 7.39 (5H, s) , 7.78 (IH, d, J=9.58 Hz)
XH NMR (DMSO-d6, δ) : 0.72 (6H, dr J=6.62 Hz), 4.89 (IH, 7-plet, J=6.62 Hz), 6.98 (IH, d, J=9.65 Hz), 7.39 (5H, s), 7.73 (2H, brs), 7.80 (IH, d, J=9.65 Hz) Example 7
A suspension of 3-amino-6- ( l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl ) -5-plenyl-2-pyrazinecarbonitrile (143 mg) in 25% hydrogen bromide solution of AcOH (1.5 ml) was stirred at 25-30°C for 2 hours. The reaction mixture was poured into a mixture of Na2Cθ3 (2 g) and ice-water (30 g) , extracted with CHC13, dried over MgS04 and concentrated under reduced pressure to give a residue. The -residue was subjected to column chromatography on silica gel eluiting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 3-amino-6- (l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -5-phenyl-2-pyrazinecarboxamide as a solid (136 mg) . m.p. : 224-226°C (MeOH) IR (KBr) : 3411, 3338, 3273, 1657, 1585 cm-1 Mass (ESI) : 373 (M+Na)+
!H NMR (CDCI3, δ) : 0.85 (6H, d, J=6.60 Hz), 5.08 (IH, 7-plet, J=6.60 Hz), 5.58 (IH, brs), 6.97 (IH, d, J=9.60 Hz), 7.33-7.41 (5H, m) , 7.61 (IH, brs), 7.68 (IH, d) XH NMR (DMSO-d6, δ) : 0.71 (6H, d, J=6.60 Hz), 4.87 (IH, 7-plet, J=6.60 Hz) , 6.97 (IH, d, J=9.70 Hz), 7.39 (5H, s) , 7.72 (IH, brs), 7.88 (2H, brs), 8.26 (IH, d, J=9.70 Hz) , 8.29 (IH, brs) Example 8
A suspension of 3~amino-6- ( l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -5-phenyl-2-pyrazinecarboxamide (1.02 g) in a mixture of cone. HCl (40 mi) and dioxane (10 ml) was heated at 90-95°C for 20 hours. Under ice-cooling, the reaction mixture was adjusted to pH 4 with 4N aq. ΝaOH solution to yield a precipitate. The precipitate was collected by filtration and dried at 60°C under reduced pressure to give 3-amino-6- ( l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) - 5-phenyl-2-pyrazinecarboxylic acid as a solid (878 mg) . m.p. : 233-235°C (water) IR (KBr) : 3433, 3303, 1711, 1649, 1639, 1595, 1581 cm"1 Mass (ESI) : 374 (M+Νa)+, 352 (M+H)+, 330 (M+Na-C02) +
!HNMR (DMSO-de, δ) : 0.72 (6H, d, J=6.60 Hz), 4.88 (IH, 7-plet, J=6.60 Hz), 7.01 (IH, d, J=9.63 Hz), 7.36-7.43 (5H, m) , 7.72 (2H, brs), 8.00 (IH, d, J=9.63 Hz), 13.17 (IH, brs) Example 9 A suspension of 3-amino-6- (l-isopropyl-6-oxo-
1, 6-dihydro-3-pyridazinyl) -5-phenyl-2—pyrazinecarboxylic acid (250 mg) in o-dichlorobenzene (1.25 ml) was refluxed for 2 hours. After cooling, IPE (2.5 ml) was added to the reaction mixture to yield a precipitate. The precipitate was collected by filtration to give 6- (5-amino-3-p-henyl-2-pyrazinyl) - 2-isopropyl-3 (2if) -pyridazinone as a solid (205 mg) . m.p. : 204-206°C (EtOAc)
IR (KBr) : 3406, 3294, 3176, 1649, 1587, 1564, 1537 cm"1 Mass (ESI) : 637 (2M+Na)+, 330 (M+Na)+, 308 (M+H) +
1H NMR (CDC13, δ) : 0.85 (6H, d, J=6. 60 Hz), 4.94 (2H, brs), 5.08 (IH, 7-plet, J=6.60Hz), 6.94 (IH, d, J=9.60Hz), 7.27-7.40 (5H, m) , 7.73 (IH, d, J=9.60 Hz), 7. 98 (IH, s) Example 10 A suspension of 3-amino-6- (1-i sopropyl-6-oxo-
1, 6-dihydro-3-pyridazinyl) -5-phenyl— 2-pyrazinecarbonitrile (1.00 g) in a mixture of 2N aq. NaOH sol ution (20 ml) and dioxane (2 ml) was refluxed for 3 hours. The reaction mixture was adjusted to pH 5 with cone. HCl to yield a precipitate. The precipitate was collected by filtration and dried at 60°C under reduced pressure to give 3-amino-6- l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -5-phenyl—2-pyrazinecarboxylic acid as a solid (1.01 g) . m.p. : 233-235°C (water) IR (KBr) : 3433, 3303, 1711, 1649, 1639, 1595, 1581 cm"1 Mass (ESI) : 374 (M+Na)+, 352 (M+H)+, 330 (M+Na-C02) + :H NMR (DMSO-de, δ) : 0.72 (6H, d, J=6. 60 Hz), 4.88 (IH, 7-plet, J=6.60 Hz), 7.01 (IH, d, J=9.63 Hz), 7.36-7.43 (5H, m) , 7.72 (2H, brs), 8.00 (IH, d, J=9.63 Hz), 13.17 (IH, brs) Example 11
5- (l-Ethyl-6-oxo-l, 6-dihydro-3-pyridazinyl ) -6-phenyl- 2, 3-pyrazinedicarbonitrile
The title compound was obtained in a similar manner to that of Example 4. m.p. : 201-203°C (acetone suspension) IR (KBr) : 2247, 1668, 1512 cm"1 Mass (ESI) : 351 (M+Na)+, 329 (M+H)+
XH NMR (DMSO-de, δ) : 0.78 (3H, t, J=7.20Hz), 3.76 (2H, q, J=7.20 Hz), 7.09 (IH, d, J=9.71 Hz), 7.43-7.62 (5H, m) , 7.94 (IH, d, J=9.71 Hz) Example 12
6- (l-Ethyl-6-oxo-l, 6-dihydro-3-pyridaziny2L) -
3- [ ( 4-methoxybenzyl) amino] -5-phenyl-2-pyr azinecarbonitrile The title compound was obtained in a similar manner to that of Example 5. m.p. : 165.5-167.5°C (acetone - n-hexane)
IR (KBr) : 3365, 2220, 1669, 1666, 1570 cm"1
Mass (ESI) : 461 (M+Na)+, 439 (M+H)+ XH NMR (CDC13, δ) : 0.95 (3H, t, J=7.22 Hz), 3.82 (3H, s) , 3.90
(2H, q, J=7.22 Hz) , 4.72 (2H, d, J=5.50 Hz) , 5.78 (IH, t, J=5.50
Hz), 6.88-6.96 (3H, m) , 7.27-7.46 (7H, m) , 7.63 (IH, d, J=9.60
Hz)
Example 13 3-Amino-6- ( l-ethyl-6-oxo-l , 6-dihydro-3-pyridazinyl ) -
5-phenyl-2-pyrazinecarbonitrile
The title compound was obtained in a s±milar manner to that of Example 6. m.p. : >250°C (acetone suspension)
IR (KBr) : 3406, 3170, 2227, 1643, 1583, 1547 cm"1
Mass (ESI) : 659 (2M+Na)+, 341 (M+Na)+, 319 (M+H)+
XH NMR (DMSO-d6, δ) : 0.77 (3H, t, J=7.17 Hz) , 3.74 (2H, q, J=7.17
Hz), 6.97 (IH, d, J=9.63 Hz), 7.40 (5H, s), 7.71 (IH, d) , 7.74 (2H, s)
Example 14
3-Amino-6- (l-ethyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -
5-phenyl-2-pyrazinecarboxamide
The title compound was obtained in a similar manner to that of Example 7. m.p. : >250°C (acetone suspension)
IR (KBr) : 3448, 3408, 3261, 3161, 1682, 1653, 1616, 1587 cm"1
Mass (ESI) : 359 (M+Na)+
XHNMR (DMSO-de, δ) : 0.74 (3H, t, J=7.15 Hz) , 3-67 (2H, q, J=7.15 Hz) , 6.97 (IH, d, J=9.64 Hz) , 7.39 (5H, s) , 7.7-8.1 (2H, br-peak) ,
7.72 (IH, brs), 8.21 (IH, d, J=9.64 Hz), 8. 27 (IH, brs)
Example 15
5- (l-Methyl-6-oxo-l, 6-dihydro-3-pyridaziny3_ ) -6-phenyl-
2, 3-pyrazinedicarbonitrile The title compound was obtained in a similar manner to that of Example 4. m.p. : 210-212°C (acetone suspension) IR (KBr) : 2247, 1672, 1591, 1514 cm"1 Mass (ESI) : 315 (M+H)+
1U NMR (DMSO-de, δ) : 3.39 (3H, s), 7.04 (IH, d, J=9.68 Hz),
7.44-7.61 (5H, m) , 7.78 (IH, d, J=9.68 Hz)
Example 16
3- [ (4-Methoxybenzyl) amino] -6- (l-methyl-6-oxo-l, 6-cdihydro- 3-pyridazinyl) -5-phenyl-2-pyrazinecarbonitrile
The title compound was obtained in a similar manner to that of Example 5. m.p. : 166.5-168°C (acetone - n-hexane)
IR (KBr) : 3361, 2218, 1672, 1574 cm"1 Mass (ESI) : 871 (2M+Na)+, 447 (M+Na)+, 425 (M+H)4
XH NMR (CDC13, δ) : 3.54 (3H, s) , 3.82 (3H, s), 4.72 (2H, d,
J=5.42 Hz), 5.75 (IH, t, J=5.42 Hz), 6.85-6.93 (3H, m) ,
7.26-7.49 (8H, )
Example 17 3-Amino-6- (1-methyl-6-oxo-l, 6-dihydro-3-pyrida in yl ) -
5-phenyl-2-pyrazinecarbonitrile
The title compound was obtained in a similar? manner to that of Example 6. m.p. : >250°C (acetone suspension) IR (KBr) : 3330, 3172, 2222, 1649, 1626, 1579, 1531 cm"1
Mass (ESI) : 631 (2M+Na)+, 327 (M+Na)+, 305 (M+H)+ λU NMR (DMSO-d6, δ) : 3.33 (3H, s), 6.91 (IH, d, J=9.62 Hz),
7.41 (5H, s), 7.55 (IH, d, J=9.62 Hz), 7.75 (2H, brs) Example 18
3-Amino-6- (l-methyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -
5-phenyl-2-pyrazinecarboxamide
The title compound was obtained in a similar manner to that of Example 7. m.p. : >250°C (acetone suspension)
IR (KBr) : 3367, 3269, 3219, 1658, 1591 cm"1
Mass (ESI) : 345 (M+Na)+, 323 (M+H)+
XU NMR (DMSO-de, δ) : 3.33 (3H, s), 6.94 (IH, d, J=9.70 Hz)r
7.39 (5H, s), 7.7-8.1 (2H, br-peak), 7.73 (IH, brs), 8.14(1HΛ d, J=9.70 Hz), 8.26 (IH, brs)
Example 19
3-Amino-6- (l-methyl-6-oxo-l, 6-dihydro-3-pyrιdazinyl) -
5-phenyl-2-pyrazinecarboxylic acid
The title compound was obtained in a similar manner to that of Example 10. m.p. : 238°C (dec.) (water)
IR (KBr) : 3417, 3275, 3178, 1693, 1643, 1624, 1572, 1545, 1512 cm
Mass (ESI, Neg', 322 (M-H; H NMR (DMSO-d6, δ) : 3.32 (3H, s) , 6.95 (IH, d, J=9.62 Hz), 7.41 (5H, s), 7.73 (2H, brs), 7.78 (IH, d, J=9.62 Hz), 13.21 (IH, brs) Example 20 6- (5-Amino-3-phenyl-2-pyrazinyl) -2-methyl- 3 (2f) -pyridazinone
The title compound was obtained in a similar manner? to that of Example 9. m.p. : 202-204°C (EtOAc) IR (KBr) : 3431, 3330, 3219, 1650, 1620, 1568, 1535 cm"1 Mass (ESI) : 581
Figure imgf000074_0001
280 (M+H)+ XH NMR (CDC13, δ) : 3.65 (3H, s) , 4.92 (2H, brs), 6.78 (IH. d, J=9.60 Hz), 7.24 (IH, d, J=9.60 Hz), 7.33-7.44 (5H, m) , 8.04 (IH, s) X NMR (DMSO-d6, δ) : 3.34 (3H, s) , 6.87 (IH, d, J=9.62 Hz), 6.90 (2H, brs) , 7.35 (5H, s) , 7.52 (IH, d, J=9.62 Hz) , 7.93 (IH, s) Example 21
A suspension of 5- (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -6-phenyl-2, 3-pyrazinedicarbonitrile (l.OO g) in a mixture of 28% aq. anunonia (1 ml) and THF (3 ml) was sti-rred at 25-30°C for 40 hours. After addition of water, the mixture was extracted with CHCI3, dried over MgS04, concentrated uxider reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v). A less polar one is 3-amino-6- (l-isopropyl-6-oxo-
1, 6-dihydro-3-pyridazinyl) -5-phenyl-2-pyrazinecarbonitrile
(350 mg) and a more polar one is 3-amino-5- (l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -6-phenyl-2-pyrazinecarbonitrile
(51 mg) .
3-Amino-6- ( l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -
5-phenyl-2-pyrazinecarbonitrile m.p. : 231-233°C (acetone - n-hexane) IR (KBr) : 3410, 3325, 3305, 2227, 1639, 1583, 1543, 1525 cm"1
Mass (ESI) : 355 (M+Na)+
XH NMR (CDC13, δ) : 0.81 (6H, d, J=6.60 Hz), 5.06 (IH, 7-plet,
J=6.60 Hz), 5.44 (2H, brs), 6.98 (IH, d, J=9.58 Hz), 7.39 (5H, s) , 7.78 (IH, d, J=9.58 Hz) λU NMR (DMSO-d6, δ) : 0.72 (6H, d, J=6.60Hz), 4.88 (IH, 7-plet,
J=6.60 Hz), 6.97 (IH, d, J=9.65 Hz), 7.39 (5H, s), 7.73 (2H, brs), 7.80 (IH, d, J=9.65 Hz)
3-Amino-5- ( l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -
6-phenyl-2-pyrazinecarbonitrile m.p. : 238-241°C (acetone - n-hexane)
IR (KBr) : 3354, 3313, 3294, 3199, 2220, 1651, 1628, 1583, 1552,
1525 cm"1
Mass (ESI) : 355 (M+Na)+
XH NMR (CDCI3, δ) : 0.82 (6H, d, J=6.60 Hz), 5.06 (IH, 7-plet, J=6. 60 Hz ) , 5 . 33 ( 2H, brs) , 6. 97 ( IH, d, J=9 . 58 Hz ) , 7 . 28-7 . 40 ( 5H, m) , 7 . 77 ( IH, d, J=9 . 58 Hz ) Example 22
A suspension of 5- (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -6-phenyl-2, 3-pyrazinedicarbonitrile (100 mg) in a 2M solution of ammonia in MeOH (3 ml) was stirred at 25-35°C for 30 hours in a sealed tube . The mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 6- ( l-isopropyl-6-oxo-l, 6-dihydro-
3-pyridazinyl) -3-methoxy-5-phenyl-2-pyrazinecarbonitrile as a solid (32 mg) . m.p. : 170-172°C (acetone - n-hexane)
IR (KBr) : 2227, 1664, 1591, 1541, 1508 cm"1 Mass (ESI) : 717 (2M+Na)+, 370 (M+Na)+, 348 (M+H)+
2H NMR (CDCI3, δ) : 0.83 (6H, d, J=6.60 Hz), 4.20 (3H, s) , 5.08 (IH, 7-plet, J=6.60 Hz) , 7.01 (IH, d, J=9.58 Hz) , 7.38-7.50 (5H, m) , 7.80 (IH, d, J=9.58 Hz)
XH NMR (DMSO-de, δ) : 0.75 (6H, d, J=6.60 Hz), 4.15 (3H, s), 4.91 (IH, 7-plet, J=6.60Hz), 7.05 (IH, d, J=9.70Hz), 7.43-7.57 (5H, m) , 7.86 (IH, d, J=9.70 Hz) Example 23
To a solution of 5- (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -6-phenyl-2, 3-pyrazinedicarbonitrile (343 mg) in EtOH (10 ml) was dropwise added a solution of sodium molybdate dihydrate (12.1 mg) in a mixture of 30% hydrogen peroxide solution in water (0.57 ml) and EtOH (1.5 ml) and the mixture was stirred at 40-45°C for 3 hours. After ice-cooling, a precipitate was collected by filtration to give 3-cyano-
5- (l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -6-phenyl-
2-pyrazinecarboxamide as a solid (171 mg) .
Saturated sodium thiosulfate solution in water was added to the filtrate. After removal of EtOH under reduced pressure, the mixture was extracted with CHC1 , dried over MgS04 and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel.
With elution of a mixture of n-hexane and EtOAc (50:50 v/v) was obtained 3-cyano-6- (l-isopropyl-6-oxo-l , 6-dihydro- 3-pyridazinyl ) -5-phenyl-2-pyrazinecarboxamide as a solid (78 mg) and with elution of EtOAc was obtained 3-cyano-
5- (l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -6-phenyl-
2-pyrazinecarboxamide as a solid (22 mg) .
3-Cyano-5- ( l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) - 6-phenyl-2-pyra inecarboxamide m.p. : >250°C
IR (KBr) : 3352, 3161, 2233, 1709, 1666, 1593 cm"1
Mass (ESI) : 743 (2M+Na)+, 383 (M+Na)+
XH NMR (CDCI3, δ) : 0.85 (6H, d, J=6.60 Hz), 5.10 (IH, 7-plet, J=6.60 Hz) , 6.13 (IH, brs), 7.06 (IH, d, J=9.60 Hz), 7.42-7.56 (6H, m) , 7.89 (IH, d, J=9.60 Hz) H NMR (DMSO-d6, δ) : 0.71 (6H, d, J=6.57 Hz), 4.90 (IH, 7-plet, J=6.57 Hz) , 7.11 (IH, d, J=9.80 Hz), 7.45-7.61 (5H, m) , 8.21 (IH, brs) , 8.50 (IH, d, J=9.80 Hz), 8.66 (IH, brs)
3-Cyano-6- (l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -
5-phenyl-2-pyrazinecarboxamide m.p. : 195-197°C
IR (KBr) : 3483, 3344, 2233, 1707, 1655, 1585, 1523 cm"1 Mass (ESI) : 743 (2M+Na)+, 383 (M+Na) +
XH NMR (DMSO-d6, δ) : 0.75 (6H, d, J=6.60Hz), 4.92 (IH, 7-plet, J=6.60 Hz), 7.10 (IH, d, J=9.62 Hz), 7.44-7.50 (3H, m) , 7.68-7.74 (2H, m) , 8.01 (IH, d, J=9.62 Hz) , 8.20 (IH, brs) , 8.46 (IH, brs) Example 24
To a solution of sodium methoxide (81.5 mg) in MeOH (3 ml) , 5- ( l-isopropyl-6-oxo-l, 6-dihydro-3-pyrida∑inyl) - 6-phenyl-2, 3-pyrazinedicarbonitrile (172 mg) was added and the mixture was stirred at 25-30°C for 10 hours. After addition of cone. HCl (1.5 ml) , the reaction mixture was stirred at 25-30°C for 20 hours. Water and CHC1 were added to the mixture. An organic layer was collected, dried over MgS04, concentrated under reduced pressure and subjected to column chromatography on silica gel. With elution of a mixture of n-hexane and EtOAc (70:30 v/v) was obtained 6- (l-isopropyl-6-oxo-l, 6-dihydro-
3-pyridazinyl) -3-methoxy-5-phenyl-2-pyrazinecarbonitrile as a solid (43 mg) and with elution of a mixture of n-hexane and
EtOAc (50:50 v/v) was obtained methyl 6- (l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -3-methoxy-5-phenyl-
2-pyrazinecarboxylate as a solid (67 mg) .
6- (l-Isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -3-methoxy-
5-phenyl-2-pyrazinecarbonitrile m.p. : 170-172°C (acetone - n-hexane) IR (KBr) : 2227, 1664, 1591, 1541, 1508 cm"1
Mass (ESI) : 717 (2M+Na)+, 370 (M+Na)+, 348 (M+H)+
XH NMR (CDC13, δ) : 0.83 (6H, d, J=6.60 Hz), 4.20 (3H, s) , 5.08
(IH, 7-plet, J=6.60Hz), 7.01 (IH, d, J=9.58Hz), 7.38-7.50 (5H, m) , 7.80 (IH, d, J=9.58 Hz) XU NMR (DMSO-d6, δ) : 0.75 (6H, d, J=6.60 Hz), 4.15 (3H, s),
4.91 (IH, 7-plet, J=6.60Hz), 7.05 (IH, d, J=9.70Hz), 7.43-7.57
(5H, m) , 7.86 (IH, d, J=9.70 Hz)
Methyl 6- ( l-isopropyl-6-oxo-l , 6-dihydro-3-pyridazinyl) -
3-methoxy-5-phenyl-2-pyrazinecarboxylate m.p. : 170-171°C (acetone - n-hexane)
IR (KBr) : 1734, 1662, 1593, 1541 cm"1
Mass (ESI) : 403 (M+Na)+, 381 (M+H)+ H NMR (CDCI3, δ) : 0.84 (6H, d, J=6.60 Hz), 4.02 (3H, s), 4.17
(3H, s), 5.09 (IH, 7-plet, J=6.60 Hz), 7.00 (IH, d, J=9.56 Hz), 7 . 34 -7 . 51 ( 5H , ) , 7 . 85 ( IH, d, J=9 . 56 Hz ) Example 25
A suspension of 5- (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -6-phenyl-2, 3-pyrazinedicarbonitrile (343 mg) and sodium diformylamide (190 mg) in DMA (1 ml) was heated at 100-105°C for an hour. After addition of water, the reaction mixture was extracted with CHC13, dried over MgS04, concentrated under reduced pressure and subjected to column chromatography on silica gel. With elution of a mixture of n-hexane and EtOAc (50:50 v/v) was obtained [3-cyano-5- ( l-isopropyl-6-oxo-
1, 6-dihydro-3-pyridazinyl) -6-phenyl-2-pyrazinyl] formamide as a solid (30 mg) and with elution of a mixture of n-hexane and EtOAc (30:70 v/v) was obtained [ 3-cyano-6- ( 1-isopropyl- 6-oxo-l, 6-dihydro-3-pyridazinyl) -5-phenyl-2-pyrazinyl] - formamide as a solid (22 mg) .
[3-Cyano-5- ( 1-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl ) -
6-phenyl-2-pyrazinyl] formamide m.p. : 198-200°C (acetone - n-hexane)
IR (KBr) : 2227, 1703, 1662, 1556, 1539 cm"1 Mass (ESI) : 383 (M+Na)+, 361 (M+H) +
XH NMR (CDCI3, δ) : 0.82 (6H, d, J=6.60 Hz), 5.07 (IH, 7-plet, J=6.60 Hz), 7.02 (IH, d, J=9.58 Hz), 7.38-7.50 (5H, m) , 7.84 (IH, d, J=9.58Hz), 8.27 (IH, d, J=9.05Hz), 9.59 (IH, d, J=9.05 Hz) [3-Cyano-6- (l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) - 5-phenyl-2-pyrazinyl] formamide m.p. : 206-208°C (acetone - n-hexane) IR (KBr) : 2233, 1707, 1655, 1558 cm"1 Mass (ESI) : 383 (M+Na)+, 361 (M+H)+
XH NMR (CDC13, δ) : 0.87 (6H, d, J=6.60 Hz), 5.09 (IH, 7-plet, J=6.60 Hz), 7.02 (IH, d, J=9.62 Hz), 7.41 (5H, s) , 7.82 (IH, d, J=9.62 Hz), 8.39 (IH, brs), 9.54 (IH, brs) Example 26 To a suspension of 3-amino-6- (l-isopropyl-6-oxo-
1, 6-dihydro-3-pyridazinyl) -5-phenyl-2-pyrazinecarbonitrile (665 mg) and thioacetamide (451 mg) in DMF (3.2 ml) was added a 4 hydrogen chloride solution of dioxane (3.2 ml) and the mixture was stirred at 100-105°C for 2 hours. Water (65 ml) was added to the mixture to yield a precipitate. The precipitate was collected by filtration, subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40 : 60 v/v) to give a solid. The solid triturated with acetone and collected by filtration to give 3-amino-6- (1-isopropyl- 6-oxo-l, 6-dihydro-3-pyridazinyl) -5-phenyl-
2-pyrazinecarbothioamide as a solid (417 mg) . m.p. : >250°C (acetone suspension)
IR (KBr) : 3363, 3261, 3159, 1660, 1585, 1533 cm"1 Mass (ESI) : 389 (M+Na)+ X NMR (DMSO-de, δ) : 0.70 (6H, d, J=6.6l Hz), 4.87 (IH, 7-plet, J=6.61 Hz), 6.98 (IH, d, J=9.62 Hz), 7.40-7.48 (5H, m) , 8.29 (IH, d, J=9.62 Hz), 8.57 (2H, brs), 9.85 (IH, brs), 10.00 (IH, brs) Example 27
A solution of 3-amino-6- (l-isopropyl-6-oxo-l, 6- dihydro-3-pyridazinyl ) -5-phenyl-2-pyrazinecarbothioamide (100 mg) and 1-chloroacetone (37.9 mg) in DMF (0.27 ml) was heated at 100-105°C for 10 hours. After cooling, sat. aq. NaHC03 solution (0.5 ml) and water (1 ml) were added to the mixture to yield a precipitate. The precipitate was collected by filtration, dissolved in CHC13, dried over MgS04 and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 6- [5-amino-6- ( 4 -methyl-thiazol-2-yl) -3-phenyl-2-pyrazinyl] - 2-isopropyl-3 (2if) -pyridazinone as a solid (58 mg) . m.p. : 238-240°C (acetone - n-hexane) IR (KBr) : 3325, 1668, 1628, 1589 cm"1 Mass (ESI) : 831 (2M+Na)+, 427 (M+Na)+, 405 (M+H) +
:H NMR (CDCI3, δ) : 0.83 (6H, d, J=6.65 Hz), 2.54 (3H, s) , 5.08 (IH, 7-plet, J=6.65 Hz), 6.96-7.02 (2H, ) , 7.28-7.45 (6H, m) , 7.90 (IH, d, J=9.64 Hz) Example 28 6- [5-Amino-3-phenyl-6- (4-phenyl-thiazol-2-yl) -2-pyrazinyl] -
2-isopropyl-3 (2f) -pyridazinone
The title compound was obtained in a similar manner to that of Example 27. m.p. : 240-242°C (MeOH suspension)
IR (KBr) : 3386, 3278, 1660, 1612, 1587 cm"1
Mass (ESI) : 489 (M+Na)+, 467 (M+H)+ H NMR (CDC13, δ) : 0.76 (6H, d, J=6.60 Hz), 4.91 (IH, 7-plet,
J=6.60 Hz) , 7.06 (IH, d, J=9.65 Hz), 7.32-7.57 (8H, ), 8.02 (IH, d, J=9.65 Hz) , 8.04-8.09 (2H, m) , 8.21 (2H, brs) , 8.35 (IH, s)
Example 29
3-Amino-5— (l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -
6-phenyl-2-pyrazinecarboxamide The title compound was obtained in a similar manner to that of Example 7. m.p. : 217-220°C (acetone - n-hexane)
IR (KBr) : 3442, 3305, 1658, 1589 cm"1
Mass (ESI) : 723 (2M+Na)+, 373 (M+Na)+, 351 (M+H) + 1U NMR (CDCI3, δ) : 0.83 (6H, d, J=6.60 Hz), 5.07 (IH, 7-plet,
J=6.60 Hz), 5.60 (IH, brs), 6.97 (IH, d, J=9.56 Hz), 7.26-7.40
(5H, m) , 7'.77 (IH, brs), 7.80 (IH, d, J=9.56 Hz)
Example 30
A mixture of ethyl { [ 1- ( l-isopropyl-6-oxo-l , 6-dihydro- 3-pyridazinyl) -2 -oxo-2-phenylethyl] amino}acetate (14.0 g) and ammonium acetate (21.0 g) in AcOH (60 ml) was refluxed with stirring 'for 2 hours. Water, aq. NaHCθ3 and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgS04. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain 6- ( 5-hydroxy-3-phenyl-2-pyrazinyl) - 2-isopropyl-3 ( 2H) -pyridazinone (3.0 g) as white powder. 1H NMR (DMSO-d5, δ) : 0.73 (6H, d, =6.6 Hz), 4.87 (IH, 7-plet, J=6.6 Hz), 6.95 (IH, d, J=9.6 Hz), 7.2-7.5 (5H, m) , 7.77 (IH, d, J=9.6 Hz), 8.12 (IH, s) , 12-13 (IH, br) Mass (ESI, Neg) : 307 (M-H)+ Example 31 6- ( 5-Amino-3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2ff) - pyridazinone
The title compound was obtained in a similar manner to that of Example 3. λH NMR (DMSO-de, δ) : 0.73 (6H, d, J=6.6 Hz), 4.88 (IH, 7-plet, J=6.6 Hz), 6.89 (2H, br) , 6.95 (IH, d, J=9.6 Hz), 7.2-7.4 (5H, m) , 7.80 (IH, d, J=9.6 Hz), 7.93 (IH, s) Mass (ESI) : 308 (M+H)+, 330 (M+Na)+ Example 32
A mixture of 6- (5-amino-3-phenyl-2-pyrazinyl) - 2-isopropyl-3 (2f) -pyridazinone (50 mg) , N-chlorosuccinimide (23.9 mg) in DMF (1.5 ml) was stirred at 60°C for 2 hours. Water and EtOAc were added to the reaction mixture. The organic layer- was separated, and dried over Na2S04. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of CHC1 and MeOH. The fractions were concentrated in vacuo to obtain 6-(5-amino- 6-chloro-3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2if) - pyridazinone (30 mg) as white powder. *H NMR (DMSO-de, δ) : 0.74 (6H, d, J=6.6 Hz), 4.88 (IH, 7-plet, J=6.6Hz), 6.95 (IH, d, J=9.6 Hz), 7.26 (2H, br) , 7.3-7.5 (5H, m) , 7.76 (IH, d, J=9.6 Hz) Mass (ESI) : 364 (M+Na)+ Example 33 6- (5-Amino-6-bromo—3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2f) - pyridazinone
The title compound was obtained in a similar manner to that of Example 32. λH NMR (DMSO-de, δ) : 0.73 (6H, d, J=6.6 Hz), 4.88 (IH, 7-plet, J=6.6 Hz), 6.95 (IH, d, J=9.6 Hz), 7.18 (2H, br) , 7.3-7.5 (5H, m) , 7.76 (IH, d, J=9.6 Hz) Mass (ESI) : 408 (M+Na)+, 410 (M+Na+2)+ Example 34 6- (5-Amino-6-iodo-3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2if) - pyridazinone
The title compound was obtained in a similar manner to
that of Example 32.
XH NMR (DMSO-d6, δ) : 0.73 (6H, d, J=6.6 Hz), 4.88 (IH, 7-plet, J=6.6 Hz), 6.8-7.0 (3H, m) , 7.2-7.4 (5H, m) , 7.76 (IH, d,
J=9.6Hz)
Mass (ESI) : 456 (M+Na)+
Example 35
6- [3- (4-Fluorophenyl) -5-hydroxy-2-pyrazinyl ] -2-isopropyl- 3 (2ff) -pyridazinone
The title compound was obtained in a similar manner to that of Example 30.
XH NMR (DMSO-de, δ) : 0.77 (6H, d, J=6.6 Hz), 4.91 (IH, 7-plet,
J=6.6 Hz) , 5.0-6.0 (IH, br) , 6.94 (IH, d, J=9.6 Hz) , 7.1-7.5 (4H, m) , 7.80 (IH, d, J=9.6 Hz), 7.97 (IH, s)
Mass (ESI, Neg) : 325 (M-H) +
Example 36
6- [5-Amino-3- (4-fluorophenyl ) -2-pyrazinyl] -2-isopropyl-
3 (2if) -pyridazinone
> The title compound was obtained in a similar manner to that of Example 3.
XH NMR (DMSO-de, δ) : 0.77 (6H, d, J=6.6 Hz), 4.91 (IH, 7-plet, J=6.6 Hz), 6.91 (2H, br), 6.95 (IH, d, J=9.6 Hz) , 7.1-7.5 (4H, m) , 7.80 (IH, d, J=9.6 Hz), 7.92 (IH, s) Mass (ESI) : 326 (M+H)+ , 330 (M+Na) + Example 37
6- [5-Amino-6-chloro-3- (4-fluorophenyl) -2-pyrazinyl] - 2-isopropyl-3 (2if) -pyridazinone The title compound was obtained in a similar manner to that of Example 32.
XH NMR (DMSO-de, δ) : 0.77 (6H, d, J=6.6 Hz), 4.91 (IH, 7-plet, J=6.6 Hz), 6.96 (IH, d, J=9.6 Hz), 7.1-7.5 (6H, m) , 7.75 (IH, d, J=9.6 Hz) Mass (ESI) : 360
Figure imgf000087_0001
382 (M+Na) + Example 38 2-Isopropyl-6- (3-phenyl-2-pyrazinyl) -3 (2if) -pyridazinone
The title compound was obtained in a similar manner to that of Example 4. 2H NMR (DMSO-d6, δ) : 0.85 (6H, d, J=6.6 Hz), 5.01 (IH, 7-plet, J=6.6 Hz), 7.00 (IH, d, J=9.6 Hz), 7.2-7.5 (6H, m) , 7.87 (IH, d, J=9.6 Hz), 8.58 (IH, d, J=2.5 Hz), 8.67 (IH, d, J=2.5 Hz) Mass (ESI) : 293 (M+H)+, 315 (M+Na) + Example 39 A mixture of 6- ( 5-hydroxy-3-phenyl-2-pyrazinyl) -
2-isopropyl-3 (2if) -pyridazinone (200 mg) , 2,6-lutidine (139 mg) and trifluoromethane sulfonic anhydride (257 mg) in CH2C12 (8 ml) was stirred at 0°C for 4 hours. Water and EtOAc were added to the reaction mixture. The organic layer was washed with IN HCl, aq. NaHC03 and brine. The organic layer was separated, and dried over MgS04. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain 5- ( l-isopropyl-6-o-κo-l, 6-dihydro-3- pyridazinyl) -6-phenyl-2-pyrazinyl trifluoromethanesulfonate (174.3 mg) as white powder.
XH NMR (DMSO-de, δ) : 0.76 (6H, d, J=6.6 Hz), 4.91 (IH, 7-plet, J=6.6 Hz), 7.09 (IH, d, J=9.6 Hz), 7.3-7.6 (5H, m) , 7.94 (IH, d, J=9.6 Hz) , 9.09(1H, s)
Mass (ESI) : 441 (M+H)+, 463 (M+Na)+ Example 40
A mixture of 5- (l-isopropyl-6-o. o-l, 6-dihydro-3- pyridazinyl) -6-phenyl-2-pyrazinyl tri fluoromethanesulfonate (1.0 g) , MeOH (5.98 ml), palladium acetate (102 mg) and
1 , 3-bis (diphenylphosphino) propane (187 mg) in DMF (10 ml) was stirred with CO gas bubbling at 20°C for 30 minutes. Then the reaction mixture was stirred under CO gas at 60°C for 6 hours. Water and EtOAc were added to the reaction mixture. The organic layer was washed with IN HCl, aq. NaHC03 and brine. The organic layer was separated, and dried over gS04. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain methyl 5- (l-isσpropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -6-phenyl- 2-pyrazinecarboxylate (68 mg) as white powder. H NMR (DMSO-d6, δ) : 0.74 (6H, d, J=6.6 Hz) , 3.97 (3H, s) , 4.8-5.1 (IH, ) , 7.08 (IH, d, J=9.6 Hz), 7.3-7.6 (5H, m) , 8.02 (IH, d, J=9.6 Hz) , 9.23 (IH, s)
Mass (ESI) : 351 (M+H)+, 373 (M+Na) + Example 41
A solution of N '- [3-cyano-6- ( 4-f luorophenyl) -5- (1- isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -2-pyrazinyl] - N, N-dimethylimidof ormamide (100 mg) in 42VHCl in dioxane (2 ml) and water (2 ml) was stirred at 25°C for 15 hours. Water, aq. NaHC03 and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgS04. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain 3-amino-5- (4 -fluorophenyl) -6- ( 1-isopropyl- 6-oxo-l, 6-dihydro-3- pyridaz inyl) -2-pyrazinecarbonitrile (60 g) as white powder. λH NMR ( DMSO-d6, δ) : 0.76 (6H, d, J=6.6 Hz), 4.91 (IH, 7-plet, J=6.6Hz), 6.99 (IH, d, J=9.6 Hz), 7.0-7.5 (4H^ m) , 7.7-7.9 (2H, m)
Mass (ESI) : 351
Figure imgf000089_0001
373 (M+Na) + Example 42
A solution of 3-amino-5- ( -fluorophenyl) - β- (l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) - 2-pyrazinecarbonitrile (30 mg) in 28% hydrogen bromide solution of AcOH (2 ml) was stirred at 25°C for 3 hours. Water, aq. NaHC03 and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgS04. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of CHC13 and MeOH. The fractions were concentrated in vacuo to obtain 3-amino- 5- (4-fluorophenyl) -6- (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -2-pyrazinecarboxamide (30 g) as white powder. H NMR (DMS0-d6, δ) : 0.90 (6H, d, J=6.6Hz), 5.11 (IH, 7-plet, J=6.6 Hz), 5.55 (IH, br) , 6.98 (IH, d, J=9.6Hz), 7.0-7.5 (6H, m) , 7.5-7.65 (IH, br) , 7.69 (IH, d, J=9.6 Hz) Mass (ESI) : 391 (M+Na)+ Example 43
3-Amino-5- (3-fluorophenyl) -6- ( 1-isopropyl-6-oxo-l , 6- dihydro-3-pyridazinyl) -2-pyrazinecarbonitrile
The title compound was obtained in a similar manner to that of Example 41. XH NMR (CDC13, δ) : 0.84 (6H, d, J=6.6 Hz), 5.09 (IH, 7-plet, J=6.6 Hz) , 5.49 (2H, br) , 7.00 (IH, d, J=9.6 Hz) , 7.0-7.5 (4H, m) , 7.81 (IH, d, J=9.6 Hz) Mass (ESI) : 373 (M+Na)+ Example 44 3-Amino-5- (3-fluorophenyl) -6- (l-isopropyl-6-oxo-l, 6- dihydro-3-pyridazinyl) -2-pyrazinecarboxamide
The title compound was obtained in a similar manner to that of Example 42. XH NMR (DMSO-d6, δ) : 0.88 (6H, d, J=6.6 Hz), 5.11 (IH, 7-plet, J=6.6 Hz), 5.55 (IH, br) , 6.99 (IH, d, J=9.6 Hz), 7.0-7.5 (6H, m) , 7.60 (IH, br), 7.72 (IH, d, J=9.6 Hz) Mass (ESI) : 391 (M+Na) + Example 45 A mixture of 1- ( l-isopropyl-6-oxo-l, 6-dihydro-3 - pyridazinyl) -2-phenyl-l, 2-ethanedione (300 mg) , aminoacetamidine dihydrobromide (259 mg) and sodium methoxide (238 mg) in MeOH ( 3 ml ) was stirred for 1.5 hours. Water and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgS04. The solvent was removed i n vacuo . The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and.EtOAc. The fractions were concentrated in. vacuo to obtain 6- ( 6-amino-3-phenyl- 2-pyrazinyl) -2- isopropyl-3 (2if) -pyridazinone (25.6 mg ) as white powder.
2H NMR (DMSO-de, δ) : 0.77 (6H, d, J=6.6 Hz), 4.91 (IH, 7-plet, J=6.6 Hz), 6.74 (2H, br) , 6.98 (IH, d, J=9.6 Hz), 7.1-7.5 (5H, m) , 7.76 (IH, d, J=9.6 Hz), 8.01 (IH, s) Mass (ESI) : 308 (M+H)+, 330 (M+Na) + Example 46
A solution of 6- (l-isopropyl-6-oxo-l, 6-dihydro-3- pyridazinyl) -3- [ (4-methoxybenzyl) amino] -5-phenyl-2- pyrazinecarbonitrile (3.88 g) in a mixture of 5i\7 aq. NaOH (20 ml) and EtOH (40 ml) was heated under reflux for 50 hours . After cooling, EtOH was removed under reduced pressure and the residue was adjusted to pH 4 with IN HCl. The mixture was extracted with CHC13, dried over MgS04 and concentrated under reduced pressure to give a solid. The solid was triturated with acetone under reflux for 30 minutes and collected by filtration to give 6- (1-isopropyl- 6-oxo-l, 6-dihydro-3-pyridazinyl) -3- [ (4- methoxybenzyl) amino] -5-phenyl-2-pyrazinecarboxylic acid as a solid (3.15 g) . m.p. : 216.5-217°C (acetone suspension) IR (KBr) : 3327, 1720, 1643, 1570, 1512 cm"1 Mass (ESI, Νeg) : 470 (M-H)" H ΝMR (CDCI3, δ) : 0.87 (6H, d, J=6.60 Hz) , 3.81 (3H, s) , 4.77 (2H, d, J=5.72 Hz), 5.10 (IH, 7-plet, J=6.60 Hz), 6.89 {2U r d, J=8.57 Hz), 6.98 (IH, d, J=9.60 Hz), 7.28 (2H, d, J=8.57 Hz), 7.30-7.66 (5H, m) , 7.63 (IH, d, J=9.60 Hz) , 8.42 (IH, t, J=5.72 Hz), 10-11 (IH, br-peak) Example 47
A mixture of 5- (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) - 6-phenyl-2, 3-pyrazinedicarbonitrile (51.51 g) and (4-methoxybenzyl) amine (19.7 ml) in DMA (155 ml) was heated at 80-85°C for 90 hours. After addition of 0.5N aq. ΝaOH, a precipitate was collected by filtration, dissolved in EtOAc, washed with 0.1IV aq. ΝaOH and water, dried over MgS04 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (70:30 v/v) to give a mixture of 6- (1-isopr opyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -3- [ (4-methoxybenzyl) amino] -5-phenyl- 2-pyrazinecarbonitrile and 5- (l-isopropyl-6-oxo-l, 6- dihydro-3-pyridazinyl) - 3- [ (4-methoxybenzyl) amino] -6-phenyl- 2-pyrazinecarbonitrile as an amorphous solid (37.53 g) . The solid was crystallized f om EtOH to give 6- (l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazi yl) -3- [ ( 4-methoxybenzyl) amino] - 5-phenyl-2-pyrazinecarbonitrile .
6- ( l-i sopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl ) -
3- [ ( 4-methoxybenzyl ) amino] -5-phenyl-2-pyrazinecarbonitri le m. p . : 89-93°C
IR (KBr) : 2220, 1655, 1562, 1510 cm"1 Mass (ESI) : 927 (2M+Νa)+, 475 (M+Na) +
2U NMR (CDC13, δ) : 0.82 (6H, d, J=6.60 Hz), 3.82 (3H, s), 4.72 (2H, d, J=5.42 Hz), 5.06 (IH, 7-plet, J=6.60 Hz), 5.70 (IH, t, J=5.42 Hz), 6.89-7.00 (3H, m) , 7.26-7.43 (7H, ) , 7.76 (IH, d, J=9.70 Hz) 5- (l-isopropyl-6-oxo-l, 6-dihydro-3 -pyridazinyl) -
3- [ (4-methoxybenzyl) amino] -6-phenyl-2-pyrazinecarbonitrile αH NMR (CDC13, δ) : 4.69 (2H, d, J = 5.02 Hz) Example 48 A solution of a mixture (1:1) of 6- ( l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -3- [ (4-methoxybenzyl) amino] - 5-phenyl-2-pyrazinecarbonitrile and 5- (l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -3- [ (4-methoxybenzyl) amino] - 6-phenyl-2-pyrazinecarbonitrile (9.34 g) in a mixture of 5i\Jaq. NaOH (38 ml) and EtOH (38 ml) was heated under reflux for 5 hours . After cooling, EtOH was removed under reduced pressure and the residue was adjusted to pH 4 with 1W HCl to give a solid. The solid was collected by filtration, -washed with water and dried under reduced pressure to give a mixture of 6- (l-isopropyl-6- oxo-1 , 6-dihydro-3-pyridazinyl) -3- [( 4-methoxybenzyl) amino] - 5-phenyl-2-pyrazinecarboxylic acid and 5- ( l-isopropyl-6- oxo-1 , 6-dihydr0-3-pyridazinyl) -3- [ (4-methoxybenzyl) amino] - 6-phenyl-2-pyrazinecarboxylic acid as a solid (9.36 g) . 6- ( l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -3- [ (4-methoxybenzyl) amino] - 5-phenyl_-2-pyrazinecarboxylic acid m.p. : 216.5-217°C (acetone suspension) IR (KBr) : 3327, 1720, 1643, 1570 , 1512 cm"1 Mass (ESI, Neg) : 470 (M-H)~ H NMR (CDCI3, δ) : 0.87 (6H, d, J=S .60 Hz), 3.81 (3H, s), 4.77 (2H, d, J=5.72 Hz), 5.10 (IH, 7-plet, J=6.60 Hz) , 6.89 (2H, d, J=8.57 Hz), 6.98 (IH, d, J=9.60 Hz), 7.28 (2H, d, J=8.57 Hz), 7.30-7.66 (5H, m) , 7.63 (IH, d, J=9.60 Hz) , 8.42 (IH, t, J=5.72 Hz), 10-11 (IH, br-peak) 5- (l-isopropyl-6-oxo-l, 6— dihydro-3-pyridazinyl) -3-
[ (4-methoxybenzyl) amino] -6-phenyl-2-pyrazinecarboxylic acid
• *H NMR (CDC13, δ) : 0.74 (6H, d, J = 6.60 Hz), 4.59 (2H, d, J = 5.12 Hz) Example 49 A suspension of a mixture of 6- (l-isopropyl-6-oxo-
1, 6-dihydro-3-pyridazinyl) -3- [ (4-methoxybenzyl) amino] - 5-phenyl-2-pyrazinecarboxylic acid and 5- ( l-isopropyl-6-oxo- 1, 6-dihydro- 3 -pyridazinyl) -3- [ (4-methoxybenzyl) amino] - 6-phenyl-2-pyrazinecarboxylic acid (9.34 g) in o-dichlorobenzene (37 ml) was heated at 175-180°C for 5 hours. After cooling, the reaction mixture was purified by column chromatography on silica gel. By eluting with a mixture of n-hexane and EtOAc (50:50 v/v) was obtained 2-isopropyl- 6-{ 6- [ (4-methoxybenzyl) amino] -3-phenyl-2-pyrazinyl } -3 (2f) - pyridazinone as a solid (4.41 g) and by eluting with a mixture of n-hexane and EtOAc (40:60 v/v) was obtained 2-isopropyl- 6- { 5- [ (4-methoxybenzyl) amino] -3-pheny 1-2 -pyrazinyl } - 3 (2 if) -pyridazinone as a solid (2.38 g) . 2-isopropyl-6- { 5- [ ( 4-methoxybenzyl) amino] -3-phenyl- 2-pyrazinyl} -3 (2if) -pyridazinone m.p. : 138-140°C
IR (KBr) : 3294, 1651, 1574, 1562, 1514 cm"1
Mass (ESI) : 877 (2M+Na)+, 450 (M+lNJa)+, 428(M+H) + 1H NMR (CDC13, δ) : 0.86 (6H, d, J=6.60 Hz), 3.81 (3H, s), 4.59
(2H, d, J=5.24 Hz) , 5.07 (IH, 7-plet, J=6.60 Hz) , 5.33 (IH, brs) ,
6.87-6.95 (3H, m) , 7.26-7.41 (7H, m) , 7.71 (IH, d, J=9.54 Hz),
7.88 (IH, s)
2-isopropyl-6-{ 6- [ (4-methoxybenzyL ) amino] -3-phenyl- 2-pyrazinyl}-3 (2if) -pyridazinone m.p. : 173-174°C
IR (KBr) : 3330, 1653, 1587, 1514 cm"1
Mass (ESI) : 877 (2M+Na)+, 450 (M-t-TSIa)+, 428 (M+H) +
XH NMR (CDCI3, δ) : 0.87 (6H, d, J=6.62 Hz), 3.82 (3H, s), 4.58 (2H, s), 5.08 (IH, 7-plet, J=6.62Hz) , 5.18 (IH, brs), 6.87-6.97
(3H, m) , 7.21-7.35 (5H, m) , 7.73 (IH, d, J=9.58 Hz), 8.02 (IH, s)
Example 50
A suspension of 2-isopropyl— 6- { 6- [ (4-methoxybenzyl) amino] -3-phenyl—2-pyra inyl }-3 (2if) - pyridazinone (2.01 g) in a mixture of toluene (1 ml) and cone.
HCl (6 ml) was refluxed for 4 hours . After cooling, an organic layer was removed and an aqueous layer was adjusted to pH 8 with
8-V aq. NaOH to yield a precipitate. The precipitate was collected by filtration and dried mnder reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (30:70 v/v) to give 6- (6-amino-3-phenyl-2-pyrazinyl) -2 -isopropyl-3 (2f) - pyridazinone as a solid (680 mg) . m.p. : 214-217°C (acetone)
IR (KBr) : 3423, 3327, 3217, 1645, -1624, 1577, 1566, 1531 cm"1 Mass (ESI) : 330 (M+Na)+, 308 (M+H ) + 2H NMR (CDC13, δ) : 0.88 (6H, d, J=6.60 Hz), 4.85 (2H, brs), 5.09 (IH, 7-plet, J=6.60Hz), 6.95 (IH, d, J=9.60Hz), 7.23-7.35 (5H, m) , 7.71 (IH, d, J=9.60 Hz), 8.11 (IH, s) Example 51
6- ( 1-Isopropyl-6-oxo-l, 6-dih ydro-3-pyridazinyl) - 3- [ ( 4-methoxybenzyl) amino] -5-phenyl-2-pyrazinecarbonitrile ( 14.61 g) was added to a suspension of NaH (60% in oil suspension) (1.36 g) in DMA (36.5 ml) and the mixture was stirred at 20-25°C for an hour. After addition of 1- ( chloromethyl) - 4-methoxybenzene (4.82 ml) , the mixture was stirred at the same temperature for 20 hours. To the -reaction mixture was added water (183 ml) and a precipitate was collected by filtration. The precipitate was purified by column chromatography on silica gel (EtOAc only) to give a solid. The solid was crystallized from a mixture of n-hexane and CHCI3 to give 3- [bis (4- methoxybenzyl) amino] -6- (l-isopropyl-6-oxo-l , 6-dihydro- 3-pyridazinyl) -5-phenyl-2-pyrazinecarbonitrile (16.58 g) . m.p. : 207-209°C (CHC13 - n-hexane) IR (KBr) : 2222, 1657, 1545, 1514 cm"1 Mass (ESI) : 595 (M+Na)+, 573 (M+H)+ αH NMR (CDC13, δ) : 0.83 (6H, d, J=6.60 Hz), 3.81 (6H, s), 4.97 (4H, s), 5.04 (IH, 7-plet, J=6.60 Hz), 6.86-7.02 (5H, m) , 7.17-7.22 (4H, m) , 7.33-7.46 (5H, m) , 7.92 (IH, d, J=9.58 Hz) Example 52
A suspension of 3- [bis ( 4-methoxybenzyl) amino] - 6- (1-isopropyl-6-oxo-l, 6-dihydro-3-pyridazi nyl) -5-phenyl- 2-pyrazinecarbonitrile (3.00 g) in a mixture of 2N aq. ΝaOH (30 ml) and dioxane (21 ml) was refluxed for 36 hourrs . After cooling, the mixture was extracted with EtOAc, dried over MgS0 , concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (20:80 v/v) to give a solid. The solid was crystallized from a mixture of n-hexane and acetone to give 3- [bis (4- methoxybenzyl ) amino] -6- (1-isopropyl- 6-oxo-l , 6-dihydro- 3-pyridazinyl) -5-phenyl-2-pyrazinecarboxam±de (2.56 g). m.p. : 120-122.5°C (acetone - n-hexane) IR (KBr) : 1651, 1585, 1539, 1510 cm"1 Mass (ESI) : 613 (M+Νa)+, 591 (M+H)+
XH NMR (CDCI3, δ) : 0.87 (6H, d, J=6.62 Hz), 3.78 (6H, s) , 4.76 (4H, s), 5.09 (IH, 7-plet), 5.49 (IH, brs), 6.83 (4H, d, J=8.60 Hz) , 6.99 (IH, d, J=9.60 Hz) , 7.13 (4H, d, J=8.60 Hz) , 7.26 (IH, brs), 7.31-7.34 (3H, m) , 7.47-7.50 (2H, m) , 7.92 (IH, d, J=9.60 Hz)
Example 53 N-bromosuccinimide (875 mg) was added to a solution of 6- (5-amino-3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2Jf) — pyridazinone (1.51 g) in DMF (15 ml). The mixture w s stirred at 50-55°C for one hour and poured into water (150 ml) . The precipitate was collected by filtration, dissolved in CHCI3, dried over MgS04 and concentrated under reduced pressure to give a solid. The solid was suspended in acetone and collected by filtration to give 6- (5-amino-6-bromo-3-phenyl-2-pyrazinyl) - 2-isopropyl-3 (2if) -pyridazinone as a solid (1.26 g) . m.p. : 204-206°C (acetone) IR (KBr) : 3465, 3267, 3145, 1657, 1614, 1587, 15L8 cm"1
Mass (ESI) : 797 and 795 (2M+Na)+, 408 and 410 (M+Na) +, 386 and 388 (M+H)+ aH NMR (CDCI3, δ) : 0.82 (6H, d, J=6.62 Hz), 5.06 (IH, 7-plet, J=6.62 Hz), 5.32 (2H, brs), 6.94 (IH, d, J=9.58 Hz), 7.30-7.40 (5H, m) , 7.76 (IH, d, J=9.58 Hz) Example 54
A mixture of 6- (5-amino-6-bromo-3-phenyl-2-p;yrazinyl) - 2-isopropyl-3 (2if) -pyridazinone (11.35 g) and sodium thiomethoxide (4.12 g) in 1 , 3-dimethyl-2-imidazoli dinone (17 ml) was heated at 100-105°C for one hour. The mixture was poured into water (170 ml). The precipitate was collected toy filtration, dissolved in CHC13, dried over MgS04, concentrated -under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give 6- [5-amino-6- (methylthio) - 3-phenyl-2-pyrazinyl] -2-isopropyl-3 (27f) -pyridazinone as a solid (4.32 g) . 6- [5-amino-6- (methylthio) -3-phenyl-2-pyrazinyl] - 2-isopropyl-3 (2f) -pyridazinone m.p. : 211-214°C (acetone - hexane)
IR (KBr) : 3464, 3323, 1660, 1612, 1585 cm"1
Mass (ESI) : 729 (2M+Na)+, 376 (M+Na)+, 354 (M+H) +
XH NMR (CDC13, δ) : 0.84 (6H, d, J=6.60 Hz), 2.70 (3H, s), 5.00 (2H, brs), 5.08 (IH, 7-plet, J=6.60 Hz), 6.94 ( H, d, J=9.58 Hz), 7.26-7.37 (5H, m) , 7.79 (IH, d, J=9.58 Hz) Example 55
Under ice-cooling, m-chloroperbenzoic ac±d (70-75% purity) (2.09 g) was added to a mixture of 6- [ 5-amino- 6- (methylthio) -3-phenyl-2-pyrazinyl] -2-isoprop;yl-3 (2if) - pyridazinone (3.00 g) in CH2C12 (30 ml) and stirred at the same temperature for one hour. The mixture was washed ith saturated aq. sodium thiosulfate, saturated aq. NaHC03 and brine, dried over MgS04 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel. By eluting with a mixture of n-hexane and EtOAc (30:70 v/v) was obtained 6- [5-amino-6- (methylsulfonyl) - 3-phenyl-2-pyrazinyl] -2-isopropyl-3 (2f) -pyridazinone as a solid (0.69 g) and by eluting with a mixture of n-hexane and EtOAc (20:80 v/v) was obtained 6- [5-amino-6- (methylsulfinyl) - 3-phenyl-2-pyrazinyl] -2-isopropyl-3 (2if) -pyridazinone as a solid (2.32 g) .
6- [5-amino-6- (methylsulfinyl) -3-phenyl-2-pyrazinyl] - 2-isopropyl-3 (2if) -pyridazinone m.p. : 225-227°C (CHC13 - n-hexane)
IR (KBr) : 3375, 3282, 3184, 1666, 1653, 1618, 1583, 1520 cm"1
Mass (ESI) : 392 (M+Na)+, 370 (M+H)+
XH NMR (CDCI3, δ) : 0.79 (3H, d, J=6.60 Hz), 0.86 (3H, d, J=6.60 Hz), 3.03 (3H, s), 5.06 (IH, 7-plet, J=6.60Hz), 6.39 (2H, brrs),
6.94 (IH, d, J=9.60Hz), 7.33-7.41 (5H, m) , 7.68 (IH, d, J=9.60
Hz)
6- [5-amino-6- (methylsulfonyl) -3-phenyl-2-pyrazinyl] -
2-isopropyl-3 (2f) -pyridazinone m.p. : 249-251°C (CHC13 - n-hexane)
IR (KBr) : 3477, 3373, 1666, 1591, 1527 cm-1
Mass (ESI) : 408 (M+Na)+, 386 (M+H)+ λH NMR (CDCI3, δ) : 0.82 (6H, d, J=6.60 Hz), 3.34 (3H, s) , 5.07
(IH, 7-plet, J=6.60 Hz), 6.20 (2H, brs), 6.98 (IH, d, J=S.58 Hz ) , 7 . 39 ( 5H , m) , 7 . 76 ( IH, d, J=9 . 58 Hz ) Example 56
Under ice-cooling, m-chloroperbenzoic acid (70-75% purity) (530 mg) was added to a mixture of 6-[5-amino- 6- (methylsulfinyl) -3-phenyl-2-pyrazinyl] -2-isopropyl-3 (2ff) - pyridazinone (750 mg) in CH2C12 (7.5 ml). The mixture was stirred at 25-30°C for 5 hours, washed with saturated aq. sodium thiosulfate, saturated aq. NaHC03 and brine, dried over MgS04 and concentrated under reduced pressure to give a residue. The- residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (30:70 v/v) to give 6- [5-amino-6- (methylsulfonyl) -3-phenyl-2-pyrazinyl] -2- isopropyl-3 (2if) -pyridazinone as a solid (524 mg) . m.p. : 249-251°C (CHC13 - hexane) IR (KBr) : 3477, 3373, 1666, 1591, 1527 cm"1 Mass (ESI) : 408 (M+Na)+, 386 (M+H)+
X NMR (CDC13, δ) : 0.82 (6H, d, J=6.60 Hz), 3.34 (3H, s) , 5.07 (IH, 7-plet, J=6.60 Hz)', 6.20 (2H, brs), 6.98 (IH, d, J=9.58 Hz), 7.39 (5H, m) , 7.76 (IH, d, J=9.58 Hz) Example 57
A solution of 6- ( l-ethyl-6-oxo-l, 6-dihydro-3- pyridazinyl) -3- [ (4-methoxyben∑yl) amino] -5-phenyl-2- pyrazinecarbonitrile (1.00 g) in a mixture of 5N aq. ΝaOH ( 1 ml) and EtOH (4 ml) was refluxed for 5 hours. At 40-50°C, the mixture was adjusted to pH 4 with li\J HCl and stirred for one hour to give a precipitate. The precipitate was collected by filtration and dried under reduced pressure to give 6- (l-ethyl-6-oxo-l, 6-dihydro-3-pyridazinyl) - 3- [ (4-methoxybenzyl) amino] -5-phenyl-2-pyrazinecarboxylic acid (1.03 g) . m.p. : >250°C
IR (KBr) : 1655, 1637, 1568, 1514 cm"1 Mass (ESI) : 480 (M+Na)+, 458 (M+H)+ λU NMR (DMS0-d6, δ) : 0.81 (3H, t, J=7.16 Hz), 3.72-3.79 (5H, m) , 4.63 (2H, d, J=5.52 Hz), 6.89-6.94 (3H, m) , 7.30-7.40 (7H, m) , 7.77 (IH, d, J=9.58 Hz), 9.61 (IH, brs) Example 58
A mixture of 6- (l-ethyl-6-oxo-l, 6-dihydro-3- pyridazinyl) -3- [ (4-methoxybenzyl ) amino] -5-phenyl-2- pyrazinecarboxylic acid (1.02 g) in 1, 2-dichlorobenzene (20 ml) was refluxed for 3 hours. The mixture was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40:60 v/v) to give 2-ethyl-6-{ 5- [ (4- methoxybenzyl) amino] -3-phenyl-2-pyrazinyl }-3 (2if) - pyridazinone as a solid (783 mg) . m.p. : 148-150°C (acetone - n-hexane) IR (KBr) : 3265, 1645, 1570, 1514 cm"1 Mass (ESI) : 849 (2M+Na)+, 436 (M+Na)+, 414 (M+H)+ XH NMR (CDCI3, δ) : 1.04 (3H, t, J=7.17 Hz), 3.81 (3H, s) , 3.98 (2H, q, J=7.17 Hz) , 4.58 (2H, d, J=5.32 Hz) , 5.34 (IH, t, J=5.32 Hz), 6.81-6.92 (3H, m) , 7.26-7.48 (8H, m) , 7.90 (IH, s) Example 59 A suspension of 2-ethyl-6- { 5- [ (4-methoxybenzyl) amino] - 3-phenyl-2-pyrazinyl}-3 (2if) -pyridazinone (500 mg) in a mixture of cone. HCl (1.5 ml) and toluene (0.5 ml) was refluxed for 4 hours. After removal of an organic layer, an aqueous layer was adjusted to pH 4 with 6ΛJ aq. NaOH under ice-cooling. The precipitate was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (20:80 v/v) to give 6- (5-amino-3-phenyl-2-pyrazinyl) -2-ethyl-3 (2if) -pyridazinone (213 mg) . m.p. : 227-229°C (EtOAc) IR (KBr) : 3392, 3323, 1650, 1587, 1570, 1533 cm"1 Mass (ESI) : 609 (2M+Na)+, 316 (M+Na)+, 294 (M+H)+ 1H NMR (CDCI3, δ) : 1.03 (3H, t, J=7.17 Hz), 3.97 (2H, q, J=7.17 Hz), 4.98( 2H, brs), 6.86 (IH, d, J=9.60 Hz), 7.33-7.41 (5H, m) , 7.49 (IH, d, J=9.60 Hz), 8.02 (IH, s) XH NMR (DMSO-d6, δ) :0.78 (3H, t, J=7.20Hz), 3.73 (2H, q, J=7.20 Hz), 6.89 (2H, brs), 6.92 (IH, d, J=9.60Hz), 7.34 (5H, s), 7.69 (IH, d, J=9.60 Hz), 7.93 (IH, s) Example 60 6- ( 5-amino-6-bromo-3-phenyl-2-pyra∑inyl) -2-methyl-3 (2f) - pyridazinone
The title compound was obtained in a similar manner to that of Example 53. m.p. : 220-222°C IR (KBr) : 3417, 3396, 3292, 3194, 1649, 1630, 1579, 1543 cm"1
Mass (ESI) : 382 and 380 (M+Na)+
XH NMR (DMSO-de, δ) : 3.39 (3H, s) , 6.87 (IH, d, J=9.60 Hz),
7.19 (2H, brs), 7.37 (5H, s) , 7.44 (IH, d, J=9.60 Hz)
Example 61 6- [5-amino-6- (methylthio) -3-phenyl-2-pyrazinyl] -2-methyl-
3 (2if) -pyridazinone
The title compound was obtained in a similar manner to that of Example 54. m.p. : 204-205.5°C IR (KBr) : 3305, 3188, 1653, 1577, 1523, 1506 cm"1
Mass (ESI) : 673 (2M+Na)+, 348 (M+Na)+, 326 (M+H)+
^ NMR (DMSO-de, δ) :2.59 (3H, s), 3.31 (3H, s) , 6.73 (2H, brs),
6.93 (IH, d, J=9.58 Hz), 7.34 (5H, s) , 7.74 (IH, d, J=9.58 Hz)
Example 62 6- [5-amino-6- (methylsulfinyl) -3-phenyl-2-pyrazinyl] -
2-methyl-3 (2f) -pyridazinone and 6-[5-amino-
6- (methylsulfonyl) -3-phenyl-2-pyrazinyl] -2-methy1-
3 (2f) -pyridazinone
The title compounds were obtained in a similar manner to that of Example 55.
6- [5-amino-6- (methylsulfinyl) -3-phenyl-2-pyrazinyl] - 2-methyl-3 (2ϋ) -pyridazinone m.p. : 209-210.5°C IR (KBr) : 3361, 3257, 3180, 3149, 1657, 1620, 1583, 1522 cm"1 Mass (ESI) : 364(M+Na)+
1H NMR (CDC13, δ) : 3.03 (3H, s) , 3.53 (3H, s) , 6.45 (2H, brs), 6.85 (IH, d, J=9.65 Hz), 7.37-7.44 (6H, m) 6- [5-amino-6- (methylsulfonyl) -3-phenyl-2-pyrazinyl] - 2-methyl-3 (2if) -pyridazinone m.p. : 231-233°C
IR (KBr) : 3427, 3278, 1672, 1666, 1612, 1589 cm"1 Mass (ESI) : 380 (M+Na)+ H NMR (CDCI3, δ) : 3.33 (3H, s), 3.48 (3H, s), 6.22 (2H, brs), 6.91 (IH, d, J=9.60Hz), 7.44-7.48 (5H,-m), 7.58 (IH, d, J=9.60
Hz)
Example 63
6- [5-amino-6- (methylsulfonyl) -3-phenyl-2-pyrazinyl] -
2-methyl-3 (2if) -pyridazinone The title compound was obtained in a similar manner to that of Example 56. m.p. : 231-233°C
IR (KBr) : 3427, 3278, 1672, 1666, 1612, 1589 cm"1
Mass (ESI) : 380 (M+Na)+ XH NMR (CDCI3, δ) : 3.33 (3H, s) , 3.48 (3H, s) , 6.22 (2H, brs) , 6.91 (IH, d, J=9.60 Hz) , 7.44-7.48 (5H, m) , 7.58 (IH, d, J=9.60 Hz)
Example 64 A solution of 6- [5-amino-6- (methylsulfonyl) -3-phenyl- 2-pyrazinyl] -2-isopropyl-3 (2ff) -pyridazinone (200 mg) in a mixture of IN aq. ΝaOH (1 ml) and dioxane (2 ml) was refluxed for 6 hours. After cooling, the mixture was adjusted to pH 4 with 1NHC1 to give a precipitate. The precipitate was collected by filtration and crystallized from DMSO and water to give 6- (5-amino-6-oxo-3-phenyl-l, 6-dihydro-2-pyrazinyl) - 2-isopropyl-3 (2if) -pyridazinone (123 mg) . m.p. : >250°C (DMSO - H20) IR (KBr) : 3431, 3315, 1664, 1645, 1608, 1585, 1522 cm"1 Mass (ESI) : 346 (M+Νa)+, 324 (M+H)+
XH NMR (DMSO-d6, δ) : 1.11 (6H, d, J=6.60Hz), 5.02 (IH, 7-plet, J=6.60 Hz), 6.75 (IH, d, J=9.58 Hz), 7.03-7.35 (8H, m) , 11.90 (IH, s) Example 65 To a suspension of 6- (5-amino-3-phenyl-2-pyrazinyl ) - 2-isopropyl-3 (2if) -pyridazinone (1.01 g) was added dimethyl sulfide (0.263 ml) and N-chlorosuccinimide (435 mg) under -5°C. The mixture was stirred at -5°C for 30 minutes and at 20-25°C for 20 hours. A solution of 28% sodium methoxide in MeOH (1.13 ml) was added to the mixture and the solution was stirred at the same temperature for an hour. After addition of water (10 ml) , the organic layer was collected, dried over MgS04, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of MeOH and EtOAc (1:99 v/v) to give 6-{ 5- [ (dimethyl-lambda~4 — sulfanylidene) amino] -3-phenyl-2-pyrazin'yl } -2-isopropyl- 3 (2f) -pyridazinone as a solid (0.80 g) . m.p. : 190-194°C IR (KBr) : 1662, 1657, 1589, 1547, 1547, 1502 cm"1 Mass (ESI) : 390 (M+Na)+, 368 (M+H)+ R NMR (CDC13, δ) : 0.85 (6H, d, J=6.70 Hz), 2.81 (6H, s) , 5.07 (IH, 7-plet), 6.92 (IH, d, J=9.58 Hz), 7.27-7.42 (5H, ) , 7.74 (IH, d) , 8.07 (IH, s) Example 66
To a solution of DMSO (0.75 ml) in CH2C12 (5 ml) was added trifluoromethanesulfonic anhydride (1.5ml) dropwise at <-75°C under nitrogen. A suspension of 6- ( 5-amino-6-bromo-3-phenyl- 2-pyrazinyl) -2-isopropyl-3 (2if) -pyridazinone (3.00 g) in a mixture of DMSO (5 ml) and CH2C12 (6 ml) was added and stirred at -65°C for 2 hours and at -55°C for one hour. The reaction mixture was quenched with liV aq. NaOH (20 ml) and stirred at 15°C for 10 minutes. An organic layer was collected, dried over MgS04 and concentrated under reduced pressure to give a solid. The solid was suspended in acetone and collected by filtration to give 6- { 6-bromo-5- [ (dimethyl-lambda~4~- sulfanylidene) amino] -3-phenyl-2-pyrazinyl } -2-isopropyl- 3 (2H) -pyridazinone (3.16 g) . m.p. : 220-224°C
IR (KBr) : 1651, 1585, 1537 cm"1
Mass (ESI) : 470 and 468 (M+Na)+, 448 and 446 (M+H) + H NMR (CDC13, δ) : 0.82 (6H, d, J=6.66 Hz), 2.88 (6H, s) , 5.05 (IH, 7-plet, J=6.66Hz), 6.92 (IH, d, J=9.56Hz), 9.27-9.38 (5H, ) , 7.78 (IH, d, J=9.58 Hz)
XH NMR (DMSO-de, δ) : 0.73 (6H, d, J=6.60 Hz), 2.86 (6H, s), 4.88 (IH, 7-plet, J=6.60Hz), 6.93 (IH, d, J=9.68Hz), 7.30-7.42 (5H, m) , 7.73 (IH, d, J=9.68 Hz) Example 67 To a solution of m-chloroperbenzoic acid (70-75% purity) (1.66 g) in CH2C12 (40 ml) was added a solution of 6-{6-bromo- 5- [ (dimethyl-lambda~4~-sulfanylidene) amino] -3-phenyl- 2-pyrazinyl } -2-isopropyl-3 (2if) -pyridazinone (2.01 g) in CH2C12 (20 ml) at -10~-5°C and the mixture was stirred at the same temperature for one hour. After addition of dimethyl sulfide
(0.25 ml) , the solution was stirred at the same temperature for
30 minutes. Sat. aq. Na2C0 (50 ml) was then added to the mixture .
An organic layer was collected, dried over MgS0 , concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (70 : 30 v/v) to give 6- ( 6-bromo-5-nitroso-3-phenyl-2-pyrazinyl) - 2-isopropyl-3 (2 f) -pyridazinone as a solid (0.896 g) . m.p. : 164-166°C IR (KBr) : 1666, 1591, 1514 cm"1
Mass (ESI) : 424 and 422 (M+Na)+, 402 and 400 (M+H) + XH NMR (CDC13, δ) : 0.79 (6H, d, J=6.60 Hz), 5.06 (IH, 7-plet, J=6.60 Hz), 7.05 (IH, d, J=9.66 Hz), 7.37 (5H, s), 8.11 (IH, d, J=9.66 Hz) Example 68
A solution of tert-butyl (2- ( [1- ( l-isopropyl-6-oxo- 1, 6-di hydro- 3 -pyridaz inyl) -2-oxo-2-phenylethyl] amino} - 2-oxoethyl ) carbamate (310 mg) in 10% hydrogen chloride in MeOH (3 ml) was stirred at 20-25°C for 18 hours and the mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in pyridine (1.5 ml) and heated at 80-85°C for 10 hours. After evaporation of pyridine, the mixture was dissolved in CHC13, washed with IN HCl, sat. aq. ΝaHC03 and brine, dried over MgS04 and concentrated under reduced pressure to give syrup. The syrup was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40:60 v/v) to give 6- ( 6-hydroxy-3-phenyl-2-pyrazinyl) -2-isopropyl- 3 (2if) -pyridazinone as a solid (65 mg) . m.p. : 198-200°C IR (KBr) : 1664, 1593, 1533 cm"1
Mass (ESI) : 639 (2M+Na)+, 331 (M+Na)+, 309 (M+H)+ XH NMR (CDC13, δ) : 1.43 (6H, d, J=6.60 Hz), 5.34 (IH, 7-plet, J=6.60 Hz), 6.66 (IH, d, J=9.75 Hz), 6.79 (IH, d, J=9.75 Hz), 7.41 (5H, s) , 8.31 (IH, s) NMR (DMSO-de, δ) : 0.83 (6H, d, J=6.60 Hz), 4.94 (IH, 7-plet, J=6.60 Hz), 7.00 (IH, d, J=9.63 Hz), 7.23-7.41 (5H, m) , 7.72 (IH, d, J=9.63 Hz), 8.25 (IH, s) , 12.19 (IH, brs) Example 69 In the presence of copper (I) iodide (25 mg) and dichlorobis ( triphenylphosphine) palladium (II ) (91 mg ), triethylamine (0.397 ml) was dropwise added to a mixture of 6- (5-amino-6-bromo-3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2if) - pyridazinone (1.00 g) and ethynyl (trimethyl) silane (0.716ml) in 1, 2-dichloroethane (20 ml) under ice-cooling. The mixture was stirred at same temperature for one hour and at 25-30°C for 18 hours. After addition of water, an organic layer was collected, washed with sat. aq. sodium chloride, dried over MgS0 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (80:20 v/v) to give a solid. The solid was crystallized from a mixture of acetone and n-hexane to give 6- { 5-amino-3-phenyl- 6- [ (trimethylsilyl) ethynyl] -2-pyrazinyl } -2-isopropyl-3 (2if) - pyridazinone (431 mg) . m.p. : 213-215°C (acetone - n-hexane)
IR (KBr) : 3464, 3276, 3176, 3147, 2966, 2143, 1662, 1618, 1591 cm Mass (ESI) : 426 (M+Na)+, 404 (M+H) +
XH NMR (CDC13, δ) : 0.33 (9H, s), 0.82 (6H, d, J=6.60 Hz), 5.06 (IH, 7-plet, J=6.60 Hz), 5.34 (2H, brs), 6.94 (IH, d, J=9.56 Hz), 7.30-7.38 (5H, m) , 7.78 (IH, d, J=9.56 Hz) Example 70 In the presence of copper (I) iodide (5 mg) and dichlorobis (triphenylphosphine) palladium (II) (18 mg ), triethylamine (0.0794 ml) was dropwise added to a mixture of 6- (5-amino-6-bromo-3-pheny1-2-pyrazinyl) -2-isopropyl-3 (2if) - pyridazinone (200 mg) and ethynylbenzene (0.0626 ml) in 1, 2-dichloroethane (2 ml) at 60°C. The mixture was refluxed for 2 hours. The mixture was cooled to give a precipitate. The precipitate was collected by filtration and suspended in MeOH to give 6- [5-amino-3-phenyl-6- (phenylethynyl) -2-pyrazinyl] - 2-isopropyl-3 (2ff) -pyridazinone (104 mg) . m.p. : 239-241°C (MeOH suspension)
IR (KBr) : 3477, 3267, 3126, 2195, 1660, 1624, 1587, 1502 cm"1 Mass (ESI) : 837 (2M+Na)+, 430 (M+Na)+, 408 (M+H)+ lti NMR (DMS0-d6, δ) : 0.74 (6H, d, J=6.60Hz), 4.89 (IH, 7-plet, J=6.60 Hz), 6.97 (IH, d, J=9.60 Hz), 7.19 (2H, brs), 7.36-7.40 ( 5H, ) , 7 . 44-7 . 51 ( 3H , m) , 7 . 75-7 . 81 ( 2H, m) , 7 . 84 ( IH, d, J=9 . 60 Hz ) Example 71
In the presence of copper (I) iodide (7.5 mg) and dichlorobis (triphenylphosphine) palladium (II) (27.4 mg ), triethylamine (0.1192 ml) was dropwise added to a mixture of 6- ( 5-amino-6-bromo-3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2if) - pyridazinone (300 mg) and ethynyl (trimethyl) silane (85.6 mg) in 1, 2-dichloroethane (3 ml) at 60°C. The mixture was refluxed for 2 hours. After addition of water, an organic layer was collected, washed with sat. aq. sodium chloride, dried over MgS04 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a solid. The solid was crystallized from a mixture of acetone and n-hexane to give 6-{ 5-amino-6- [3- (methoxymethoxy) - 1-propyn-l-yl] -3-phenyl-2-pyrazinyl } -2-isopropyl- 3 (2if) -pyridazinone (233 mg) . m.p.: 133-135°C IR (KBr) : 3471, 3275, 3113, 2969, 1662, 1628, 1589, 1506 cm"1 Mass (ESI) : 428 (M+Na)+, 406 (M+H) +
:H NMR (CDC13, δ) : 0.82 (6H, d, J=6.60 Hz), 3.45 (3H, s), 4.56
(2H, s), 4.82 (2H, s) , 5.06 (IH, 7-plet, J=6.60 Hz), 5.40 (2H, brs), 6.94 (IH, d, J=9.58 Hz), 7.31-7.39 (5H, m) , 7.78 (IH, d, J=9.58 Hz)
The following 2 compounds were obtained in a similar manner to that of Example 71. Example 72
6- [5-amino-6- (1-cyclohexen-l-ylethynyl) -3-phenyl-
2-pyrazinyl] -2-isopropyl-3 (2if) -pyridazinone m.p. : 231-233°C
IR (KBr) : 3471, 3275, 3138, 2181, 1662, 1626, 1591 cm"1 Mass (ESI) : 434 (M+Na)+, 412 (M+H) + λ NMR (CDC13, δ) : 0.82 (6H, d, J=6.60 Hz), 1.63-1.76 (4H, m) ,
2.17-2.30 (4H, m) , 5.06 (IH, 7-plet, J=6.60 Hz) , 5.27 (2H, brs) ,
6.38-6.43 (IH, m) , 6.93 (IH, d, J=9.56 Hz), 7.27-7.38 (5H, m) ,
7.78 (IH, d, J=9.56 Hz) Example 73
6-{ 5-amino-6- [ (1-hydroxycyclohexyl) ethynyl] -3-phenyl-
2-pyrazinyl }-2-isopropyl-3 (2if) -pyridazinone m.p. : 238-240°C
IR (KBr) : 3471, 3261, 3178, 2220, 1647, 1614, 1579, 1508 cm"1 Mass (ESI) : 452 (M+Na)+, 430 (M+H) +
XH NMR (CDCI3, δ) : 0.82 (6H, d, J=6.62 Hz), 1.22-2.18 (10H, m) , 5.06 (IH, 7-plet, J=6.62 Hz), 5.32 (2H, brs), 6.96 (IH, d,
J=9.56 Hz), 7.27-7.38 (5H, m) , 7.78 (IH, d, J=9.56 Hz)
1 X1H,, NMR (DMSO-d6, δ) : 0.73 (6H, d, J=6.60 Hz), 1.17-1.99 (10H, m) , 4.88 (IH, 7-plet, J=6.60 Hz), 5.68 (IH, s), 6.92 (2H, brs), 6.94 (IH, d, J=9.60 Hz) , 7.33-7.41 (5H, m) , 7.79 (IH, d, J=9.60 Hz)
Example 74
In the presence of copper (I) iodide (3.7 mg) and dichlorobis (triphenylphosphine) palladium (II) (13.7 mg ), triethylamine (0.0596 ml) was dropwise added to a mixture of 6- (5-amino-6-bromo-3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2ff) - pyridazinone (150 mg) and 2-ethynylpyridine (0.0431 ml) in 1, 2-dichloroethane (1.5ml) at 30—35°C. The mixture was stirred at the same temperature for 18 hours. Water was added to the reaction mixture to give a solid. The solid was purified by column chromatography on silica gel (EtOAc only) to give a solid. The solid was suspended in acetone to give 6- [ 5-amino-3-phenyl- 6- (2-pyridylethynyl) -2-pyrazinyl] -2-isopropyl-3 (2if) - pyridazinone (88 mg) . m.p. : 245.5-247°C IR (KBr) : 3469, 3261, 3134, 3124, 2208, 1658, 1621, 1585, 1558, 1531, 1504 cm"1
Mass (ESI) : 431 (M+Na)+ HNMR (DMSO-de, δ) : 0.74 (6H, d, J=6.64 Hz), 4.89 (IH, 7-plet, J=6.64 Hz), 6.97 (IH, d, J=9.57 Hz), 7.26 (2H, brs), 7.35-7.51 (6H, m) , 7.85 (IH, d, J=9.57 Hz), 7.87-7.96 (2H, m) , 8.64-8.68 (IH, m) Example 75
In the presence of copper (I) iodide (3.7 mg) and dichlorobis (triphenylphosphine) palladium (II) (13.7 mg ), triethylamine (0.0596 ml) was dropwise added to a mixture of 6- ( 5-amino-6-bromo-3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2if) - pyridazinone (150 mg) and 5-ethynyl—l-methyl-lff-imidazole (45.4 mg) in THF (1.5 ml) at 50°C. The mixture was refluxed for 2 hours. Water was added to the reaction mixture to give a solid. The solid was purified by column chromatography on silica gel eluting with a mixture of MeOH and EtOAc (2:98 v/v) to give 6- { 5-amino-6- [ (1-methyl-lif-imidazol—5-yl ) ethynyl] -3-phenyl- 2-pyrazinyl } -2-isopropyl-3 (2if) -pyridazinone as a solid (135 mg) . m.p. : >250°C
IR (KBr) : 3473, 3275, 3141, 3074, 2195, 1658, 1630, 1587, 1518 cm"1
Mass (ESI) : 845 (2M+Na)+, 434 (M+Na)+, 412 (M+H) +
]H NMR (CDC13, δ) : 0.83 (6H, d, J=6.64 Hz) , 3.86 (3H, s) , 5.07 (IH, 7-plet, J=6.64 Hz) , 5.36 (2H, brs) , 6.96 (IH, d, J=9.60 Hz) , 7.28-7.41 (5H, m) , 7.6 (IH, brs) , 7.79 (IH, d, J=9.60 Hz) , 7.86 (IH, brs) λU NMR (DMSO-d6, δ) : 0.74 (6H, d, J~=6.60 Hz) , 3.77 (3H, s), 4.89 (IH, 7-plet, J=6.60 Hz), 6.96 (IH, d, J=9.61 Hz) , 7.14 (2H, bxs), 7.34-7.42 (5H, m) , 7.51 (IH, brs), 7.82 (IH, d, J=9.61 Hz), 7.84 (IH, brs) Example 76
Under ice-cooling, 12N aq. ΝaOH (0.9 ml) was added dropwise to a solution of 6-{ 5-amino-3-phenyl-
6— [ (trimethylsilyl) ethynyl] -2-pyrazinyl } -2- isopropyl- 3 (2if) -pyridazinone (908 mg) in a mixture of acetonitrile (0.9 ml) and THF (1.8 ml). The mixture was stirred at 25-30°C for one hour, neutralized with 6N HCl, extracted -with CHC1 , dried over MgS04 and concentrated under reduced pressure to give a syrup . The syrup was purified by column chromatography on silica gel eluting with a mixture of n-hexane and -CtOAc (30:70 v/v) to give 6- (5-amino-6-ethynyl-3-phenyl-2-pyrazinyl ) - 2 -isopropyl-3 (2f) -pyridazinone as a solid (196 mg) . m.p. : 217°C (dec.) (acetone - n-hexane)
IR (KBr) : 3469, 3297, 3140, 2102, 1657, 1620, 1585 cm"1 Mass (ESI) : 685 (2M+Νa)+, 354 (M+Na)+, 332 (M+H) + XH NMR (CDCI3, δ) : 0.81 (6H, d, J=6.63 Hz), 3.59 (IH, s), 5.06 ( IH, 7-plet, J=6.63 Hz), 5.33 (2H, brs), 6.94 (IH, d, J=9.56 Hz), 7.30-7.39 (5H, m) , 7.79 (IH, d, J=9.56 Hz) Example 77
In the presence of copper (I) iodide (4.3 mg) and dichlorobis ( triphenylphosphine) palladium (II ) (15.7 mg ), triethylamine (0.0685 ml) was dropwise added to a mixture of 6- (5-amino-6-bromo-3-phenyl-2-pyrazinyl) -2-methyl-3 (2if) - pyridazinone (150 mg) and ethynylbenzene (0.0054 ml) in DMF (1.5 ml) at 75-80°C. The mixture was stirred at the same temperature for 2 hours. To the reaction mixture, water was added to give a solid. The solid was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40:60 v/v) to give a solid. The solid was suspended in acetone to give 6- [ 5-amino-3-phenyl-6- (phenylethynyl) -2-pyrazinyl] - 2-methyl-3 (2if) -pyridazinone (96 mg) . m.p. : 234-236°C
IR (KBr) : 3465, 3278, 2195, 1666, 1626, 1587 cm"1
Mass (ESI) : 402 (M+Na)+ λH NMR (DMSO-d6, δ) : 3.46 (3H, s), 6.90 (IH, d, J=9.68 Hz),
7.20 (2H, brs), 7.39 (5H, s), 7.43-7.57 (4H, m) , 7.74-7.82 (2H, m)
Example 78
Under nitrogen atmosphere, a solution of Na2C03 (220 mg) in water (1.6 ml) was added to a suspension of 6- ( 5-amino-6-bromo-3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2ff) - pyridazinone (200 mg) , phenylboronic acid (158 mg) and tetrakis (triphenylphosphine) palladium (18 mg) in dioxane (6 ml) and the mixture was stirred at 100-105°C for 2 hours. After addition of water (6 ml), a precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a solid. The solid was suspended in acetone and collected by filtration to give 6- (5-amino-3, 6-diphenyl-2-pyrazinyl) -
2-isopropyl-3 (2if) -pyridazinone (150 mg) . m.p. : 225-226°C
IR (KBr) : 3489, 3105, 1660, 1624, 15191, 1506 cm"1
Mass (ESI) : 406 (M+Na)+, 384 (M+H) + αH NMR (CDC13, δ) : 0.84 (6H, d, J=6.70 H∑), 4.97-5.17 (3H, m) ,
6.94 (IH, d, J=9.56 Hz), 7.32-7.55 (8H, m) , 7.80-7.90 (3H, m)
The following 11 compounds were obtained in a similar manner to that of Example 78.
Example 79
6- [5 -ami no- 3 -phenyl- 6- (3-thienyl) -2 -pyrazinyl] -2 - isopropyl - 3 (2 if) -pyridazinone m.p. : 228-230°C
IR (KBr) : 3479, 3124, 2979, 1657, 1624, 1591, 1527, 1504 cm"1
Mass (ESI) : 412 (M+Na)+, 390 (M+H) +
XH NMR (CDCI3, δ) :0.84 (6H, d, J=6.60 Hz), 5.08 (IH, 7-plet, J=6.60 Hz) , 5.16 (2H, brs) , 6.95 (IH, d, J=9.54 Hz) , 7.33-7.44
(5H, m) , 7.49-7.53 (IH, m) , 7.64-7.68 (IH, m) , 7.67-7.90 (2H, m)
Example 80
6- [5-arnino-3-phenyl-6- (2-thienyl) -2-pyrazinyl] -2-isopropyl- 3 (2ff) -pyridazinone m.p. : 181-183°C
IR (KBr) : 3168, 1630A 1576, 1523, 1504 cm"1
Mass (ESI) : 801 (2M+lSIa)+, 412 (M+Na)+, 390 (M+H) + XH NMR (CDC13, δ) : 0.83 (6H, d, J=6.65 Hz), 5.07 (IH, 7-plet,
J=6.65 Hz), 6.21 (2H, tors), 6.98 (IH, d, J=9.63 Hz), 7.20 (IH, dd, J=3.71, 5.12 Hz), 7.33-7.43 (5H, m) , 7.48-7.52 (IH, m) ,
7.64-7.67 (IH, ) , 7.91 (IH, d, J=9.63 Hz)
Example 81 6- [ 5 -amino- 6- (3-f uryl ) -3 -phenyl -2 -pyrazinyl] -2-isoprop l-
3 (2if) -pyridazinone m.p. : 233-235°C
IR (KBr) : 3494, 3267, 3113, 2979, 1657, 1622, 1589, 151 cm"1
Mass (ESI) : 396 (M+Na)+, 374 (M+H) + Η NMR (CDCl3,'δ) : 0.84 (6H, d, J=6.60 Hz), 4.99-5.16 (3H, m) ,
6.96 (IH, d, J=9.56 Hz), 7.02 (IH, s), 7.30-7.44 (5H, m) ,
7.58-7.61 (IH, m) , 7.86 (IH, d, J=9.56 Hz), 8.05 (IH, s)
Example 82
6- [5 -amino- 3 -phenyl- 6 - ( -pyridyl) -2-pyrazinyl] - -isopropyl - 3 (2if) -pyridazinone m.p. : 222-224°C
IR (KBr) : 3325, 3197, 1658, 1653, 1641, 1587, 1556, 1531, 1506
Mass (ESI) : 791 (2M-t-TS!a) +, 407 (M+Na)+, 385 (M+H) + XH NMR (CDCI3, δ) : 0.84 (6H, d, J=6.60 Hz) , 5.08 (IH, 7-plet, J=6.60 Hz) , 5.15 (2H, tors) , 6.97 (IH, d, J=9.58 Hz) , 7.30-7.48 (5H, m) , 7.88-7.93 (33H, ) , 8.77-8.81 (2H, m) Example 83 6- [5-amino-6- (6-methoxy-3-pyridyl) -3-phenyl-2-pyra∑inyl] -2 — isopropyl-3 (2 if) -pyridazinone m.p. : 230-232.5°C
IR (KBr) : 3425, 3329, 3201, 2974, 1657, 1626, 1585, 1539, 1506 cm"1 Mass (ESI) : 851 (2M+Na)+, 437 (M+Na)+, 415 (M+H) + τU NMR (CDCI3, δ) : 0. 84 (6H, d, J=6.60 Hz), 4.02 (3H, s) ,
4.99-5.15 (3H, m) , 6.91 (IH, d, J=8.58 Hz) , 6.94 (IH, d, J=9.56
Hz), 7.30-7.46 (5H, m) , 7.84 (IH, d, J=9.56 Hz) , 8.06 (IH, dd ,
J=2.48, 8.58 Hz), 8.68 (IH, d, J=2.48 Hz) Example 84
6- [5-amino-3-phenyl-6 - (3-pyridyl) -2-pyrazinyl] -2-isopropyl —
3 (2f) -pyridazinone m.p. : 224-225.5°C
IR (KBr) : 3394, 3330, 3167, 1647, 1585, 1531, 1506 cm"1 Mass (ESI) : 791 (2M-t-Na)+, 407 (M+Na)+, 385 (M+H) +
XH NMR (DMSO-de, δ) : 0.74 (6H, d, J=6.60 Hz), 4.90 (IH, 7-plet, J=6.60 Hz), 6.83 (2H, tors), 6.96 (IH, d, J=9.65 Hz), 7.32-7.42 (5H, m), 7.54 (IH, dd , J=4.75, 7.95 Hz), 7.92 (IH, d, J=9.65 Hz), 8.17-8.24 (IH, m), 8.65 (IH, dd, J=1.65, 4.75 Hz), 9.00 (IH, d, J=1.65 Hz)
Example 85
6- (5-amino-3, 6-diphenyl-2-pyrazinyl) -2-methyl-
3 (2if) -pyridazinone m.p. : 220-221.5°C
IR (KBr) : 3494, 3477, 3269, 3143, 1662, 1618, 1585, 1508 cm"1
Mass (ESI) : 733 (2M+Na)+, 378 (M+Na)+, 356 (M+H) + λU NMR (CDC13, δ) : 3.55 (3H, s) , 5.11 (2H, brs) , 6.85 (IH, d,
J=9.68 Hz) , 7.36-7.58 (9H, m) , 7.57-7.84 (2H, m) Example 86
6- [5-amino-3-phenyl-6- (2-thienyl) -2-pyrazinyl] -2-methyl-
3 (2if) -pyridazinone m.p. : 177°C (dec.)
IR (KBr) : 3417, 3303, 3188, 1645, 1574, 1525, 1502 cm"1 Mass (ESI) : 745 (2M+Na)+, 384 (M+Na)+, 362 (M+H)+ lR NMR (DMSO-de, δ) : 3.34 ( 3HL , s) , 6.88 (2H, brs) , 6.97 (IH, d, J=9.62 Hz) , 7.22 (IH, dd, =3.75, 5.05 Hz), 7.35-7.47 (5H, m) , 7.68-7.74 (2H, m) , 7.82 (IH, m) Example 87 6-{ 5-amino-3-phenyl-6- [ (E) -2— phenylvinyl] -2-pyrazinyl } - 2-isopropyl-3 (2ff) -pyridazinone m.p. : 244.5-245°C
IR (KBr) : 3334, 3207, 1633, 1576, 1531, 1506 cm"1 Mass (ESI) : 432 (M+Na)+, 410 (M+H) + 2H NMR (DMSO-d6, δ) : 0.74 (6H, d, J=6.60Hz), 4.90 (IH, 7-plet, J=6.60 Hz) , 6.98-7.03 (3H, m) , 7.29-7.47 (8H, m) , 7.60-7.79 (4H, m) , 8.01 (IH, d, J=9.56 Hz) Example 88 6- [5-amino-6- (2-furyl) -3-phen-yl-2-pyrazinyl] -2-isopropyl- 3 (2if) -pyridazinone m.p. : 211-213°C
IR (KBr) : 3475, 3134, 1662, 1630, 1591, 1535, 1506 cm"1 Mass (ESI) : 396 (M+Na)+, 374 (M+H)+ λH NMR (CDCI3, δ) :0.84 (6H, d, J=6.60 Hz), 5.08 (IH, 7-plet, J=6.60 Hz), 5.87 (2H, brs), 5.63-6.65 (IH, m) , 6.97 (IH, d, J=9.58 Hz) , 7.20-7.23 (IH, m) , V .32-7.41 (5H, m) , 7.61-7.63 (IH, m) , 7.86 (IH, d, J=9.58 Hz) Example 89 6- [5-amino-6- (2-furyl) -3-phen-yl-2-pyrazinyl] -2-methyl- 3 (2ff) -pyridazinone m.p. : 186-188°C
IR (KBr) : 3471, 3290, 3155, 1658, 1626, 1583, 1535, 1512 cm"1 Mass (ESI) : 713 (2M+Na)+, 368 (M+Na)+, 346 (M+H) + ^ NMR (DMSO-de, δ) : 3.36 (3H, s), 6.72-6.76 (IH, m) , 6.93 (IH, d, J=9.58 Hz) , 6.96 (2H, brs) , 7.20-7.23 ( IH, m) , 7.35-7.44 (5H, m) , 7.71 (IH, d, J=9.58 Hz), 7.90-7.91 (IH, )
Example 90 Under nitrogen atmosphere, a solution of sodium carbonate (330 mg) in water (2.4 ml) was added to a suspension of 6- (5-amino-6-bromo-3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2if) - pyridazinone (300 mg) , tert-butyl 4- < 4 , 4 , 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl) -lif-pyrazole—1-carboxylate (573 mg) and tetrakis (triphenylphosphine) palladium (27 mg) in dioxane (6 ml) and the mixture was stirred at 100-105°C for 4 hours. After addition of water (30 ml) , a precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (10:90 v/v) to give a solid. The solid was suspended in acetone and collected by filtration to give 6- [5-amino-3-ph-enyl-6- ( lif-pyrazol- 4-yl ) -2-pyrazinyl] -2-isopropyl-3 (2if) —pyridazinone (211 mg) . m.p. : >250°C IR (KBr) : 3384, 3305, 3209, 1657, 1591 cm"1
Mass (ESI) : 769 (2M+Na)+, 396 (M+Na) +, 374 (M+H)+ H NMR (DMSO-de, δ) :0.74 (6H, d, J=6. O Hz), 4.90 (IH, 7-plet, J=6.60 Hz) , 6.57 (2H, brs) , 6.97 (IH, d, J=9.60 Hz) , 7.26-7.38 (5H, m) , 7.98 (IH, d, J=9.60 Hz) , 8.15 (IH, brs) , 8.41 (IH, brs) , 13.23 (IH, brs) Example 91
Under ice-cooling, sodium borohydride (30.7 mg) was added to a solution of 4- [3-amino-6- ( 1-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -5-phenyl-2-pyrazinyl ] —1-methylpyridinium iodide (142 mg) in MeOH (4.26 ml) and the mixture was stirred at the same temperature for 30 minutes. After addition of IN HCl (0.6 ml) , MeOH was evaporated under reduced pressure to give a residue. The residue was dissolved in CHC13, dried over MgS04 and purified by column chromatography on silica ςjel eluting with a mixture of MeOH and EtOAc (5:95 v/v) to give a solid. The solid was suspended in acetone and collected by filtration to give 6- [5-amino-6- (1-methyl-1, 2,3, 6-tetrahydro-4-pyridyl) - 3-phenyl-2-pyrazinyl] -2-isopropyl-3 (2if) -pyridazinone ( 15 mg) . m.p. : 209-211°C
IR (KBr) : 3411, 3323, 2978, 1662, 1630, 1585, 1527, 1502 cm"1
Mass (ESI) : 403 (M+H)+
XH ΝMR (CDC13, δ) : 0.82 (6H, d, J=6.60 Hz) , 2.60 (3H, s) , 2.90-2.96 (4H, m) , 3.64-3.40 (2H, m) , 5.06 (IH, 7-plet, J=6.60
Hz), 5.24 (2H, brs) , 6.35 (IH, brs) , 6.93 (IH, d, J=9.60 Hz) ,
7.26-7.40 (5H, m) , 7.78 (IH, d, J=9.60 Hz)
Example 92
6- [5 -ami no- 6- (1 -me thy 1-1, 2,5, 6-tetrahydro-3-pyridyl ) - 3-phenyl-2-pyrazinyl] -2-isopropyl-3 (2 if) -pyricdazinone
The title compound was obtained in a similar manner to that of Example 91. m.p. : 191-193°C
IR (KBr) : 3433, 3271, 3159, 2780, 1657, 1622, L587, 1529, 1506 cm"1
Mass ( ESI ) : 403 (M+H) +
XH NMR (CDCI3, δ) : 0.82 (6H, d, J=6.60 Hz), 2.60 (3H, s), 2.90-2.96 (4H, m) , 3.64-3.40 (2H, m) , 5.06 <1H, 7-plet, J=6.60 Hz), 5.24 (2H, brs), 6.35 (IH, brs), 6.93 CIH, d, J=9.60 Hz), 7.26-7.40 (5H, m) , 7.78 (IH, d, J=9.60 Hz) Example 93
Under nitrogen atmosphere, 6- [5-ami-no-3-phenyl- 6- (lif-pyrazol-4-yl) -2-pyrazinyl] -2-isopropyl-3 (2if) - pyridazinone (120 mg) was added to a suspen-sion of NaH (60% in oil) (14.2 mg) and the mixture was stirrecd at 25-30°C for 30 minutes. The mixture was cooled in an ice bath and iodomethane
(0.1 ml) was added. The mixture was stirreed at the same time for 30 minutes and at 20-30°C for one hour _ After addition of water (3.6 ml) , a precipitate was collected by filtration and purified by column chromatography on silica gel (EtOAc only) to give a solid. The solid was suspended in acetone and collected by filtration to give 6- [5-amino-6- ( l-met_hyl- lif-pyrazol-4-yl) -3-phenyl-2-pyra∑inyl] -2—isopropyl-3 (2if) - pyridazinone (70 mg) . m.p. : 201-203°C
IR (KBr) : 3444, 3346, 1657, 1581, 1568, 1504 cm"1 Mass (ESI) : 797 (2M+Na)+, 410 (M+Na)+, 3S8 (M+H) + !H NMR (CDCI3, δ) : 0.84 (6H, d, J=6.60 Hz), 4.02 (3H, s) , 5.07 (IH, 7-plet, J=6.60 Hz), 5.23 (2H, brs), 6.96 (IH, d, J=9.60 Hz), 7.30-7.47 (5H, m) , 7.84 (IH, d, J=9.60 Hz), 7,99 (IH, s), 8.05 (IH, s) Example 94 In the presence of palladium acetate (8.7 rag) ,
1, 3-bis (diphenylphosphino) propane (35.3 mg) and potassium carbonate (215 mg) , a mixture of 6- (5-amino-6-br omo- 3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2if) -pyridazinone (501 mg) in butyl vinyl ether (1.5 ml) was refluxed for 20 hours. After addition of water, the mixture was extracted with CHC13 dried over MgS04 and concentrated under reduced pres sure to give syrup . The syrup was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give a solid. The solid was suspended in acetone and collected by filtration to give 6- ( 6-acetyl-5-amino-3-pheπ.yl- 2-pyrazinyl ) -2-isopropyl-3 (2if) -pyridazinone (28 mg) . m.p. : 234-236.5°C
IR (KBr) : 3419, 3278, 1672, 1662, 1591, 1537, 1508 cm"1 Mass (ESI) : 721 (2M+Na)+, 372 (M+Na)+, 350 (M+H) + HNMR (CDCI3, δ) : 0.82 (6H, d, J=6.70 Hz), 2.76 ( 3H, s) , 5.07 (IH, 7-plet, J=6.70Hz), 7.00 (IH, d, J=9.60Hz), 7.35-7.46 (5H, m) , 7.85 (IH, d, J=9.60 Hz)
XR NMR (DMSO-de, δ) : 0.73 (6H, d, J=6.61 Hz), 2.67 (3H, s) , 4.89 (IH, 7-plet, J=6.61 Hz) , 7.03 (IH, d, J=9.65 Hz ) , 7.35-7.44 ( 5H, m) , 7 . 97 ( IH , d, J=9 . 65 Hz ) , 8 . 01 ( 2H, brs ) Example 95
In the presence of palladium acetate (14.6 mg) and triphenylphosphine (34.0 mg) , diisopropylethylamine (0.687 ml) was added to a mixture of 6- (5-amino-6-bromo-
3-phenyl-2-pyrazinyl ) -2-isopropyl-3 (2f) -pyridazinone ( 501 mg) in DMF (2 ml) and the mixture was heated at lOO-lOδ^C for 20 hours. After addition of water, a precipitate was collected by filtration and purified by column chromatography on -silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give a solid. The solid was suspended in acetone and col-Lected by filtration to give ethyl 3- [3-amino-6- (l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -5-phenyl-2-pyrazinyl] acryleite (95 mg) . m.p. : 233-236°C
IR (KBr) : 3421, 3319, 3197, 1697, 1653, 1581, 1541 cm-1 Mass (ESI) : 833 (2M+Na)+, 428 (M+Na)+ λH NMR (CDC13, δ) : E-isomer ; 0.82 (6H, d, J=6.56 Hz), 1.36 (3H, t, J=7.18 Hz), 4.29 (2H, q, J=7.18 Hz), 4.97-5.12 (3 H, ) , 6.98 (IH, d, J=9.56 Hz), 7.04 (IH, d, J=15.36 Hz), 7.30-7.49 (5H, m) , 7.73 (IH, d, J=15.36' Hz), 7.88 (IH, d, J=9.56 Hz) Z-isomer ; 6.85 (IH, d, J=9.54 Hz) Example 96
A mixture of 6- (5-amino-6-bromo-3-phenyl-2-pyraz-inyl) - 2-isopropyl-3 (2f) -pyridazinone (100 mg) and benzylamine (0.085 ml) in DMA (0.2 ml) was heated at 120-125°C for 50 houαrs. After addition of water (4 ml) , an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHC13, dried over MgS04, concentrated under reduced pressure and purified by preparative TLC on silica gel (CHC13 only) . A less polar zone was gave 6- [5-amino-6- (dimethylamino) - 3-phenyl-2-pyrazinyl] -2-isopropyl-3 (2f) -pyridazinone as a solid (18 mg) and a more polar zone was gave 6-[5-amino— 6- (benzylamino) -3-phenyl-2-pyrazinyl] -2-isopropyl- 3 (2if) -pyridazinone as a solid (67 mg) . 6- [5-amino- 6- (benzylamino) -3-phenyl-2-pyrazinyl] - 2-isopropyl-3 (2if) -pyridazinone m.p. : 181-183.5°C IR (KBr) : 3375, 3332, 3249, 3203, 1645, 1579, 1552, 1518 cm"1 Mass (ESI) : 847 (2M+Na)+, 435
Figure imgf000129_0001
413 (M+H) + λU NMR (CDCI3, δ) : 0.83 (6H, d, J=6.60 Hz), 4.68 (2H, d, J=_5.24 Hz), 4.93-5.18 (IH, m) , 6.84 (IH, d, J=9.56Hz), 7.17-7.45 (5H, m) , 7.66 (IH, d, J=9.56 Hz) 6- [5-amino-6- (dimethylamino) -3-phenyl-2-pyrazinyl] - 2-isopropyl-3 (2if) -pyridazinone m.p. : 174-176°C
IR (KBr) : 3494, 3255, 3155, 3122, 2979, 1660, 1614, 1589, 1500 cm-1 Mass (ESI) : 723 (2M+Na)+, 373 (M+Na)+, 351 (M+H)+ ' XH NMR (CDC13, δ) : 0.83 (6H, d, J=6.60 Hz), 2.91 (6H, s) , 4.97 (2H, brs), 5.06 (IH, 7-plet, J=6.60 Hz), 6.93 (IH, d, J=9.56 Hz), 7.23-7.35 (5H, m) , 7.81 (IH, d, J=9.56 Hz)
The following compounds were obtained in a similar manner to that of Example 96.
Example 97
6- ( 5-amino- 6- [ ( 4-methoxybenzyl ) amino] -3-phenyl- 2-pyrazinyl } -2-isopropyl-3 ( 2 f) -pyridazinone m . p . : 188 . 5-191 . 5°C
IR (KBr) : 3398, 3313, 3249, 3199, 1647, 1581, 1547, 1512 cm"1
Mass (ESI) : 907
Figure imgf000130_0001
465 (M+Na)+, 443 (M+H)+
XH NMR (CDCI3, δ) : 0.84 (6H, d, J=6.60 Hz), 3.80 (3H, s) , 4.61 (2H, d, J=5.18 Hz), 4.95-5.13 (4H, m) , 6.84-6.93 (3H, m) ,
7.17-7.36 (7H, m) , 7.71 (IH, d, J=9.58 Hz)
Example 98
6-{ 5-amino-3-phenyl-6- [ (2-pyridylmethyl) amino] -
2-pyrazinyl } -2-isopropyl-3 (2f) -pyridazinone and 6- [5-amino-6- (dimethylamino) -3-phenyl-2-pyrazinyl] -
2-isopropyl-3 (2if) -pyridazinone
6-{ 5-amino-3-phenyl-6- [ (2-pyridylmethyl) amino] -
2-pyrazinyl } -2-isopropyl-3 (2if) -pyridazinone m.p. : 192-194°C IR (KBr) : 3396, 3334, 3251, 3211, 1645, 1576, 1522 cm"1 Mass (ESI) : 849 (2M+Na)+, 436 (M+Na)+, 414 (M+H)+
XH NMR (CDC13, δ) : 0.86 (6H, d, J=6.62 Hz), 4.84 (2H, d, J=3.94 Hz), 5.06 (IH, 7-plet, J=6.62 Hz), 6.26 (IH, brs), 6.89 (IH, d, J=9.56 Hz), 7.18-7.45 (9H, m) , 7.65 (IH, d, J=9.56 Hz), 7.70-7.80 (IH, m) , 8.51 (IH, d, J=4.42 Hz) 6- [5-amino-6- (dimethylamino) -3-phenyl-2-pyrazinyl] - 2-isopropyl-3 (2if) -pyridazinone m.p. : 174-176°C IR (KBr) : 3494, 3255, 3155, 3122, 2979, 1660, 1614, 1589, 1500 cm"1
Mass (ESI) : 723 (2M+Na)+, 373 (M+Na)+, 351 (M+H)+ aH NMR (CDCI3, δ) : 0.83(6H, d, J=6.60 Hz), 2.91 (6H, s), 4.97 (2H, brs), 5.06 (IH, 7-plet, J=6.60 Hz), 6.93 (IH, d, J=9.56 Hz), 7.23-7.35 (5H, m) , 7.81 (IH, d, (J=9.56 Hz)
Example 99
In a sealed tube, a mixture of 6- ( 5-amino-6-bromo- 3-phenyl-2-pyrazinyl) -2-isopropyl-3 (2ff) -pyridazinone (150 mg) and butylamine (0.116 ml) in 1, 3-dimethyl-
2-imidazolidinone (0.3 ml) was heated at 120-125°C for 50 hours . After addition of water (3 ml) , a precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give a solid. The solid was suspended in acetone to give
6- [5-amino-6- (butylamino) -3-phenyl-2-pyrazinyl] -
2-isopropyl-3 (2f) -pyridazinone (71 mg) . m.p. : 200-202°C IR (KBr) : 3379, 3286, 3240, 3194, 1653, 1576, 1554, 1518 cm"1
Mass (ESI) : 779 (2M+Na)+, 401 (M+Na)+, 379 (M+H)+
XH NMR (CDCI3, δ) : 0.85 (6H, d, J=6.60 Hz), 0.99 (3H, t, J=7.22
Hz), 1.37-1.77 (4H, m) , 3.45-3.57 (2H„ m) , 4.54 (IH, brs), 4.73
(2H, brs), 5.07 (IH, 7-plet, J=6.60 Hz), 6.92 (IH, d, J=9.54 Hz), 7.19-7.33 (5H, m) , 7.78 (IH, d, J=9.54 Hz)
Example 100
6- [5-amino-6- (butylamino) -3-phenyl-2-pyrazinyl] -2-methyl-
3 (2if) -pyridazinone
The title compound was obtained in a similar manner to that of Example 99. m.p. : 253-255°C
IR (KBr) : 3450, 3363, 3224, 1649, 1581, 1574, 1550, 1520, 1508 cm"1
Mass (ESI) : 373 (M+Na)+, 351 (M+H)+ lH NMR (DMSO-d6, δ) : 0.93 (3H, t, J=7.21 Hz), 1.30-1.50 (2H, m) , 1.54-1.69 (2H, m) , 3.33 (3H, s) , 3.32-3.45 (2H, m) ,
6.36-6.44 (3H, m) , 6.89 (IH, d, J=9.58 Hz), 7.18-7.29 (5H, m) ,
7.59 (IH, d, J=9.58 Hz)
Example 101 A mixture of 6- (5-amino-6-bromo-3-phenyl-2-pyrazinyl) - 2-isopropyl-3 (2if) -pyridazinone (150 mg) and allylamine (0.0881 ml) in 1, 3-dimethyl-2-imidazolidinone (0.3 ml) was heated at 120-125°C for 50 hours. After addition of water (3 ml), an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHC13, dried over MgS04 and concentrated under reduced pressure to give syrup. The syrup was crystallized from a mixture of acetone and hexane to give 6- [6- (allylamino) -5-amino-3-phenyl-2-pyrazinyl] - 2-isopropyl-3 (2f) -pyridazinone (71 mg) . m.p. : 208-210°C
IR (KBr) : 3398, 3340, 3182, 1645, 1583, 1554, 1525 cm"1 Mass (ESI) : 747 (2M+Na)+, 385 (M+Na)+, 363 (M+H)+
XH NMR (CDCI3, δ) : 0.84 (6H, d, J=6.60 Hz), 4.11-4.20 (2H, m) , 4.73-4.88 (3H, m) , 5.06 (IH, 7-plet, J=6.60 Hz) , 5.15-5.37 (2H, m) , 5.95-6.15 (IH, m) , 6.92 (IH, d, J=9.56 Hz) , 7.20-7.33 (5H, ) , 7.78 (IH, d, J=9.56 Hz)
The following 30 compounds were obtained in a similar manner to that of Example 101. Example 102
6- { 5-amino-6- [ (2-methoxyethyl) amino] -3-phenyl-2-pyrazinyl }- 2-isopropyl-3 (2if) -pyridazinone m.p. : 208-209.5°C IR (KBr) : 3398, 3340, 3180, 1651, 1579, 1554, 1525 cm"1
Mass (ESI) : 403 (M+Na)+, 381 (M+H) + λH NMR (CDC13, δ) : 0.86 (6H, d, J=6.62 Hz), 3.41 (3H, s) ,
3.63-3.77 (4H, m) , 4.78 (2H, brs), 4.91 (IH, brs), 5.07 (IH, 7-plet, J=6.62 Hz), 6.92 (IH, d, J=9.54 Hz), 7.18-7.33 (5H, m) ,
7.74 (IH, d, J=9.54 Hz)
Example 103
6- ( 5-amino-3-phenyl-6- { [2- (1-piperidinyl) ethyl] amino }-
2-pyrazinyl) -2-isopropyl-3 (2if) -pyridazinone m.p. : 204.5-207°C
IR (KBr) : 3398, 3342, 3238, 3203, 2933, 1653, 1579, 1552, 1522,
1512 cm"1
Mass (ESI) : 889 (2M+Na)+, 456 (M+Na) , 434 (M+H)+
XH NMR (CDC13, δ) : 0.85 (6H, d, J=6.60 Hz), 1.48-1.72 (6H, m) , 2.47-2.55 (4H, m) , 2.67-2.80 (2H, m) , 3.53-3.65 (2H, m) , 4.83
(2H, brs), 5.07 (IH, 7-plet, J=6.60 Hz), 5.42 (IH, t, J=4.33
Hz), 6.90 (IH, d, J=9.54 Hz), 7.15-7.34 (5H, m) , 7.75 (IH, d,
J=9.54 Hz)
Example 104 6- ( 5-amino-6- { [ 2- ( 4 -morpholinyl ) ethyl] amino } -3-phenyl-
2-pyra zinyl ) -2-isopropyl-3 ( 2ff) -pyridazinone m . p . : 230-232 . 5°C
IR (KBr) : 3394, 3363, 3211, 3188, 16449, 1579, 1554, 1525 cm"1
Mass (ESI) : 458 (M+Na)+, 436 (M+H)+ XH NMR (CDCI3, δ) : 0.85 (6H, d, J=6.62 Hz), 2.58-2.71 (4H, m) , 2.79 (2H, t, J=5.81 Hz), 3.57-3.68 (2H, m) , 3.75-3.82 (4H, m) , 4.74 (2H, brs), 5.07 (IH, 7-plet, J=6.62Hz), 5.24 (IH, t, J=4.39 Hz), 6.91 (IH, d, J=9.56 Hz), 7.15-7.32 (5H, m) , 7.74 (IH, d, J=9.56 Hz) Example 105
6- { 5-amino-6- [ (cyclohexylmethyl) amino] -3-phenyl- 2-pyrazinyl } -2-isopropyl-3 (2if) -pyridazinone m.p. : 219-221°C IR (KBr) : 3373, 3319, 3232, 3197, 2925, 1651, 1577, 1550, 1512 cm"1
Mass (ESI) : 859 (2M+Na)+, 441 (M+Na)+, 419 (M+H)+ αH NMR (CDCI3, δ) : 0.86 (6H, d, J=6.62 Hz), 0.84-2.30 (11H, m) , 3.31-3.39 (2H, m) , 4.79 (IH, brs), 4.89 (2H, brs), 5.07 (IH, 7-plet, J=6.62 Hz) , 6.93 (IH, d, J=9.56 Hz) , 7.17-7.33 (5H, m) , 7.76 (IH, d, J=9.56 Hz) Example 106
6- ( 5-amino-3-phenyl-6- { [2- (2-pyridyl) ethyl] amino } - 2-pyrazinyl) -2-isopropyl-3 (2ff) -pyridazinone m.p. : 204-206°C
IR (KBr) : 3396, 3342, 3251, 3205, 1647, 1577, 1523 cm"1 Mass (ESI) : 877 (2M+Na)+, 450 (M+Na)+, 428 (M+H)+ XH NMR (CDCI3, δ) : 0.85 (6H, d, J=6.60Hz), 3.21 (2H, t, J=6.14 Hz), 3.90 (2H, t, J=6.14 Hz), 4.77 (2H, brs), 5.06 (IH, 7-plet, J=6.60 Hz) , 6.80 (IH, brs) , 6.91 (IH, d, J=9.54 Hz) , 7.16-7.35
(lUr m) , 7.64-7.74 (IH, m) , 7.76 (IH, d, J=9.54 Hz), 8.54 (IH, d, J=4.28 Hz)
Example 107 6-{ 5-amino-6- [ (l-benzyl-4-piperidinyl) amino] -3-phenyl-
2-pyrazinyl } -2-isopropyl-3 (2 if) -pyridazinone m.p. : 214-216.5°C
IR (KBr) : 3369, 3190, 2939, 1643, 1576, 1547, 1523 cm-1
Mass (ESI) : 518 (M+Na)+, 496 (M+H) + !H NMR (CDC13, δ) : 0.86 (6H, d, J=6.60 Hz), 1.52-2.32 (6H, m) ,
2.88-3.02 (2H, m) , 3.58 (2H, s), 3.94-4.06 (IH, m) , 4.48 (IH, d, J=6.84 Hz), 4.63 (2H, brs), 5.07 (IH, 7-plet, J=6.60 Hz),
6.91 (IH, d, J=9.55 Hz) , 7.17-7.36 (10H, m) , 7.67 (IH, d, J=9.55
Hz) Example 108
6- [ 5-amino-3-phenyl-6- ( 1 -piperidinyl ) -2-pyrazinyl] -
2-i sopropyl-3 (2if) -pyridazinone m.p. : 183-185°C
IR (KBr) : 3450, 3265, 3161, 2935, 1666, 1614, 1589, 1502 cm"1 Mass (ESI) : 803 (2M+Na)+, 413 (M+Na)+, 391 (M+H) +
'HNMR (CDCI3, δ) : 0.83 (6H, d, J=6.60 Hz), 1.67-1.80 (6H, m) ,
3.16-3.24 (4H, m) , 4.98 (2H, brs) , 5.06 (IH, 7-plet, J=6.60 Hz) ,
6.93 (IH, d, J=9.56 Hz) , 7.21-7.35 (5H, m) , 7.80 (IH, d, J=9.56
Hz) Example 109
6-{ 5-amino-6- [3- (dimethylamino) -1-pyrrolidinyl] -3-phenyl-
2-pyrazinyl } -2-isopropyl-3 (2f) -pyridazinone m.p. : 150-152°C IR (KBr) : 3448, 3286, 3185, 2974, 1657, 1622, 1589, 1529 cm"1
Mass (ESI) : 442 (M+Na)+, 420 (M+H) + H NMR (CDC13, δ) : 0.82 (3H, d, J=6.60Hz), 0.87 (3H, d, J=6.60
Hz), 1.90-2.10 (IH, m) , 2.15-2.30 (IH, m) , 2.40 (6H, s) ,
2.83-2.97 (IH, m) , 3.50-3.75 (4H, m) , 4.79 (2H, brs), 5.06 (IH, 7-plet, J=6.60 Hz) , 6.91 (IH, d, J=9.56 Hz) , 7.17-7.37 (5H, m) ,
7.77 (IH, d, J=9.56 Hz)
Example 110
6- [5-amino-6- (4-methoxy-l-piperidinyl) -3-phenyl-
2-pyrazinyl] -2-isopropyl-3 (2if) -pyridazinone m.p. : 179-181°C
IR (KBr) : 3487, 3248, 3113, 1660, 1589, 1506 cm"1
Mass (ESI) : 863 (2M+Na)+, 443 (M+Na)+, 421 (M+H) + y NMR (CDCI3, δ) : 0.83 (6H, d, J=6.62 Hz), 1.70-1.85 (2H, m) ,
2.05-2.17 (2H, m) , 2.96-3.09 (2H, ) , 3.41 (3H, s), 3.41-3.61 (3H, m) , 4.96-5.14 (3H, m) , 6.92 (IH, d, J=9.54 Hz), 7.23-7.37
(5H, m) , 7.78 (IH, d, J=9.54 Hz)
Example 111
N- { 1- [3 -amino- 6- ( 1 -isopropyl -6-oxo-l, 6-dihydro-
3-pyridazinyl) -5-phenyl-2-pyrazinyl] - 4-piperidinyl}methanesulfonamide m.p. : 220-222°C
IR (KBr) : 3411, 3257, 3156, 1662, 1626, 1593, 1506 cm"1 Mass (ESI) : 989
Figure imgf000138_0001
506 (M+Na)+, 484 (M+H) + XH NMR (CDCI3, δ) : 0.83 (6H, d, J=6.60 Hz), 1.65-1.85 (2H, m) , 2.14-2.23 (2H, m) , 2.91-3.04 (2H, m) , 3.04 (3H, s) , 3.48-3.68 (3H, m) , 4.68 (IH, d, J=7.58 Hz) , 4.96-5.11 (3H, m) , 6.94 (IH, d, J=9.60 Hz), 7.22-7.36 (5H, m) , 7.75 (IH, d, J=9.60 Hz) XH NMR (DMSO-dg, δ) : 0.73 (6H, d, J=6.60 Hz) , 1.65-1.81 (2H, m) , 1.91-2.00 (2H, m) , 2.78-2.93 (2H, m) , 2.96 (3H, s) ,
3.31-3.45 (IH, m) , 3.54-3.64 (2H, m) , 4.88 (IH, 7-plet, J=6.60 Hz) , 6.41 (2H, brs) , 6.95 (IH, d, J=9.56Hz), 7.16-7.37 (5H, m) , 7.83 (IH, d, J=9.56Hz) Example 112 6- [5-amino-3-phenyl-6- (1 -piperazinyl) -2-pyrazinyl] - 2-isopropyl-3 (2 if) -pyridazinone m.p. : 157-159°C
IR (KBr) : 3446, 3321, 1651, 1579, 1541, 1506 cm"1 Mass (ESI) : 805 (2M+Na)+, 414 (M+Na)+, 392 (M+H) + aH NMR (CDCI3, δ) : 0.86 (6H, d, J=6.60 Hz) , 3.07-3.16 (4H, m) , 3.22-3.30 (4H, m), 4.86 (2H, brs) , 5.06 (IH, 7-plet, J=6.60 Hz) , 6.93 (IH, d, J=9.54 Hz) , 7.23-7.35 (5H, m) , 7.79 (IH, d, J=9.54 Hz) Example 113 6- [5-amino-6- (4-methyl-l-piperazinyl) -3-phenyl- 2-pyrazinyl] -2-isopropyl-3 (2if) -pyridazinone m.p. : 155-157°C
IR (KBr) : 3440, 3261, 3132, 2968, 1664, 1622, 1587, 1506 cm"1 Mass (ESI) : 833 (2M+Na)+, 428 (M+Na)+, 406 (M+H) +
1H NMR (CDC13, δ) : 0.83 (6H, d, J=6.60 Hz), 2.43 (3H, s) ,
2.64-2.71 (4H, m) , 3.32-3.39 (4H, ) , 4.84 (2H, brs), 5.06 (IH,
7-plet, J=6.60 Hz ) , 6.93 (IH, d, J=9.56 Hz) , 7.22-7.36 (5H, m) ,
7.78 (IH, d, J=9.56 Hz) Example 114
6-{ 5-amino-3-phenyl-6- [4- (2-pyridylmethyl) -1 -piperazinyl] -
2-pyrazinyl}-2-isopropyl-3 (2if) -pyridazinone m.p. : 88-91°C
IR (KBr) : 3384, 3294, 3136, 1660, 1633, 1587, 1504 cm"1 Mass (ESI) : 505 (M+Na)+, 483 (M+H) +
0.83 (6H, d, J=6.60 Hz) , 2.75-2.82 (4H, m) , 3.32-3.42 (4H, m) ,
3.82 (2H, s), 4.85 (2H, brs), 5.06 (IH, 7-plet, J=6.60Hz), 6.92
(IH, d, J=9.62 Hz), 7.18-7.36 (6H, m) , 7.48-7.54 (IH, m) ,
7.65-7.75 (IH, m) , 7.78 (IH, d, J=9.62 Hz), 8.58-8.62 (IH, m) Example 115
6- [5-amino-3-phenyl-6- (4-phenyl-l-piperazinyl) -
2-pyrazinyl] -2-i sopropyl-3 (2if) -pyridazinone m.p. : 193-195°C
IR (KBr) : 3404, 3278, 3182, 1652, 1624, 1583, 1558, 1539 cm"1 Mass (ESI) : 490 (M+Na)+, 468 (M+H) +
0.84 (6H, d, J=6.60 Hz) , 3.36-3.51 (8H, ) , 4.93 (2H, brs), 5.06
(IH, 7-plet, J=6.60 Hz), 6.87-7.07 (4H, m) , 7.26-7.39 (7H, m) ,
7.80 (IH, d, J=9.60 Hz) Example 116
6- {5 -amino- 6- [4- (4-methoxyphenyl) -1 -piperazinyl] -3-phenyl-
2 -pyrazinyl }-2-isopropyl-3 (2f) -pyridazinone m.p. : 194-196°C
IR (KBr) : 3437, 3261, 3130, 2974, 2835, 1672, 1618, 1593, 1510 cm"1
Mass (ESI) : 520 (M+Na)+, 498 (M+H) +
XH NMR (CDC13, δ) : 0.83 (6H, d, J=6.60 Hz) , 3.25-3.33 (4H, ) ,
3.44-3.51 (4H, m) , 3.78 (3H, s) , 4.91 (2H, brs), 5.07 (IH, 7-plet,
J=6.60 Hz), 6.85-7.05 (5H, m) , 7.23-7.39 (5H, m) , 7.80 (IH, d, J=9.54 Hz)
Example 117
6- [6- ( 4-acetyl-1-piperazinyl) -5-amino-3-phenyl-
2-pyrazinyl] -2-isopropyl-3 (2if) -pyridazinone m.p. : 221-225°C IR (KBr) : 3359, 3290, 3170, 1664, 1649, 1626, 1591, 1541, 1504
Mass (ESI) : 456 (M+Na)+, 434 (M+H) +
XH NMR (CDCI3, δ) : 0.83 (6H, d, J=6.60 Hz), 2.17 (3H, s),
3.21-3.34 (4H, m) , 3.61-3.71 (2H, m) , 3.79-3.85 (2H, m) , 4.96-5.15 (3H, m) , 6.93 (IH, d, J=9.56 Hz) , 7.28-7.37| (5H, m) , 7.74 (IH, d, J=9.56 Hz) Example 118
6- [5-amino-6- (hexahydropyrrolo [1, 2-a] pyrazin-2 (lif) -yl) - 3-phenyl-2-pyra∑inyl] -2-isopropyl-3 (2if) -pyridazinone m.p. : 205-207.5°C
IR (KBr) : 3477, 3444, 3267, 3132, 1662, 1620, 1589, 1504 cm"1 Mass (ESI) : 885 (2M+Na)+, 454 (M+Na)+, 432 (M+H) + H NMR (CDC13, δ) : 0.83 (3H, cd, J=6.60 Hz) , 0.84 (3H, d, J=6.60 Hz), 1.50-1.62 (IH, m) , 1.80-2.00 (3H, m) , 2.27-2.90 (3H, m) ,
2.78-2.90 (IH, m) , 3.06-3.25 (3H, m) , 3.63-3.80 (2H, m) , 4.84
(2H, brs) , 5.06 (IH, 7-plet, J=6.60 Hz) , 6.93 (IH, d, J=9.56
Hz), 7.20-7.35 (5H, m) , 7.77 (IH, d, J=9.56 Hz)
Example 119 6- [5-amino-6- ( 8-oxa-3-azabicyclo [3.2.1] oct-3-yl) -3-phenyl-
2-pyrazinyl] -2-isopropyl-3 ( 2ff) -pyridazinone m.p. : 235-238°C
IR (KBr) : 3469, 3261, 3157, 3130, 1664, 1616, 1593, 1506 cm"1
Mass (ESI) : 441 (M+Na)+, 419 (M+H) + XH NMR (DMSO-de, δ) : 0.73 (6H, d, J=6.60 Hz), 1.79-1.86 (2H, m) , 2.08-2.20 (2H, ) , 2.95-3.02 (2H, m) , 3.32-3.40 (2H, m) ,
4.39 (2H, brs), 4.88 (IH, 7-plet, J=6.60 Hz), 6.16 (2H, brs),
6.95 (IH, d, J=9.60 Hz) , 7.21-7.38 (5H, m) , 7.84 (IH, d, J=9.60
Hz) Example 120
6- { 5-amino-6- [ (2-methoxyethyl ) amino] -3-phenyl-2-pyrazinyl } - 2-methyl-3 (2if) -pyridazinone m.p. : 231-232.5°C IR (KBr) : 3383, 3313, 3201, 1649, 1585, 1576, 1548 cm"1 Mass (ESI) : 375 (M+Na)+, 353 (M+H)+ αH NMR (CDC13, δ) : 3.42 (3H, s), 3.57 (3H, s), 3.61-3.77 (4H, m) , 4.74 (2H, brs), 4.85 (IH, brs), 6.82 (IH, d, J=9.56 Hz), 7.26-7.36 (5H, m) , 7.43 (IH, d, J=9.56 Hz) XU NMR (DMSO-de, δ) : 3.30 (3H, s), 3.32 (3H, s), 3.55-3.63 (4H, m) , 6.48 (2H, brs), 6.57 (IH, brs), 6.88 (IH, d, J=9.60 Hz),
7.20-7.31 (5H, m) , 7.59 (IH, d, J=9.60 Hz)
Example 121
6- (5-amino-3-phenyl-6-{ [2- ( 1—piperidinyl ) ethyl] amino }- 2-pyrazinyl) -2-methyl-3 (2if) -pyridazinone m.p. : 155-157°C
IR (KBr) : 3396, 3249, 3174, 2933, 1645, 1579, 1556 cm"1
Mass (ESI) : 428 (M+Na)+, 406 (M+H)+ H NMR (CDCI3, δ) : 1.47-1.73 (6H, m) , 2.38-2.51 (4H, m) , 2.68 (2H, t, J=5.79 Hz), 3.55-3.65 (2H, m) , 3.58 (3H, s), 4.88 (2H, brs), 5.44 (IH, t, J=4.45Hz), 6.79 (IH, d, J=9.56Hz), 7.26-7.36
(5H, m) , 7.40 (IH, d, J=9.56 Hz)
Example 122
6- (5-amino-6- { [2- (4-morpholinyl) ethyl] amino} -3-phenyl- 2-pyrazinyl) -2-methyl-3 (2 if) -pyridazinone m.p. : 226-229°C
IR (KBr) : 3388, 3330, 3307, 3215, 1649, 1577, 1572, 1545, 1516 cm Mass (ESI) : 430 (M+Na)+, 408 (M+H)+
XH NMR (CDC13, δ) : 2.61-2.69 (2H, m) , 2.77-2.86 (2H, m) ,
3.52-3.71 (4H, m) , 3.58 (3H, s), 3.78-3.85 (4H^ m) , 4.79 (2H, brs), 5.35 ( IH, brs) , 6.80 (IH, d, J=9.58 Hz) , 7.26-7.42 (6H, m) Example 123
6-{ 5-amino-6- [ (2-anilinoethyl) amino] -3-phenyl -2-pyrazinyl } -
2-methyl-3 (2f) -pyridazinone m.p. : 181-183°C
IR (KBr) : 3394, 3327, 3188, 1645, 1572, 1506 cm"1 Mass (ESI) : 849 (2M+Na)+, 436 (M+Na)+, 414 (M+H) +
XH NMR (CDCI3, δ) : 3.47 (2H, t, J=5.64 Hz), 3.59 (3H, s),
3.75-3.86 (2H, m) , 5.02 (2H, brs), 5.27 (IH, brs), 6.64-6.82
(4H, m) , 7.12-7.20 (2H, m) , 7.27-7.46 (7H, m)
Example 124 6-{ 5-amino- 6- [ (2-furylmethyl) amino] -3-phenyl—2-pyrazinyl } -
2-methyl-3 (2if) -pyridazinone m.p. : 249-252°C
IR (KBr) : 3438, 3348, 1647, 1574, 1554, 1522, 1504 cm" -1
Mass (ESI) : 397 (M+Na)4, 375 (M+H; lU NMR (CDCI3, δ) : 3.53 (3H, s) , 4.69 (2H, d, J=5.26 Hz), 4.86 (IH, brs) , 5.19 (2H, brs) , 6.31-6.37 (IH, ra) , 6.84 (IH, d, J=9.56 Hz) , 7.26-7.38 (7H, ) , 7.50 (IH, d, J=9.56 Hz)
XH NMR (DMSO-de, δ) : 3.32 (3H, s) , 4.61 (2H, d, J=5.10 Hz) , 6.36-6.44 (2H, m) , 6.49 (2H, brs), 6.86-6.94 (2H, m) , 7.25-7.30 (5H, m) , 7.58-7.64 (2H, m) Example 125
6- { 5 -amino- 3 -phenyl -6- [ (2-phenylethyl) amino] -2-pyrazinyl } - 2-rαethyl-3 (2 f) -pyridazinone m.p. : 232-234°C
IR (KBr) : 3375, 3311, 3251, 3157, 1643, 1572, 1547, 1527 cm"1 Mass (ESI) : 819
Figure imgf000144_0001
421 (M+Na)+, 399 (M+H) + H NMR (CDCI3, δ) : 3.01 (2H, t, J=7.02 Hz) , 3.58 (3H, s) , 3.74-3.85 (2H, m) , 4.65 (IH, brs) , 4.75 (2H, brs) , 6.83. (IH, d, J=9.58 Hz) , 7.19-7.37 (10H, m) , 7.50 (IH, d, J=9.58 Hz) Example 126
6- { 5-amino-3-phenyl-6- [ (3-phenylpropyl ) amino] -2-pyrazinyl } - 2-methyl-3 (2 if) -pyridazinone m.p. : 196-197.5°C IR (KBr) : 3429, 3365, 1651, 1583, 1568, 1543, 1520 cm"1 Mass (ESI) : 847 (2M+Na)+, 435 (M+Na)\ 413 (M+H) + XH NMR (CDCI3, δ) : 1.96-2.19 (2H, m) , 2.78 (2H, t, J=7.41 Hz), 3. 51-3.73 (2H, m) , 3.56 (3H, s) , 4.52 (IH, brs) , 4.62 (2H, brs) , 6. 82 (IH, d, J=9.60 Hz) , 7.17-7.40 (10H, rn) , 7.44 (IH, d, J=9.60 Hz)
Example 127
6— (5-amino-3-phenyl-6-{ [2- (2-pyridyl) ethyl ] amino}-
2— pyrazinyl) -2-methyl-3 (2if) -pyridazinone m.p. : 224-227°C
IR (KBr) : 3404, 3356, 3188, 1651, 1585, 1570, 1543 cm"1
Mass (ESI) : 422 (M+Na)+, 400 (M+H) +
XH NMR (CDC13, δ) : 3.18 (2H, t, J=6.18 Hz) , 3.56 (3H, s) ,
3.85-3.94 (2H, m) , 4.79 (2H, brs), 5.86 (IH, brs), 6.81 (IH, d, J=9.6 Hz), 7.14-7.34 (7H, m) , 7.45 (IH, d, J=9.60 Hz) ,
7.62-7.71 (IH, m) , 8.51-8.56 (IH, m)
E-xample 128
6 - { 5-amino-6- [ ( l-benzyl-3-pyrrolidinyl) amino] -3-phenyl-
2— pyrazinyl} -2 -methyl- 3 (2 if) -pyridazinone m.p. : 183-185°C
IR (KBr) : 3384, 3226, 1647, 1576, 1550, 1520 cm"1
Mass (ESI) : 476 (M+Na)+, 454 (M+H) + λH NMR (CDCI3, δ) : 1.75-1.83 (IH, m) , 2.36-2.52 (2H, ) , 2.76-2.82 (2H, m) , 2.91-3.02 (IH, m) , 3.51 (3H, s) , 3.70 (2H, s) , 4.63-4.73 (3H, m) ,■ 5.05 (IH, d, J=7.42 Hz), 6.83 (IH, d, CT=9.60 HZ) , 7.26-7.41 (10H, m) , 7.48 (IH, d, J=9.60 Hz) Example 129
6- { 5 -ami no- 6- [ ( 1 -benzyl- 4 -piperidinyl) amino] -3 -phenyl - 2 -pyrazinyl } -2-methyl-3 (2ff) -pyridazinone m.p. : 191-194°C
IR (KBr) : 3373, 3238, 2943, 1649, 1576, 1549, 1520, 1508 cm"1
Mass (ESI) : 490 (M+Na)+, 468 (M+H)+
XH NMR (CDC13, δ) : 0.82-0.91 (IH, m) , 1.55-1.77 (2H, m) , 2.12-2.49 (3HL, m) , 2.90-2.99 (2H, m) , 3.52 (3H, s) , 3.60 (2H, s) , 3.94-4.07 (IH, m) , 4.60 (IH, d, J=6.84 Hz), 4.71 (2H, brs) ,
6.84 (IH, d, J"=9.60 Hz) , 7.26-7.42 (10H, m) , 7.47 (IH, d, J=9.60
Hz)
Example 130 6- [ 5-amino-3— phenyl-6- ( 4-phenyl-l-piperazinyl) -
2-pyrazinyl] — 2-methyl-3 (2 if) -pyridazinone m.p. : 155-157°C
IR (KBr) : 3454, 3292, 3182, 3126, 2841, 1655, 1599r 1579, 1508 cm"1 Mass (ESI) : 901 (2M+Na)+, 462 (M+Na)+, 440 (M+H) + lU NMR (CDCI3, δ) : 3.35-3.52 (8H, m) , 3.54 (3H, s) , 4.95 (2H, brs) , 6.84-7.05 (4H, m) , 7.26-7.39 (7H, m) , 7.57 (IH, d, J=9.58
Hz)
Example 131 6- [5-amino-6— (hexahydropyrrolo [ 1, 2 -a] pyrazin-2 ( 1 B) -yl) -
3-phenyl-2-pyrazinyl] -2-methyl-3 (2f) -pyridazinone m.p. : 177-179°C
IR (KBr) : 3491, 3373, 3126, 2952, 1668, 1657, 1616, 1583, 1508 cm-1 Mass (ESI) : 404 (M+H)+
:H NMR (CDCI3, δ) : 1.53-2.02 (4H, m) , 2.27-2.63 (3H, m) , 2.77-2.91 (IH, m) , 3.05-3.27 (3H, m) , 3.49 (3H, s) , 3.63-3.80 (2H, m), 4.85 (2H, brs), 6.87 (IH, d, J=9.60Hz), 7.26-7.38 (5H, m) , 7.57 (IH, d, J=9.60 Hz)
Example 132
A mixture of 6- (5-amino-6-bromo-3-phenyl-2-pyrazinyl) - 2-isopropyl-3 (2if) -pyridazinone (150 mg) and N, N-dirnethyl- 1, 2-ethanediamine (0.127 ml) in 1, 2-dimethyl-
2-imiciazolidinone (0.3 ml) was heated at 120-125°C for 50 hours. After addition of water (3 ml), the mixture was extracted with CHCI3, dried over MgS04, concentrated under reduced pressure and pmrified by column chromatography on silica gel [Chromatorex® NH] eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a syrup. The syrup was crystallized from a mixture of acetone and n-hexane to give 6- ( 5-amino- 6-{ [2— (dimethylamino) ethyl] amino} -3-phenyl-2-pyraz inyl) - 2-isopropyl-3 (2if) -pyridazinone (36 mg) . m.p. : 188-189°C
IR (KBr) : 3415, 3342, 2974, 1649, 1577, 1508 cm"1 Mass (ESI) : 416 (M+Na)+, 394 (M+H) +
XH NMR (CDCI3, δ) : 0.86 (6H, d, J=6.60 Hz), 2.40 ( 6H, s), 2.17-2.78 (2H, t, J=5.69 Hz) , 3.55-3.68 (2H, m) , 4.82 (2H, brs) , 5.07 (IH, 7-plet, J=6.60 Hz) , 5.35 (IH, t, J=4.56 Hz), 6.90 (IH, d, J=9.56 Hz), 7.18-7.32 (5H, m) , 7.74 (IH, d, J=9.56 Hz) Example 133
A mixture of 6- (5-amino-6-bromo-3-phenyl-2-pyrazinyl ) - 2-isopropyl-3 (2if) -pyridazinone (150 mg) and
N- (2-aminoethyl) acetamide (0.112 ml) in 1, 2-dimethyl- 2-imidazolidinone (0.3 ml) was heated at 120-125°C for 50 hours . After addition of water (3 ml) , an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHC13, dried over MgS04, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of MeOH and EtOAc (3:97 v/v) to give a solid. The solid was suspended in acetone to give N- (2-{ [3-amino- 6- (l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -5-phenyl — 2-pyrazinyl] amino} ethyl ) acetamide (28 mg) . m.p. : 147-149°C
IR (KBr) : 3433, 3369, 3253, 1645, 1577, 1550, 1525 cm-1 Mass (ESI) : 430 (M+Na)+, 408 (M+H) + lU NMR (CDCI3, δ) : 0. 84 (6H, d, J=6.60 Hz) , 1.94 (3H, s) , 3.48-3.66 (4H, m) , 5.06 (IH, 7-plet, J=6.60 Hz) , 6.63 (IH, brs) ,
6.80 (IH, brs) , 6.91 (IH, d, J=9.56 Hz) , 7.26-7.38 (5H, m) , 7.70 (IH, d, J=9.56 Hz) λH NMR (DMSO-de, δ) : 0.74 (6H, d, J=6.60 Hz) , 1.81 (3H, s) , 3.28-3.48 (4H, m) , 4.88 (IH, 7-plet, J=6.60 Hz) , 6.39 (2H, brs) , 6.58 (IH, t, J=5.03 Hz), 6.92 (IH, d, J=9.58 Hz), 7.12-7.33 (5H, m) , 7.83 (IH, d, J=9.58 Hz), 7.98 (IH, t, J=5.30 Hz)
The following 10 compounds were obtained in a similar manner to that of Example 133. Example 134
6-{ 5 -amino- 6- [ (2-f υrylmethyl) amino] -3-phenyl-2 -pyrazinyl } - 2-isopropyl-3 (2if) -pyridazinone m.p. : 206.5-209°C IR (KBr) : 3396, 3336, 3251, 3205, 1647, 1577, 1523 cm"1 Mass (ESI) : 827 ( 2M+Na)+, 425 (M+Na)+, 403 (M+H)+ lU NMR (CDC13, δ) : C85 (6H, d, J=6.62 Hz), 4.69 (2H, d, J=5.26 Hz), 4.96-5.21 (4H„ m) , 6.29-6.37 (2H> m) , 6.91 (IH, d, J=9.54 Hz), 7.18-7.38 ( 6Ht , m) , 7.76 (IH, d, J=9.54 Hz) Example 135 -
6- { 5-amino-3-phenyl-6- [ (2-phenylethyl ) amino] -2-pyrazinyl } —
2-isopropyl-3 (2if) —pyridazinone m.p. : 204.5-207°C
IR (KBr) : 3394, 3356, 3199, 1647, 1577, 1550, 15233369, 3334, 3240, 3197, 1647, 1576, 1554, 1523, 1508 cm"1
Mass (ESI) : 875 (2M+Na)+, 449 (M+Na)+, 427 (M+H)+ XH NMR (CDCI3, δ) : 0.85 (6H, d, J=6.62 Hz), 3.01 (2H, t, J=7.06 Hz), 3.73-3.83 (2H, ) , 4.82-5.14 (4H, m) , 6.91 (IH, d, J=9.56 Hz), 7.17-7.38 (lOH, m) , 7.78 (IH, d, J=9.56 Hz)
14S Example 136
6-{ 5-amino-3-phenyl-6— [ (3-phenylpropyl) amino] -2-pyrazinyl } —
2-isopropyl-3 (2 if) -pyridazinone m.p. : 185.5-187°C IR (KBr) : 3394, 3356, 3199, 1647, 1577, 1550, 1523 cm"1
Mass (ESI) : 903 (2M+Na)+, 463 (M+Na)+, 441 (M+H) +
XH NMR (CDC13, δ) : 0.83 (6H, d, J=6.60 Hz), 1.98-2.18 (2H, m) ,
2.78 (2H, t, J=7.39 Hz) , 3.50-3.62 (2H, m) , 4.71 (IH, brs) , 4.86 (2H, brs) , 5.05 (IH, 7-plet, J=6.60 Hz), 6.90 (IH, d, J=9.56 Hz), 7.17-7.35 (10H, rn) , 7.68 (IH, d, J=9.56 Hz)
Example 137
6- [5-amino-6- (cyclohe-xylamino) -3-phenyl-2-pyrazinyl] -
2-isopropyl-3 (2 if) -pyridazinone m.p. : 227-228.5°C IR (KBr) : 3396, 3367, 3340, 3178, 1649, 1579, 1547, 1522 cm-1
Mass (ESI) : 831 (2M+IN!a)+, 427 (M+Na)+, 405 (M+H) +
XH NMR (CDCI3, δ) : 0.86 (6H, d, J=6.60 Hz), 1.14-2.18 (10H, m) , 3.90-4.05 (IH, m) r 4.60-4.75 (IH, m) , 4.95-5.15 (3H, m) ,
6.92 (IH, d, J=9.56 Hz) , 7.18-7.33 (5H, m) , 7.71 (IH, d, J=9.56 Hz)
Example 138
6-{ 5-amino-6- [ ( l-benzyl-3-pyrrolidinyl) amino] -3-phenyl-
2 -pyrazinyl } -2 -isopropyl- 3 (2 if) -pyridazinone m.p. : 86-91°C IR (KBr) : 3363, 3240, 2970, 2792, 1645, 1576, 1550, 1516 cra"1
Mass (ESI) : 985 (2M+Na)+, 504 (M+Na)+, 482 (M+H) +
H-NMR (CDC13, δ) : 0.84 (3H, d, J=6.60 Hz), 0.86 (3H, d, J=6.60
Hz), 2.35-3.10 (7H, m) , 3.75 (2H, s), 4.75 (2H, brs), 4.95-5.25 (2H, 2) , 6.89 (IH, d, J=9.54 Hz) , 7.18-7.46 (10H, m) , 7.69 (IH, d, J=9.54 Hz)
Example 139
6- (5-amino-6-anilino-3-phenyl-2-pyrazinyl) -2-isopropyl-
3 (2if) -pyridazinone m.p. : >250oC
IR (KBr) : 3371, 3273, 3197, 1643, 1602, 1577, 1552, 1500 cm"1
Mass (ESI) : 421 (M+Na)+, 399 (M+H)+
XH NMR (DMSO-d6, δ) : 0.83 (6H, d, J=6.60Hz), 4.93 (IH, 7-plet,
J=6.60 Hz), 6.80 (2H, brs), 6.90-7.02 (2H, m) , 7.20-7.36 (7H, m) , 7.67 (IH, d, J=9.57 Hz) , 7.81 (2H, d, J=7.82 Hz) , 8.47 (IH, s)
Example 140
6- [5-amino-6- (4-morpholinyl ) —3-phenyl-2-pyrazinyl] -
2-isopropyl-3 (2if) -pyridazinone m.p. : 212-214.5°C
IR (KBr) : 3487, 3253, 3114, 29"78, 2852, 1664, 1616, 1591, 1535,
1502 cm"1
Mass (ESI) : 807 (2M+Na)+, 415 (M+Na)+, 393 (M+H) +
XH NMR (CDCI3, δ) : 0.83 (6H, d, J=6.60 Hz) , 3.28 (4H, t, J=4.67 Hz), 3.90 (4H, t, J=4.67 Hz) , 4.89 (2H, brs), 5.06 (IH, 7-plet, J=6.60 Hz), 6.94 (IH, d, J=9.58 Hz) , 7.24-7.36 (5H, m) , 7.79 (IH, d, J=9.58 Hz) Example 141 6- [5-amino-3-phenyl-6- (1-pyrrolidinyl) -2-pyrazinyl] - 2-isopropyl-3 (2f) -pyridazinone m.p. : 192-194.5°C
IR (KBr) : 3487, 3269, 3122, 2964, 1657, 1622, 1589, 1533, 1504 cm"1 Mass (ESI) : 399 (M+Na) ", 377 (M+H) +
■ J NMR (CDC13, δ) : 0.84 ( 6H, d, J=6.60 Hz) , 1.95-2.05 (4H, m) , 3.55-3.65 (4H, m) , 4.91 ( 2H, brs) , 5.06 (IH, 7-plet) , 6.91 (IH, d, J=9.55 Hz) , 7.18-7.37 (5H, m) , 7.79 (IH, d, J=9.55 Hz) Example 142 6- { 5 -amino- 3 -phenyl -6- [4- (2 -pyridyl) -1-piperazinyl] - 2-pyrazinyl }-2-isopropyl-3 (2 if) -pyridazinone m.p. : 163-165°C
IR (KBr) : 3458, 3292, 3182, 1654, 1612, 1585, 1504 cm"1 Mass (ESI) : 491 (M+Na)4", 469 (M+H) + XH NMR (CDCI3, δ) : 0.83 ( 6H, d, J=6.62 Hz) , 3.38-3.44 (4H, m) , 3.73-3.79 (4H, m) , 4.92 (2H, brs) , 5.06 (IH, 7-plet) , 6.66-6.78 (2H, m) , 6.93 (IH, d, J=9.56 Hz) , 7.24-7.36 (5H, m) , 7.51-7.61 (IH, m) , 7.78 (IH, d, J=9.56 Hz) , 8.22-8.26 (IH, m) Example 143 6-{ 5-amino-6- [benzyl (2-hydroxyethyl) amino] -3-phenyl- 2-pyrazinyl}-2-methyl-3 (2f) -pyrida zinone m.p. : 210-212°C
IR (KBr) : 3417, 3323, 3161, 1653, 1587, 1537 cm"1 Mass (ESI) : 879 (2M+Na)+, 451 (M+ Ja)+, 429 (M+H) +
XH NMR (CDC13, δ) : 3.57 (3H, s) , 4 .67 (2H, s) , 6.77 (IH, d, J=9.60 Hz), 7.15 (IH, d, J=9.60 Hz)
Example 144 A mixture of 6- (5-amino-6-bromo-3-phenyl-2-pyrazinyl ) - 2-methyl-3 (2if) -pyridazinone (150 mg) and benzylamine (0.138 ml) in DMA (0.3 ml) was heated at 120-125°C for 50 hours. After addition of water (4 ml), an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHC13, dried over MgS04, concentrated under reduced pressure and purified by column chromatography on silica gel. By elution with a mixture of n-hexane and EtOAc (60:40 v/v) was obtained 6- [5-amino-6- (dimethylamino) -3-phe nyl-2-pyrazinyl] - 2-methyl-3 (2if) -pyridazinone as a solid (83 mg) and by elution with a mixture of n-hexane and EtOAc (20:80 v/v) was obtained 6- [5-amino-6- (benzylamino) -3-pheny 1-2-pyrazinyl] -2-methyl- 3 (2ff) -pyridazinone as a solid (48 mg) .
6- [5-amino-6- (benzylamino) -3-pheny 1-2-pyrazinyl] -2-methyl- 3 (2if) -pyridazinone as a solid m.p. : >250°C
IR (KBr) : 3433, 3344, 3188, 1647, 1576, 1518 cm"1 Mass (ESI) : 791 (2M+Na)+, 407 (M+Na)+, 385 (M+H) + lU NMR (DMSO-de, δ) : 3.30 (3H, s) , 4.62 (2H, d, J=5.30 Hz), 6.50 (2H, brs), 6.86 (IH, d, J=9.60 Hz) , 7.00 (IH, t, J=5.30 Hz), 7.19-7.55 (10H, m) , 7.65 (IH, d, J=9.60 Hz) 6- [ 5-amino-6- (dimethylamino) -3-phenyl-2-pyrazinyl] - 2-methyl-3 (2 if) -pyridazinone m.p. : 150-152°C IR (KBr) : 3423, 3400, 3313, 3205, 1647, 1620, 1577, 1539, 1504 cm"1
Mass (ESI) : 667 (2M+Na)+, 345 (M+Na)+, 323 (M+H) + λ NMR (CDC13, δ) : 2.91 (6H, s) , 3.51 (3H, s) , 4.88 (2H, brs), 6.84 (IH, d, J=9.60 Hz), 7.26-7.45 (5H, m) , 7.54 (IH, d, J=9.60 Hz)
The following compounds were obtained in a similar manner to that of Example 144. Example 145 6- { 5 -amino- 6- [ (4-methoxybenzyl) amino] - 3 -phenyl - 2-pyrazinyl } -2-methyl-3 (2f) -pyridazinone and 6- [5-amino-6- (dimethylamino) -3-phenyl-2-pyrazinyl] - 2-methyl-3 (2 if) -pyridazinone 6- ( 5-amino-6- [ (4-methoxybenzyl) a ino] -3-phenyl- 2-pyrazinyl}-2-methyl-3 (2 if) -pyridazinone m.p. : >250°C ■
IR (KBr) : 3396, 3309, 3163, 1651, 1576, 1549, 1514 cm"1 Mass (ESI) : 851 (2M+Na)+, 437 (M+Na)+, 415 (M+H) + XH NMR (DMSO-de, δ) : 3.32 (3H, s) , 3.73 (3_H, s) , 4.54 (2H, d, J=5.11 Hz), 6.47 (2H, brs) , 6.84-6.94 (4H, m) , 7.18-7.31 (5H, m) , 7.33 (2H, d, J=8.61 Hz) , 7.55 (IH, d, J=9.58 Hz) 6- [5-amino-6- (dimethylamino) -3-pheny 1-2 -pyrazinyl] - 2-methyl-3 (2 if) -pyridazinone m.p. : 150-152°C
IR (KBr) : 3423, 3400, 3313, 3205, 1647, 1620, 1577, 1539, 1504
Mass (ESI) : 667 (2M+Na)+, 345 (M+Na)+, 323 (M+H) + H NMR. (CDCI3, δ) : 2.91 (6H, s), 3.51 (3H, s) , 4.88 (2H, brs) , 6.84 (IH, d, J=9.60 Hz) , 7.26-7.45 (5H, m) , 7.54 (IH, d, J=9.60
Hz)
Example 146
6- { 5-amino-3-phenyl-6- [ (2-pyridylmethyl ) -amino] -
2-pyrazinyl }-2-methyl-3 (2f) -pyridazinone and 6- [5 -amino- 6- (dimethylamino) -3-pheny 1-2 -pyrazinyl] -
2-methyl-3 (2 if) -pyridazinone
6-{ 5-amino-3-phenyl-6- [ (2-pyridylmethyl ) amino] -
2-pyrazinyl } -2-methyl-3 (2 if) -pyridazinone m.p. : >250°C IR (KBr) : 3433, 3359, 3192, 1647, 1576, 1554, 1522 cm"1 Mass (ESI) : 795 (2M+Na)+, 408 (M+Na)+, 386 (M+H)4" λU NMR (CDC13, δ) : 3.28 (3H, s), 4.71 (2H, d, J=5.40 Hz), 6.55 (2H, brs) , 6.83 (IH, d, J=9.58 Hz) , 7.13-7.32 (7H, m) , 7.39-7.46 (2H, m) , 7.71-7.81 (IH, m) , 8.54 (IH, d, J=5.10 Hz) 6- [5-amino-6- (dimethylamino) -3-phenyl-2-pyrazinyl ] - 2-methyl-3 (2if) -pyridazinone m.p. : 150-152°C IR (KBr) : 3423, 3400, 3313, 3205, 1647, 1620, 1577, 1539, 1504 cm"1
Mass (ESI) : 667 (2M+Na)+, 345 (M+Na)+, 323 (M+H)"*" λ NMR (CDCI3, δ) : 2.91 (6H, s) , 3.51 (3H, s), 4.88 (2H, brs),
6.84 (IH, d, J=9.60 Hz), 7.26-7.45 (5H, ), 7.54 (IH, d, J=9.60
Hz)
Example 147
To a suspension of NaH (60% in oil suspension ) (77.7 mg) in dioxane (0.6 ml) was added lif-pyrrole (0.161 ml) and the mixture was stirred at 25-30°C for 30 minutes. After addition of 6- (5-amino-6-bromo-3-phenyl-2-pyrazinyl) -2-isopropyl-
3 (2ff) -pyridazinone (150 mg), the mixture was heated at 100-105°C for 2 hours. A mixture of water and chloroform was added to the reaction mixture. An organic layer was collected, dried over MgS04, concentrated under reduced pressure and purified by column chromatography on silica gel eluting wit-ti a mixture of n-hexane and EtOAc (75:25 v/v) to give a solid. The solid was crystallized from a mixture of IPE and n-hexane to give 6- [5-amino-3-phenyl-6- (lif-pyrrol-1-yl) -2-pyraz inyl] - 2-isopropyl-3 (2if) -pyridazinone (38 mg) . m.p. : 132-136°C
IR (KBr) : 3475, 3280, 3193, 3167, 3124, 2862, 1693, 1660, 1624, 1589, 1558, 1506 cm"1 Mass (ESI) : 395 (M+Na)+ H NMR (CDC13, δ) : 0.84 (6H, d, J=6.60 Hz), 5.C7 (IH, 7-plet,
J=6.60 Hz), 5.14 (2H, brs), 6.43-6.56 (2H, m) , 6.94 (IH, d,
J=9.60 Hz), 7.30-7.44 (7H, m) , 7.80 (IH, d, J=9.60 Hz)
Example 148
6- [5-amino-3-phenyl-6- (lif-pyrrol-1-yl) -2-pyrazinyl] - 2-methyl-3 (2if) -pyridazinone
The title compound was obtained in a similar manner to that of Example 147. m.p. : 2Q2-205°C
IR (KBr) : 3367, 3336, 3303, 3273, 3193, 1695, 1657, 1624, 1585, 1560, 1508 cm"1
Mass (ESI) : 711 (2M+Na)+, 367 (M+Na)+
XH NMR (CDCI3, δ) : 3.53 (3H, s), 5.19 (2H, brs), 6.43-6.46 (2H, m) , 6.86 (IH, d, J=9.60 Hz), 7.28-7.47 (7H, m) , 7.53 (IH, d,
J=9.60 Hz) Example 149
To a suspension of NaH (60% in oil suspension) (23.3 ing) in 1, 2-dimethyl-2-imidazolidinone (0.3 ml) was added lff-pyrazole (42.3 mg) and the mixture was stirred at 25-30°C for 30 minutes. After addition of 6- (S-amino-δ-bromo-S-phenyl- 2-pyrazinyl) -2-isopropyl-3 (2if) -pyridazinone (150 mg) , the. mixture was heated at 120-125°C for 15 hours. To the reaction mixture was added water (3 ml) to give a precipitate. The precipitate was dissolved in CHC13, dried over MgS04 and concentrated under reduced pressure to
Figure imgf000158_0001
a solid. The so-Lid was suspended in acetone and collected by filtration to give 6- [5-amino-3-phenyl-6- (lif-pyrazol-1-yl) -2-pyrazinyl] - 2-isopropyl-3 (2if) -pyridazinone (66 mg) . m.p. : 210-212°C IR (KBr) : 3386, 3342, 3261, 3143, 2979, 1660, 1616, 1591, 1508
Mass (ESI) : 769 (2M+Na)+, 396 (M+Na)+, 374 (M+H)+ λR NMR (CDC13, δ) : 0.87 (6H, d, J=6.64 Hz) , 5.09 (IH, 7-plet,
J=6.64 Hz) , 6.53-6.57 (IH, ) , 6.97 (IH, d, J=9.60 Hz) , 7.01 (2H, brs), 7.30-7.44 (5H, m) , 7.72-7.79 (2H, m) , 8.63 (IH, d,
J=3.16 Hz)
XH NMR (DMS0-d6, δ) : 0.75 (6H, d, J=6.60 Hz) , 4.90 (IH, 7-plet, J=6.60 Hz) , 6.68-6.71 (IH, m) , 6.99 (IH, d, J=9.60 Hz), 7.32-7.42 (5H, m) , 7.83 (2H, brs), 7.94-7.96 (IH, m) , 8.05 (HH, d, J=9 . 60 Hz ) , 8 . 79-8 . 82 ( IH , m)
The following compounds were obtained in a similar manner to that of Example 149. Example 150
6- [5-amino-6- ( lif-imidazol-1-yl) -3-phenyl-2-pyrazinyl] - 2-isopropyl-3 (2if) -pyridazinone m.p. : >250°C
IR (KBr) : 3303, 3170, 1643, 1585, 1560, 1508 cm"1 Mass (ESI) : 769 (2M+Na)+, 396 (M+Na)+, 374 (M+H)+ lH NMR (CDC13, δ) : 0.84 (6H, d, J=6.65 Hz), 5.08 (IH, 7-plet, J=6.65 Hz), 5.21 (2H, brs), 6.95 (IH, d, J=9.60 Hz), 7.30-7.43 (6H, m) , 7.53-7.55 (IH, m) , 7.75 (IH, d, J=9.60 Hz), 8.24 (IH, s) Example 151
6- [5-amino-3-phenyl-6- (lif-1, 2, 4-triazol-l-yl) -2-pyrazinyl] -
2-isopropyl-3 (2ff) -pyridazinone m.p. : 240-241.5°C
IR (KBr) : 3446, 3286, 3161, 1651, 1581, 1533, 1504 cm"1 Mass (ESI) : 771 (2M+Na)+, 397 (M+Na)+ αH NMR (CDCI3, δ) : 0.87 (6H, d, J=6.62 Hz), 5.10 (IH, 7-plet, J=6.62 Hz), 6.82 (2H, brs), 6.99 (IH, d, J=9.54 Hz), 7.33-7.45(5H, ), 7.72 (IH, d, J=9.54 Hz), 8.20 (IH, s) , 9.21 (IH, s) Example 152
6- [5-amino-6- (lif-benzimidazol-1-yl) -3-phenyl-2-pyrazin yl] -
2-isopropyl-3 (2f) -pyridazinone m.p. : >250°C IR (KBr) : 3454, 3271, 3143, 3114, 3099, 2976, 1658, 1626, 1587,
15556, 1506 cm"1
Mass (ESI) : 869 (2M+Na)+, 446 (M+Na)+, 424 (M+H)+
XH NMR (CDC13, δ) :.0.85 (6H, d, J=6.60 Hz), 5.08 (IH, 7-plet,
J=6.60 Hz) , 5.20 (2H, brs) , 6.93 (IH, d, J=9.60 Hz) , 7.3S-7.74 (8H, m) , 7.74 (IH, d, J=9.60 Hz), 7.86-7.94 (IH, m) , 8.40 (IH, s)
Example 153
6- [5-amino-3-phenyl-6- ( lff-pyrazol-1-yl) -2-pyrazinyl] -
2-methyl-3 (2 if) -pyridazinone m.p. : 187-189.5°C
IR (KBr) : 3404, 3383, 3261, 3153, 1657, 1620, 1587, 1518, cm"1
Mass (ESI) : 368 (M+Na)+, 346 (M+H)+
XH NMR (CDCI3, δ) : 3.56 (3H, s), 6.53-6.56 (IH, m) , 6.8S (IH, d, J=9.60 Hz), 7.00 (2H, brs) , 7.35-7.46 (5H, m) , 7.50 (IH, d, J=9.60 Hz) , 7.78 (IH, d, J=2.06 Hz) , 8.64 (IH, d, J=3.16 Hz)
Example 154
6- [5 -amino- 6- ( lif-imidazol-1-yl) - 3-pheny 1-2-pyra zinyl ] —
2-methyl-3 (2if) -pyridazinone m.p. : >250°C IR (KBr) : 3357, 3307, 3159, 1645, 1587, 1560, 1508 cm"1 Mass (ESI) : 713 (2M+Na)+, 368 (M+Na)+, 346 (M+H)+ Hi NMR (CDC13, δ) : 3.55 (3H, s), 5.21 (2H, brs), 6.86 (IH, d, J=9.70 Hz), 7.30 (IH, s) , 7.40-7.53 (7H, m) , 8.17 (IH, s) Example 155
6- [5-amino-3-phenyl-6- (lif-1, 2, 4-triazol-l-yl) -2-pyrazinyl] - 2-methyl-3 (2if) -pyridazinone m.p. : >250°C
IR (KBr) : 3425, 3294, 3099, 1660, 1649, 1614, 1601, 1579, 1508 cm"1
Mass (ESI) : 369 (M+Na)+ H NMR (CDCI3, δ) : 3.58 (3H, s), 6.74 (2H, brs), 6.89 (IH, d,
J=9.56 Hz), 7.35-7.48 (6H, m) , 8.20 (IH, s) , 9.23 (IH, s)
Example 156 6- [ 5 -amino- 6- ( lif-benzimida zol-1-yl ) -3 -phenyl -2 -pyrazinyl ] -
2-methyl-3 ( 2if) -pyrida zinone m . p . : >250°C
IR (KBr) : 3317, 3176, 1670, 1655, 1587, 1556, 1504 cm"1
Mass (ESI) : 813 (2M+Na)+, 418 (M+Na)+, 396 (M+H)+ 2H NMR (CDCI3, δ) : 3.54 (3H, s) , 5.26 (2H, brs), 6.85 (IH, d,
J=9.58 Hz), 7.39-7.56 (9H, m) , 7.88-7.93 (IH, m) , 8.48 (IH, s)
Example 157
A suspension of 6- [5-amino-6- (methylsulfonyl) - 3-phenyl-2-pyrazinyl] -2-isopropyl-3 (2if) -pyridazinone (205 mg) and sodium methoxide (57.7 mg) in MeOH (0.6 m) was refluxed for 24 hours. Water (3 ml) was added to the reaction mixture to give a precipitate. The precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a solid. The solid was suspended in acetone and collected by filtration to give 6- (5-amino-6-methoxy-3-phenyl- 2-pyrazinyl) -2-isopropyl-3 (2f) -pyridazinone (154 mg) . m.p. : 211-214°C (acetone - n-hexane)
IR (KBr) : 3464, 3323, 1660, 1612, 1585, 1520 cm"1 Mass (ESI) : 729 (2M+Na)+, 376
Figure imgf000162_0001
354 (M+H) + αH NMR (CDC13, δ) : 0.84 (6H, d, J=6.60 Hz), 2.70 (3H, s) , 5.00 (2H, brs), 5.08 (IH, 7-plet, J=6.60 Hz), 6.94 (IH, d, J=9.58 Hz), 7.26-7.37 (5H, m) , 7.79 (IH, d, J=9.58 Hz) Example 158
To a suspension of NaH (60% in oil suspension) (31.1 mg) in DMA (0.6 ml) was added 4-fluorophenol (87.3 mg) and the mixture was stirred at 25-30°C for 30 minutes. 6-[5-Amino- 6- (methylsulfonyl) -3-phenyl-2-pyrazinyl] -2-isopropyl-3 (2ff) — pyridazinone (150 mg) was added and the mixture was heated atz 100-105°C for 15 hours. After addition of 0. IN HCl (3 ml), an aqueous layer was removed by decantation to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a solid. The solid was crystallized from a mixture of acetone and n-hexane to give 6- [5-amino-6- (4-fluorophenoxy) -3-phenyl- 2-pyrazinyl] -2-isopropyl-3 (2f) -pyridazinone (70 mg) . m.p. : 173-175°C
IR (KBr) : 3483, 3294, 3163, 1660, 1626, 1587, 1504 cm"1 Mass (ESI) : 857 (2M+Na)+, 440 (M+Na)+, 418 (M+H)+
Hi NMR (CDC13, δ) : 0.81 (6H, d, J=6.60 Hz), 5.03 (IH, 7-plet,
J=6.60 Hz), 5.35 (2H, brs), 6.79 (IH, d, J=9.58 Hz), 7.08-7.40 (10H, m)
Example 159
6-{ 5-amino-6- [ (4-fluorophenyl) thio] -3-phenyl-2-pyrazinyl } -
2-isopropyl-3 (2H) -pyridazinone
The title compound was obtained in a similar manner to that of Example 158. m.p. : 148-150°C
IR (KBr) : 3275, 3138, 1653, 1624, 1583, 1523 cm"1
Mass (ESI) : 889 (2M+Na)+, 456 (M+Na)+, 434 (M+H)+
XH NMR (CDCI3, δ) : 0.80 (6H, d, J=6.60 Hz), 5.03 (IH, 7-plet, J=6.60 Hz), 5.28 (2H, brs), 6.83 (IH, d, J=9.60 Hz), 7.08-7.59
(10H, m)
Example 160
In a sealed tube, NaH (60% in oil suspension) (31.1 mg) was added 2-propanol (0.6 ml) and the mixture was stirred at 25-30°C for 30 minutes. 6- [5-Amino-6- (methylsulfonyl) - 3-phenyl-2-pyrazinyl] -2-isopropyl-3 (2f) -pyridazinone (150 mg) was added and the mixture was heated at 100-105°C for 15 hours . After addition of 0. IN HCl (3 ml) was added to the mixture and an aqueous layer was removed by decantation to give a residue . The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (70:30 v/v) to give a solid. The solid was crystallized from a mixture of acetone and n-hexane to give 6- (5-amino-6-isopropoxy-3-phenyl- 2-pyrazinyl) -2-isopropyl-3 (2if) -pyridazinone (102 mg) . m.p. : 198-200°C
IR (KBr) : 3491, 3267, 3143, 2979, 1666, 1620, 1591, 1508 cm"1 Mass (ESI) : 753 (2M+Νa)+, 388 (M+Na)+, 366 (M+H)+ XH NMR (CDC13, δ) : 0.71 (6H, d, J=6.60 Hz), 0.85 (6H, d, J=6.60 Hz), 5.07 (IH, 7-plet, J=6.60 Hz), 5.23 (2H, brs), 5.41 (IH, 7-plet, J=6.60 Hz) , 6.91 (IH, d, J=9.56 Hz) , 7.22-7.39 (5H, m) , 7.66 (IH, d, J=9.56 Hz) Example 161
To a suspension of NaH (60% in oil suspension) (31.1 mg) in DMA (0.6ml) was added cyclohexanol (0.081ml) and the mixture was stirred at 25-30°C for 30 minutes. 6-[5-Amino- 6- (methylsulfonyl) -3-phenyl-2-pyrazinyl] -2-isopropyl-3 (2if) - pyridazinone (150 mg) was added and the mixture was heated at 100-105°C for 15 hours. After addition of 0. IN HCl (3 ml) was added to the mixture and an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHC13, dried over MgS04, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a solid. The solid was crystallized from a mixture of acetone and n-hexane (60:40 v/v) to give 6- [5-amino-6- (cyclohexyloxy) - 3-phenyl-2-pyrazinyl] -2-isopropyl-3 (2if) -pyridazinone ( 55 mg) . m.p. : 161-163°C
IR (KBr) : 3489, 3276, 3143, 2935, 1664, 1618, 1591 cm"1 Mass (ESI) : 833 (2M+Na)+, 428 (M+Na)+, 406 (M+H)+ H NMR (CDC13, δ) : 0.86 (6H, d, J=6.60 Hz), 1.33-2.18 (10H, m) , 5.00-5.29 (4H, m) , 6.90 (IH, d, J=9.60 Hz), 7.22-7.40 (5H, m) , 7.62 (IH, d, J=9.60 Hz)
The following 3 compounds were obtained in a similar manner to that of Example 161. Example 162 6- [5-amino-6- (benzyloxy) -3-phenyl-2-pyrazinyl] -2-isopropyl- 3 (2if) -pyridazinone m.p. : 118-120°C
IR (KBr) : 3479, 3280, 3143, 1664, 1626, 1508 cm"1 Mass (ESI) : 436 (M+Na)+, 414 (M+H)+ XH NMR (CDCI3, δ) : 0.87 (6H, d, J=6.62 Hz), 5.08 (IH, 7-plet,
J=6.62 Hz), 5.15 (2H, brs), 5.49 (2H, s), 6.91 (IH, d, J=9.56
Hz), 7.22-7.51 (10H, m) , 7.65 (IH, d, J=9.56 Hz)
Example 163 6- [5-amino-3-phenyl-6- (2-pyridylmethoxy) -2-pyrazinyl] -
2-isopropyl-3 (2if) -pyridazinone m.p. : 150-151°C
IR (KBr) : 3309, 1660, 1626, 1577 cm"1
Mass (ESI) : 437 (M+Na)+, 415 (M+H)+ XH NMR (CDCI3, δ) : 0.85 (6H, d, J=6.62 Hz), 5.06 (IH, 7-plet,
J=6.62 Hz), 5.23 (2H, brs), 5.64 (2H, s), 6.88 (IH, d, J=9.56
Hz), 7.22-7.34 (6H, m) , 7.49 (IH, d, J=7.82 Hz), 7.59 (IH, d,
J=9.56 Hz), 7.72-7.82 (IH, ) , 8.66 (IH, d, J=5.00 Hz)
Example 164 6- [5-amino-6- (2-furylmethoxy) -3-phenyl-2-pyrazinyl] -
2-isopropyl-3 (2if) -pyridazinone m.p. : 172-174oC
IR (KBr) : 3479, 3276, 3147, 1664, 1624, 1591, 1508 cm"1
Mass (ESI) : 426 (M+Na)+, 404 (M+H)+ XH NMR (CDCI3, δ) : 0.87 (6H, d, J=6.62 Hz), 5.09 (IH, 7-plet,
J=6.62 Hz), 5.15 (2H, brs), 5.45 (2H, s), 6.40-6.43 (IH, m) ,
6.50-6.52 (IH, m) , 6.93 (IH, d, J=9.56 Hz), 7.22-7.35 (5H, m) ,
7.47-7.49 (IH, m) , 7.71 (IH, d, J=9.56 Hz) Example 165
To a suspension of NaH (60% in oil suspension) (31.1 mg) in 1, 2-dimethyl-2-imidazolidinone (0.6 ml) was added to 1-butanol (0.0716 ml) and the mixture was stirred at 25-30°C for 30 minutes. 6- [5-Amino-6- (methylsulfonyl) -3-phenyl- 2-pyrazinyl] -2-isopropyl-3 (2if) -pyridazinone (150 mg) was added and the mixture was heated at 100-105°C for 15 hours. After addition of 0.1N HCl (3 ml) was added to the mixture and a precipitate was collected by filtration. The precipitate was dissolved in CHC13, dried over MgS04, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (80:20 v/v) to give a solid. The solid was suspended in hexane and collected by filtration to give 6- (5-amino-6-butoxy-3-phenyl- 2-pyrazinyl) -2-isopropyl-3 (2ff) -pyridazinone (83 mg) . m.p. : 130-131.5°C
IR (KBr) : 3489, 3276, 3147, 2954, 1666, 1622, 1593, 1510 cm"1 Mass (ESI) : 781 (2M+Na)+, 402 (M+Na)+, 380 (M+H)+ y NMR (CDCI3, δ) : 0.85 (6H, d, J=6.60 Hz), 1.01 (3H, t, J=7.29 Hz), 1.42-1.63 (2H, m) , 1.76-1.91 (2H, ra) , 4.45 (2H, t, J=6.54 Hz), 5.07 (IH, 7-plet, J=6.60 Hz), 5.18 (2H, brs), 6.92 (IH, d, J=9.56 Hz), 7.21-7.38 (5H, m) , 7.69 (IH, d, J=9.56 Hz)
The following 8 compounds were obtained in a similar manner to that of Example 165.
Example 166
6— [ 5-amino-6- (2-methoxyethoxy) -3-phenyl-2-pyrazinyl] -
2 — isopropyl-3 (2if) -pyridazinone m.p. : 128-130°C
IR (KBr) : 3487, 3278, 3145, 1666, 1620, 1591, 1508 cm"1
Mass (ESI) : 785 (2M+Na)+, 404 (M+Na)+, 382 (M+H) +
1H NMR (CDC13, δ) : 0.85 (6H, d, J=6.60 Hz), 3.46 (3H, s),
3.79-3.84 (2H, m) , 4.59-4.65 (2H, m) , 5.07 (IH, 7-plet, J=6.60 Hz) , 5.22 (2H, brs), 6.91 (IH, d, J=9.58 Hz), 7.22-7.42 (5H, m) , 7.66 (IH, d, J=9.58 Hz)
Example 167
6— [5-amino-6- (2-tert-butoxyethoxy) -3-phenyl-2-pyrazinyl] -
2 — isopropyl-3 (2if) -pyridazinone m.p. : 163-165°C
IR (KBr) : 3483, 3450, 3423, 3280, 2974, 1666, 1620, 1591 cm"1
Mass (ESI) : 446 (M+Na)+, 424 (M+H) +
XH NMR (CDCI3, δ) : 0.85 (6H, d, J=6.60 Hz), 1.25 (9H, s) , 3.77
(2H, t, J=5.12 Hz), 4.56 (2H, t, J=5.12 Hz), 5.10 (IH, 7-plet, J=6.60 Hz) , 5.18 (2H, brs) , 6.91 (IH, d, J=9.56 Hz) , 7.24-7.34
(5H, m) , 7.69 (IH, d)
Example 168
6— {5 -amino- 6- [2- (benzyloxy) ethoxy] -3 -phenyl- 2 -pyrazinyl } -
2 — isopropyl-3 (2if) -pyridazinone m. p . : 120- 122°C
IR (KBr) : 3483, 3463, 3327, 3134, 1655, 1624, 1585 cm-1
Mass (ESI) : 480 (M+Na)+, 458 (M+H)+ λH NMR (CDC13, δ) : 0.85 (6H, d, J=6.60Hz), 3.90 (2H, t, J=9.52 Hz), 4.61-4.66 (4H, m), 5.06 (IH, 7-plet, J=6.60 Hz) , 5.13 (2H, brs), 6.89 (IH, d, J=9.54 Hz), 7.21-7.38 (10H, m) , 7.62 (IH, d, J=9.54 Hz)
Example 169
6- { 5-amino-6- [4- (benzyloxy) butoxy] -3-phenyl-2-pyrazinyl } - 2-isopropyl-3 (2if) -pyridazinone m.p. : 96.5-97.5°C
IR (KBr) : 3494, 3278, 3149, 2951, 1651, 1622, 1581, 1504 cm"1
Mass (ESI) : 508 (M+Na)+, 486 (M+H)+
XH NMR (CDCI3, δ) : 0.85 (6H, d, J=6.60 Hz), 1.74-2.18 (4H, m) , 3.57 (2H, t, J=6.13Hz), 4.47 (2H, t, J=6.13Hz), 4.53 (2H, s),
5.06 (IH, 7-plet, J=6.60Hz), 5.15 (2H, brs), 6.89 (IH, d, J=9.60
Hz), 7.22-7.35 (10H, m) , 7.66 (IH, d, J=9.60 Hz)
Example 170
6- { 5-amino-6- [2- (dimethylamino) ethoxy] -3-phenyl- 2-pyrazinyl } -2-isopropyl-3 (2f) -pyridazinone m.p. : 136-137.5°C
IR (KBr) : 3487, 3456, 3273, 3134, 2978, 1660, 1635, 1591 cm'1
Mass (ESI) : 417 (M+Na)+, 395 (M+H)+
2H NMR (CDCI3, δ) : 0.86 (6H, d, J=6.62 Hz), 2.41 (6H, s) , 2.85 (2H, t, J=5.62 Hz) , 4.56 (2H, t, J=5.62 Hz), 5.07 (IH, 7-plet,
J=6.62 Hz), 5.37 (2H, brs), 6.90 (IH, d, J=9.56 Hz), 7.24-7.34
(5H, m) , 7.67 (IH, d, J=9.56 Hz)
Example 171 6- [5-amino-3-phenyl-6- (2, 2, 2-trif luoroethoxy) -2-pyrazinyl] -
2-isopropyl-3 (2 if) -pyridazinone m.p. : 233-235°C
IR (KBr) : 3492, 3278, 3155, 2974, 1666, 1624, 1593, 1510 cm"1
Mass (ESI) : 833 (2M+Na) + , 428 (M+Na)+, 406 (M+H) + 2H NMR (CDCI3, δ) : 0.85 (6H, d, J=6.60 Hz) , 4.87 (2H, q, J=8.32
Hz), 5.08 (IH, 7-plet, J=6.60 Hz), 5.22 (2H, brs), 6.93 (IH, d, J=9.62 Hz), 7.27-7.39 (5H, m) , 7.61 (IH, d, J=9.62 Hz)
Example 172
6-( 5-amino-6- [2- ( 4-morpholinyl) ethoxy] - 3-pheny 1- 2-pyrazinyl } -2-isopropyl-3 (2ff) -pyridazinone m.p. : 139-143°C
IR (KBr) : 3483, 3450, 3305, 3195-3105, 2964, 1657, 1635, 1589 cm
Mass (ESI) : 459 (M+Na)+, 437 (M+H) +
XH NMR (CDCI3, δ) : 0.86 (6H, d, J=6.60 Hz) , 2.60-2.72 (4H, m) , 2.92 (2H, t, J=5.72 Hz) , 3.69-3.81 (4H, m) , 4.59 (2H, t, J=5.72 Hz) , 5.07 (IH, 7-plet, J=6.60 Hz) , 5.29 (2H, brs) , 6.90 (IH, d, J=9.58 Hz) , 7.22-7.41 (5H, m) , 7.65 (IH, d, J=9.58 Hz) Example 173 2- (2-{ [3-amino-6- ( 1-isopropyl- 6-oxo-l , 6-dihydro- 3-pyridazinyl) -5-phenyl-2-pyrazinyl] oxy }ethyl) - lif-isoindole-1, 3 (2if) -dione m.p. : 208-210°C IR (KBr) : 3458, 3437, 3282, 3155, 1768, 1718, 1666, 1626, 1589 cm"1
Mass (ESI) : 519 (M+Na)+,,497 (M+H)+
Hi NMR (CDC13, δ) : 0.82(6H, d, J=6.62 Hz), 4.20 (2H, t, J=5.10 Hz), 4.66 (2H, t, J=5.10Hz), 5.04 (IH, 7-plet, J=6.62Hz), 5.23 (2H, brs) , 6.89 (IH, d, J=9.60 Hz) , 7.22-7.32 (5H, m) , 7.65 (IH, d, J=9.60 Hz), 7.67-7.77 (2H, m) , 7.82-7.88 (2H, m)
Example 174
To a suspension of NaH (60% in oil suspension) (31.1 mg) in 1, 2-dimethyl-2-imidazolidinone (0.6 ml) was added
2-phenylethanol (0.094 ml) and the mixture was stirred at 25-30°C for 30 minutes. 6- [5-Amino-6- (methylsulfonyl) - 3-phenyl-2-pyrazinyl] -2-isopropyl-3 (2if) -pyridazinone (150 mg) was added and the mixture was heated at 100-105°C for 15 hours. To the mixture was added 0. IN HCl (3 ml) and an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHC13, dried over MgS04, concentrated under reduced pressure and purified by column chromatography on silica gel. By elution with a mixture. of n-hexane and EtOAc (60:40 v/v) was obtained 6- [5-amino-3-phenyl- 6- (2-phenylethoxy) -2-pyrazinyl] -2-isopropyl-3 (2if) - pyridazinone as a solid (9 mg) . By elution with a mixture of MeOH and EtOAc (1:99 v/v) was obtained 6- (5-amino-6-oxo- 3-phenyl-l, 6-dihydro-2-pyrazinyl) -2-isopropyl-3 (2if) - pyridazinone as a solid (89 mg) .
6- [5-amino-3-phenyl-6- (2-phenylethoxy) -2-pyrazinyl] - 2-isoρropyl-3 (2ff) -pyridazinone m.p. : 173-176°C IR (KBr) : 3477, 3448, 3406, 3280, 1662, 1620, 1591, 1506 cm"1
Mass (ESI) : 877 (2M+Na)+, 450
Figure imgf000172_0001
428 (M+H) +
XU NMR (CDC13, δ) : 0.85 (6H, d, J=6.60 Hz), 3.17 (2H, t, J=6.98
Hz) , 4.67 (2H, t, J=6.98 Hz) , 5.07 (IH, 7-plet, J=6.60 Hz) , 5.23
(2H, brs), 6.91 (IH, d, J=9.56 Hz), 7.23-7.39 (10H, m) , 7.66 (IH, d, J=9.56 Hz)
6- (5-amino-6-oxo — 3-phenyl-l, 6-dihydro-2-pyrazinyl) -
2-isopropyl-3 (2if) -pyridazinone m.p. : >250°C (DMSO - H20)
IR (KBr) : 3431, 3315, 1664, 1645, 1608, 1585, 1522 cm"1 Mass (ESI) : 346 (M+Na)+, 324 (M+H)+
1H NMR (DMSO-de, δ) : 1.11 (6H, d, J=6.60 Hz) , 5.02 (IH, 7-plet, J=6.60 Hz) , 6.75 (IH, d, J=9.58 Hz) , 7.03-7.35 (8H, m) , 11.90 (IH, s) The following 12 compounds were obtained in a similar manner to that of Example 165.
Example 175
6- [5-amino-3-phenyl-6- (3-phenylpropoxy) -2-pyrazinyl] - 2-isopropyl-3 (2if) -pyridazinone m.p. : 105-106.5°C
IR (KBr) : 3483, 3269, 3143, 1666, 1622, 1591 cm"1
Mass (ESI) : 464 (M+Na)+, 442 (M+H) +
1H NMR (CDC13, δ) : 0.84 (6H, d, J=6.60 Hz) , 2.12-2.29 (2H, m) , 2.84 (2H, t, J=7.44 Hz) , 4.49 (2H, t, J=6.40 Hz) , 4.98-5.18 (3H, m) , 6.91 (IH, d, J=9.58 Hz) , 7.17-7.38 (10H, m) , 7.66 (IH, d,
J=9.58 Hz)
Example 176
6- { 5 -ami no- 6- [ (l-benzyl-3-pyrrolidinyl) oxy] -3 -phenyl - 2-pyrazinyl } -2-isopropyl-3 (2ff) -pyridazinone m.p. : 179-181°C
IR (KBr) : 3483, 3267, 3140, 2978, 2783, 1666, 1622, 1591 cm"1
Mass (ESI) : 505 (M+Na)+, 483 (M+H) +
XH NMR (CDCI3, δ) : 0.85 (6H, d, J=6.60 Hz), 2.03-2.18 (IH, m) , 2.40-2.64 (2H, m) , 2.88-3.08 (3H, m) , 3.70 (IH, d, J=12.88 Hz), 3.79 (IH, d, J=12.88 Hz) , 5.06 (IH, 7-plet, J=6.60 Hz) , 5.14 (2H, brs) , 5.50-5.61 ( IH, m) , 6.88 (IH, d, J=9.60 Hz) , 7.21-7.41 (10H, m) , 7.60 (IH, d, J=9.60 Hz) Example 177 6-{ 5-amino-6- [ (1-benzyl-3—piperidinyl) oxy] -3-pheny1- 2-pyrazinyl } -2-isopropyl-3 (2if) -pyridazinone
IR (Neat) : 3477, 3309, 3209, 2939, 2862, 2806, 1662, 1635, 1624, 1587, 1506 cm"1 Mass (ESI) : 519 (M+Na)+, 497 (M+H)+
1U NMR (CDC13, δ) : 0.81 (3H, d, J=6.60 Hz), 0.86 (3H, d, J=6.60
Hz), 5.05 (IH, 7-plet, J=6.60 Hz), 5.26 (2H, brs), 6.87(1H, d,
J=9.56 Hz), 7.22-7.34 (10H, m) , 7.42 (IH, d, J=9.56 Hz)
Example 178 6-{ 5-amino-6- [ ( 1-benzyl-4—piperidinyl) oxy] -3-pheny1-
2-pyrazinyl } -2-isopropyl-3 (2if) -pyridazinone m.p. : 148-150.5°C
IR (KBr) : 3485, 3275, 3145, 1666, 1620, 1589 cm"1
Mass (ESI) : 519 (M+Na)+, 497 (M+H)+ XH NMR (CDCI3, δ) : 0.86 (6H, d, J=6.60 Hz) , 1.90-2.03 (2H, m) ,
2.13-2.25 (2H, m) , 2.38-2.50 (2H, m) , 2.76-2.92 (2H, m) , 3.62
(2H, s), 4.98-5.27 (4H, m) , 6.90 (IH, d, J=9.60 Hz), 7.21-7.38
(10H, s), 7.59 (IH, d, J=9.60 Hz)
Example 179 6- ( 5-amino- 6-butoxy-3-phenyl-2-pyrazinyl ) -2-methyl-
3 ( 2if) -pyridazinone m . p . : 143-144°C
IR (KBr) : 3433, 3404, 3307, 3215, 2954, 1651, 1614, 1581 cm"1
Mass (ESI) : 725 (2M+Na)+, 374 (M+Na)+, 352 (M+H)+ XH NMR (CDCI3, δ) : 1.01 (3H, t, J=7.30 Hz), 1.42-1.62 (2H, m) ,
1.76-1.91 (2H, m) , 3.55 (3H, s), 4.46 (2H, t), 5.25 (2H, brs),
6.82 (IH, d, J=9.60 Hz), 7.26-7.38 (5H, m) , 7.41 (IH, d, J=9.60
Hz) Example 180
6- [5-amino-6- (2-methoxyethoxy) -3-phenyl-2-pyrazinyl] -
2-methyl-3 (2 if) -pyridazinone m.p. : 139-141°C
IR (KBr) : 3494, 3471, 3386, 3288, 3188, 1664, 1653, 1583 cm"1 Mass (ESI) : 376
Figure imgf000175_0001
354 (M+H)+
Hi NMR (CDCI3, δ) : 3.45 (3H, s), 3.55 '(3H, s), 3.78-3.84 (2H, m) , 4.60-4.66 (2H, m) , 5.26 (2H, brs) , 6.82 (IH, d, J=9.60 Hz) ,
7.29-7.38 (5H, m) , 7.39 (IH, d, J=9.60 Hz)
Example 181 6- { 5-amino-6- [2- (4-morpholinyl) ethoxy] -3-phenyl-
2-pyrazinyl } -2-methyl-3 (2if) -pyridazinone m.p. : 185-187°C
IR (KBr) : 3435, 3307, 3182, 1653, 1574 cm"1
Mass (ESI) : 839 (2M+Na)+, 431 (M+Na)+, 409 (M+H) + XH NMR (CDCI3, δ) : 2.63-2.70 (4H, m) , 2.92 (2H, t, J=5.70 Hz),
3.56 (3H, s), 3.74-3.84 (4H, m) , 4.61 (2H, t, J=5.70 Hz), 5.37
(2H, brs), 6.80 (IH, d, J=9.70 Hz), 7.28-7.41 (6H, m)
Example 182
6- [5 -amino- 6- (benzyloxy) -3 -phenyl -2 -pyra inyl] -2 -methyl - 3 (2f) -pyridazinone m.p. : 185-187°C
IR (KBr) : 3406, 3305, 3211, 1649, 1616, 1577, 1547 cm"1 Mass (ESI) : 793 (2M+Na)+, 408 (M+NFa)+, 386 (M+H) + lH NMR (CDC13, δ) : 3.56 (3H, s), 5.27 (2H, brs), 5.50 (2H, s), 6.83 (IH, d, J=9.60 Hz), 7.29-7.52 (11H, m) Example 183
6- [5-amino-3-phenyl-6- (3-phenylpropoxy) -2-pyrazinyl] - 2-methyl-3 (2if) -pyridazinone m.p. : 91-94°C
IR (KBr) : 3384, 3296, 3195, 1666, 1658, 1624, 1585 cm"1 Mass (ESI) : 849 (2M+Na)+, 436 (M+Na)+, 414 (M+H) +
1H NMR (CDCI3, δ) : 2.13-2.27 (2H, m) , 2.83 (2H, t, J=7.45 Hz) , 3.54 (3H, s), 4.49 (2H, t, J=6.38Hz), 5.05 (2H, brs), 6.81 (IH, d, J=9.62 Hz), 7.17-7.41 (11H, m) Example 184
6- [5-amino-6- (2-f urylmethoxy) -3-phenyl-2-pyrazinyl] - 2-methyl-3 (2if) -pyridazinone m.p. : 158-159.5°C IR (KBr) : 3471, 3284, 3151, 1664, 1631, 1587 cm"1 Mass (ESI) : 773 (2M+Na)+, 398 (M+Na)+, 376 (M+H) + 1H NMR (CDCI3, δ) : 3.57 (3H, s) , 5.21 (2H, brs), 5.46 (2H, s), 6.40-6.43 (IH, m) , 6.51-6.54 (IH, m) , 6.84 (IH, d, J=9.60 Hz), 7.28-7.38 (5H, m) , 7.42 (IH, d, J=9.60 Hz) , 7.46-7.48 (IH, m) Example 185
6- { 5-amino-6- [ ( l-benzyl-4-piperidinyl) oxy] -3-phenyl-
2-pyrazinyl}-2-methyl-3 (2 if) -pyridazinone m.p. : 147-149°C IR (KBr) : 3491, 3278, 3151, 2941, 1668 1620, 1589 cm-1
Mass (ESI) : 959 (2M+Na)+, 491
Figure imgf000177_0001
469 (M+H) +
XH NMR (CDC13, δ) : 1.90-2.90 (8H, m) , 3.53 (3H, s) , 3.64 (2H, brs) , 5.05 (2H, brs), 5.15-5.35 (IH, m) , 6.82 (IH, d, J=9.64
Hz ) , 7.28-7.40 (11H, m) Example 186
6- [5 -ami no- 6- ( 4-f luorophenoxy) -3 -phenyl — 2-pyrazinyl] -
2-rnethyl-3 (2if) -pyridazinone m.p. : 229-231°C
IR (KBr) : 3485, 3282, 3153, 1651, 1622, 1587, 1504 cm"1 Mass (ESI) : 801 (2M+Na)+, 412 (M+Na)+, 390 (M+H) +
XH NMR (CDCI3, δ) : 3.27 (3H, s), 6.83 (IH, d, J=9.58 Hz), 7.11 (2H, brs), 7.23-7.42 (10H, m)
Example 187 To a suspension of NaH (60% in oil suspension) (33.6 mg) in 1, 2-dimethyl-2-imidazolidinone (0.6 ml) was added 2-phenylethanol (0.101 ml) and the mixture was stirred at 25 — 30°C for 30 minutes. 6- [5-Amino-6- (methylsulf onyl) - 3-phenyl-2-pyrazinyl] -2-methyl-3 (2 if) -py idazinone (150 mg) was added and the mixture was heated at 100-105°C for 15 hours. To the mixture was added 0. IN HCl (3 ml) and a precipitate was collected by filtration. The precipitate was suspended in CHC13 and collected by filtration to give 6- (5-amino-6-hydroxy- 3-phenyl-2-pyrazinyl) -2-methyl-3 (2if) -pyridazinone (60 mg) . The CHCI3 solution was dried over MgS04, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give a solid. The solid was suspended in acetone and collected by filtration to give 6- [5-amino-3-phenyl-
6- (2-phenylethoxy) -2-pyrazinyl] -2-methyl-3 (2if) -pyridazinone (7 mg) . " 6- [ 5-amino-3-phenyl-6- (2-phenylethoxy) -2-pyrazinyl] - 2-methyl-3 (2if) -pyridazinone m.p. : 156-159°C
IR (KBr) : 3489, 3404, 3383, 3261, 3091, 1662, 1612 cm"1 Mass (ESI) : 821 (2M+Na)+, 422 (M+Na)+, 400 (M+H) + XH NMR (CDCI3, δ) : 3.16 (2H, t, J=6.97 Hz), 3.55 (3H, s) , 4.67 (2H, t, J=6.97 Hz), 5.21 (2H, brs), 6.82 ( IH, d, J=9.60 Hz), 7.21-7.41 (11H, m)
6- ( 5-amino-6-hydroxy-3-phenyl-2-pyrazinyl ) -2-methyl-
3 (2if) -pyridazinone m.p. : >250°C
IR (KBr) : 3404, 3307, 3203, 3130, 3041, 1675, 1655, 1620, 1583, 1520 cm"1
Mass (ESI) : 613 (2M+Na)+, 318 (M+Na)+, 296 (M+H) +
XH NMR (DMS0-d6, δ) : 3.67 (3H, s) , 6.69 (IH, d, J=9.66 Hz), 6.75 (IH, d, T=9.65 HZ) , 7.09 (2H, brs), 7.36 (5H, s), 11.70 (IH, brs) Example 188
Under nitrogen atmosphere, a solution of Na2CC>3 (427 mg) in water (8.8 ml) was added to a suspension of N'- [6-chloro- 3 -cyano- 5- ( 1 -isopropyl -6-oxo-l, 6-dihydro-3-pyrida zinyl) - 2-pyrazinyl] -NJ, N-dimethylimidof ormamide (346 mg) , (2-bromophenyl ) boronic acid (503 mg) and tetrakis (triph-enylphosphine) palladium (35 mg) in dioxane (22 ml) and the mixture was stirred at 100-105°C for 4 hours . Dioxane was evaporated under reduced pressure to give a residue. The residue was dissolved in CHC13, dried over MgS04, concentrated under reduced pressure and purified by column chromatography on silica gel. By elution with a mixture of n-hexane and EtOAc (70:30 v/v) was obtained 3-amino-5- (2-bromophenyl ) - 6- ( 1 -isopropyl -6-oxo-l , 6 -di hydro- 3 -pyridazinyl) - 2-pyrazinecarbonitrile as a solid (42 mg) and by elution with a mixture of n-hexane and EtOAc (50:50 v/v) was obtained N ' - [ 6- (2-bromophenyl ) -3-cyano-5- ( l-isopropyl-6-oxo- 1, 6-dihydro-3 — pyridazinyl) -2-pyrazinyl] - N, N-dimethylimidof ormamide as a solid (360 mg) . N' - [6- (2-bromophenyl) -3 -cyano- 5- ( 1 -isopropyl- 6 -oxo-
1, 6-dihydro-3-pyridazinyl) -2-pyrazinyl] -
N, N-dimethylimidof ormamide m.p. : 197-199°C IR (KBr) : 3455-3405, 2233, 1672, 1620, 1531, 1504 cm"1
Mass (ESI) : 957 and 955 (2M+Na)+, 490 and 488 (M+Na)+, 468 and
466 (M+H)+ λH NMR (DMSO-d6, δ) : 0.72 (6H, d, J=6.65 Hz), 3.17 (3H, s),
3.21 (3H, s), 4.89 (IH, 7-plet, J=6.65 Hz), 7.00 (IH, d, J=9.70 Hz) , 7.33-7.41 (IH, m) , 7.52-7.55 (2H, m) , 7.67 (IH, d, J=7.96
Hz) , 7.97 (IH, d, J=9.70 Hz), 8.69 (IH, s)
3-amino-5- (2-bromophenyl) -6- (l-isopropyl-6-oxo-l, 6-dihydro-
3 -pyridaz inyl ) -2-pyrazinecarbonitrile m.p. : 240-243°C IR (KBr) : 3415, 3303, 3190-3145, 2227, 1647, 1585, 1547, 1510
Mass (ESI) : 435 and 423 (M+Na)+, 413 and 411 (M+H)+ X NMR (DMSO-d6, δ) : 0.71 (6H, d, J=6.60 Hz), 4.89 (IH, 7-plet, J=6.60 Hz), 6.96 (IH, d, J=9.68 Hz), 7.30-7.69 (4H, m) , 7.93 (2H, brs), 7.90 (IH, d, J=9.68 Hz) Example 189
A solution of '- [6- (2-bromophenyl ) -3-cyano- 5- ( 1— isopropyl -6-oxo-l, 6 -di hydro- 3 -pyridaz inyl ) - 2-pyr:azinyl] -N, N-dimethylimidoformamide (285 mg) in a mixture of water (2 ml) and 4N hydrogen chloride in dioxane (6 ml) was stirred at 20-25°C for 18 hours. After addition of water (18 ml), the mixture was neutralized with INaq. NaOH to give a solid. The solid was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give 3-amino-5- (2-bromophenyl ) - 6- (l-isopropyl-6-oxo-l , 6-dihydro-3-pyridazinyl) - 2-pyrazinecarbonitrile as a solid (163 mg) . m.p. : 240-243°C IR (KBr) : 3415, 3303, 3190-3145, 2227, 1647, 1585, 1547, 1510 cm"1 Mass (ESI) : 435 and 423 (M+Na)+, 413 and 411 (M+H) + λU NMR (DMSO-de, δ) : 0.71 (6H, d, J=6.60Hz), 4.89 (IH, 7-plet, J=6.60 Hz), 6.96 (IH, d, J=9.68 Hz), 7.30-7.69 (4H, m) , 7.93 (2H, brs), 7.90 (IH, d, J=9.68 Hz) Example 190
A mixture of 3-amino-5- (2-bromophenyl) -6- ( l-isopropyl- 6-oxo-l, 6-dihydro-3-pyridazinyl) -2-pyrazinecarbonitrile (59 mg) in 25% hydrogen bromide in AcOH (0.36 ml) was stirred at 20-25°C for 5 hours. Dioxane (3 ml) was added to the mixture to give a precipitate- The precipitate was collected boy filtration and suspended in sat. aq. NaHC03 to give a solid. The solid was collected by filtration and dried under reduced pressure to give 3-amino-5- (2-bromophenyl) -6- ( 1-isopropyl- 6-oxo-l , 6-dihydro-3-pyrida zinyl ) -2-pyrazinecarboxamide ( 17 mg ) . m . p . : 132-135°C
IR (KBr) : 3470-3415, 3325-3295, 1655, 1581 cm"1 Mass (ESI) : 453 and 451 (->.+Na)+, 431 and 429 (M+H) +
*H NMR (DMSO-d6, δ) : 0.69 (3H, d, J=6.75Hz), 0.72 (3H, d, J=6.75 Hz), 4.90 (IH, 7-plet, J=6.75 Hz), 6.94 (IH, d, J=9.70 Hz), 7.27-8.15 (7H, m) , 8.41 (IH, brs), 8.43 (IH, d, J=9.70 Hz) Example 191 Under nitrogen atmosphere, a solution of Na2C03 (138 mg) in water (0.8 ml) was added t o a suspension of 3-amino-5-chloro- 6- ( l-isopropyl-6-oxo-l, 6-dihydro-3-pyrida∑inyl) - 2-pyrazinecarboxamide (100 mg) , 2-thienylboronic acid (104 mg) and tetrakis (triphenylphosphine) palladium (11.3 mg) in dioxane (2 ml) and the mixture was stirred at 100-105°C for 4 hours. After addition of water (10 ml), a precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40: 60 v/v) to give 3-amino-6- ( 1— isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -5- (2-thienyl) -2-pyrazinecarboxamide as a solid (85 mg) . m.p. : 238-240°C
IR (KBr) : 3383, 3280, 1653, 1585, 1529 cm"1 Mass (ESI) : 379(M+Na)+, 357(M+H) + αH NMR (CDCI3, δ) : 1.02 (6H, d, J=6.60 Hz), 5.08 (IH, 7-plet, J=6.60 Hz), 7.02-7.09 (3H, m) , 7.65-8.15 (6H, m)
The following 3 compounds were obtained in a similar manner to that of Example 191. Example 192
3-amino-5- (2-bromophenyl) -6- (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -2-pyrazinecarboxamide m.p. : 240-243°C IR (KBr) : 3415, 3303, 3190-3145, 2227, 1647, 1585, 1547, 1510 cm"1 Mass (ESI) : 435and423 (M+Na) +, 413and411 (M+H) + H NMR (DMSO-de, δ) : 0.71 (6H, d, J=6.60Hz), 4.89 (IH, 7-plet,
J=6.60 Hz), 6.96 (IH, d, J=9.68 Hz), 7.30-7.69 (4H, m) , 7.93 (2H, brs), 7.90 (IH, d, J=9.68 Hz)
Example 193
3-amino-6- ( l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) -
5- (4-pyridyl) -2-pyrazinecarboxamide
Mass (ESI) : 374 (M+Na)+, 352 (M+H) + XH NMR (CDCI3, δ) : 0.82 (6H, d, J=6.62 Hz) , 5.09 (IH, 7-plet,
J=6.62 Hz), 5.65 (IH, brs) , 7.02 ,(1H, d, J=9.58 Hz), 7.38-7.43
(2H, m) , 7.60 (IH, brs) , 7.81 (IH, , J=9.58 Hz), 8.66-8.70 (2H, m)
Example 194 3-amino-6- (l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) - 5- (6-methoxy-3-pyridyl) -2-pyraz inecarboxamide m.p. : 250-252°C
IR (KBr) : 3390, 3251, 3167, 1664, 1591 cm"1 Mass (ESI) : 404 (M+Na)+
1H NMR (DMSO-d6, δ) : 0.77 (6H, d, J=6.62 Hz), 3.85 (3H, s) , 4.92 (IH, 7-plet, J=6.62Hz), 6.87 (IH, d, J=8.62Hz), 6.98 (IH, d, J=9.62 Hz) , 7.7-8.2 (2H, br-peak) , 7.74 (IH, brs) , 7.77 (IH, dd, J=2.38,8.62 Hz) , 8.21 (IH, d, J=2.38 Hz) , 8.30 (IH, d, J=9.62 Hz), 8.32 (IH, brs)
Example 195
A mixture of 1- (2-bromoph enyl) -2- (l-isopropyl-6-oxo-
1, 6-dihydro-3-pyridazinyl) -1, 2— ethanedione (5.30 g) and (2Z) -2, 3-diamino-2-butenedinit ile (1.65 g) in a solution of
DMSO (0.25 ml) and toluene (25 ml) was refluxed for 8 hours.
The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (85:15 v/v) to give 5- (2-bromophenyl ) — 6- ( l-isopropyl-6-oxo-
1 , 6-dihydro-3-pyridazinyl) -2, 3—pyrazinedicarbonitrile as a solid (3.58 g) . m.p. : 159.5-161°C
IR (KBr) : 2227, 1666, 1589, 1516 cm"1 Mass (ESI) : 445 and 443 (M+Na)+, 423 and 421 (M+H) + X NMR (CDC13, δ) : 0.79 (6H„ brs), 5.08 (IH, 7-plet, J=6.52 Hz) , 7.04 (IH, d, J=10.02 Hz) , 7.32-7.42 (IH, m) , 7.52-7.63 (3H, m) , 8.09 (IH, d) XH NMR (DMSO-de, δ) : 0.73 (6H, d, J=6.62Hz), 4.92 (IH, 7-plet, J=6.62 Hz), 7.11 (IH, d, J=9.78 Hz), 7.43-7.49 (IH, ) , 7.58-7.64 (2H, m) , 7.74-7.77 (IH, m) , 8.14 (IH, d, J=9.78 Hz) Example 196
To a solution of 5- (2—bromophenyl) -6- (1-isopropyl-
1 6-oxo-l, 6-dihydro-3-pyridazinyl) -2, 3-pyrazinedicarbonitrile (3.00 g) in 1, 3-dimethyl-2-imidazolidinone (6 ml), (4-methoxybenzyl) amine (0.96 ml) was added and the mixture was stirred at 25-30°C for 100 hours. After addition of 0.5N aq. NaOH (15 ml), the mixture was stirred for one hour and a precipitate was collected by filtration to give a solid. The solid was dissolved in EtOAc, washed with water, dried over MgS04 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (70:30 v/v) to give 5- (2-bromophenyl) -6- ( 1 -isopropyl- 6-oxo-l , 6-dihydro- 3 -pyridaz inyl) -3- [ (4-methoxybenzyl) amino] - 2-pyrazinecarbonitrile as an amorphous solid (2.58 g) containing 6- (2-bromophenyl ) -5- ( l-isopropyl-6-oxo- 1,6-dihydro- 3-pyridazinyl) -3- [( 4-methoxybenzyl) amino] - 2-pyrazinecarbonitrile .
5- (2-bromophenyl) -6- (l-isopropyl-6-oxco-l, 6-dihydro- 3-pyridazinyl) -3- [ (4-methoxybenzyl) amino] - 2-pyrazinecarbonitrile m.p. : 76-78C
IR (KBr) : 2217, 1658, 1570, 1512 cm Mass (ESI) : 555 and 553 (M+Na) , 533 and 531 (M+H) XH NMR (CDC13, δ) : 0.78 (6H, brs), 3.82 (3H, s) , 4.66 (2H, d, J=5.50 Hz), 5.05 (IH, 7-plet, J=6.62 HTz), 5.74 (IH, t, J=5.50 Hz), 6.87-6.98 (3H, m) , 7.25-7.31 (3H, m) , 7.40-7.60 (3H, m) , 7.90 (IH, d, J=9.60 Hz) Example 197
To a solution of 5- (2-bromophenyl) -
6- ( l-isopropyl-6-oxo-l , 6-dihydro-3-p;yridazinyl ) - 3- [( 4-methoxybenzyl) amino] -2-pyrazinecarbonitrile (2.05 g) containing 6- (2-bromophenyl) -5- (l-isopropyl-6-oxo- 1, 6-dihydro- 3-pyridazinyl) -3- [ (4-methoxybenzyl) amino] - 2-pyrazinecarbonitrile in CHCI3 (60 ml) , water (3 ml) and 2, 3-dichloro-5, 6-dicyano-l, 4-benzoqinone (2.63 g) were added and the mixture was stirred at 25-30°C for 24 hours. The mixture was washed with IN aq. NaOH, dried over MgS04 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel. By elution of a mixture of n-hexane and EtOAc (70:30 v/v) was obtained 3-amino-5- (2-bromophenyl) -6- (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -2-pyrazinecarbonitrile as a solid (941 mg) and by elution of a mixture of n-hexane and EtOAc (50:50 v/v) was obtained 3-amino-6- (2-bromophenyl) -5- (l-isopropyl-6-oxo- 1, 6-dihydro-3-pyridazinyl) -2-pyrazinecarbonitrile as a solid (92 mg) .
3-amino-5- (2-bromophenyl) -6- (l-isopropyl-6-oxo-l, 6-dihydro- 3-pyridazinyl) -2-pyrazinecarbonitrile m.p. : 240-243°C IR (KBr) : 3415, 3303, 3190-3145, 2227, 1647, 1585, 1547, 1510 cm"1 Mass (ESI) : 435 and 423 (M+Na)+, 413 and 411 (M+H) + λ NMR (DMS0-d6, δ) : 0.71 (6H, d, J=6.60Hz), 4.89 (IH, 7-plet,
J=6.60 Hz), 6.96 (IH, d, J=9.68 Hz), 7.30-7.69 (4H, m) , 7.93 (2H, brs), 7.90(1H, d, J=9.68 Hz)
3-amino-6- (2-bromophenyl) -5- (1-isopropyl- 6- oxo-1, 6-dihydro-
3-pyridazinyl) -2-pyrazinecarbonitrile m.p. : 241-243°C
IR (KBr) : 3340, 3303, 3176, 2222, 1651, 1587, 1552, 1529 cm"1 Mass (ESI) : 847, 845 and 843 (2M+Na)+, 435 and 433 (M+Na)+,
413 and 412 (M+H)+ lR NMR (DMS0-d6, δ) : 0.71 (6H, d, J=6.60 Hz) , 4.89 (IH, 7-plet,
J=6.60 Hz), 7.06 (IH, d, J=9.72 Hz), 7.26-7.37 (IH, m) ,
7.46-7.50 (2H, m) , 7.64 (IH, d, J=7.86 Hz) , 7.74 (2H, brs) , 7.94 ( IH, d, J=9 . 72 Hz ) Example 198
A solution of 3-amino-5- (2-bromophenyl) - 6- (l-isopropyl-6-oxo-l, 6-dihydro-3-pyridazinyl) - 2-pyrazinecarboxamide (695 mg) in a mixture of 5N aq. NaOH (4 ml) and EtOH (4 ml) was refluxed for 4 hours. After removal of EtOH by evaporation, the mixture was adjusted to pH 4 with IN HCl to give a precipitate. The precipitate was collected by filtration and dried under reduced pressure to give 3-amino- 5- (2-bromophenyl) -6- ( l-isopropyl-6-oxo-l , 6-dihydro- 3-pyridazinyl) -2-pyrazinecarboxylic acid (664 mg) . m.p. : 237°C (dec.)
IR (KBr) : 3415, 3271, 1714, 1643, 1606, 1574 cm"1 Mass (ESI) : 454 and 452 (M+Na)+ 2H NMR (DMSO-de, δ) : 0.72 (6H, d, J=6.60Hz) , 4.90 (IH, 7-plet, J=6.60 Hz), 6.98 (IH, d, J=9.62 Hz), 7.29-7.38 (IH, m) , 7.43-7.55 (2H, m) , 7.65 (IH, d, J=7.86 Hz) , 7.79 (2H, brs) , 8.12 (IH, d, J=9.62 Hz), 13.3 (IH, br-peak) Example 199 A mixture of 3-amino-5- (2-bromophenyl) -6- (1-isopropyl- 6-oxo-l, 6-dihydro-3-pyridazinyl) -2-pyrazinecarboxylic acid (601 mg) in 1 , 2-dichlorobenzene (3 ml) was refluxed for 2 hours . After cooling, the mixture was purified by column chromatography on silica gel (EtOAc only) to give a solid. The solid was suspended with acetone and collected by filtration to give 6- [5-amino-3- (2-bromophenyl) -2-pyrazi -nyl] - 2-isopropyl-3 (2if) -pyridazinone as a solid (554 mg) . m.p. : 189-191°C IR (KBr) : 3346, 3307, 3178, 1651, 1643, 1587, 1572, 1537 cm"1 Mass (ESI) : 410 and 408 (M+Na)+, 388 and 386 (M+H) +
XH NMR (DMSO-de, δ) : 0.71 (6H, d, J=6.62Hz), 4.88 (IH, 7-plet, J=6.62 Hz) , 6.92 (IH, d, J=9.66 Hz) , 6.95 (2H, brs) , 7.24-7.46 (3H, m), 7.59-7.64 (IH, m) , 7.92 (IH, d, J=9.66 Hz), 7.99 (IH, s)
Example 200
A mixture of N ' - [ 6-chloro-3-cyano-5- ( 1- Isopropyl- 6-oxo-l, 6-dihydro-3-pyridazinyl) -2-pyrazinyl] - N, N-dimethylimidoformamide (100 mg) , 4-fluorophenylboronic acid (122 mg), tetrakistriphenylphosphine palladium (lOmg) and Na2C03 (123 mg) in dioxane (5 ml) and water (1 rnl) was stirred at 90°C for 15 hours. Water and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgS04. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain N '-[ 3-cyano-6- (4-fluorophenyl) -5- (1-isopropyl- 6-oxo-l, 6-dihydro-3-pyridazinyl) -2-pyrazinyl] - N, -dimethylimidoformamide (121 mg) as white powder. XH NMR (DMSO-d6, δ) : 0.86 (6H, d, J=6.6 Hz), 3.2i (3H, s) , 3.26 (3H, s), 5.09 (IH, 7-plet, J=6.6 Hz), 6.98 (IH, d, J=9.6 Hz), 7.0-7.5 (4H, m) , 7.86 (IH, d, J=9.6 Hz), 8.72 (IH, s) Mass (ESI) : 406 (M+H)+, 428 (M+Na)+ Example 201
A mixture of N ' - [ 6-chloro-3-cyano-5- (1-isopropyl- 6-oxo-l, 6-dihydro-3-pyridazinyl) -2-pyrazinyl] — N, N-dimethylimidoformamide (200 mg) , 3-fluorophenylboronic acid (243 mg) , tetrakistriphenylphosphine palladium (20.1 mg) and Na2C0 (246 mg) in dioxane (10 ml) and water (2 ml) was stirred at 90°C for 15 hours. Water and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgS04. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with e mixture of n-hexane and EtOAc. The fractions were concent -rated in vacuo to obtain N ' - [3-cyano-6- (3-fluorophenyl) -5- ( 1—isopropyl- 6-oxo-l, 6-dihydro-3-pyridazinyl) -2-pyrazinyl] — N, N-dimethylimidoformamide (100 mg) as white powder.
^ NMR (DMSO-de, δ) : 0.85 (6H, d, J=6.6Hz), 3.22 (3H, s), 3.26 (3H, s), 5.09 (IH, 7-plet, J=6.6 Hz), 6.99 (IH, d, J=9.6 Hz), 7.0-7.5 (4H, m) , 7.89 (IH, d, J=9.6 Hz), 8.73<1H, s) Mass (ESI) : 406 (M+H)\ 428 (M+Na) +

Claims

1. A pyrazine compound shown by the following fo-rrmula (I) :
Figure imgf000191_0001
wherein
R1 is hydrogen or optionally substituted lower alkyl; X is hydrogen, halogen, hydroxy, mercapto, cyano or acyl, or lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, cyclo (lower ) alkoxy, lower alkylthio, aryloxy, arylthio, amino, aryl, heterocyclic group or heterocyclyloxy, each of which is optionally substituted; Y is hydrogen, halogen, hydroxy, mercapto, cyano, acyl or lower alkyl, lower alkoxy, lower alkylthio, aminό, aryl or heteroaryl, each of which is optionally substituted; and Z is aryl or heteroaryl, each of which is optionally substituted; or a salt thereof.
2. A pyrazine compound of claim 1, wherein R1 is hydrogen or lower alkyl; and
Y is hydrogen, hydroxy, lower alkoxy, cyano, -acyl or optionally substituted amino; or a salt thereof.
3. A pyrazine compound of claim 2, wherein
R1 is lower alkyl;
Y is hydrogen, amino or dimethylsul anylidenearnino; and Z is phenyl, pyridyl or thienyl, each of whic-h is • optionally substituted; or a salt thereof.
4. A pyrazine compound of claim 3, wherein
X is hydrogen, halogen, hydroxy, cyano, carboxy, lower alkyl carbonyl, lower alkoxy carbonyl, lower alkyl sulfinyl, lower alkyl sulfonyl; or a salt thereof.
5. A pyrazine compound of claim 3, wherein X is lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, cyclo (lower) alkoxy, lower alkylthio, carbamoyl, thiocarbamoyl, aryloxy, arylthio, amino, aryl, heterocyclic group or heterocyclyloxy, each of which is optionally substituted; or a salt thereof.
6. A pyrazine compound of claim 3, wherein
Y is hydrogen or amino; and Z is phenyl or thienyl, each of -which is optionally substituted; or a salt thereof.
7. A pyrazine compound of claim 6, therein X is hydrogen, chloro, bromo, hydroxy, cyano, methylcarbonyl, methylthio,. carbamoyl, furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, phenoxy, fluorophenoxy, pyrrolidinyloxy, benzylpyrrolidinyloxy, thia-azolyl, methylthiazolyl or phenylttiiazolyl; or a salt thereof.
8. A pyrazine compound of claim 6, wherein
X is amino, vinyl, ethynyl or lower alkoxy, each of which is optionally substituted; or a salt thereof.
9. A pyrazine compound of claim 1, wherein
R1 is methyl, ethyl or isopropyl ; X is hydrogen, chloro, bromo, hydroxy, cyano, methylcarbonyl, carbamoyl, pyrazolyl, triazolyl, methylthiazolyl, pyridylmethylamino, methoxyethy1amino, furylmeth lamino, cyclohexylethynyl, trifluoromethylmethoxy or butoxy;
Y is amino; and
Z is phenyl or fluorophenyl; or a salt thereof.
10. A pyrazine compound of claim 1, wherein
R1 is lower alkyl;
X is hydrogen, carbamoyl or triazolyl; Y is amino; and Z is phenyl; or a salt thereof.
11. A pyrazine compound of claim 10, which is selected from the group consisting of 1) 3-amino-6- ( l-isopropyl- -oxc* -1, 6-dihydro-
3-pyridazinyl) -5-phenyl-2-pyrazinecarboxamide,
2) 6- (5-amino-3-phenyl-2-pyrazi nyl) -2-isopropyl- 3 (2ff) -pyridazinone,
3) 3-amino- 6- ( 1-ethyl-6-oxo-1 , 6> -dihydro- 3-pyridazinyl) -5-pher-yl-2-pyrazinecarboxamide, 3-amino-6- ( 1 -methyl- 6-oxo-l , 6-dihydro- 3-pyridazinyl) -5-phenyl-2-pyrazinecarboxamide,
5) 6- (5-amino-3-phenyl- 2-pyrazinyl) -2-methyl- 3 (2H) -pyridazinone,
6) 6- (5-amino-3-phenyl- 2-pyrazinyl) -2-ethyl- 3 (2f) -pyridazinone,
7) 6- [5-amino-3-phenyl- 6- (lif-1, 2, 4-triazol-l-yl) - 2-pyrazinyl] -2-isopr opyl-3 (2 if) -pyridazinone, 8) 6- [5 -amino- 3-pheny 1- 6- (lif-1, 2, 4-triazol- l-yl) -2-pyra∑inyl]-2 -methyl-3 (2 if) -pyridazinone, or a salt thereof.
12. A process for preparing the pyrazine compound of the following formula (I):
Figure imgf000195_0001
wherein R1, X, Y and Z are each as defined in claim 1, or a salt thereof; which comprises
(1) halogenation of a connpound of the formula (Id) :
Figure imgf000195_0002
wherein R1, Y and Z are each as defined above, or a salt thereof with N-halosuccinimide to give a compound of the formula (Ie) :
Figure imgf000196_0001
wherein R1, Y, Z and Hal are each as defined above, or a salt thereof,
2 ) pyrazine ring-formation of a compound of the formula
Figure imgf000196_0002
1 wherein R and Z are each as defined above, or a salt thereof, which is prepared in two steps from a compound of the formula (XVII) :
IXVII
Figure imgf000196_0003
wherein Z is as defined above, or a salt thereof , with 2 , 3-diamino-2-butenedinitrile , to give a compound of the formula ( If ) :
Figure imgf000197_0001
wherein R and Z are each as defined above, or a salt thereof, (3) nucleophilic substitution of a compound of the formula (Ig) :
Figure imgf000197_0002
wherein R , X and Z are each as defined above, or a salt thereof, with a compound of the formula (VI) :
Figure imgf000197_0003
wherein R ,4 is lower al koxy; or a salt thereof to give a compound of the formula (lh)
Figure imgf000197_0004
wherein R , R , X and Z- are each as defined above, or a salt thereof, (4) reacting a compound of the formula (VII) :
Figure imgf000198_0001
wherein R is as defined above, or a salt thereof, which is prepareci in three steps from a compound of the formula
Figure imgf000198_0002
wherein R is as defined above, or a salt thereof, with an organoboron compund of the formula (VIII)
Z-BW2 (VIII) wherein Z is as defined above; and BW2 is a constituent of boronic acid, or a salt thereof, to give a compound of the formula (Ii) :
Figure imgf000198_0003
wherein R and Z are each as defined above , or a s alt thereof .
pharmaceutical composition comprising the compoun d of claim 1 ox a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.
14. 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-resmscitation, 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, gout, bronchial asthma, hyperuricemia, sudden infant death syndrome, immunosuppression, diabetes, ulcer, anemia, pancreat tis, Meniere's syndrome, dialysis-induced hypotension, constipation, ischemic bowel diseas e, 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.
15. Amethod or preventing or treating a disease selected from the group consisting of depression, dementia, Parkinson's disease, anxiety, cerebrovascular disease and cerebral infarction, which comprises administering the compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.
16. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof as a medicament.
17. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof as an adenosine antagonist.
18. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof as an Ai receptor and A2 receptor dual antagonist.
19. A process for preparing a pharmaceutical composition which comprises admixing the compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.
20. 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 .
21. A method for evaluation of adenosine antagonism which comprises use of compound of claim 1 or a pharmaceutically acceptable salt thereof.
PCT/JP2005/005663 2004-04-01 2005-03-22 Pyrazine derivatives and pharmaceutical use thereof as adenosine antagonists WO2005095384A1 (en)

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WO2006071548A2 (en) * 2004-12-27 2006-07-06 Alcon, Inc. Aminopyrazine analogs for treating glaucoma and other rho kinase-mediated diseases
WO2006071548A3 (en) * 2004-12-27 2006-09-08 Alcon Inc Aminopyrazine analogs for treating glaucoma and other rho kinase-mediated diseases
EP2001476A2 (en) * 2006-03-20 2008-12-17 Synta Pharmaceuticals Corporation Benzoimidazolyl-parazine compounds for inflammation and immune-related uses
EP2001476A4 (en) * 2006-03-20 2010-12-22 Synta Pharmaceuticals Corp Benzoimidazolyl-parazine compounds for inflammation and immune-related uses
US8119643B2 (en) 2006-03-20 2012-02-21 Synta Pharmaceuticals Corp. Benzoimidazolyl-pyrazine compounds for inflammation and immune-related uses
US8614321B2 (en) 2006-03-20 2013-12-24 Synta Pharmaceuticals Corp. Benzoimidazolyl-pyrazine compounds for inflammation and immune-related uses
US9598372B2 (en) 2013-10-18 2017-03-21 Celgene Quanticel Research, Inc. Bromodomain inhibitors
US9115114B2 (en) 2013-10-18 2015-08-25 Quanticel Pharmaceuticals, Inc. Bromodomain inhibitors
US11884680B2 (en) 2013-10-18 2024-01-30 Celgene Quanticel Research, Inc. Bromodomain inhibitors
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US10941160B2 (en) 2013-10-18 2021-03-09 Celgene Quanticel Research, Inc. Bromodomain inhibitors
EP3831383A1 (en) 2015-04-15 2021-06-09 Celgene Quanticel Research, Inc. Bromodomain inhibitors
WO2017184462A1 (en) 2016-04-18 2017-10-26 Celgene Quanticel Research, Inc. Therapeutic compounds
EP4011876A1 (en) 2016-04-19 2022-06-15 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
WO2017184491A1 (en) 2016-04-19 2017-10-26 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
US11020380B2 (en) 2017-04-18 2021-06-01 Celgene Quanticel Research, Inc. Therapeutic compounds
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EP3911325A4 (en) * 2019-01-18 2022-10-12 Nuvation Bio Inc. Heterocyclic compounds as adenosine antagonists
EP3911323A4 (en) * 2019-01-18 2022-11-16 Nuvation Bio Inc. Heterocyclic compounds as adenosine antagonists

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CN1938296A (en) 2007-03-28
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JP2007530434A (en) 2007-11-01
TW200536545A (en) 2005-11-16
EP1737841A1 (en) 2007-01-03
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JP4978192B2 (en) 2012-07-18
AR053301A1 (en) 2007-05-02

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