WO2002083111A2 - Imidazole, thiazole and oxazole derivatives and their use for the manufacture of a medicament for the treatment and/or prevention of pollakiuria or urinary incontinence - Google Patents

Imidazole, thiazole and oxazole derivatives and their use for the manufacture of a medicament for the treatment and/or prevention of pollakiuria or urinary incontinence Download PDF

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Publication number
WO2002083111A2
WO2002083111A2 PCT/JP2002/003723 JP0203723W WO02083111A2 WO 2002083111 A2 WO2002083111 A2 WO 2002083111A2 JP 0203723 W JP0203723 W JP 0203723W WO 02083111 A2 WO02083111 A2 WO 02083111A2
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Prior art keywords
group
substituted
lower alkyl
alkyl group
mono
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PCT/JP2002/003723
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French (fr)
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WO2002083111A3 (en
Inventor
Mitsuya Hongu
Thoshihiro Hosaka
Toshihiko Kashiwagi
Rikako Kono
Hiroyuki Kobayashi
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Tanabe Seiyaku Co., Ltd.
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Priority to JP2002580915A priority Critical patent/JP4073786B2/en
Application filed by Tanabe Seiyaku Co., Ltd. filed Critical Tanabe Seiyaku Co., Ltd.
Priority to BR0208956-4A priority patent/BR0208956A/en
Priority to IL15816802A priority patent/IL158168A0/en
Priority to KR1020037013493A priority patent/KR100863659B1/en
Priority to NZ529043A priority patent/NZ529043A/en
Priority to HU0303829A priority patent/HUP0303829A3/en
Priority to AU2002246397A priority patent/AU2002246397B2/en
Priority to US10/474,850 priority patent/US7759373B2/en
Priority to CA002444596A priority patent/CA2444596A1/en
Priority to EP02714577A priority patent/EP1432690A2/en
Publication of WO2002083111A2 publication Critical patent/WO2002083111A2/en
Publication of WO2002083111A3 publication Critical patent/WO2002083111A3/en
Priority to US12/795,323 priority patent/US20100256165A1/en

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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes

Definitions

  • This invention relates to an excellent large conductance calcium-activated K channel opener containing a nitrogen- containing 5-membered heterocyclic compound as an active ingredient, which is useful for treatment of disorders or diseases such as polla iuria, urinary incontinence, cerebral infarction, subarachnoid hemorrhage, and the like.
  • Potassium is the most abundant intracelluar cation, and is very important in maintaining physiological homeostasis. Potassium channels are present in almost all vertebrate cells, and the potassium influx through these channels is indispensable for maintaining hyperpolarized resting membrane potential.
  • maxi-K channels Large conductance calcium activated potassium channels (also BK channels or maxi-K channels) are expressed especially in neurons and smooth muscle cells. Because both of the increase of intracellular calcium concentration and membrane depolarization can activate maxi-K channels, maxi-K channels have been thought to play a pivotal role in regulating voltage-dependent calcium influx. Increase in the intracellular calcium concentration mediates many processes such as release of neurotransmitters, contraction of smooth muscles, cell growth and death, and the like. Actually, the opening of maxi-K channels causes strong membrane hyperpolarization, and inhibits these calcium-induced responses thereby.
  • a substance having an activity of opening maxi-K channels is expected to have potential for the treatment of diseases such as cerebral infarction, subarachnoid hemorrhage, pollakiuria, urinary incontinence, and the like.
  • a compound having a similar structure to the nitrogen- containing 5-membered heterocyclic compound which is an active ingredient of the present invention has been disclosed.
  • oxazole derivatives have been reported in Japanese Provisional Patent Publications No. 36614/1984, No. 152382/ 1984 and No. 172488/1984, but their uses are limited only to antihypolipidemic agent .
  • imidazole derivatives have been reported but their uses are limited only to a cardiotonic, an antithrombosis, an antipyretic analgesic or an anti-inflammation agent.
  • An object of the present invention is to provide an excellent large conductance calcium-activated K channel opener containing a nitrogen-containing 5-membered heterocyclic compound as an active ingredient.
  • the present inventors have studied intensively to solve the problems, and as a result, they have found that a certain kind of a nitrogen-containing 5-membered heterocyclic compound has an excellent large conductance calcium-activated K channel opening activity, whereby they have accomplished the present invention.
  • the present invention relates to a large conductance calcium-activated K channel opener comprising a nitrogen-containing 5-membered heterocyclic compound represented by the following formula (I) :
  • R 1 and R 2 are different from each other and each independently represents hydrogen atom, a halogen atom, carboxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted lower alkyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted lower alkenyl group, a cyclo-lower alkyl group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted heterocyclic group-substituted carbonyl group, R 3 represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted lower alkyl group, and R 4 represents hydrogen atom,
  • the aryl group is a monocyclic, dicyclic or tricyclic 6- to
  • aryl group may include a phenyl group, a naphthyl group and the like . Of these, a phenyl group or a naphthyl group is preferred.
  • the heterocyclic group or the heterocyclic group portion of the heterocyclic group-substituted carbonyl group is a monocyclic, dicyclic or tricyclic 6- to 14-membered aromatic hydrocarbon cyclic group, containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, which may be partially or wholly saturated.
  • the monocyclic heterocyclic group a 5- to 7-membered heterocyclic group, containing 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which may be partially or wholly saturated is preferred, and specific examples of the monocyclic heterocyclic group may include furyl group, thienyl group, thiazolyl group, thiazolidinyl group, isoxazolyl group, pyrrolidinyl group, pyrrolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, tetrazolyl group, and the like.
  • dicyclic heterocyclic group a dicyclic heterocyclic group in which two of the above-mentioned monocyclic heterocyclic groups are fused or a dicyclic heterocyclic group in which the above monocyclic heterocyclic group and a benzene ring are fused is preferred, and specific examples of the dicyclic heterocyclic group may include indolyl group, quinolyl group, tetrahydroquinolyl group, isoquinolyl group, quinoxalyl group, benzofuryl group, dihydrobenzofuryl group, benzothienyl group, benzodioxanyl group, trihydrocyclo- pentathienyl group, benzothianyl group, benzothiazolyl group, imidazopyridyl group, indolyl group, indolinyl group, chromanyl group, thiophenopyridyl group, furanopyridyl group, and the like.
  • tricyclic heterocyclic group a tricyclic heterocyclic group in which the above-mentioned monocyclic heterocyclic group and the above-mentioned dicyclic heterocyclic group are fused or a tricyclic heterocyclic group in which the above- mentioned monocyclic heterocyclic group and two benzene rings are fused is preferred, and specific examples of the tricyclic heterocyclic group may include carbazolyl group, carbolinyl group and the like.
  • heterocyclic groups more specifically preferred are furyl group, thienyl group, thiazolyl group, isoxazolyl group, pyrrolidinyl group, pyrrolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, tetrazolyl group, indolyl group, quinolyl group, isoquinolyl group, benzofuryl group, benzothienyl group, dihydrobenzofuryl group, thiophenopyridyl group and benzodioxanyl group.
  • substituent for the amino group of R 1 or R 2 there may be mentioned, for example, a group selected from formyl group, a lower alkyl group, a lower alkanoyl group, a lower alkylsulfonyl group and a lower alkoxycarbonyl group.
  • a substituent for the lower alkyl group there may be mentioned, for example, a group selected from a halogen atom, hydroxyl group, cyano group, carboxyl group, carbamoyl group, amino group, aminosulfonyl group, a halogenosulfonyl group, amidinothio group, a mono- or di-lower alkylamino group, a lower alkanoylamino group, a lower alkylsulfonylamino group, hydroxyamino group, a mono- or di-lower alkylcarbamoyl group, trifluoromethyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a lower alkoxycarbamoyl group, a lower alkylsulfonyl
  • substituent for the lower alkenyl group there may be mentioned, for example, carboxyl group or a lower alkoxycarbonyl group.
  • substituent for the carbamoyl group there may be mentioned, for example, a group selected from a lower alkyl group, a lower alkoxy group and a lower alkylsulfonyl group.
  • a substituent for the aryl group there may be mentioned, for example, a group selected from nitro group, amino group, hydroxyl group, carbamoyl group, cyano group, carboxyl group, trifluoromethyl group, a lower alkoxycarbonyl group, a halogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkoxy-lower alkoxy group, a mono- or di-lower alkylamino group, a mono- or di-lower alkanoylamino group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, sulfamoyl group, a mono- or di-lower alkylsulfamoyl group, a lower alkylGulfonylamino group .and a phenyl-lower alkoxy
  • a substituent for the heterocyclic group there may be mentioned, for example, a group selected from nitro group, amino group, hydroxyl group, formyl group, carbamoyl group, cyano group, carboxyl group, a lower alkoxycarbonyl group, a halogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a mono- or di-lower alkylamino group, a mono- or di-lower alkanoylamino group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, sulfamoyl group and a mono- or di-lower alkylsulfamoyl group.
  • a substituent on the heterocyclic group for the heterocyclic group-substituted carbonyl group there may be mentioned, for example, a group selected from nitro group, hydroxyl group, carbamoyl group, cyano group, carboxyl group, a lower alkoxycarbonyl group, a halogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a mono- or di-lower alkylamino group, a mono- or di-lower alkanoylamino group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, sulfamoyl group and a mono- or di-lower alkylsulfamoyl group.
  • the above-mentioned amino group, lower alkyl group, carbamoyl group, aryl group, heterocyclic group and heterocyclic group-substituted carbonyl group may be substituted by the same or different 1 to 3 above-mentioned substituents.
  • a substituent for the aryl group of R 3 there maybe mentioned, for example, a group selected from cyano group, nitro group, amino group, a halogen atom, trifluoromethyl group, carboxyl group, hydroxyl group, carbamoyl group, a mono- or di-lower alkylamino group, a mono- or di-lower alkylamino-lower alkyl group, a mono- or di-lower alkylcarbamoyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkanoyloxy-lower alkyl group, sulfo group, a lower alkylthio group, a lower alkylthio-lower alkyl group, a lower alkylsulfonyl group,
  • a substituent for the heterocyclic group there may be mentioned, for example, a group selected from oxo group, cyano group, nitro group, amino group, a halogen atom, carboxyl group, hydroxyl group, formyl group, carbamoyl group, a mono- or di-lower alkylamino group, a N-lower alkyl-N-cyclo-lower alkylamino group, a mono- or di-lower alkylamino-lower alkyl group, a mono- or di-lower alkylcarbamoyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkoxy-lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, sulfo group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkyl
  • alkyl group there may be mentioned, for example, a group selected from hydroxyl group, cyano group, carboxyl group, carbamoyl group, amino group, a mono- or di-lower alkylamino group, a lower alkanoylamino group, a lower alkylsulfonylamino group, hydroxyamino group, a mono- or di-lower alkylcarbamoyl group, trifluoromethyl group, a halogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, sulfamoyl group, a mono- or di-lower alkylsulfamoyl group, a lower alkoxycarbonyl group and a heterocyclic group.
  • a substituent for the alkyl group there may be mentioned, for example, a group selected from hydroxyl group,
  • aryl group, heterocyclic group and lower alkyl group may be substituted by the same or different above-mentioned 1 to 3 substituents .
  • the lower alkyl group of R 4 As a substituent for the lower alkyl group of R 4 , there may be mentioned a mono- or di-lower alkylamino group .
  • the lower alkyl group may be substituted by the same or different above-mentioned 1 to 2 substituents.
  • preferred compounds may be compounds wherein X is N-R 4 , 0 or S; R 1 or R 2 is independently hydrogen atom, a lower alkyl group, a lower alkyl group substituted by a heterocyclic group, a di-lower alkylamino group, a carboxy-lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylsulfinyl-lower alkyl group, a lower alkylsulfonyl-lower alkyl group, a lower alkylthio-lower alkyl group, a trifluoromethyl-lower alkyl group, a cyclo-lower alkyl group, an aryl group, a trifluoromethylaryl group, a cyanoaryl group, a halogenoaryl group, a dihalogenoaryl group,
  • X is N-R 4 , 0 or S;
  • R 1 or R 2 is independently hydrogen atom, a lower alkyl group, a lower alkyl group substituted by a heterocyclic group, a lower alkylamino group, a di-lower alkylamino group, a cyano-lower alkyl group, a hydroxy-lower alkyl group, a carboxy-lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylsulfinyl-lower alkyl group, a lower alkylthio-lower alkyl group, a cyclo-lower alkyl group, an aryl group, a trifluoromethylaryl group, a hydroxyaryl group, a halogenoaryl group, a dihalogenoaryl group, a lower alkylaryl group, a di-low
  • R 1 or R 2 is independently a carboxy-lower alkyl group, a lower alkyl group substituted by a heterocyclic group, an aryl group, a halogenoaryl group, a di-halogenoaryl group, a di-lower alkoxyaryl group, a lower alkylthioaryl group, a heterocyclic group, a halogeno-heterocyclic group, or a lower alkyl-heterocyclic group; and R 3 is a halogenoaryl group, a lower alkylaryl group, a di-lower alkylaminoaryl group, a lower alkylthioaryl group, a lower alkoxyaryl group, a heterocyclic group, a halogeno-heterocyclic group, a lower alkyl-heterocyclic group, a lower alkoxy-heterocyclic group, a lower alkoxy-heterocyclic group, a lower alkyl group
  • R 1 is (1) a lower alkyl group which may be substituted by carboxyl group, a lower alkoxycarbonyl group or a heterocyclic group, (2) an aryl group which may be substituted by one or two halogen atoms, or (3) a heterocyclic group which may be substituted by a halogen atom
  • R 2 is (1) a lower alkyl group which may be substituted by carboxyl group, a lower alkoxycarbonyl group or a heterocyclic group, (2) a heterocyclic group which may be substituted by a halogen atom, or (3) an aryl group which may be substituted by one or two halogen atoms
  • R 3 is (1) a heterocyclic group which may be substituted by one or two groups selected from amino group, a halogen atom, a lower alkyl group, a lower alkoxy group, a mono- or di-lower
  • R 4 is hydrogen atom or a lower alkyl group.
  • R 1 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxycarbonyl-lower alkyl group, (3) a lower alkyl group substituted by a tetrazolyl group, (4) a phenyl group which may be substituted by one or two halogen atoms, or (5) a thienyl group which may be substituted by a halogen atom
  • R 2 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxycarbonyl-lower alkyl group, (3) a lower alkyl group substituted by a tetrazolyl group, (4) a thienyl group which may be substituted by a halogen atom, or (5) a phenyl group which may be substituted by one or two halogen atoms
  • R 3 is (1) a benzothienyl group which may be substituted by a halogen atom, (2) a
  • R 1 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxycarbonyl-lower alkyl group, (3) a phenyl group which may be substituted by one or two halogen atoms, or (4) a thienyl group which may be substituted by a halogen atom
  • R 2 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxycarbonyl-lower alkyl group, (3) a thienyl group which may be substituted by a halogen atom, or (4) a phenyl group which may be substituted by one or two halogen atoms
  • R 3 is (1) a benzothienyl group which may be substituted by a halogen atom
  • a phenyl group which may be substituted by a halogen atom, a lower alkylthio group, a lower alkoxy group or a di-lower alkylamino group
  • a pyridyl group which may be substituted by a lower alkoxy group or a di-lower alkylamino group
  • a pyrimidinyl group which may be substituted by a di-lower alkylamino group
  • a thienyl group which may be substituted by a di-lower alkyl group
  • (6) thieno [3, 2-b] pyridyl group or (7) an indolyl group which may be substituted by a lower alkyl group .
  • the most preferred compound in view of pharmaceutical effects is the compound selected from the group consisting of: 4- (5-chlorothiophen-2-yl) -2- (2-benzo [b] thienyl) thiazol-5-yl acetic acid, 5- (4-chlorophenyl) -2- (2-N, N-dimethylaminopyrimidin-5-yl) - oxazol-4-yl acetic acid,
  • R 1 and R 2 are a thienyl group substituted by a chlorine atom, and the other is a carboxyl-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group or a lower alkyl group substituted by a tetrazolyl group; and R 3 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group.
  • R 3 is (1) an aryl group which may be substituted by one or two substituents selected from a halogen atom, a di-lower alkylamino group, a lower alkylthio group and a lower alkoxy group, or (2) a heterocyclic group which may be substituted by one or two substituents selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group and a mono- or di-lower alkylamino group.
  • particularly preferred compounds are compounds wherein one of R 1 and R 2 is a thienyl group substituted by a chlorine atom, and the other is a carboxyl-lower alkyl group or a lower alkoxycarbonyl-lower alkyl group; the aryl group is phenyl group; and the heterocyclic group is a thienyl group, a pyridyl group, a pyrimidinyl group, a benzothienyl group, a benzofuryl group, a dihydrobenzofuryl group, an indolyl group or a thieno [3, 2-b] pyridyl group.
  • R 3 is a phenyl group which is substituted by a halogen atom or a lower alkylthio group; a thienyl group which is substituted by one or two lower alkyl groups; a pyrimidinyl group which is substituted by a di-lower alkylamino group; a benzothienyl group which may be substituted by a halogen atom; an indolyl group which may be substituted by a lower alkyl group; or a thieno [3, 2-b] pyridyl group.
  • X is S
  • one of R 1 and R 2 is a thienyl group substituted by a chlorine atom
  • the other is a carboxyl-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group or a lower alkyl group substituted by a tetrazolyl group
  • R 3 is a substituted or unsubstituted heterocyclic group, where said heterocyclic group is selected from a pyridyl group, a pyrimidinyl group, a benzothienyl group, an indolyl group and a thieno [3, 2-b] - pyridyl group.
  • R 3 is a heterocyclic group which may be substituted by one or two substituents selected from a halogen atom, a lower alkoxy group, a mono- or di- lower alkyl group, a lower alkylthio group and a mono- or di-lower alkylamino group, where said heterocyclic group is selected from a pyridyl group, a pyrimidinyl group, a benzothienyl group, and a thieno [3, 2-b] pyridyl group.
  • one of R 1 and R 2 is a thienyl group substituted by a chlorine atom, and the other is a carboxyl-lower alkyl group or a lower alkoxycarbonyl-lower alkyl group;
  • R 3 is a pyridyl group which may be substituted by a di-lower alkylamino group; a pyrimidinyl group which may be substituted by a mono- or di-lower alkylamino group; or a benzothienyl group which may be substituted by a halogen atom.
  • an optical isomer based on an asymmetric carbon may be present depending on a kind of a substituent (s) .
  • Either of the optical isomer or a mixture thereof may be used as the active ingredient of the present invention.
  • the active ingredient (I) of the present invention can be used in the free form or in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts of the compound (I) include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, and organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate or maleate.
  • salts with a base for example, alkali metal salts such as a sodium salt and a potassium salt or alkaline earth metal salts such as a calcium salt
  • the compound (I) or pharmaceutically acceptable salts thereof includes its internal salts, addition products, solvates and hydrates .
  • the active ingredient (I) of the present invention or pharmaceutically acceptable salts thereof can be administered orally or parenterally and used as common pharmaceutical preparations such as tablets, granules, capsules, powders, injection solution and inhalants.
  • a pharmaceutically acceptable carrier for a preparation of oral administration there may be mentioned a material commonly used, for example, a binder (such as syrup, Gum Arabic, gelatin, sorbit, tragacanth and polyvinyl pyrrolidone) , an excipient (such as lactose, sugar, corn starch, potassium phosphate, sorbit and glycine) , a lubricant (such as magnesium stearate, talc, polyethylene glycol and silica) , a disintegrator (such as potato starch) and a humectant (such as lauryl sodium sulfate) .
  • a binder such as syrup, Gum Arabic, gelatin, sorbit, tragacanth and polyvinyl
  • the active ingredient of the present invention when administered non-orally, it may be formulated into the form of an injection or a drip infusion by using distilled water for injection, physiological saline, an aqueous glucose solution and the like, or a suppository.
  • a dose of the compound (I) or a pharmaceutically acceptable salt thereof may vary depending on an administration method, an age, weight, conditions or a kind or degree of disease of a patient, and generally about 0.1 to 50 mg/kg per day, more preferably about 0.3 to 30 mg/kg per day.
  • the compound (I) or a pharmaceutically acceptable salt thereof has an excellent large conductance calcium-activated K channel opening activity and hyperpolarizes a membrane electric potential of cells, so that it may be used for a prophylactic, relief and/or treatment agent of, for example, hypertension, asthma, premature birth, irritable bowel syndrome, chronic heart failure, angina, cardiac infarction, cerebral infarction, subarachnoid hemorrhage, cerebral vasospasm, cerebral hypoxia, peripheral blood vessel disorder, anxiety, male-pattern baldness, erectile dysfunction, diabetes, diabetic peripheral nerve disorder, other diabetic complication, sterility, urolithiasis and pain accompanied thereby, pollakiuria, urinary incontinence, nocturnal enuresis, and the like.
  • a prophylactic, relief and/or treatment agent of, for example, hypertension, asthma, premature birth, irritable bowel syndrome, chronic heart failure, angina, cardiac infarction, cerebral infarction, subarachnoid
  • the lower alkyl group a hydroxy lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkoxysulfonyl group, a lower alkylsulfamoyl group, a lower alkylcarbamoyl group, a lower alkylamino group, or a lower alkylsulfonylamino group
  • those which are straight or branched and having 1 to 6 carbon atoms particularly those which are straight or branched and having
  • a lower alkenyl group a lower alkanoyl group, a lower alkanoyloxy group, a lower alkanoylamino group or a lower alkoxycarbonyl group
  • those which are a straight or branched and having 2 to 7 carbon atoms particularly those which are a straight or branched and having
  • cyclo-lower alkyl group there may be mentioned those having 3 to 6 carbon atoms .
  • halogen atom there may be mentioned fluorine atom, chlorine atom, bromine atom or iodine atom.
  • the nitrogen-containing 5-membered heterocyclic compound (I) which is an active ingredient of the present invention can be prepared by the following Method A, Method B, Method C or Method D, but the preparation methods are not limited to these methods .
  • a compound (I-a) can be prepared by reacting the compound represented by the formula (II) or a salt thereof with a condensation reagent.
  • condensation reagent there may be suitably used, when X 1 is NH, for example, ammonia or an ammonium salt (such as ammonium acetate, ammonium formate, ammonium carbonate, ammonium benzoate and ammonium picolate) , when X 1 is 0, for example, phosphorus oxychloride, thionyl chloride, acetyl chloride, triphenylphosphine-iodine, triphenylphosphine- phosgene, sulfuric acid, polyphosphoric acid, p-toluene- sulfonic acid, etc., and when X 1 is S, for example, phosphorus pentasulfide, Lawesson' s reagent (2, 4-bis (4-methoxyphenyl) - 1, 3-dithia-2, 4-diphosphetan-2, 4-disulfide) , and the like.
  • X 1 is NH
  • the present reaction can be carried out in a suitable solvent or in the absence of a solvent.
  • a solvent it is not particularly limited so long as it does not disturbdisturb the reaction, and there may be used, for example, acetic acid, dimethylformamide, benzene, toluene, tetrahydrofuran, chloroform, methylene chloride, acetonitrile or a mixed solvent of the above-mentioned solvents.
  • the present reaction proceeds suitably at 15 to 150 °C, particularly at room temperature to 120 °C,
  • a compound (I-b) can be prepared by reacting a compound represented by the formula (III) or a salt thereof with a compound represented by the formula (IV) or a salt thereof in the presence of a base.
  • a base there may be suitably used, for example, an alkali metal carbonate, an alkali metal hydride, an alkali metal alkoxide, an alkali metal hydroxide, and the like.
  • the present reaction can be carried out in a suitable solvent or in the absence of a solvent.
  • a solvent it is not particularly limited so long as it does not disturb the reaction, and there may be used, for example, acetonitrile, methanol, ethanol, chloroform, methylene chloride, dimethylformamide, acetone, tetrahydrofuran or a mixed solvent of the above- mentioned solvents.
  • the present reaction proceeds suitably at 30 to 150°C, particularly at 60 to 120°C.
  • the compound (I) can be also prepared by reacting a compound represented by the formula (V) with a compound represented by the formula (VI) or a compound represented by the formula (VII) in the presence of a palladium catalyst.
  • a palladium catalyst there may be suitably used a zero-valent or divalent palladium catalyst, for example, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, etc.
  • Method C When Method C is carried out by using the compound (VI) , it is preferably carried out in the presence of a base.
  • a base there may be suitably used, for example, an inorganic base such as an alkali metal carbonate, an alkali metal hydroxide, an alkali metal phosphate, an alkali metal fluoride, and the like, or an organic base such as triethylamine, and the like.
  • the present reaction can be carried out in a suitable solvent or in the absence of a solvent.
  • a solvent it is not particularly limited so long as it does not disturb the reaction, and there may be used, for example, dimethoxyethane, tetra- hydrofuran, dimethylformamide, methanol, ethanol, toluene, benzene, chloroform or a mixed solvent of the above-mentioned solvents .
  • the present reaction proceeds suitably at 60 to 150°C, particularly at 80 to 120°C.
  • a compound (I-b) can be prepared by reacting a compound represented by the formula (VIII) or a salt thereof with a compound represented by the formula (IX) and a salt thereof in the presence of ammonia or an ammonium salt.
  • ammonium salt there may be suitably used, for example, ammonium acetate, ammonium formate, ammonium carbonate, ammonium benzoate, ammonium picolate, and the like.
  • the present reaction can be carried out in a suitable solvent or in the absence of a solvent.
  • a solvent it is not particularly limited so long as it does not disturb the reaction, and there may be used, for example, acetic acid, methanol, ethanol, dimethoxyethane, tetrahydrofuran, dimethylformamide or a mixed solvent of the above-mentioned solvents .
  • the present reaction proceeds suitably at 0 to 150°C, particularly at 30 to 120°C.
  • the compounds (II), (III), (IV) , (V) , (VIII) or (IX) may be used as a salt of an inorganic acid such as hydrochloride, sulfate, etc., or a salt of an inorganic base such as an alkali metal salt, an alkaline earth metal salt, etc.
  • a halogen atom is suitably used as the reactive residue of Z 1 and Z 2 .
  • the nitrogen-containing 5-membered heterocyclic compound (I) can be prepared by converting ob ective compounds obtained from one of the above methods into other objective compounds. Such conversion reactions may be suitably used depending on a substituent (s) in a compound, and it can be carried out, for example, by a conventional method as mentioned in the following Methods (a) to (v) .
  • a compound (I) wherein R 1 or R 2 is a halogen atom can be prepared by reacting a compound (I) where corresponding R 1 or R 2 is a hydrogen atom with a halogenating agent.
  • a halogenating agent there may be suitably used bromine, chlorine, iodine, [bis (trifluoroacetoxy) iodo] benzene, N-bromosuccinic imide and the like. This reaction proceeds suitably at 0°C to 30°C.
  • a compound (I) wherein R 1 or R 2 is a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group can be prepared by reaction of a compound (I) where corresponding R 1 or R 2 is a halogen atom with a (tri-lower alkyl) (a substituted or unsubstituted aryl) tin compound, or (tri-lower alkyl) (a substituted or unsubstituted heterocyclic) tin compound in the presence of a catalyst.
  • a zero-valent or divalent palladium catalyst such as bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), etc.
  • this reaction proceeds more suitably in the presence of a zinc salt such as zinc chloride, zinc bromide, zinc iodide, etc. This reaction proceeds suitably at 50°C to 120°C.
  • this reaction may be carried out by using a corresponding boric acid or its ester in place of the tin compound, in the presence of a base.
  • a corresponding boric acid or its ester in place of the tin compound, in the presence of a base.
  • the palladium catalyst and the base those as mentioned in the above Method C are suitably used. This reaction proceeds suitably at 60°C to 120°C.
  • a compound (I) wherein R 1 or R 2 is a substituted or unsubstituted heterocyclic group-substituted carbonyl group can be prepared by reacting a compound (I) where corresponding R 1 or R 2 is a substituted carbamoyl group with a substituted or unsubstituted heterocyclyl lithium. This reaction proceeds suitably at -78 °C to 30 °C.
  • the substituted or unsubstituted heterocyclyl lithium can be prepared by lithiation of a corresponding halogeno-heterocyclic compound with n-butyl lithium, etc.
  • a compound (I) where X is N-R 4 and R 4 is a substituted or unsubstituted alkyl group can be prepared by reaction of a compound (I) where corresponding X is N-R 4 and R 4 is hydrogen atom with a substituted or unsubstituted lower alkyl halide (such as a lower alkyl iodide, a lower alkyl chloride and a lower alkyl bromide) or a lower alkyl sulfonate (such as a lower alkyl trifluoromethanesulfonate and a lower alkyl methanesulfonate) in the presence of a base.
  • a substituted or unsubstituted lower alkyl halide such as a lower alkyl iodide, a lower alkyl chloride and a lower alkyl bromide
  • a lower alkyl sulfonate such as a lower alkyl trifluoromethanesulf
  • an alkali metal hydride As the base, there may be suitably used an alkali metal hydride, an alkali metal carbonate, an alkali metal alkoxide, an alkali metal hydroxide, and the like. This reaction proceeds suitably at 30°C to 80°C.
  • a compound (I) where R 1 or R 2 is a formylamino group or an N-lower alkyl-N-formylamino group can be prepared by reacting a compound (I) where corresponding R 1 or R 2 is an amino group or an N-lower alkylamino group with a formic acid lower alkyl ester (such as methyl ester and ethyl ester) . This reaction proceeds suitably at 60°C to 100°C.
  • a formic acid lower alkyl ester such as methyl ester and ethyl ester
  • a compound (I) where R 1 or R 2 is an N-methylamino group, an N-lower alkyl-N-methylamino group or an N-ethylamino group can be prepared by reacting a compound (I) where corresponding R 1 or R 2 is a formylamino group, an N-lower alkyl-N-formylamino group or an N-acetylamino group with a reducing agent.
  • a reducing agent there may be suitably used a borane complex (such as borane • dimethylsulfide complex), lithium aluminum hydride, and the like. This reaction proceeds suitably at 0°C to 60°C.
  • a compound (I) where R 1 or R 2 is a lower alkoxycarbonylamino group can be prepared by reacting a compound (I) where corresponding R 1 or R 2 is an amino group with a lower alkoxycarbonyl halide in the presence of a base.
  • a base there may be suitably used pyridine, triethylamine, an alkali metal carbonate, an alkali metal lower alkoxide, an alkali metal hydride and the like. This reaction proceeds suitably at 0°C to 30°C.
  • a compound (I) where R 1 or R 2 is a hydroxy-lower alkyl group can be prepared by reacting a compound (I) where corresponding R 1 or R 2 is a hydrogen atom with formaldehyde or a lower alkyl aldehyde in the presence of a base.
  • a base there may be suitably used an alkali metal carbonate, an alkali metal lower alkoxide, triethylamine, and the like. This reaction proceeds suitably at 60°C to 120°C.
  • a compound (I) where R 1 or R 2 is a halogeno-lower alkyl group can be prepared by reacting a compound (I) where corresponding R 1 or R 2 is a hydroxy-lower alkyl group with a halogenating agent.
  • a halogenating agent there may be suitably used thionyl chloride, thionyl bromide and the like. This reaction proceeds suitably at 0°C to 50°C.
  • a compound (I) where R 1 or R 2 is a lower alkoxy-lower alkyl group can be prepared by reacting a compound (I) where corresponding R 1 or R 2 is a halogeno-lower alkyl group with a lower alkanol.
  • a compound (I) where corresponding R 1 or R 2 is a halogeno-lower alkyl group with a lower alkanol.
  • the lower alkanol there may be suitably used methanol, ethanol and the like. This reaction proceeds suitably at 30 °C to 80°C.
  • a compound (I) where R 1 or R 2 is a lower alkylthio-lower alkyl group can be prepared by reacting a compound (I) where corresponding R 1 or R 2 is a halogeno-lower alkyl group with a lower alkyl sulfide salt.
  • a lower alkyl sulfide salt there may be suitably used an alkali metal lower alkyl sulfide such as sodiummethyl sulfide and the like .
  • This reaction is preferably carried out in the presence of a base.
  • the base there may be suitably used triethylamine, pyridine, an alkali metal carbonate, an alkali metal alkoxide and the like . This reaction proceeds suitably at 0°C to 60°C.
  • a compound (I) where R 1 or R 2 is a lower alkylsulfinyl-lower alkyl group or a lower alkylsulfonyl-lower alkyl group can be prepared by reacting a compound (I) where corresponding R 1 or R 2 is a lower alkylthio-lower alkyl group with an oxidizing agent .
  • an oxidizing agent there may be suitably used metachloro- perbenzoic acid, aqueous hydrogen peroxide solution and the like. This reaction proceeds suitably at -20°C to 30°C.
  • a compound (I) where R 1 or R 2 is a carboxy-lower alkyl group or a carboxy-lower alkenyl group can be prepared by hydrolysis of a compound (I) where corresponding R 1 or R 2 is a lower alkoxycarbonyl-lower alkyl or a cyano-lower alkyl group or a lower alkoxycarbonyl-lower alkenyl or a cyano-lower alkeny group with a base or an acid.
  • a base an alkali metal hydroxide and the like may be suitably used.
  • As the acid hydrochloric acid or boron tribromide and the like may be suitably used. This reaction proceeds suitably at 0°C to 80°C.
  • a compound (I) where R 3 is a heterocyclic group substituted by a sulfo group can be prepared by reaction of a compound (I) where corresponding R 3 is a heterocyclic group (which may be substituted onto the other position of the heterocyclic ring than that to which the sulfo group is to be bonded) with halogenosulfonic acid (such as chlorosulfonic acid) , and then, treating with a basic aqueous solution (such as aqueous ammonia) .
  • halogenosulfonic acid such as chlorosulfonic acid
  • a basic aqueous solution such as aqueous ammonia
  • a compound (I) where R 3 is a heterocyclic group substituted by sulfamoyl group can be prepared by treating a compound (I) where corresponding R 3 is a heterocyclic group substituted by chlorosulfonyl group with ammonia. This reaction proceeds suitably at 0°C to 60°C.
  • a compound (I) where R 1 , R 2 or R 3 is a heterocyclic group substituted by a hydroxy-lower alkyl group or R 1 or R 2 is a hydroxy-lower alkyl group can be prepared by reacting a compound (I) where corresponding R 1 , R 2 or R 3 is a heterocyclic group substituted by a lower alkoxycarbonyl group or corresponding R 1 or R 2 is a lower alkoxycarbonyl-lower alkyl group with a reducing agent.
  • the reducing agent there may be suitably used lithium aluminum hydride, lithium borohydride, a borane complex (such as borane •dimethylsulfide complex) and the like. This reaction proceeds suitably at 0°C to 60°C.
  • a compound (I) where R 1 or R 2 is a substituted or unsubstituted carbamoyl group can be prepared by reaction of a compound (I) where corresponding R 1 or R 2 is a carboxyl group with a corresponding substituted or unsubstituted amine in the presence of a condensing agent.
  • a condensing agent there may be suitably used 3-ethyl-l- (3-dimethylaminopropyl) - carbodiimide hydrochloride, diethylcyanophosphate and the like. This reaction proceeds suitably at 0°C to 50°C.
  • a compound (I) where R 3 is a pyridyl group substituted with a mono- or di- lower alkylamino group or R 3 is a pyrazinyl group substituted with a mono- or di lower alkylamino group can be prepared by reacting a compound (I) where corresponding R 3 is a halogenopyridyl group or a halogenopyrazinyl group with a corresponding mono- or di- lower alkylamine. This reaction proceeds suitably at 30°C to 120°C.
  • Method (s) is
  • a compound (I) where R 3 is a pyrimidinyl group substituted with a mono- or di- lower alkylamino group can be prepared by reacting a compound (I) where corresponding R 3 is a pyrimidinyl group substituted with a lower alkylthio group with a oxidizing agent, followed by reacting the resulting compound with corresponding mono- or di- lower alkylamine.
  • a oxidizing agent may be m-chloroperbenzoic acid, hydrogen peroxide, and the like. This reaction proceeds suitably at 0°C to 30°C.
  • a compound (I) where R 1 or R 2 is a substituted or unsubstituted carbamoyl-lower alkyl group can be prepared by reacting a compound (I) where corresponding R 1 or R 2 is a carboxy-lower alkyl group with a corresponding amine in the presence of a condensing agent.
  • a condensing agent may be 3-ethyl-l- (3-dimethylaminopropyl) carbodiimide hydrochloride, diethyl cyanophosphonate, and the like. This reaction proceeds suitably at 0°C to 50°C.
  • a compound (I) where R 1 or R 2 is a cyano-lower alkyl group can be prepared by reacting a compound (I) where corresponding R 1 or R 2 is a carbamoyl-lower alkylamino group with a dehydrating agent.
  • a dehydrating agent may be phosphorus oxychloride, acetic anhydride, thionyl chloride and the like. This reaction proceeds suitably at 50°C to 100°C.
  • a compound (I) where R 1 or R 2 is a tetrazolyl-lower alkyl group can be prepared by reacting a compound (I) where corresponding
  • R 1 or R 2 is a cyano-lower alkyl group with an azide compound.
  • the azide compound may be sodium azide, a tri- alkyltin azide, a trialkylsilyl azide, and the like. This reaction proceeds suitably at 80°C to 120°C.
  • the reactions mentioned in the above Methods (a) to (v) can be carried out in an inert solvent to the reaction or in the absence of a solvent, which is not specifically limited, and the solvent may be mentioned, for example, methylene chloride, chloroform, tetrahydrofuran, methanol, ethanol, isopropanol, dimethylformamide, dimethylsulfoxide, water, ethyl acetate, dimethoxyethane, toluene, benzene, and the like, or a mixed solvent of the above solvents.
  • a solvent which is not specifically limited, and the solvent may be mentioned, for example, methylene chloride, chloroform, tetrahydrofuran, methanol, ethanol, isopropanol, dimethylformamide, dimethylsulfoxide, water, ethyl acetate, dimethoxyethane, toluene, benzene, and the like, or a mixed solvent of the above solvents.
  • the starting compound (II) or (III) of the present invention can be prepared, for example, according to the method described in J.Med. Chem., 29, 333-341 (1986), Chem. Pharm. Bull. , 34(8), 3111-3120 (1986) or Japanese Provisional Patent Publication No. 167676/1986.
  • the compound (II) can be prepared specifically by the conventional method as mentioned below.
  • a compound (V-a) wherein R 2 is a halogen atom can be prepared specifically by the conventional method as mentioned below.
  • the active ingredients of the present invention can be exemplified by the following Preparation examples but they are not limited thereto.
  • Preparation examples 103 and 104 The following compounds shown in Table 9 were prepared in a manner similar to Preparation example 102 by using corresponding starting materials.
  • Table 50a The following compounds listed in Table 50a were prepared in amanner similar to Example 608 or 632 , or similar to thatdescribed in Japanese Provisional Patent Publication No. 167685/1986. Table 50a
  • acetic acid (1.35 ml) was added to the mixture and the resulting mixture was stirred at 80 °C for 1.5 hours. After cooling, to the reaction mixture were added water and ethyl acetate, the organic layer was collected, washed successively with a 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure.
  • Urinary bladder was isolated from Male NZW rabbits (2.0-3.5kg) and immersed in ice-cold Krebs-bicarbonate solution (inmM: 118
  • the urinarybladder was cut into longitudinal strips (5mm length, 3-4mm width) after mucosal layer was removed. Preparations were mounted in organbaths containing 10ml of Krebs solution maintained at 37 °C and gassed with 95% 0 2 /5% C0 2 . Accordingly, preparations were stretchedwith an initial tension of 2.0+1.0g, and changes in isometric tension were measured by force-displacement transducer.
  • the preparations were pre-contracted by changing organ-bath solution into high-K + (30mM) Krebs solution (inmM: 92.7 NaCl, 30 KCl, 1.2, 2.5 CaCl 2 , MgS0, 1.2 KH 2 P0 4 , 11 glucose, 25 NaHC0 3 ) .
  • Sprague-Dawley female rats (9 to 12 weeks old) weighing between 200 to 300 g were used.
  • cannulae were placed in both right and left femoral veins .
  • One intravenous catheter was used foradministrationofcompounds, and the other was for the substance P (0.33 ⁇ g/kg/min) infusion.
  • Polyethylene catheters were inserted into carotid artery for continuous monitoring of arterial blood pressure and heart rate.
  • transurethral bladder catheter was inserted into the bladder through the urethra and tied in place by a ligature around the urethral orifice.
  • One end of the catheter was attachedto apressure transducer in order tomeasure intravesical pressure.
  • the other end of the catheter was used for infusion of saline into the bladder.
  • cystometry was performedby filling the bladder slowlywith about 0.6ml of saline.
  • intravenous infusion of substance P (0.33 ⁇ g/kg/min) was started for stabilization of the micturition reflex.
  • Compounds were administered after stable rhythmicbladder contractionwas obtainedover 15minutes . All compounds were dissolved or suspended in saline containing 0.5% Tween 80 for intravenous administration (0.1 ml/kg) . The rhythmic contraction frequency and the intravesical pressure were observed for 35 minutes after administration of the test compound.
  • the compounds of the present invention decreased the frequency of bladder rhythmic contraction without changing the amplitude of contraction. Also, we determined a time
  • a 100% inhibition time (minute) of the selected compounds of the present invention is shown in the following Table 65 with a rank of A, B or C. These ranges are as mentioned below. A>20>B>10>C (minute)
  • the urinary bladder strips were prepared according to the same manner as described in Experimental example 1. Briefly, the isolated urinary bladder was cut into longitudinal strips in ice-coldKrebs-bicarbonate solution, andmountedin organbaths . The initial tension was 2.0+/-1.0g. The preparations were contracted by high-K + (20mM or 60mM) Krebs solution.
  • Active ingredients of the present invention showed relaxation effect on 20mM K + -contracted preparation and the effect was blocked by iberiotoxin, a selective large conductance calcium-activated K channel blocker.
  • the active ingredients of the present invention have a detrusor relaxing activity through the large conductance calcium-activated K channel .
  • the compounds which are active ingredients of the present invention were effective for prophylaxis and treatment of diseases such as pollakiuria, urinary incontinence and the like through the large conductance calcium-activated K channel opening activity.
  • the nitrogen-containing 5-membered heterocyclic compound (I) or a pharmaceutically acceptable salt which is an active ingredient of the present invention has an excellent large conductance calcium-activated K channel opening activity and hyperpolarizes a membrane electric potential of cells, so that it is useful for a prophylactic, relief and/or treatment agent of, for example, hypertension, asthma, premature birth, irritable bowel syndrome, chronicheart failure, angina, cardiac infarction, cerebral infarction, subarachnoid hemorrhage, cerebral vasospasm, cerebral hypoxia, peripheral blood vessel disorder, anxiety, male-pattern baldness, erectile dysfunction, diabetes, diabetic peripheral nerve disorder, other diabetic complication, sterility, urolithiasis and pain accompanied thereby, pollakiuria, urinary incontinence, nocturnal enuresis, and the like.
  • the nitrogen-containing 5-membered heterocyclic compound (I) or a pharmaceutically acceptable salt has a low toxicity, so that it has high safety as a medicine.

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Abstract

A large conductance calcium-activated K channel opener comprising as an active ingredient a nitrogen-containing 5-membered heterocyclic compound represented by the following formula (I): wherein X represents N-R4, O or S, R1 and R 2 each independently represent hydrogen, halogen carboxyl, amino, lower alkyl, lower alkoxycarbonyl, lower alkenyl, cyclo-lower alkyl, carbamoyl, aryl, heterocyclic or heterocyclic-substituted carbonyl group, R3 represents aryl, heterocyclic or lower alkyl group, and R4 represents hydrogen or lower alkyl group, or a pharmaceutically acceptable salt thereof and its use for the preparation of a medicament for the phophylaxis and/or treatment of pollakiuria or urinary incontinence.

Description

DESCRIPTION
LARGE CONDUCTANCE CALCIUM-ACTIVATED K CHANNEL OPENER
FIELD OF THE INVENTION
This invention relates to an excellent large conductance calcium-activated K channel opener containing a nitrogen- containing 5-membered heterocyclic compound as an active ingredient, which is useful for treatment of disorders or diseases such as polla iuria, urinary incontinence, cerebral infarction, subarachnoid hemorrhage, and the like.
BACKGROUND OF THE INVENTION
Potassium is the most abundant intracelluar cation, and is very important in maintaining physiological homeostasis. Potassium channels are present in almost all vertebrate cells, and the potassium influx through these channels is indispensable for maintaining hyperpolarized resting membrane potential.
Large conductance calcium activated potassium channels (also BK channels or maxi-K channels) are expressed especially in neurons and smooth muscle cells. Because both of the increase of intracellular calcium concentration and membrane depolarization can activate maxi-K channels, maxi-K channels have been thought to play a pivotal role in regulating voltage-dependent calcium influx. Increase in the intracellular calcium concentration mediates many processes such as release of neurotransmitters, contraction of smooth muscles, cell growth and death, and the like. Actually, the opening of maxi-K channels causes strong membrane hyperpolarization, and inhibits these calcium-induced responses thereby. Accordingly, by inhibiting various depolarization-mediated physiological responses, a substance having an activity of opening maxi-K channels is expected to have potential for the treatment of diseases such as cerebral infarction, subarachnoid hemorrhage, pollakiuria, urinary incontinence, and the like.
There have been various reports on a large conductance calcium-activated potassium channel opener, and examples of such channel opener are as follows; a pyrrole derivative disclosed in International Publication WO96/40634, a furan derivative disclosed in Japanese Provisional Patent Publication No. 2000-351773, and a nitrogen-containing 5-membered derivative in which the nitrogen atom is substituted by phenyl group or benzyl group disclosed in International Publication WO98/04135.
Also, a compound having a similar structure to the nitrogen- containing 5-membered heterocyclic compound which is an active ingredient of the present invention has been disclosed. For example, oxazole derivatives have been reported in Japanese Provisional Patent Publications No. 36614/1984, No. 152382/ 1984 and No. 172488/1984, but their uses are limited only to antihypolipidemic agent . Also, in Japanese Provisional Patent Publications No.150591/1983, No.34951/1985 and No.54369/1988, imidazole derivatives have been reported but their uses are limited only to a cardiotonic, an antithrombosis, an antipyretic analgesic or an anti-inflammation agent.
SUMMARY OF THE INVENTION
An object of the present invention is to provide an excellent large conductance calcium-activated K channel opener containing a nitrogen-containing 5-membered heterocyclic compound as an active ingredient.
The present inventors have studied intensively to solve the problems, and as a result, they have found that a certain kind of a nitrogen-containing 5-membered heterocyclic compound has an excellent large conductance calcium-activated K channel opening activity, whereby they have accomplished the present invention.
That is, the present invention relates to a large conductance calcium-activated K channel opener comprising a nitrogen-containing 5-membered heterocyclic compound represented by the following formula (I) :
Figure imgf000004_0001
wherein X represents N-R4, 0 or S, R1 and R2 are different from each other and each independently represents hydrogen atom, a halogen atom, carboxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted lower alkyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted lower alkenyl group, a cyclo-lower alkyl group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted heterocyclic group-substituted carbonyl group, R3 represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted lower alkyl group, and R4 represents hydrogen atom or a substituted or unsubstituted lower alkyl group, or a pharmaceutically acceptable salt thereof as an active ingredient. BEST MODE FOR CARRYING OUT THE INVENTION
In the nitrogen-containing 5-membered heterocyclic compound (I) which is an active ingredient of the present invention, the aryl group is a monocyclic, dicyclic or tricyclic 6- to
14-membered aromatic hydrocarbon cyclic group , and specific examples of the aryl group may include a phenyl group, a naphthyl group and the like . Of these, a phenyl group or a naphthyl group is preferred.
The heterocyclic group or the heterocyclic group portion of the heterocyclic group-substituted carbonyl group is a monocyclic, dicyclic or tricyclic 6- to 14-membered aromatic hydrocarbon cyclic group, containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, which may be partially or wholly saturated.
As the monocyclic heterocyclic group, a 5- to 7-membered heterocyclic group, containing 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which may be partially or wholly saturated is preferred, and specific examples of the monocyclic heterocyclic group may include furyl group, thienyl group, thiazolyl group, thiazolidinyl group, isoxazolyl group, pyrrolidinyl group, pyrrolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, tetrazolyl group, and the like.
As the dicyclic heterocyclic group, a dicyclic heterocyclic group in which two of the above-mentioned monocyclic heterocyclic groups are fused or a dicyclic heterocyclic group in which the above monocyclic heterocyclic group and a benzene ring are fused is preferred, and specific examples of the dicyclic heterocyclic group may include indolyl group, quinolyl group, tetrahydroquinolyl group, isoquinolyl group, quinoxalyl group, benzofuryl group, dihydrobenzofuryl group, benzothienyl group, benzodioxanyl group, trihydrocyclo- pentathienyl group, benzothianyl group, benzothiazolyl group, imidazopyridyl group, indolyl group, indolinyl group, chromanyl group, thiophenopyridyl group, furanopyridyl group, and the like.
As the tricyclic heterocyclic group, a tricyclic heterocyclic group in which the above-mentioned monocyclic heterocyclic group and the above-mentioned dicyclic heterocyclic group are fused or a tricyclic heterocyclic group in which the above- mentioned monocyclic heterocyclic group and two benzene rings are fused is preferred, and specific examples of the tricyclic heterocyclic group may include carbazolyl group, carbolinyl group and the like.
Of these heterocyclic groups, more specifically preferred are furyl group, thienyl group, thiazolyl group, isoxazolyl group, pyrrolidinyl group, pyrrolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, tetrazolyl group, indolyl group, quinolyl group, isoquinolyl group, benzofuryl group, benzothienyl group, dihydrobenzofuryl group, thiophenopyridyl group and benzodioxanyl group.
As a substituent for the amino group of R1 or R2, there may be mentioned, for example, a group selected from formyl group, a lower alkyl group, a lower alkanoyl group, a lower alkylsulfonyl group and a lower alkoxycarbonyl group.
As a substituent for the lower alkyl group, there may be mentioned, for example, a group selected from a halogen atom, hydroxyl group, cyano group, carboxyl group, carbamoyl group, amino group, aminosulfonyl group, a halogenosulfonyl group, amidinothio group, a mono- or di-lower alkylamino group, a lower alkanoylamino group, a lower alkylsulfonylamino group, hydroxyamino group, a mono- or di-lower alkylcarbamoyl group, trifluoromethyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a lower alkoxycarbamoyl group, a lower alkylsulfonylcarbamoyl group, sulfamoyl group, a mono- or di-lower alkylsulfamoyl group, a lower alkoxycarbonyl group, a heterocyclic group, a heterocyclic group-substituted carbamoyl group, a heterocyclic group-substituted lower alkylcarbamoyl group and a heterocyclic group-substituted sulfonylcarbamoyl group.
As a substituent for the lower alkenyl group, there may be mentioned, for example, carboxyl group or a lower alkoxycarbonyl group.
As a substituent for the carbamoyl group, there may be mentioned, for example, a group selected from a lower alkyl group, a lower alkoxy group and a lower alkylsulfonyl group.
As a substituent for the aryl group, there may be mentioned, for example, a group selected from nitro group, amino group, hydroxyl group, carbamoyl group, cyano group, carboxyl group, trifluoromethyl group, a lower alkoxycarbonyl group, a halogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkoxy-lower alkoxy group, a mono- or di-lower alkylamino group, a mono- or di-lower alkanoylamino group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, sulfamoyl group, a mono- or di-lower alkylsulfamoyl group, a lower alkylGulfonylamino group .and a phenyl-lower alkoxy group.
As a substituent for the heterocyclic group, there may be mentioned, for example, a group selected from nitro group, amino group, hydroxyl group, formyl group, carbamoyl group, cyano group, carboxyl group, a lower alkoxycarbonyl group, a halogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a mono- or di-lower alkylamino group, a mono- or di-lower alkanoylamino group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, sulfamoyl group and a mono- or di-lower alkylsulfamoyl group.
As a substituent on the heterocyclic group for the heterocyclic group-substituted carbonyl group, there may be mentioned, for example, a group selected from nitro group, hydroxyl group, carbamoyl group, cyano group, carboxyl group, a lower alkoxycarbonyl group, a halogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a mono- or di-lower alkylamino group, a mono- or di-lower alkanoylamino group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, sulfamoyl group and a mono- or di-lower alkylsulfamoyl group.
The above-mentioned amino group, lower alkyl group, carbamoyl group, aryl group, heterocyclic group and heterocyclic group-substituted carbonyl group may be substituted by the same or different 1 to 3 above-mentioned substituents.
As a substituent for the aryl group of R3, there maybe mentioned, for example, a group selected from cyano group, nitro group, amino group, a halogen atom, trifluoromethyl group, carboxyl group, hydroxyl group, carbamoyl group, a mono- or di-lower alkylamino group, a mono- or di-lower alkylamino-lower alkyl group, a mono- or di-lower alkylcarbamoyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkanoyloxy-lower alkyl group, sulfo group, a lower alkylthio group, a lower alkylthio-lower alkyl group, a lower alkylsulfonyl group, a lower alkylsulfamoyl group and a lower alkylsulfinyl group.
As a substituent for the heterocyclic group, there may be mentioned, for example, a group selected from oxo group, cyano group, nitro group, amino group, a halogen atom, carboxyl group, hydroxyl group, formyl group, carbamoyl group, a mono- or di-lower alkylamino group, a N-lower alkyl-N-cyclo-lower alkylamino group, a mono- or di-lower alkylamino-lower alkyl group, a mono- or di-lower alkylcarbamoyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkoxy-lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, sulfo group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfamoyl group, a lower alkylsulfinyl group and a heterocyclic group.
As a substituent for the alkyl group, there may be mentioned, for example, a group selected from hydroxyl group, cyano group, carboxyl group, carbamoyl group, amino group, a mono- or di-lower alkylamino group, a lower alkanoylamino group, a lower alkylsulfonylamino group, hydroxyamino group, a mono- or di-lower alkylcarbamoyl group, trifluoromethyl group, a halogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, sulfamoyl group, a mono- or di-lower alkylsulfamoyl group, a lower alkoxycarbonyl group and a heterocyclic group.
The above-mentioned aryl group, heterocyclic group and lower alkyl group may be substituted by the same or different above-mentioned 1 to 3 substituents .
As a substituent for the lower alkyl group of R4, there may be mentioned a mono- or di-lower alkylamino group . The lower alkyl group may be substituted by the same or different above-mentioned 1 to 2 substituents.
Of the compounds (I) which are active ingredients of the present invention, preferred compounds may be compounds wherein X is N-R4, 0 or S; R1 or R2 is independently hydrogen atom, a lower alkyl group, a lower alkyl group substituted by a heterocyclic group, a di-lower alkylamino group, a carboxy-lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylsulfinyl-lower alkyl group, a lower alkylsulfonyl-lower alkyl group, a lower alkylthio-lower alkyl group, a trifluoromethyl-lower alkyl group, a cyclo-lower alkyl group, an aryl group, a trifluoromethylaryl group, a cyanoaryl group, a halogenoaryl group, a dihalogenoaryl group, a lower alkylaryl group, a lower alkoxyaryl group, a mono- or di-lower alkylaminoaryl group, a heterocyclic group, a lower alkyl- heterocyclic group, a haogeno-heterocyclic group, or a heterocyclic group substituted by a halogen atom and a lower alkyl group; R3 is an aryl group, a halogenoaryl group, a hydroxyaryl group, a cyanoaryl group, a nitroaryl group, a lower alkylaryl group, a lower alkoxyaryl group, a lower alkylthio- aryl group, a heterocyclic group, a lower alkoxycarbonyl- heterocyclic group, a cyano- heterocyclic group, a halogeno- heterocyclic group, a lower alkyl-heterocyclic group, a di-lower alkyl-heterocyclic group, a heterocyclic group substituted by a di-lower alkylamino group, a heterocyclic group substituted by a halogen atom and a lower alkyl group, or a heterocyclic group substituted by a halogen atom and a hydroxy-lower alkyl group; and R4 is hydrogen atom.
In another preferred embodiment of the present invention, X is N-R4, 0 or S; R1 or R2 is independently hydrogen atom, a lower alkyl group, a lower alkyl group substituted by a heterocyclic group, a lower alkylamino group, a di-lower alkylamino group, a cyano-lower alkyl group, a hydroxy-lower alkyl group, a carboxy-lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylsulfinyl-lower alkyl group, a lower alkylthio-lower alkyl group, a cyclo-lower alkyl group, an aryl group, a trifluoromethylaryl group, a hydroxyaryl group, a halogenoaryl group, a dihalogenoaryl group, a lower alkylaryl group, a di-lower alkoxyaryl group, a di-lower alkylaminoaryl group, a lower alkylsulfonylaminoaryl group, an aryl group substituted by hydroxyl group and a lower alkoxy group, an aryl group substituted by hydroxyl group and a halogen atom, an aryl group substituted by a halogen atom and a lower alkoxy group, an aryl group substituted by a halogen atom and a lower alkoxy group, an aryl group substituted by a halogen atom and a di-lower alkoxy group, a heterocyclic group, a halogeno-heterocyclic group, a lower alkyl-heterocyclic group, a hydroxy-lower alkyl-heterocyclic group, a heterocyclic group substituted by a halogen atom and a lower alkyl group, a heterocyclic group substituted by a lower alkyl group and a hydroxy-lower alkyl group, or a heterocyclic group-substituted carbonyl group; R is a halogenoaryl group, a hydroxyaryl group, a cyanoaryl group, a lower alkylaryl group, a lower alkoxyaryl group, a lower alkylthioaryl group, an aryl group substituted by a hydroxyl group and a lower alkoxy group, a heterocyclic group, a cyano-heterocyclic group, a halogeno-heterocyclic group, a lower alkyl-heterocyclic group, a di-lower alkyl- heterocyclic group, a hydroxy-lower alkyl-heterocyclic group, a di-lower aralkyla ino-heterocyclic group, a heterocyclic group substituted by a halogen atom and a sulfo group, a heterocyclic group substituted by a halogen atom and a sulfamoyl group, or a heterocyclic group substituted by a halogen atom and a lower alkyl group; and R4 is hydrogen atom or a lower alkyl group .
Of these, particularly preferred compounds are compounds wherein X is 0 or S; R1 or R2 is independently a carboxy-lower alkyl group, a lower alkyl group substituted by a heterocyclic group, an aryl group, a halogenoaryl group, a di-halogenoaryl group, a di-lower alkoxyaryl group, a lower alkylthioaryl group, a heterocyclic group, a halogeno-heterocyclic group, or a lower alkyl-heterocyclic group; and R3 is a halogenoaryl group, a lower alkylaryl group, a di-lower alkylaminoaryl group, a lower alkylthioaryl group, a lower alkoxyaryl group, a heterocyclic group, a halogeno-heterocyclic group, a lower alkyl-heterocyclic group, a lower alkoxy-heterocyclic group, a lower alkylthio-heterocyclic group, or a di-lower alkylamino- heterocyclic group.
Among the nitrogen-containing 5-membered heterocyclic compounds (I), more preferred compounds in view of pharmaceutical effects are compounds wherein R1 is (1) a lower alkyl group which may be substituted by carboxyl group, a lower alkoxycarbonyl group or a heterocyclic group, (2) an aryl group which may be substituted by one or two halogen atoms, or (3) a heterocyclic group which may be substituted by a halogen atom, R2 is (1) a lower alkyl group which may be substituted by carboxyl group, a lower alkoxycarbonyl group or a heterocyclic group, (2) a heterocyclic group which may be substituted by a halogen atom, or (3) an aryl group which may be substituted by one or two halogen atoms; R3 is (1) a heterocyclic group which may be substituted by one or two groups selected from amino group, a halogen atom, a lower alkyl group, a lower alkoxy group, a mono- or di-lower alkylamino group and a lower alkylthio group, or
(2) an aryl group which may be substituted by amino group, a halogen atom, a lower alkyl group, a lower alkylthio group, a lower alkoxy group or a mono- or di-lower alkylamino group; and R4 is hydrogen atom or a lower alkyl group.
Of these, more preferred compounds are compounds wherein R1 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxycarbonyl-lower alkyl group, (3) a lower alkyl group substituted by a tetrazolyl group, (4) a phenyl group which may be substituted by one or two halogen atoms, or (5) a thienyl group which may be substituted by a halogen atom; R2 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxycarbonyl-lower alkyl group, (3) a lower alkyl group substituted by a tetrazolyl group, (4) a thienyl group which may be substituted by a halogen atom, or (5) a phenyl group which may be substituted by one or two halogen atoms; and R3 is (1) a benzothienyl group which may be substituted by a halogen atom, (2) a phenyl group which may be substituted by a halogen atom, a lower alkylthio group, a lower alkoxy group or a di-lower alkylamino group, (3) a pyridyl group which may be substituted by a lower alkyl group, a lower alkoxy group or a di-lower alkylamino group, (4) a pyrimidinyl group which may be substituted by a di-lower alkylamino group or a lower alkylthio group, (5) a thienyl group which may be substituted by one or two lower alkyl groups, (6) thieno- [3, 2-b]pyridyl group, (7) benzofuryl group, (8) dihydrobenzofuryl group or (9) an indolyl group which may be substituted by a lower alkyl group.
Of these, particularly preferred compounds are compounds wherein X is 0 or S; R1 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxycarbonyl-lower alkyl group, (3) a phenyl group which may be substituted by one or two halogen atoms, or (4) a thienyl group which may be substituted by a halogen atom; R2 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxycarbonyl-lower alkyl group, (3) a thienyl group which may be substituted by a halogen atom, or (4) a phenyl group which may be substituted by one or two halogen atoms; and R3 is (1) a benzothienyl group which may be substituted by a halogen atom,
(2) a phenyl group which may be substituted by a halogen atom, a lower alkylthio group, a lower alkoxy group or a di-lower alkylamino group, (3) a pyridyl group which may be substituted by a lower alkoxy group or a di-lower alkylamino group, (4) a pyrimidinyl group which may be substituted by a di-lower alkylamino group, (5) a thienyl group which may be substituted by a di-lower alkyl group, (6) thieno [3, 2-b] pyridyl group, or (7) an indolyl group which may be substituted by a lower alkyl group .
The most preferred compound in view of pharmaceutical effects is the compound selected from the group consisting of: 4- (5-chlorothiophen-2-yl) -2- (2-benzo [b] thienyl) thiazol-5-yl acetic acid, 5- (4-chlorophenyl) -2- (2-N, N-dimethylaminopyrimidin-5-yl) - oxazol-4-yl acetic acid,
4- (5-chlorothiophen-2-yl) -2- (4-methoxyphenyl) thiazol-5-yl acetic acid, 5- (5-chlorothiophen-2-yl) -2- (4, 5-dimethylthiophen-2-yl) - oxazol-4-yl acetic acid,
4- (5-chlorothiophen-2-yl) -2- (2-N,N-dimethylaminopyrimidin- 5-yl) thiazol-5-yl acetic acid,
4- (5-chlorothiophen-2-yl) -2- (2-N,N-dimethylaminopyridin-
5-yl) thiazol-5-yl acetic acid,
5- (4-chlorophenyl) -2- (4-fluorophenyl) oxazol-4-yl acetic acid,
5- (4-chlorophenyl) -2- (2-benzo [b] thienyl) oxazol-4-yl acetic acid,
4- (5-chlorothiophen-2-yl) -2- (2-benzo [b] thienyl) oxazol-5-yl acetic acid, 5- (5-chlorothiophen-2-yl) -2- (2-N,N-dimethylaminopyrimidin-
5-yl) oxazol-4-yl acetic acid,
4- (4-chlorophenyl) -2- (2-N,N-dimethylaminopyrimidin-5-yl) - thiazol-5-yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (2-benzo [b] thienyl) oxazol-4-yl acetic acid,
4- (4-chlorophenyl) -2- (4-methoxyphenyl) thiazol-5-yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) oxazol-4-yl acetic acid, 5- (5-chlorothiophen-2-yl) -2- ( 6-fluorobenzo [b] thiophene-2- yl) oxazol-4-yl acetic acid,
5- (3-thienyl) -2- (2-benzo [b] thienyl) oxazol-4-yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (2-thieno [3, 2-b] pyridyl) - oxazol-4-yl acetic acid, 5- (3-fluoro-4-chlorophenyl) -2- (2-benzo [b] thienyl) oxazol-4- yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (2-benzo [b] thienyl) thiazol-4-yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (4-methylthiophenyl) oxazol-4-yl acetic acid,
4- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) oxazol-5-yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (4-chlorophenyl) oxazol-4-yl acetic acid, 4- (3-fluoro-4-chlorophenyl) -2- (4-methoxyphenyl) thiazol-5-yl acetic acid, 4- (5-chlorothiophen-2-yl) -2- (4, 5-dimethylthiophen-2-yl) - thiazol-5-yl acetic acid,
4- (3-fluoro-4-chlorophenyl) -2- (4-fluorophenyl) thiazol-5-yl acetic acid, 4- (4-chlorophenyl) -2- (2-N,N-dimethylaminopyridin-5-yl) - thiazol-5-yl acetic acid,
4- (5-chlorothiophen-2-yl) -2- (4-N,N-dimethylaminophenyl) - thiazol-5-yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (N-methylindol-2-yl) oxazol-4-yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (4, 5-dimethylthiophen-2-yl) - thiazol-4-yl acetic acid; a lower alkyl ester of these compounds; and a pharmaceutically acceptable salt of these compounds.
In still another preferred embodiment of the present invention,
X is 0, one of R1 and R2 is a thienyl group substituted by a chlorine atom, and the other is a carboxyl-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group or a lower alkyl group substituted by a tetrazolyl group; and R3 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group.
Of these, more preferred compounds are compounds wherein R3 is (1) an aryl group which may be substituted by one or two substituents selected from a halogen atom, a di-lower alkylamino group, a lower alkylthio group and a lower alkoxy group, or (2) a heterocyclic group which may be substituted by one or two substituents selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group and a mono- or di-lower alkylamino group.
Of these, particularly preferred compounds are compounds wherein one of R1 and R2 is a thienyl group substituted by a chlorine atom, and the other is a carboxyl-lower alkyl group or a lower alkoxycarbonyl-lower alkyl group; the aryl group is phenyl group; and the heterocyclic group is a thienyl group, a pyridyl group, a pyrimidinyl group, a benzothienyl group, a benzofuryl group, a dihydrobenzofuryl group, an indolyl group or a thieno [3, 2-b] pyridyl group.
Of these, further preferred compounds are compounds wherein R3 is a phenyl group which is substituted by a halogen atom or a lower alkylthio group; a thienyl group which is substituted by one or two lower alkyl groups; a pyrimidinyl group which is substituted by a di-lower alkylamino group; a benzothienyl group which may be substituted by a halogen atom; an indolyl group which may be substituted by a lower alkyl group; or a thieno [3, 2-b] pyridyl group..
In still another preferred embodiment of the present invention, X is S, one of R1 and R2 is a thienyl group substituted by a chlorine atom, and the other is a carboxyl-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group or a lower alkyl group substituted by a tetrazolyl group, and R3 is a substituted or unsubstituted heterocyclic group, where said heterocyclic group is selected from a pyridyl group, a pyrimidinyl group, a benzothienyl group, an indolyl group and a thieno [3, 2-b] - pyridyl group.
In a more preferred embodiment, R3 is a heterocyclic group which may be substituted by one or two substituents selected from a halogen atom, a lower alkoxy group, a mono- or di- lower alkyl group, a lower alkylthio group and a mono- or di-lower alkylamino group, where said heterocyclic group is selected from a pyridyl group, a pyrimidinyl group, a benzothienyl group, and a thieno [3, 2-b] pyridyl group.
In a further preferred embodiment, one of R1 and R2 is a thienyl group substituted by a chlorine atom, and the other is a carboxyl-lower alkyl group or a lower alkoxycarbonyl-lower alkyl group; R3 is a pyridyl group which may be substituted by a di-lower alkylamino group; a pyrimidinyl group which may be substituted by a mono- or di-lower alkylamino group; or a benzothienyl group which may be substituted by a halogen atom.
In the compound (I), an optical isomer based on an asymmetric carbon may be present depending on a kind of a substituent (s) . Either of the optical isomer or a mixture thereof may be used as the active ingredient of the present invention.
The active ingredient (I) of the present invention can be used in the free form or in the form of a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts of the compound (I) include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, and organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate or maleate. In addition, in case of a compound with substituents such as a carboxyl group, salts with a base (for example, alkali metal salts such as a sodium salt and a potassium salt or alkaline earth metal salts such as a calcium salt) can be mentioned.
The compound (I) or pharmaceutically acceptable salts thereof includes its internal salts, addition products, solvates and hydrates .
The active ingredient (I) of the present invention or pharmaceutically acceptable salts thereof can be administered orally or parenterally and used as common pharmaceutical preparations such as tablets, granules, capsules, powders, injection solution and inhalants. As a pharmaceutically acceptable carrier for a preparation of oral administration, there may be mentioned a material commonly used, for example, a binder (such as syrup, Gum Arabic, gelatin, sorbit, tragacanth and polyvinyl pyrrolidone) , an excipient (such as lactose, sugar, corn starch, potassium phosphate, sorbit and glycine) , a lubricant (such as magnesium stearate, talc, polyethylene glycol and silica) , a disintegrator (such as potato starch) and a humectant (such as lauryl sodium sulfate) .
On the other hand, when the active ingredient of the present invention is administered non-orally, it may be formulated into the form of an injection or a drip infusion by using distilled water for injection, physiological saline, an aqueous glucose solution and the like, or a suppository.
A dose of the compound (I) or a pharmaceutically acceptable salt thereof may vary depending on an administration method, an age, weight, conditions or a kind or degree of disease of a patient, and generally about 0.1 to 50 mg/kg per day, more preferably about 0.3 to 30 mg/kg per day.
The compound (I) or a pharmaceutically acceptable salt thereof has an excellent large conductance calcium-activated K channel opening activity and hyperpolarizes a membrane electric potential of cells, so that it may be used for a prophylactic, relief and/or treatment agent of, for example, hypertension, asthma, premature birth, irritable bowel syndrome, chronic heart failure, angina, cardiac infarction, cerebral infarction, subarachnoid hemorrhage, cerebral vasospasm, cerebral hypoxia, peripheral blood vessel disorder, anxiety, male-pattern baldness, erectile dysfunction, diabetes, diabetic peripheral nerve disorder, other diabetic complication, sterility, urolithiasis and pain accompanied thereby, pollakiuria, urinary incontinence, nocturnal enuresis, and the like. In the present specification, as the lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkoxysulfonyl group, a lower alkylsulfamoyl group, a lower alkylcarbamoyl group, a lower alkylamino group, or a lower alkylsulfonylamino group, there may be mentioned those which are straight or branched and having 1 to 6 carbon atoms, particularly those which are straight or branched and having
1 to 4 carbon atoms .
As a lower alkenyl group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkanoylamino group or a lower alkoxycarbonyl group, there may be mentioned those which are a straight or branched and having 2 to 7 carbon atoms, particularly those which are a straight or branched and having
2 to 5 carbon atoms .
As a cyclo-lower alkyl group, there may be mentioned those having 3 to 6 carbon atoms .
As a halogen atom, there may be mentioned fluorine atom, chlorine atom, bromine atom or iodine atom.
The nitrogen-containing 5-membered heterocyclic compound (I) which is an active ingredient of the present invention can be prepared by the following Method A, Method B, Method C or Method D, but the preparation methods are not limited to these methods .
(Method A) Condensation cyclization agent
Figure imgf000020_0001
Figure imgf000020_0002
( II )
( I-a ) wherein X1 represents NH, O or S, and other symbols have the same meanings as defined above.
Among the nitrogen-containing 5-membered heterocyclic compound (I) , a compound (I-a) can be prepared by reacting the compound represented by the formula (II) or a salt thereof with a condensation reagent.
As the condensation reagent, there may be suitably used, when X1 is NH, for example, ammonia or an ammonium salt (such as ammonium acetate, ammonium formate, ammonium carbonate, ammonium benzoate and ammonium picolate) , when X1 is 0, for example, phosphorus oxychloride, thionyl chloride, acetyl chloride, triphenylphosphine-iodine, triphenylphosphine- phosgene, sulfuric acid, polyphosphoric acid, p-toluene- sulfonic acid, etc., and when X1 is S, for example, phosphorus pentasulfide, Lawesson' s reagent (2, 4-bis (4-methoxyphenyl) - 1, 3-dithia-2, 4-diphosphetan-2, 4-disulfide) , and the like.
The present reaction can be carried out in a suitable solvent or in the absence of a solvent. As the solvent, it is not particularly limited so long as it does not disturbdisturb the reaction, and there may be used, for example, acetic acid, dimethylformamide, benzene, toluene, tetrahydrofuran, chloroform, methylene chloride, acetonitrile or a mixed solvent of the above-mentioned solvents. The present reaction proceeds suitably at 15 to 150 °C, particularly at room temperature to 120 °C,
(Method B)
Figure imgf000021_0001
(I-b) wherein Z1 represents a reactive residue, and other symbols have the same meanings as defined above.
Also, among the compound (I), a compound (I-b)can be prepared by reacting a compound represented by the formula (III) or a salt thereof with a compound represented by the formula (IV) or a salt thereof in the presence of a base. As the base, there may be suitably used, for example, an alkali metal carbonate, an alkali metal hydride, an alkali metal alkoxide, an alkali metal hydroxide, and the like.
The present reaction can be carried out in a suitable solvent or in the absence of a solvent. As the solvent, it is not particularly limited so long as it does not disturb the reaction, and there may be used, for example, acetonitrile, methanol, ethanol, chloroform, methylene chloride, dimethylformamide, acetone, tetrahydrofuran or a mixed solvent of the above- mentioned solvents. The present reaction proceeds suitably at 30 to 150°C, particularly at 60 to 120°C.
(Method C)
Figure imgf000022_0001
(V) (I) wherein Z2 represents a reactive residue, W1 represents hydrogen atom or a lower alkyl group, W2 represents a lower alkyl group, and other symbols have the same meanings as defined above.
The compound (I) can be also prepared by reacting a compound represented by the formula (V) with a compound represented by the formula (VI) or a compound represented by the formula (VII) in the presence of a palladium catalyst. As the palladium catalyst, there may be suitably used a zero-valent or divalent palladium catalyst, for example, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, etc.
When Method C is carried out by using the compound (VI) , it is preferably carried out in the presence of a base. As the base, there may be suitably used, for example, an inorganic base such as an alkali metal carbonate, an alkali metal hydroxide, an alkali metal phosphate, an alkali metal fluoride, and the like, or an organic base such as triethylamine, and the like.
The present reaction can be carried out in a suitable solvent or in the absence of a solvent. As the solvent, it is not particularly limited so long as it does not disturb the reaction, and there may be used, for example, dimethoxyethane, tetra- hydrofuran, dimethylformamide, methanol, ethanol, toluene, benzene, chloroform or a mixed solvent of the above-mentioned solvents . The present reaction proceeds suitably at 60 to 150°C, particularly at 80 to 120°C.
Figure imgf000023_0001
(I-b ) wherein the symbols have the same meanings as defined above .
Also, among the compound (I), a compound (I-b) can be prepared by reacting a compound represented by the formula (VIII) or a salt thereof with a compound represented by the formula (IX) and a salt thereof in the presence of ammonia or an ammonium salt.
As the ammonium salt, there may be suitably used, for example, ammonium acetate, ammonium formate, ammonium carbonate, ammonium benzoate, ammonium picolate, and the like.
The present reaction can be carried out in a suitable solvent or in the absence of a solvent. As the solvent, it is not particularly limited so long as it does not disturb the reaction, and there may be used, for example, acetic acid, methanol, ethanol, dimethoxyethane, tetrahydrofuran, dimethylformamide or a mixed solvent of the above-mentioned solvents . The present reaction proceeds suitably at 0 to 150°C, particularly at 30 to 120°C.
In the above-mentioned Methods A to D, the compounds (II), (III), (IV) , (V) , (VIII) or (IX) may be used as a salt of an inorganic acid such as hydrochloride, sulfate, etc., or a salt of an inorganic base such as an alkali metal salt, an alkaline earth metal salt, etc.
As the reactive residue of Z1 and Z2, a halogen atom is suitably used.
The nitrogen-containing 5-membered heterocyclic compound (I) can be prepared by converting ob ective compounds obtained from one of the above methods into other objective compounds. Such conversion reactions may be suitably used depending on a substituent (s) in a compound, and it can be carried out, for example, by a conventional method as mentioned in the following Methods (a) to (v) .
Method (a) :
A compound (I) wherein R1 or R2 is a halogen atom can be prepared by reacting a compound (I) where corresponding R1 or R2 is a hydrogen atom with a halogenating agent. As the halogenating agent, there may be suitably used bromine, chlorine, iodine, [bis (trifluoroacetoxy) iodo] benzene, N-bromosuccinic imide and the like. This reaction proceeds suitably at 0°C to 30°C.
Method (b) :
A compound (I) wherein R1 or R2 is a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group can be prepared by reaction of a compound (I) where corresponding R1 or R2 is a halogen atom with a (tri-lower alkyl) (a substituted or unsubstituted aryl) tin compound, or (tri-lower alkyl) (a substituted or unsubstituted heterocyclic) tin compound in the presence of a catalyst. As the catalyst, there may be suitably used a zero-valent or divalent palladium catalyst such as bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), etc. Also this reaction proceeds more suitably in the presence of a zinc salt such as zinc chloride, zinc bromide, zinc iodide, etc. This reaction proceeds suitably at 50°C to 120°C.
Also, this reaction may be carried out by using a corresponding boric acid or its ester in place of the tin compound, in the presence of a base. As the palladium catalyst and the base, those as mentioned in the above Method C are suitably used. This reaction proceeds suitably at 60°C to 120°C.
Method (c) :
A compound (I) wherein R1 or R2 is a substituted or unsubstituted heterocyclic group-substituted carbonyl group can be prepared by reacting a compound (I) where corresponding R1 or R2 is a substituted carbamoyl group with a substituted or unsubstituted heterocyclyl lithium. This reaction proceeds suitably at -78 °C to 30 °C. The substituted or unsubstituted heterocyclyl lithium can be prepared by lithiation of a corresponding halogeno-heterocyclic compound with n-butyl lithium, etc.
Method (d) :
A compound (I) where X is N-R4 and R4 is a substituted or unsubstituted alkyl group can be prepared by reaction of a compound (I) where corresponding X is N-R4 and R4 is hydrogen atom with a substituted or unsubstituted lower alkyl halide (such as a lower alkyl iodide, a lower alkyl chloride and a lower alkyl bromide) or a lower alkyl sulfonate (such as a lower alkyl trifluoromethanesulfonate and a lower alkyl methanesulfonate) in the presence of a base. As the base, there may be suitably used an alkali metal hydride, an alkali metal carbonate, an alkali metal alkoxide, an alkali metal hydroxide, and the like. This reaction proceeds suitably at 30°C to 80°C.
Method (e) A compound (I) where R1 or R2 is a formylamino group or an N-lower alkyl-N-formylamino group can be prepared by reacting a compound (I) where corresponding R1 or R2 is an amino group or an N-lower alkylamino group with a formic acid lower alkyl ester (such as methyl ester and ethyl ester) . This reaction proceeds suitably at 60°C to 100°C.
Method (f) :
A compound (I) where R1 or R2 is an N-methylamino group, an N-lower alkyl-N-methylamino group or an N-ethylamino group can be prepared by reacting a compound (I) where corresponding R1 or R2 is a formylamino group, an N-lower alkyl-N-formylamino group or an N-acetylamino group with a reducing agent. As the reducing agent, there may be suitably used a borane complex (such as borane • dimethylsulfide complex), lithium aluminum hydride, and the like. This reaction proceeds suitably at 0°C to 60°C.
Method (g) :
A compound (I) where R1 or R2 is a lower alkoxycarbonylamino group can be prepared by reacting a compound (I) where corresponding R1 or R2 is an amino group with a lower alkoxycarbonyl halide in the presence of a base. As the base, there may be suitably used pyridine, triethylamine, an alkali metal carbonate, an alkali metal lower alkoxide, an alkali metal hydride and the like. This reaction proceeds suitably at 0°C to 30°C.
Method (h) :
A compound (I) where R1 or R2 is a hydroxy-lower alkyl group can be prepared by reacting a compound (I) where corresponding R1 or R2 is a hydrogen atom with formaldehyde or a lower alkyl aldehyde in the presence of a base. As the base, there may be suitably used an alkali metal carbonate, an alkali metal lower alkoxide, triethylamine, and the like. This reaction proceeds suitably at 60°C to 120°C.
Method (i)
A compound (I) where R1 or R2 is a halogeno-lower alkyl group can be prepared by reacting a compound (I) where corresponding R1 or R2 is a hydroxy-lower alkyl group with a halogenating agent. As the halogenating agent, there may be suitably used thionyl chloride, thionyl bromide and the like. This reaction proceeds suitably at 0°C to 50°C.
Method (j) :
A compound (I) where R1 or R2 is a lower alkoxy-lower alkyl group can be prepared by reacting a compound (I) where corresponding R1 or R2 is a halogeno-lower alkyl group with a lower alkanol. As the lower alkanol, there may be suitably used methanol, ethanol and the like. This reaction proceeds suitably at 30 °C to 80°C.
Method (k) :
A compound (I) where R1 or R2 is a lower alkylthio-lower alkyl group can be prepared by reacting a compound (I) where corresponding R1 or R2 is a halogeno-lower alkyl group with a lower alkyl sulfide salt. As the lower alkyl sulfide salt, there may be suitably used an alkali metal lower alkyl sulfide such as sodiummethyl sulfide and the like . This reaction is preferably carried out in the presence of a base. As the base, there may be suitably used triethylamine, pyridine, an alkali metal carbonate, an alkali metal alkoxide and the like . This reaction proceeds suitably at 0°C to 60°C.
Method (1) : A compound (I) where R1 or R2 is a lower alkylsulfinyl-lower alkyl group or a lower alkylsulfonyl-lower alkyl group can be prepared by reacting a compound (I) where corresponding R1 or R2 is a lower alkylthio-lower alkyl group with an oxidizing agent . As the oxidizing agent, there may be suitably used metachloro- perbenzoic acid, aqueous hydrogen peroxide solution and the like. This reaction proceeds suitably at -20°C to 30°C.
Method (m) :
A compound (I) where R1 or R2 is a carboxy-lower alkyl group or a carboxy-lower alkenyl group can be prepared by hydrolysis of a compound (I) where corresponding R1 or R2 is a lower alkoxycarbonyl-lower alkyl or a cyano-lower alkyl group or a lower alkoxycarbonyl-lower alkenyl or a cyano-lower alkeny group with a base or an acid. As the base, an alkali metal hydroxide and the like may be suitably used. As the acid, hydrochloric acid or boron tribromide and the like may be suitably used. This reaction proceeds suitably at 0°C to 80°C.
Method (n)
A compound (I) where R3 is a heterocyclic group substituted by a sulfo group can be prepared by reaction of a compound (I) where corresponding R3 is a heterocyclic group (which may be substituted onto the other position of the heterocyclic ring than that to which the sulfo group is to be bonded) with halogenosulfonic acid (such as chlorosulfonic acid) , and then, treating with a basic aqueous solution (such as aqueous ammonia) . This reaction proceeds suitably at 0°C to 50°C.
Method (o) :
A compound (I) where R3 is a heterocyclic group substituted by sulfamoyl group can be prepared by treating a compound (I) where corresponding R3 is a heterocyclic group substituted by chlorosulfonyl group with ammonia. This reaction proceeds suitably at 0°C to 60°C.
Method (p) :
A compound (I) where R1, R2 or R3 is a heterocyclic group substituted by a hydroxy-lower alkyl group or R1 or R2 is a hydroxy-lower alkyl group can be prepared by reacting a compound (I) where corresponding R1, R2 or R3 is a heterocyclic group substituted by a lower alkoxycarbonyl group or corresponding R1 or R2 is a lower alkoxycarbonyl-lower alkyl group with a reducing agent. As the reducing agent, there may be suitably used lithium aluminum hydride, lithium borohydride, a borane complex (such as borane •dimethylsulfide complex) and the like. This reaction proceeds suitably at 0°C to 60°C.
Method (q) :
A compound (I) where R1 or R2 is a substituted or unsubstituted carbamoyl group can be prepared by reaction of a compound (I) where corresponding R1 or R2 is a carboxyl group with a corresponding substituted or unsubstituted amine in the presence of a condensing agent. As the condensing agent, there may be suitably used 3-ethyl-l- (3-dimethylaminopropyl) - carbodiimide hydrochloride, diethylcyanophosphate and the like. This reaction proceeds suitably at 0°C to 50°C.
Method (r) :
A compound (I) where R3 is a pyridyl group substituted with a mono- or di- lower alkylamino group or R3 is a pyrazinyl group substituted with a mono- or di lower alkylamino group can be prepared by reacting a compound (I) where corresponding R3 is a halogenopyridyl group or a halogenopyrazinyl group with a corresponding mono- or di- lower alkylamine. This reaction proceeds suitably at 30°C to 120°C. Method (s) :
A compound (I) where R3 is a pyrimidinyl group substituted with a mono- or di- lower alkylamino group can be prepared by reacting a compound (I) where corresponding R3 is a pyrimidinyl group substituted with a lower alkylthio group with a oxidizing agent, followed by reacting the resulting compound with corresponding mono- or di- lower alkylamine. Examples of the oxidizing agent may be m-chloroperbenzoic acid, hydrogen peroxide, and the like. This reaction proceeds suitably at 0°C to 30°C.
Method (t) :
A compound (I) where R1 or R2 is a substituted or unsubstituted carbamoyl-lower alkyl group can be prepared by reacting a compound (I) where corresponding R1 or R2 is a carboxy-lower alkyl group with a corresponding amine in the presence of a condensing agent. Examples of the condensing agent may be 3-ethyl-l- (3-dimethylaminopropyl) carbodiimide hydrochloride, diethyl cyanophosphonate, and the like. This reaction proceeds suitably at 0°C to 50°C.
Method (u) :
A compound (I) where R1 or R2 is a cyano-lower alkyl group can be prepared by reacting a compound (I) where corresponding R1 or R2 is a carbamoyl-lower alkylamino group with a dehydrating agent. Examples of the dehydrating agent may be phosphorus oxychloride, acetic anhydride, thionyl chloride and the like. This reaction proceeds suitably at 50°C to 100°C.
Method (v) :
A compound (I) where R1 or R2 is a tetrazolyl-lower alkyl group can be prepared by reacting a compound (I) where corresponding
R1 or R2 is a cyano-lower alkyl group with an azide compound. Examples of the azide compound may be sodium azide, a tri- alkyltin azide, a trialkylsilyl azide, and the like. This reaction proceeds suitably at 80°C to 120°C.
The reactions mentioned in the above Methods (a) to (v) can be carried out in an inert solvent to the reaction or in the absence of a solvent, which is not specifically limited, and the solvent may be mentioned, for example, methylene chloride, chloroform, tetrahydrofuran, methanol, ethanol, isopropanol, dimethylformamide, dimethylsulfoxide, water, ethyl acetate, dimethoxyethane, toluene, benzene, and the like, or a mixed solvent of the above solvents.
Also, among the compounds (I) , known compounds are included and these known compounds have been reported in, for example,
Japanese Provisional Patent Publications No. 5832/1972, No. 29771/1973, 172488/1984, 34951/1985, No. 188371/1985 and No. 167676/1986, U.S. Patents No. 3,470,195, No. 3,476,766, No. 3,546,342, No. 3,574,228 and No. 3,905,961, International Publications No. WO95/04724 and No. WO99/01128, Chem. Pharm. Bull., 34(8), 3111-3120 (1986), Chem. Pharm.Bull . , 36(11), 4435-4440 (1988), Chem. Pharm.Bull . , 40(12), 3206-3213 (1992), Angew. Chem., 85(13), 584-585 (1973), J.Heterocyclic Chem., 22(2), 569-574 (1985), J.Med. Chem., 29(3), 333-341 (1986), J.Med.Chem., 31(6), 1197-1204 (1988) and the like. However, there is no description in these references that these compounds have large conductance calcium-activated K channel opening activity.
Incidentally, the starting compound (II) or (III) of the present invention can be prepared, for example, according to the method described in J.Med. Chem., 29, 333-341 (1986), Chem. Pharm. Bull. , 34(8), 3111-3120 (1986) or Japanese Provisional Patent Publication No. 167676/1986.
The compound (II) can be prepared specifically by the conventional method as mentioned below.
Figure imgf000032_0001
(II) wherein the symbols have the same meanings as defined above .
Also, among the compounds (V) , a compound (V-a) wherein R2 is a halogen atom can be prepared specifically by the conventional method as mentioned below.
Condensation-
Formylation cyclization agent
Figure imgf000032_0002
Figure imgf000032_0003
Figure imgf000032_0004
(V-a) wherein Z3 represents a halogen atom, and the other symbols have the same meaning as defined above.
The active ingredients of the present invention can be exemplified by the following Preparation examples but they are not limited thereto.
Preparation example
Preparation example 1
A crude product of 2- (6-methylnicotinoylamino) -1- (3-pyridyl) - 1-butanone (425 mg) was dissolved in acetic acid (5 ml) , and ammoniumacetate (2.30g) was added to the solution. The resulting mixture was stirred under reflux for one hour. After cooling, 28% of aqueous ammonia was added to the reaction mixture and the mixture was extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. To the residue was added hydrogen chloride-methanol solution, and the solvent was again removedunder reducedpressure . The resulting residue was triturated with acetone to obtain 5-ethyl-2- (2-methyl- pyridin-5-yl) -4- (3-pyridyl) imidazole trihydrochloride (369 mg) as pale yellowish crystalline powder. Melting point: 270 to 273°C (decomposed) MS-APCI (m/z): 265 (MH+)
Preparation examples 2 to 42
The following compounds shown in Table 1 were prepared in a manner similar to Preparation example 1 by using corresponding starting materials . Table 1
Figure imgf000034_0001
Table 1 (contd.)
Figure imgf000035_0001
Table 1 (contd,
Figure imgf000036_0001
Table 1 (contd.
Figure imgf000037_0001
Table 1 (contd.)
Figure imgf000038_0001
Table 1 (contd.)
Figure imgf000039_0001
Table 1 (contd.)
Figure imgf000040_0001
Table 1 (contd.)
Figure imgf000041_0001
Table 1 (contd.)
Figure imgf000042_0001
Table 1 (contd.
Figure imgf000043_0001
Table 1 (contd.)
Figure imgf000044_0001
Preparation example 43
4-Cyano-2- (4-fluorobenzoylamino) -1- (3-pyridyl) -1-butanone (500 mg) was dissolved in acetic acid (3 ml) , and ammonium acetate (2.99 g) was added to the solution and the resulting mixture was refluxed overnight. After cooling, 28% of aqueous ammonia was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silicagel flush column chromatography (solvent: hexane : ethyl acetate=l :2) and treated with hydrogen chloride-ethanol to obtain 5- (2-cyanoethyl) -2- (4-fluorophenyl) -4- (3-pyridyl) - imidazole dihydrochloride (172 mg) as colorless powder. MS-APCI (m/z): 293 (MH+)
Preparation examples 44 to 62
The following compounds shown in Table 2 were prepared in a manner similarto Preparationexample 43 byusingcorresponding starting materials . Table 2
Figure imgf000045_0001
Table 2 (contd.)
Figure imgf000046_0001
Table 2 (contd.)
Figure imgf000047_0001
Table 2 (contd.
Figure imgf000048_0001
Table 2 (contd.)
Figure imgf000049_0001
Preparation example 63
Under ice-cooling, phosphorus oxychloride (0.24 ml) was added dropwise to a solution of 2- (5-chlorothiophen-2-yl) amino-1- (3-pyridyl) -1-butanone (610mg) inN,N-dimethylformamide (7ml), and the resulting mixture was stirred at room temperature overnight and further at 60°C overnight. After cooling, the reaction mixture was poured into ice water, neutralized by a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate . The organic layer was washed with water andbrine, and then, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromato- graphy (solvent: chloroform : ethyl acetate=2 : 1) and treated with hydrogen chloride-ethanol solution to obtain 2- (5- chlorothiophen-2-yl) -4-ethyl-5- (3-pyridyl) oxazole hydrochloride (466 mg) as pale yellowish powder. Melting point: 201 to 204°C MS-APCI (m/z): 291/293 (MH+)
Preparation examples 64 and 65
The following compounds shown in Table 3 were prepared in a manner similar to Preparationexample 63 byusingcorresponding starting materials .
Table 3
Figure imgf000051_0001
Preparation example 66
A mixture of 2-bromo-2' -methoxy-acetophenone (514 mg) , 4-fluorobenzamidine hydrochloride (392 mg) and potassium carbonate (930 mg) in acetonitrile (5 ml) was refluxed for 2 hours. After cooling, to the reaction mixture were added chloroform and water, the organic layer was collected and driedover anhydrous sodiumsulfate, and the solventwas removed under reduced pressure . The resulting residue was recrystal- lized from methanol to obtain 2- (4-fluorophenyl) -4- (2- met oxyphenyl) imidazole (1.54 g) as pale yellowish crystal. This compound was treated with hydrogen chloride-ethanol solution to be converted into a hydrochloride salt form. Melting point: 165 to 167 °C (free material) Melting point: 245 to 248 °C (hydrochloride) MS-APCI (m/z): 269 (MH+) (hydrochloride)
Preparation example 67
Amixture of 5-ethyl-2-iodo-4- (3-pyridyl) - imidazole (150mg) , 3-hydroxymethylthiophene-2-boric acid (105 mg) and tetrakis (triphenylphosphine) palladium (0) (58 mg) in an aqueous 2M sodiumcarbonate solution (1ml) anddimethoxyethane (3 ml) was stirred under argon atmosphere at 100°C for 2.5 hours . After cooling, to the reactionmixture were addedwater and ethyl acetate . The organic layer was collected, and after washing with brine, it was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by NH silica gel flush column chromatography (solvent: ethyl acetate) and treated with hydrogen chloride-dioxane solution to obtain 5-ethyl-2- (3-hydroxymethylthiphen-2-yl) -4- (3-pyridyl) imidazole dihydrochloride (110 mg) as colorless powder. MS-APCI (m/z): 286 (MH+)
Preparation examples 68
The following compounds shown in Table 4 were prepared in a manner similar to Preparation example 67 byusing corresponding starting materials.
Table 4
Figure imgf000053_0001
Preparation example 69
A mixture of ethyl 2, 3-diketovalerate (8.00 g) , 4-fluoro- benzaldehyde (11.30 g) and ammonium acetate (35.00 g) in acetic acid (120 ml) was stirred under argon atmosphere at 70 to 80 °C for 40 minutes. After cooling, water was added to the reaction mixture and the reaction mixture was extracted with a mixed solution of ethyl acetate-diethyl ether. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solutionandbrine, driedover anhydrous sodiumsulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: hexane : ethyl acetate=3:l) and recrystallized from ethyl acetate-diethyl ether to obtain ethyl 5-ethyl-2- (4-fluorophenyl) imidazol-4-carboxylate (5.16 g) as colorless crystal. Melting point: 197 to 198°C MS-APCI (m/z): 263 (MH+)
Preparation example 70
A mixture of ethyl 5-ethyl-2- (4-fluorophenyl) imidazol-4- carboxylate (2.81 g) , 4N aqueous sodium hydroxide solution (14 ml) , ethanol (35 ml) and tetrahydrofuran (15 ml) was stirred at roomtemperature overnight, followedby refluxing for 3 hours . 4N aqueous sodium hydroxide solution (28 ml) was added to the mixture and the mixture was refluxed overnight. After cooling, the reaction mixture was concentrated under reduced pressure and neutralizedby 10% hydrochloric acid, and precipitated solid was collected by filtration. The solid was dissolved in tetrahydrofuran, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with diethyl ether to obtain first crop of 5-ethyl-2- (4-fluorophenyl) imidazol-4-carboxylic acid (1.06 g) as colorless powder. Moreover, the filtrate was purifiedbyHP-20 resin (trade name, available fromNipponRensui K.K.) (solvent: water -^ methanol) to give second crop of 5-ethyl-2- (4-fluorophenyl) imidazol-4-carboxylic acid (1.60 g).
ESI -MS (m/z) : 233 (M-H)
Preparation example 71
A mixture of 5-ethyl-2- (4-fluorophenyl) imidazol-4-carboxylic acid (600mg) , N, O-dimethylhydroxylamine hydrochloride (325 mg) , 3-ethyl-l- (3-dimethylaminopropyl) carbodiimide hydrochloride (540 mg) , 1-hydroxybenzotriazole (381 mg) and triethylamine (0.54 ml) in N,N-dimethylformamide (9 ml) was stirred at room temperature overnight . Water was added to the reactionmixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: hexane : ethyl acetate=2:l) to obtain 5-ethyl-2- (4-fluorophenyl) -4- (N- methoxy-N-methylcarbamoyl) imidazole (656 mg) as colorless powder. MS-APCI (m/z): 278 (MH+) Preparation example 72
To a solution of 2-bromopyridine (855 mg) in tetrahydrofuran (16 ml) was added dropwise 1.6M n-butyl lithium (3.38 ml, hexane solution) under argon gas atmosphere at -78 °C, and after stirring the mixture at the same temperature for 30 minutes, a solution of 5-ethyl-2- (4-fluorophenyl) -4- (N-methoxy-N-methylcarba- moyl) imidazole (300 mg) in tetrahydrofuran (4 ml) was added dropwise to the mixture . After the reaction mixture was stirred under ice-acetone cooling for 30 minutes, a saturated aqueous ammonium chloride solution was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was triturated with diethyl ether-hexane to obtain 5-ethyl-2- (4-fluorophenyl) -imidazol-4-yl- (2- pyridyl) ketone (324 mg) . 132 mg of the product was treated with hydrogen chloride-dioxane solution to obtain the dihydrochloride salt (73 mg) as colorless solid. MS-APCI (m/z): 296 (MH+)
Preparation example 73
The following compounds shown in Table 5 were prepared in amanner similar to Preparationexample 72 byusingcorresponding starting materials .
Table 5
Figure imgf000056_0001
Preparation example 74
In acetonitrile (80ml) were dissolved2, 2-dichlorobutanal (16.2 g) and 4-fluorobenzaldehyde (14.9 g). To the solution was added dropwise 28% aqueous ammonia (135 ml) under ice-cooling, and the resultingmixture was stirred at room temperature for 4 days . Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was crystallized from methanol-diethyl ether to obtain 4-ethyl- 2-(4- fluorophenyl) imidazole (9.36 g) . MS-APCI (m/z): 191 (MH+)
Preparation examples 75 and 76
The following compounds shown in Table 6 were prepared in a manner similar to Preparation example 74 byusingcorresponding starting materials . Table 6
Figure imgf000057_0001
Preparation example 77
To a suspension of 4-ethyl-2- (4-fluorophenyl) imidazole (4.90 g)in chloroform (100 ml) was added bromine (4.53 g) , and the mixture was stirred at room temperature for 3 hours . To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was collected . The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was crystallized from chloroform to obtain 5-bromo-4-ethyl-2- (4-fluorophenyl) - imidazole (5.16 g) as colorless crystal. 53 mg of the product was treated with 4N hydrogen chloride-dioxane solution to obtain 5-bromo-4-ethyl-2- (4-fluorophenyl) imidazole (60 mg) as colorless crystal. Melting point: 192 to 193 °C (Free material) MS-APCI (m/z) : 269/271 (MH+) (Free material)
Melting point: 219 to 221°C (decomposed) (Hydrochloride)
MS-APCI (m/z) : 269/271 (MH+) (Hydrochloride)
Preparation examples 78 and 79
The following compounds shown in Table 7 were prepared in a manner similarto Preparationexample 77 byusing corresponding starting materials .
Table 7
Figure imgf000058_0001
Preparation example 80
Amixture of 5-bromo-4-ethyl-2- (4-fluorophenyl) imidazole (100 mg) , tributyl (3-pyridyl) tin (206 mg) , zinc chloride (53 mg) and bis (triphenylphosphine) palladium (II) dichloride (26 mg) in N,N-dimethylformamide (3ml) was refluxedunder argonatmosphere for 5 hours. After cooling, a 10% aqueous potassium fluoride solution was added to the reaction mixture and the mixture was extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane : ethyl acetate=l : 4) , and recrystallized from ethyl acetate- hexane and treated with hydrogen chloride-methanol solution to obtain 5-ethyl-2- (4-fluorophenyl) -4- (3-pyridyl) imidazole dihydrochloride (48 mg) as colorless powder. MS-APCI (m/z): 268 (MH+)
Preparation examples 81 to 101
The following compounds shown in Table 8 were prepared in a manner similar to Preparationexample 80 byusingcorresponding starting materials .
Table 8
Figure imgf000060_0001
Table 8 (contd.)
Figure imgf000061_0001
Table 8 (contd.)
Figure imgf000062_0001
Table 8 (contd.)
Figure imgf000063_0001
Table 8 (contd.
Figure imgf000064_0001
Table 8 (contd . )
Figure imgf000065_0001
Preparation example 102
To a solution of 5-ethyl-2- (4-fluorophenyl) -4- (3-pyridyl) - imidazole (481 mg) in N,N-dimethylformamide (7 ml) was added sodiumhydride (79 mg, 60% mineral oil) under ice-acetone cooling, and the mixture was stirred for 15 minutes. To the mixture was added methyl iodide (307 mg) and the mixture was stirred at room temperature for one hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: chloroform : methanol=95 : 5) , and treated with hydrogen chloride-methanol solution to obtain 5-ethyl-2- (4-fluoro- phenyl) -l-methyl-4- (3-pyridyl) imidazole dihydrochloride (285 mg) . MS-APCI (m/z): 282 (MH+)
Preparation examples 103 and 104 The following compounds shown in Table 9 were prepared in a manner similar to Preparation example 102 by using corresponding starting materials.
Table 9
Figure imgf000066_0001
Preparation example 105
A mixture of 5-amino-2- (4-fluorophenyl) -4-phenylimidazole (1.00 g) and ethyl formate (10 ml) was refluxed for 15 hours. After cooling, the reaction mixture was concentrated under reduced pressure and crystallized from diethyl ether to obtain 5-formylamino-2- (4-fluorophenyl) -4-phenylimidazole (1.17 g) as colorless crystal.
Melting point: 245 to 247°C MS-APCI (m/z): 282 (MH+) Preparation example 106
A mixture of 5-methylamino-2- (4-fluorophenyl) -4-phenylimidazole (560mg) in ethyl formate (20ml) was refluxedovernight . After cooling, the reaction mixture was concentrated under reduced pressure and crystallized from diethyl ether-hexane to obtain 5-formylmethylamino-2- (4-fluorophenyl) -4-phenylimidazole (480 mg) as colorless crystal. Melting point: 256 to 258°C MS-APCI (m/z): 296 (MH+)
Preparation example 107
To a solution of 5-formylamino-2- (4-fluorophenyl) -4-phenylimidazole (1.06 g) in tetrahydrofuran (15 ml) was added dropwise 10M borane -dimethylsulfide complex (1.90 ml), and the mixture was stirred under argon atmosphere at roomtemperature for 2.5 hours . To the reaction mixture was slowly added 10% hydrochloric acid, and the mixture was refluxed for one hour. After cooling, the mixture was neutralized by adding a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: hexane : ethyl acetate=5:l) to obtain 5-methylamino-2- (4-fluorophenyl) -4- phenylimidazole (702 mg) as colorless powder. 88 mg of the product was treated with hydrogen chloride-methanol solution to obtain the hydrochloride salt (84 mg) as colorless powder. Melting point: 253 to 255°C MS-APCI (m/z): 268 (MH+)
Preparation example 108
To a solution of 5-formylmethylamino-2- (4-fluorophenyl) - 4-phenylimidazole (200 mg)in tetrahydrofuran (5 ml) was added dropwise 10M borane -dimethylsulfide complex (0.34 ml), and the mixture was stirred under argon atmosphere at room temperature for overnight. To the reaction mixture was slowly added 10% hydrochloric acid, and the mixture was refluxed for one hour. After cooling, the mixture was neutralized by adding a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: hexane : ethyl acetate=5 : 1) , and then, treated with hydrogen chloride-methanol solution to obtain 5-dimethylamino-2- (4- fluorophenyl) -4-phenylimidazole hydrochloride (174 mg) as colorless powder.
MS-APCI (m/z): 282 (MH+)
Preparation example 109
To a solution of 5-amino-2- (4-fluorophenyl) -4-phenylimidazole
(63 mg) and pyridine (40 mg) in methylene chloride (5 ml) was added methyl chlorocarbonate (28 mg) under ice-cooling and the mixture was stirred at room temperature overnight. To the reaction mixture was added diethyl ether, and the solvent was removed under reduced pressure. The resulting residue was triturated with diethyl ether and the powder was collected by filtration. The powder was treated with hydrogen chloride- methanol solution to obtain 5-methoxycarbonylamino-2- (4- fluorophenyl) -4-phenylimidazole hydrochloride (67 mg) as colorless powder.
MS-APCI (m/z): 312 (MH+)
Preparation example 110
To a solution of 5-acetylamino-2- (4-fluorophenyl) -4-phenylimidazole (142 mg) in tetrahydrofuran (7 ml) was added 10M borane -tetrahydrofuran complex (12 ml, tetrahydrofuran solution) , and the mixture was stirred under argon atmosphere at room temperature for 2 days. To the reaction mixture was slowly added 10% hydrochloric acid, and the mixture was stirred at 60°C for 10 minutes. After cooling, the mixture was neutralized by adding a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: hexane : ethyl acetate=l :2) , and then, treatedwith hydrogen chloride-methanol solution to obtain 5-ethylamino-2- (4-fluorophenyl) -4-phenylimidazole hydrochloride (89 mg) as colorless powder. MS-APCI (m/z): 282 (MH+)
Preparation example 111
A mixture of 5-ethylamino-2- (4-fluorophenyl) -4-phenyl- imidazole (145 mg) in ethyl formate (8 ml) was refluxed for 8 hours. After cooling, the mixture was concentrated under reduced pressure, and crystallized from diethyl ether to obtain 5-formylethylamino-2- (4-fluorophenyl) -4-phenylimidazole (136 mg) as colorless crystal. Melting point: 201 to 202°C MS-APCI (m/z): 310 (MH+)
Preparation example 112
Amixtureof 2- (5-chlorothiophen-2-yl) -4- (3-pyridyl) imidazole (1.07 g) , 35% formalin aqueous solution (35 ml), potassium carbonate (1.70 g) , isopropanol (30 ml) and N,N-dimethyl- formamide (10 ml) was stirred at 90°C for 2 hours . After cooling, water was added to the mixture and precipitated solid was collected by filtration. The solid was dissolved in methanol and, after removing insolubles by filtration, the solvent was removed under reduced pressure. The resulting residue was triturated with ethyl acetate to obtain 2- (5-chlorothio-o phen-2-yl) -5-hydroxymethyl-4- (3-pyridyl) imidazole (519 mg) as colorless powder. MS-APCI (m/z): 292/294 (MH+)
Preparation examples 113 and 118
The following compounds shown in Table 10 were prepared in a manner similar to Preparation example 112 by using corresponding starting materials.
Table 10
Figure imgf000070_0001
Table 10 (contd.)
Figure imgf000071_0001
Table 10 (contd.)
Figure imgf000072_0001
Preparation example 119
To a solution of 2- (5-chlorothiophen-2-yl) -5-hydroxy- methyl-4- (3-pyridyl) imidazole (200 mg) inmethylene chloride (5 ml) was addedthionyl chloride (5ml) , andthemixture was refluxed for one hour. After cooling, the reaction mixture was concentrated under reduced pressure to obtain a crude product of 2- (5-chlorothiophen-2-yl) -5-chloromethyl-4- (3-pyridyl) - imidazole dihydrochloride (260 mg) as yellowish powder.
Preparation example 120
In methanol (10 ml) was dissolved a crude product of 2- (5-chlorothiophen-2-yl) -5-chloromethyl-4- (3-pyridyl) - imidazole dihydrochloride (260 mg) and the mixture was refluxed for 2 hours . After cooling, a saturated aqueous sodiumhydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with a mixed solution of ethyl acetate- tetrahydrofuran. The organic layer was washedwithbrine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform : methanol=40 : 1) , and then, treated with hydrogen chloride- dioxane solution to obtain 2- (5-chlorothiophen-2-yl) - 5-methoxymethyl-4- (3-pyridyl) imidazole dihydrochloride (63 mg) as pale yellowish powder. Melting point: 245 to 248 °C (decomposed) MS-APCI (m/z): 306/308 (MH+)
Preparation examples 121 to 128
The following compounds shown in Table 11 were prepared in a manner similar to Preparation example 112 or 120 by using corresponding starting materials.
Table 11
Figure imgf000074_0001
Table 11 (contd.)
Figure imgf000075_0001
Preparation example 129
To a solution of 2- (3-fluorophenyl) -5-hydroxymethyl-4- (3-pyridyl) imidazole (389mg) in methylene chloride (10ml) was added thionyl chloride (10 ml), and the mixture was refluxed for one hour. After cooling, the reaction mixture was concentrated under reduced pressure to obtain a crude product of 2- (3-fluorophenyl) -5-chloromethyl-4- (3-pyridyl) imidazole dihydrochloride (508 mg) as colorless powder.
Preparation example 130
To a suspension of a crude product of 2- (3-fluorophenyl) - 5-chloromethyl-4- (3-pyridyl) imidazole dihydrochloride (268 mg) in tetrahydrofuran (10 ml) were added 15% aqueous sodium methyl sulfide solution (0.95 ml) and triethylamine (206 mg) , and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform : methanol=19 : 1) to obtain 2- (3- fluorophenyl) -5-methylthiomethyl-4- (3-pyridyl) imidazole (198 mg) as colorless powder. MS-APCI (m/z): 300 (MH+)
Preparation examples 131 to 134
The following compounds shown in Table 12 were prepared in a manner similar to Preparation example 130 by using corresponding starting materials. Table 12
Figure imgf000077_0001
Preparation example 135
To a solution of 2- (3-fluorophenyl) -5-methylthiomethyl- 4- (3-pyridyl) imidazole (152 mg) in tetrahydrofuran (10 ml) was added metachloroperbenzoic acid (97 mg, 70% purity) under ice-cooling, and the mixture was stirred at room temperature for 5 hours . To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate . The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform : methanol= 19:1), and then, treated with hydrogen chloride-dioxane solution to obtain 2- (3-fluorophenyl) -5- methylsulfinylmethyl-4- (3-pyridyl) imidazole (140 mg) as colorless powder. MS-APCI (m/z) : 316 (MH+)
Preparation examples 136 to 140
The following compounds shown in Table 13 were prepared in a manner similar to Preparation example 135 byusing corresponding starting materials.
Table 13
Figure imgf000079_0001
Table 13 (contd.)
Figure imgf000080_0001
Preparation example 141
A mixture of ethyl 2- (5-chlorothioρhen-2-yl) -5- (3-pyridyl) - oxazole-4-yl acetate (68 mg), lithium hydroxide (9mg), ethanol (4 ml) and water (4 ml) was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, acidified to pH 4 with 10% hydrochloric acid, and precipitated solid was collected by filtration. This solid was treated with hydrogen chloride-dioxane solution to obtain 2- (5-chlorothiophen-2-yl) -5- (3-pyridyl) oxazole-4-yl acetic acid hydrochloride (50 mg) as pale yellowish powder. Melting point: 234 to 238 °C (decomposed) MS-APCI (m/z): 321/323 (MH+)
Preparation example 142
The following compounds shown in Table 14 were prepared in a manner similar to Preparation example 141 by using corresponding starting materials. Table 14
Figure imgf000081_0001
Preparation examples 143 and 144
Amixture of 2- (5-chlorothiophen-3-yl) -5-ethyl-4- (3-pyridyl) - imidazole (2.00 g) in chlorosulfonic acid (15 ml) was stirred at room temperature for one week. The mixture was slowly added dropwise to 28% aqueous ammonia (500 ml) , and the resulting mixture was stirred for 30 minutes and then concentrated under reduced pressure. The resulting residue was dissolved in methanol-tetrahydrofuran (5:1), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure . The residue was purified by silica gel flush column chromatography (solvent: chloroform : methanol=10 : 1 -> 2.5:1), and then, by NH silica gel flush column chromatography (solvent: chloroform : methanol=10 :1 -i 4:1) to obtain 2- (5-chloro-2-sulfothio- phen-3-yl) -5-ethyl-4- (3-pyridyl) imidazole and 2-(5-chloro- 2-sulfamoylthiophen-3-yl) -5-ethyl-4- (3-pyridyl) imidazole . Eachproduct was treatedwithhydrogen chloride-dioxane solution to obtain 2- (5-chloro-2-sulfothiophen-3-yl) -5-ethyl-4- (3- pyridyl) imidazole dihydrochloride (741 mg) and 2-(5-chloro- 2-sulfamoylthiophen-3-yl) -5-ethyl-4- (3-pyridyl) imidazole dihydrochloride (105 mg) each as colorless powder.
2- (5-Chloro-2-sulfothiophen-3-yl) -5-ethyl-4- (3-pyridyl) - imidazole dihydrochloride (Preparation example 143) ESI -MS (m/z) : 368 (M-H)
2- (5-Chloro-2-sulfamoylthiophen-3-yl) -5-ethyl-4- (3-pyridyl) imidazole dihydrochloride (Preparation example 144) MS-APCI (m/z): 369 (MH+)
Preparation example 145
To a solution of 2- (2-ethoxycarbonylthiophen-3-yl) -5- ethyl-4- (3-pyridyl) imidazole (879 mg) in tetrahydrofuran (20 ml) was added lithiumaluminumhydride (204mg) under ice-cooling, and the mixture was stirred under argon atmosphere at the same temperature for 1.5 hours. Under ice-cooling, an aqueous potassium sodiumtartarate solution and ethyl acetate were added to the mixture and the organic layer was collected. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform : methanol=19: 1) , and then, treated with hydrogen chloride-ethanol solution to obtain 2- (2-hydroxymethylthiophen-3-yl) -5-ethyl-4- (3- pyridyl) imidazole dihydrochloride (788 mg) as colorless powder . MS-APCI (m/z) : 286 (MH+)
Preparation example 146
To a solution of ethyl 2- (5-chlorothiophen-2-yl) -4- (3- pyridyl) imidazol-5-yl acetate (122 mg) in tetrahydrofuran (3.5 ml) was added lithiumaluminumhydride (15mg) under ice-cooling, and the mixture was stirred under ice-cooling for 2.5 hours. Under ice-cooling, anaqueous sodiumhydroxide solutionandethyl acetate were added to the mixture, and the organic layer was collected . The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (TLC) (silica gel; solvent: chloroform : methanol=20 : 1) to obtain 2-(5-chloro- thiophen-2-yl) -5-hydroxyethyl-4- (3-pyridyl) imidazole (109 mg) as colorless crystalline powder. 27 mg of the product was treated with hydrogen chloride-dioxane solution to obtain the dihydrochloride salt (26 mg) as colorless powder. Melting point: 179 to 180 °C (free material) MS-APCI (m/z): 306 (MH+) (hydrochloride)
Preparation example 147
A mixture of ethyl 4- (4-fluorobenzoylamino) -4- (2-thienyl) - 3-ketobutyrate (349 mg) , and phosphorus oxychloride (0.12 ml) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 2.5 hours. The reaction mixture was poured into water, neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure . The resulting residue was purified by silica gel flush column chromatography (solvent: hexane : ethyl acetate=20 : 1) to obtain ethyl 2- (4-fluorophenyl) -4- (2-thienyl) oxazol-5-yl acetate ( 95 mg) as pale yellowish powder. MS-APCI (m/z): 332 (MH+)
Preparation example 148
To a solution of ethyl 2- (4-fluorophenyl) -4- (2-thienyl) - oxazol-5-yl acetate (94mg) in tetrahydrofuran (3ml) and ethanol (3 ml) was added IN aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at room temperature for one hour. To the reaction mixture was added 10% hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was dissolved in methanol (5 ml) , 0.5M sodium methoxide (556 μl, methanol solution) was added to the solution and the solvent was removed under reduced pressure to obtain sodium 2- (4-fluorophenyl) -4- (2-thienyl) oxazol-5-yl acetate (90mg) as pale brownish powder. ESI -MS (m/z): 302 (M-H)
Preparation example 149
To a solution of ethyl 2- (4-fluorophenyl) oxazol-4-yl acetate (11.10 g) in chloroform (110 ml) was added bromine (2.47 ml) at room temperature and the mixture was stirred at room temperature for one hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium thiosulfate solution, and the organic layer was collected . The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was crystallized from hexane-diethyl ether to obtain ethyl 5-bromo-2- (4-fluorophenyl) oxazol-4-yl acetate (7.47 g) as colorless crystal. Further, the filtrate was purifiedby silica gel flush column chromatography (solvent: n-hexane : ethyl acetate=10 : 1) to obtain ethyl 5-bromo-2- (4-fluorophenyl) - oxazol-4-yl acetate (3.57 g) as pale yellowish crystal. Melting point: 84 to 85°C MS-APCI (m/z): 323/330 (MH+)
Preparation example 150
A mixture of ethyl 2- (4-fluorophenyl) oxazol-4-yl acetate (249 mg) , iodine (127 mg) and [bis (trifluoroacetoxy) ] iodo] benzene (244 mg) in chloroform (3 ml) was stirred at room temperature for 4 hours. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium thiosulfate solution, and the organic layer was collected. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure . The resulting residue was purified by silica gel flush column chromatography (solvent: n-hexane : ethyl acetate=8 :1) to obtain ethyl 2- (4-fluorophenyl) -5-iodoxazol- 4-yl acetate (300 mg) as colorless crystal. Melting point: 120 to 122°C MS-APCI (m/z): 376 (MH+)
Preparation example 151
A mixture of ethyl 5-bromo-2- (4-fluorophenyl) oxazol-4-yl acetate (328 mg) , 5-chlorothiophen-2-boric acid (244 mg) , bis (triphenylphosphine) palladium (II) dichloride (35 mg) in 2M aqueous sodium carbonate solution (1.5ml) and dimethoxyethane (5 ml) was refluxed for one hour. After cooling, to the reaction mixture were added water and ethyl acetate, the organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: n-hexane : ethyl acetate=6: 1) to obtain ethyl 5- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) oxazol-4-yl acetate (181 mg) as pale yellowish crystal. Melting point: 129 to 130°C MS-APCI (m/z): 366/368 (MH+)
Preparation example 152
To a solution of ethyl 5- (5-chlorothiophen-2-yl) -2- (4- fluorophenyl) oxazol-4-yl acetate (115 mg) in methanol (5 ml) was added 4N aqueous sodium hydroxide solution (1 ml) , and the mixture was refluxed for 30 minutes. After cooling, ethyl acetate and 10% hydrochloric acid were added to the reaction mixture, and the organic layer was collected. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was dissolved in methanol (5 ml) , 0.5M sodium methoxide (605 μl, methanol solution) was added to the solution and the solvent was removed under reduced pressure. The resulting residue was triturated with acetone to obtain 5-(5-chloro- thiophen-2-yl) -2- (4-fluorophenyl) oxazol-4-yl acetic acid sodium salt (100 mg) as pale yellowish powder. ESI -MS (m/z) : 336 (M-H)
Preparation examples 153 to 166
The following compounds shown in Table 15 were prepared in a manner similar to Preparation example 63, 151 or 152 by using corresponding starting materials.
Table 15
Figure imgf000087_0001
Table 15 (contd.)
Figure imgf000088_0001
Table 15 (contd.)
Figure imgf000089_0001
Table 15 (contd.)
Figure imgf000090_0001
Preparation examples 167 to 202
The following compounds shown in Table 16 were prepared in a manner similartoone ofthe above-mentionedPreparationexamples, or conventionally known preparation processes as described in Japanese Provisional Patent Publications No. 5832/1972, No. 29771/1973 and the like.
Table 16
Figure imgf000091_0001
Table 16 (contd.)
Figure imgf000092_0001
Table 16 (contd.)
Figure imgf000093_0001
Table 16 (contd.)
Figure imgf000094_0001
Table 16 (contd.)
Figure imgf000095_0001
Table 16 (contd.)
Figure imgf000096_0001
Table 16 (contd.)
Figure imgf000097_0001
Table 16 (contd.)
Figure imgf000098_0001
Table 16 (contd.)
Figure imgf000099_0001
Table 16 (contd.)
Preparation Chemical structure Salt Physical example No. property, etc,
Free Crystal Melting point: CH3 material
202 123-125°C MS-APCI (m/z) : 327 (M+H)+
Preparation example 203
A mixture of ethyl 3-amino-4- (5-chlorothiophen-2-yl) - 4-oxobutyrate hydrochloride (300 mg) , benzo[b] furan-5- carboxylic acid (245 mg) , 3-ethyl-l- (3-dimethylamino- propyl) carbodiimide hydrochloride (289 mg) , 1-hydroxy- benzotriazole (204 mg) and triethylamine (0.35 ml) in methylene chloride ( 4.5 ml) was stirred at room temperature for overnight . A saturated aqueous sodiumhydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure . The resulting residue was purified by silica gel column chromatography (solvent: hexane : ethyl acetate=4 : 1) , and then, triturated with diisopropyl ether to obtain ethyl 3-[(5- benzo [b] furoyl) amino-4- (5-chlorothiophen-2-yl) -4-oxo- butyrate (352 mg) as colorless powder.
To a solution of the resulting ethyl 3- [ (5-benzo[b] furoyl) - amino-4- (5-chlorothiophen-2-yl) -4-oxobutyrate (331 mg) in N,N-dimethylformamide (4.08 ml) was added phosphoryl chloride (0.23 ml) under ice-cooling, and the mixture was stirred at 60 °C overnight . To the reactionmixture was added a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform : ethyl acetate= 20:1), and then, triturated with diisopropyl ether to obtain ethyl 2- (5- benzo [b] furyl) -5- (5-chlorothiophen-2-yl) oxazol-4-yl acetate (257 mg) as colorless powder. MS-APCI (m/z): 388/390 (MH+)
Preparation examples 204 to 226
The following compounds shown in Table 17 were prepared in a manner similar to Preparation example 203 by using corresponding starting materials.
Table 17
Figure imgf000102_0001
Table 17 (contd.)
Figure imgf000103_0001
Table 17 (contd.)
Figure imgf000104_0001
Table 17 (contd.)
Figure imgf000105_0001
Table 17 (contd.)
Figure imgf000106_0001
Table 17 (contd.)
Figure imgf000107_0001
Preparation example 227
To a solution of 4- [ (5-benzo[b] furoyl) aminoacetyl] -2- chlorothiophene (543 mg) in N,N-dimethylformamide (10 ml) was added sodiumhydride (71.3mg, 60% mineral oil) under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. After ice-cooling, ethyl bromoacetate (0.21 ml) was added dropwise to the mixture, and the resulting mixture was stirred at room temperature for 40 minutes. After cooling, 5% aqueous citric acid solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product of ethyl 3- [ (5-benzo [b] furoyl) amino] - 4- (5-chlorothiophen-3-yl) -4-oxobutyrate (896 mg) .
To a solution of the resulting crude product of ethyl 3- [ (5-benzo [b] furoyl) amino] -4- (5-chlorothiophen-3-yl) -4- oxobutyrate (896 mg) in N,N-dimethylformamide (7 ml) was added phosphoryl chloride (0.48 ml) at room temperature, and the mixture was stirred at the same temperature overnight. To the reaction mixture was added water, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane : acetone=7 : 1) , and then, triturated with diethyl ether to obtain ethyl 2- (5-benzo [b] furyl) -5- (5-chloro- thiophen-3-yl) oxazol-4-yl acetate (349 mg) as colorless powder . MS-APCI (m/z): 388 (MH+)
Preparation examples 228 to 232
The following compounds shown in Table 18 were prepared in a manner similar to Preparation example 227 by using corresponding starting materials.
Table 18
Figure imgf000109_0001
Table 18 (contd.)
Figure imgf000110_0001
Preparation examples 233 to 293
The following compounds shown in Table 19 were prepared in a manner similar to Preparation example 148 or 152 by using corresponding starting materials.
Table 19
Figure imgf000111_0001
- Ill -
Table 19 (contd.)
Figure imgf000112_0001
Table 19 (contd.
Figure imgf000113_0001
Table 19 (contd.)
Figure imgf000114_0001
Table 19 (contd.)
Figure imgf000115_0001
Table 19 (contd.)
Figure imgf000116_0001
Table 19 (contd.)
Figure imgf000117_0001
Table 19 (contd.
Figure imgf000118_0001
Table 19 (contd.)
Figure imgf000119_0001
Table 19 (contd.)
Figure imgf000120_0001
Table 19 (contd.)
Figure imgf000121_0001
Table 19 (contd.)
Figure imgf000122_0001
Table 19 (contd.
Figure imgf000123_0001
Table 19 (contd.)
Figure imgf000124_0001
Table 19 (contd.)
Figure imgf000125_0001
Table 19 (contd.)
Figure imgf000126_0001
Preparation examples 294 and 295
The following compounds shown in Table 20 were prepared in a manner similar to Preparation example 149 by using corresponding starting materials.
Table 20
Figure imgf000127_0001
Preparation example 296
A mixture of ethyl 5-bromo-2- (4-fluorophenyl) oxazol-4-yl acetate (164 mg) , phenylboric acid (91 mg) and bis (triphenylphosphine) palladium (II) chloride (18 mg) in 2M aqueous sodium carbonate solution (0.75 ml) and dimethoxyethane (3 ml) was stirred under argon atmosphere at 100°C for one hour. After cooling, to the reaction mixture were added water and ethyl acetate, the organic layer was collected, washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane : ethyl acetate=6:l) to obtain ethyl 2-(4-fluoro- phenyl) -5-phenyloxazol-4-yl acetate (144 mg) as colorless powder.
Melting point: 118 to 120 °C MS-APCI (m/z) : 326 (MH+)
Preparation examples 297 to 320
The following compounds shown in Table 21 were prepared in a manner similar to Preparation example 296 by using corresponding starting materials.
Table 21
Figure imgf000129_0001
Table 21 (contd. )
Figure imgf000130_0001
Table 21 (contd.)
Figure imgf000131_0001
Table 21 (contd.)
Figure imgf000132_0001
Table 21 (contd.)
Figure imgf000133_0001
Table 21 (contd. )
Figure imgf000134_0001
Preparation example 321
To a suspension of ethyl 2- (4-fluorophenyl) 5- (2-thienyl) - oxazol-4-yl acetate (166 mg) in chloroform (1.5 ml) and acetic acid (1.5 ml) was added N-bromosuccinimide (94 mg) , and the mixture was stirred at room temperature overnight. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was collected. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure . The resulting residue was crystallized fromdiethyl ether-n-hexane to obtain ethyl 2- (4-fluorophenyl) - 5- (5-bromothiophen-2-yl) oxazol-4-yl acetate (147 mg) . MS-APCI (m/z): 410/412 (MH+)
Preparation example 322
The following compound shown in Table 22 was prepared in a manner similar to Preparation example 321 by using corresponding starting materials.
Table 22
Figure imgf000135_0001
Preparation example 323 A mixed solution of ethyl 2- (4-fluorophenyl) -5- [3- (2- methylpropyloxy) -4-methoxymethoxyphenyl] oxazol-4-yl acetate (300 mg) , 4N hydrogen chloride-dioxane solution (5 ml) and ethanol (5 ml) was stirred at room temperature overnight. After the solvent was removed under reduced pressure, the residue was triturated with diethyl ether and washed with n-hexane to obtain ethyl 2- (4-fluorophenyl) -5- [3- (2-methylpropyloxy) -4- hydroxyphenyl] oxazol-4-yl acetate (269 mg) . MS-APCI (m/z): 414 (MH+)
Preparation example 324
The following compound shown in Table 23 was prepared in a manner similar to Preparation example 323 by using corresponding starting materials.
Table 23
Figure imgf000136_0001
Preparation example 325
To a mixed solution of ethyl 2- (4-fluorophenyl) -5- (5- formyl-4-methylthiophen-2-yl) oxazol-4-yl acetate (175 mg) in ethanol (5 ml) and tetrahydrofuran (5 ml) was added sodium borohydride (54 mg) , and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added water and ethyl acetate, the organic layer was collected, washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane : ethyl acetate=2:l) to obtain ethyl
2- (4-fluorophenyl) -5- (5-hydroxymethyl-4-methylthiophen-2- yl) oxazol-4-yl acetate (125 mg) as pale yellowish powder. MS-APCI (m/z): 376 (MH+)
Preparation example 326
The following compound shown in Table 24 was prepared in a manner similar to Preparation example 325 by using corresponding starting materials.
Table 24
Figure imgf000137_0001
Preparation example 327
To a solution of ethyl 5- (3-benzyloxyphenyl) -2- (4-fluorophenyl) oxazol-4-yl acetate (349mg) inmethanol (20ml) was added 10% palladium-carbon (350 mg), and the mixture was stirred under hydrogen atmosphere at room temperature for 2 hours. After the reaction, palladium-carbon was removed by filtration, the residue was washed with methanol and the filtrate was concentrated under reduced pressure . The resulting residue was crystallized from diisopropyl ether to obtain ethyl 2- (4- fluorophenyl) -5- (3-hydroxyphenyl) oxazol-4-yl acetate (195 mg) as colorless crystal. Melting point: 175 to 111 ° C MS-APCI (m/z): 342 (MH+)
Preparation example 328
To a solution of ethyl 2- [2- (4-fluorophenyl) -5- (3-thienyl) - oxazol-4-yl] -2-methylpropionate (54 mg) in methylene chloride (3 ml) was added boron tribromide (0.45 ml, 1. OM methylene chloride solution) underice-cooling, andthemixturewas allowed to warm to room temperature. To the mixture, another portion of boron tribromide (1.05 ml, 1.0M methylene chloride solution) was added to the mixture, and the resulting mixture was stirred at room temperature for 18 hours. To the reaction mixture were added water and ethyl acetate, the organic layer was collected, washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform : methanol= 15:1) to obtain 2- [2- (4- fluorophenyl) -5- (3-thienyl) oxazol-4-yl] -2-methylpropionic acid (32 mg) . The product was dissolved in methanol, sodium methoxide (0.19 ml, 0.5M methanol solution) was added to the solution and after the mixture was stirred for 10 minutes, the solvent was removed under reduced pressure. The resulting residue was triturated with acetone to obtain sodium 2- [2- (4-fluorophenyl) -5- (3-thienyl) oxazol-4-yl] -2-methy1- propionate (30 mg) as pale brownish powder. MS-ESI (m/z): 330 (M-Na)
Preparation example 329
To a solution of ethyl 2- (4-fluorophenyl) -5- (3-thienyl) - oxazol-4-yl acetate (130 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (47 mg, 60% mineral oil) under ice-cooling, and the mixture was stirred at room temperature under argon atmosphere for 20 minutes . To the mixture was added methyl iodide (0.06ml) in an ice bath, and the resulting mixture was stirred at room temperature for 14 hours. To the reaction mixturewere addeda saturatedaqueous ammoniumchloride solution and ethyl acetate, the organic layer was collected.The organic layerwas washedwithwater andbrine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane : diisopropyl ether=5:l) to obtain ethyl 2- [2- (4-fluorophenyl) -5- (3-thienyl) oxazol- 4-yl] -2-methylpropionate (62 mg) as colorless oil. MS-APCI (m/z): 360 (MH+)
Preparation example 330
A solution of ethyl 2- (6-chloropyridin-3-yl) -5- (5-chloro- thiophen-2-yl) oxazol-4-yl acetate (150 mg) in 50% aqueous dimethylamine solution (656 mg) and ethanol (3 ml) was refluxed for 16 hours . After cooling, water and ethyl acetate were added to the reaction mixture, and the organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform : ethyl acetate=7 : 1) to obtain ethyl 2- (6-dimethylaminopyridin-3-yl) - 5- (5-chlorothiophen-2-yl) oxazol-4-yl acetate (54 mg) as pale yellowish solid. MS-APCI (m/z) : 392/394 (MH+)
Preparation examples 331 and 332
The following compounds shown in Table 25 were prepared in a manner similar to Preparation example 330 by using corresponding starting materials. Table 25
Figure imgf000140_0001
Preparation example 333
A mixture of methyl 3- (5-benzo [b] furoylamino) -4- (3-thienyl) - 4-oxobutyrate (240 mg) and phosphorus oxychloride (0.19 ml) in N,N-dimethylformamide (4.8 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water, neutralized by a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure . The resulting residue was purified by silica gel column chromatography (solvent: hexane : ethyl acetate=20:l) to obtain methyl 2- (5-benzo [b] furyl) -5- (3-thienyl) oxazole-4-yl acetate (121 mg) as colorless powder. MS-APCI (m/z): 340 (MH+)
Preparation examples 334 to 336
The following compounds shown in Table 26 were prepared in a manner similar to one ofthe above-mentionedPreparationexamples, or conventionally known preparation processes as described in U.S. Patent No. 3,470,195 and the like.
Table 26
Figure imgf000142_0001
Preparation example 337
To a solution of 2- [ (4-fluorobenzoylamino) acetyl] thiophene (527 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (88 mg, 60% mineral oil) under ice-cooling, and the mixture was stirred under argon atmosphere at room temperature for one hour. After ice-cooling, acrylonitrile (127 ml) was added to the mixture and the mixture was stirred at room temperature for 3 hours. After addition of ice-water, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure . The resulting residue was dissolved in N,N-dimethylformamide (10 ml) , and phosphoryl chloride (240 μl) was added to the solution under ice-cooling. The mixture was stirred under argon atmosphere at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure . The resulting residue was purified by silica gel column chromatography (solvent: hexane : ethyl acetate= 9:1-^7:1), and triturated with hexane and ethyl acetate to obtain 4- (2-cyanoethyl) -2- (4-fluorophenyl) -5- (2-thienyl) oxazole (132 mg) as colorless powder. MS-APCI (m/z): 299 (MH+)
Preparation example 338
A mixture of 4- (2-cyanoethyl) -2- (4-fluorophenyl) -5- (2- thienyl) oxazole (95 mg) , cone, hydrochloric acid (3 ml) and formic acid (4 ml) was stirred at 60°C overnight. After addition of cone, hydrochloric acid (1 ml), the mixture was stirred at 70°C for 6 hours . After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform : methanol= 19 : 1) . The resulting colorless powder was dissolved in methanol (5 ml) , 0.5M sodium methoxide (600 μl, methanol solution) was added to the solution and the solvent was removed under reduced pressure . The resulting residue was triturated with acetone to obtain 2- (4-fluorophenyl) -5- (2-thienyl) oxazole-4-yl propionic acid sodium salt (103 mg) as pale brownish powder. MS-ESI (m/z): 316 (M-Na)
Preparation example 339
(1) To a suspension of tellurium powder (153 mg) in ethanol (3 ml) was added sodium borohydride (108 mg) , and the mixture was refluxed under argon atmosphere for 15 minutes. Under ice-cooling, acetic acid (160 μl) and a solution of ethyl 5- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) oxazole-4-yl acrylate (302 mg) in tetrahydrofuran (4 ml) were added to the mixture, and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was filtered through Cellite and the residue was washed with ethyl acetate. The filtrate was washedwithwater andbrine, dried over anhydrous sodium sulfate and the solvent was removed under reducedpressure . The resulting reside was purified by silica gel column chromatography (solvent: hexane : ethyl acetate=30: 1) , and triturated with hexane to obtain a crude product of ethyl 5- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) oxazole-4-yl propionate (263 mg) as colorless powder.
(2) To a solution of the product obtained in the above-mentioned (1) (63 mg) in tetrahydrofuran (1 ml) and ethanol (2 ml) was added IN aqueous sodium hydroxide solution (170 μl) and the resulting mixture was refluxed for 1.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with acetone to obtain 5- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) oxazole-4-yl propionic acid sodium salt (60 mg) as colorless powder. MS-ESI (m/z): 350/352 (M-Na) Preparation example 340
(1) A mixture of 5- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) -4-hydroxymethyloxazole (1.44 g) and manganese dioxide (4.76 g) in tetrahydrofuran (20 ml) was refluxed for 3 hours. The reaction mixture was filtered through Cellite and the filtrate was concentrated under reduced pressure. The resulting reside was triturated with diethyl ether to obtain 5- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) -4-formyl- oxazole (943 mg) as colorless powder. MS-APCI (m/z): 308 (MH+)
(2) To a solution of ethyl diethylphosphonoacetate (740 μl) in tetrahydrofuran (12 ml) was added sodium hydride (153 mg, 60% mineral oil) in an ice-acetone bath, and the resulting mixture was stirred at the same temperature for 15 minutes. 5- (5- Chlorothiophen-2-yl) -2- (4-fluorophenyl) -4-formyloxazole (400 mg) was added to the mixture and the mixture was allowed to warm to room temperature for one hour. After cooling, the reactionmixture was neutralizedby a saturated aqueous ammonium chloride solution and extractedwith ethyl acetate . The organic layerwas washedwithwater andbrine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure . The resulting residue was purified by silica gel column chromatography (solvent: hexane : ethyl acetate=30 : 1) , andthen, triturated with diethyl ether and hexane to obtain 404 mg of ethyl 5- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) oxazole- 4-yl acrylate as colorless powder. MS-APCI (m/z): 378 (MH+)
Preparation example 341
A mixture of 5- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) -4- methoxycarbonyloxazole (1.8 g) and lithiumborohydride (580mg) in tetrahydrofuran (40 ml) was stirred at room temperature for one hour, and then, refluxed for 1.5 hours . After cooling, water and 10% hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layerwas washedwithwater andbrine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure . The resulting residue was triturated with diethyl ether-ethyl acetate to obtain 5- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) -4-hydroxymethyloxazole (1.48 g) as colorless powder. MS-APCI (m/z): 310/312 (MH+)
Preparation example 342
In a manner similar to Preparation example 341 by using the corresponding starting materials, 5- (4-chloro-3-fluoro- phenyl) -2- (4-fluorophenyl) -4-hydroxymethyloxazole was obtained.
MS-APCI (m/z): 322/324 (MH+)
Preparation example 343
To a solution of ethyl 2- (4-fluorophenyl) oxazole-4-carboxylate
(7.44 g) in chloroform (100 ml) was added dropwise bromine (8.1 ml) at room temperature, and the resulting mixture was stirred at room temperature for 30 minutes and then refluxed for 8 hours .
After cooling the reaction mixture, 10% aqueous sodium thiosulfate solution was added to the mixture and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent: ethyl acetate : n-hexane=l:9) to obtain ethyl 5-bromo-2- (4-fluorophenyl) - oxazol-4-carboxylate (9.21 g) as pale yellowish powder. MS-APCI (m/z): 314/316 (MH+)
Preparation example 344 To a solution of methyl 3- (5-chlorothiophen-2-yl) -2- (4- fluorobenzoylamino) -3-oxopropionate (7.25 g) in N,N-dimethyl- formamide (80ml) was added dropwise phosphorus oxychloride (5.7 ml) under ice-cooling, and the mixture was then stirred at room temperature for 3 days. After cooling, water was added to the reactionmixture and themixture was extractedwith ethyl acetate . The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure . The resulting residue was purified by silica gel column chromatography (solvent: hexane : ethyl acetate= 100:1), and then, triturated with diethyl ether-hexane to obtain methyl 5- (5-chloro-thiophen-2-yl) -2- (4-fluorophenyl) oxazol- 4-carboxylate (2.8 g) as colorless powder. MS-APCI (m/z): 338/340 (MH+)
Preparation example 345
In a manner similar to Preparation example 344 by using the corresponding starting materials, methyl 5- (3-thienyl) -2- (4- fluorophenyl) oxazol-4-carboxylate was obtained.
Preparation example 346
A mixture of ethyl 5-bromo-2- (4-fluorophenyl) oxazol-4- carboxylate (600 mg) , 0.05M (4-chloro-3-fluorophenyl) zinc bromide (6 ml, tetrahydrofuran solution), and tetrakis- (triphenylphosphine) palladium (231 mg) in tetrahydrofuran (5 ml) was stirred under argon atmosphere at room temperature for 2 hours, followed by refluxing for 40 minutes. The reaction mixture was cooled and concentrated under reduced pressure, and water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was successively washed with 10% hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solutionandbrine, driedover anhydrous sodiumsulfate and the solvent was removed under reduced pressure . The residue was purifiedby silica gel column chromatography (solvent: ethyl acetate : n-hexane=l:8) to obtain ethyl 5- (4-chloro-3-fluoro- phenyl) -2- (4-fluorophenyl) oxazol-4-carboxylate (580 mg) as pale reddish solid. MS-APCI (m/z): 364/366 (MH+)
Preparation example 347
A mixture of p-fluorobenzamide (5 g) , ethyl bromopyruvate (9.92 ml), and sodium hydrogen carbonate (15 g) in tetrahydrofuran (150 ml) was refluxed for 20 hours. After cooling the reaction mixture, insoluble material was removed by filtration through Cellite andthe filtratewas concentratedunder reducedpressure . The residue was dissolved in tetrahydrofuran (30 ml) and trifluoroacetic anhydride (30 ml) was added to the mixture in an ice bath. After stirring at room temperature for one hour, a saturated aqueous sodiumhydrogen carbonate solution was added to the mixture in an ice bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: ethyl acetate : n-hexane=l : 9) to obtain ethyl 2- (4-fluorophenyl) oxazol-4- carboxylate (7.44 g) as colorless solid. MS-APCI (m/z): 236 (MH+)
Preparation example 348
(1) Chlorine gas was bubbled through a suspension of
2- [5- (4-chloro-3-fluorophenyl) -2- (4-fluorophenyl) oxazol-4- yl] methylthiourea (200 mg) in water (15 ml) under ice-cooling for 5 minutes . The mixture was stirred at the same temperature for 30 minutes followed by stirring at room temperature for 30 minutes. Waterwas addedto the reactionmixture, andthemixture was extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product of 5- (4-chloro-3-fluorophenyl) -2- (4-fluorophenyl) - oxazol-4-yl methanesulfonyl chloride.
(2) The product obtained in (1) was dissolved in tetrahydrofuran (3 ml) , 28% aqueous ammonia (2 ml) was added to the solution, and the mixture was stirred at room temperature for 3 hours . The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: chloroform : methanol= 20:1) to obtain 5-(4-chloro- 3-fluorophenyl) -2- (4-fluorophenyl) oxazol-4-ylmethanesulfon- amide (164 mg) as pale yellowish solid. MS-APCI (m/z): 385/387 (MH+)
(3) To a solution of 5- (4-chloro-3-fluorophenyl) -2- (4-fluoro- phenyl) oxazol-4-ylmethanesulfonamide obtained in (2) (125 mg) in methanol was added 0.5M sodium methoxide (0.64 ml, methanol solution) . The solvent was removed under reduced pressure, and the resulting residue was triturated with acetone to obtain 5- (4-chloro-3-fluorophenyl) -2- (4-fluorophenyl) oxazol-4-yl methanesulfonamide sodium salt (80 mg) . MS-APCI (m/z): 383/385 (MH+)
Preparation example 349
(1) A solution of 5- (4-chloro-3-fluorophenyl) -2- (4-fluorophenyl) -4-hydroxymethyloxazole (965 mg) and thionyl chloride (1.1 ml) in tetrahydrofuran (30 ml) was stirred at 0°C for 30 minutes, followed by stirring at room temperature for 2 hours. Additional thionyl chloride (1.1 ml) was added to the mixture and the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure. The remaining volatiles were removed by evaporation with toluene, and further dried under reduced pressure to obtain a crude product of 5- (4-chloro-3-fluorophenyl) -4-chloromethyl-2- (4-fluoro- phenyl) oxazole (925 mg) . (2) A solution of the crude product obtained in (1) (925 mg) and thiourea (269 mg) in tetrahydrofuran (50 ml) was refluxed for 15 hours . The reaction mixture was concentrated under reduced pressure to one-third volume, and the residue was triturated with adding diethyl ether to obtain 2- [5- (4- chloro-3-fluorophenyl) -2- (4-fluorophenyl) -oxazol-4-yl] - methylthiourea hydrochloride (954 mg) . MS-APCI (m/z): 380/382 (MH+)
Preparation example 350
To a solution of 5- (2-cyanoethyl) -2- (4-fluorophenyl) -4- (2- methoxyphenyl) imidazole (40 mg) in dichloromethane ( 10 ml) was added dropwise boron tribromide (94 mg) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added dropwise a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and then, the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reducedpressure . The residue was purifiedbypreparative TLC (solvent: hexane : ethyl acetate=l: 1) , and further purified by NH silica gel column chromatography (solvent: hexane : ethyl acetate=l : 1) . To the product was added hydrogen chloride- ethanol solution and the mixture was concentrated to obtain 5- (2-cyanoethyl) -2- (4-fluorophenyl) -4- (2-hydroxyphenyl) - imidazole hydrochloride (6 mg) as colorless solid. MS-APCI (m/z): 308 (MH+)
Preparation examples 351 to 355
The following compounds shown in Table 27 were prepared in a manner similarto Preparationexamples 43 andPreparation example 152 by using the corresponding starting materials. Table 27
Figure imgf000151_0001
Table 27 (contd.)
Figure imgf000152_0001
Preparation example 356
A mixture of ethyl 2- (6-aminopyridin-3-yl) -5- (5-chloro- thiophen-2-yl) oxazol-4-yl acetate (70 mg) and 40% aqueous chloroacetoaldehyde solution (47 μl) in ethanol (2.1 ml) was refluxed for 3 hours, and 40% aqueous chloroacetoaldehyde solution (16 μl) was addedto themixtureandtheresultingmixture was refluxed for one hour. After cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure . The resulting residue was purified by silica gel column chromatography (solvent: chloroform : methanol= 49:1~>97:3) to obtain ethyl 2- (imidazo [a, l]pyridin-5-yl) - 5- (5-chlorothiophen-2-yl)oxazol-4-yl acetate (65 mg) . MS-APCI (m/z): 388/390 (MH+)
Preparation example 357
(1) To a solution of ethyl 2- (6-chloropyridin-3-yl) -5- (5-chlorothiophen-2-yl)oxazol-4-yl acetate (1 g) in N,N-di- methylformaldehyde (10 ml) was added sodium azide (1.7 g) , and the mixture was refluxed overnight. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and the solvent was removedunder reducedpressure . The resulting residue was purified by silica gel column chromatography (solvent: chloroform : ethyl acetate=8 : 1) to obtain ethyl 2- (6-azidopyridin-3-yl) -5- (5-chlorothiophen- 2-yl) oxazol-4-yl acetate (401 mg) as yellowish powder.
(2) A mixture of ethyl 2- (6-azidopyridin-3-yl) -5- (5- chlorothiophen-2-yl) oxazol-4-yl acetate (401 mg) and 540 mg of triphenylphosphine (540 mg) in water (2 ml) and acetic acid (8 ml) was refluxed for 2 hours. After cooling, water was added to the reaction mixture and the mixture was extractedwith ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform : ethyl acetate=5 : l->2 :3->l :2) , and then, trituratedwith diethyl ether to obtain ethyl 2- (6-aminopyridin-3-yl) -5- (5-chlorothio- phen-2-yl) oxazol-4-yl acetate (177 mg) as yellowish powder. MS-APCI (m/z): 364/366 (MH+)
Preparation example 358
A mixture of ethyl 5- (5-chlorothiophen-2-yl) -2- (1-formyl- indolin-5-yl) oxazol-4-yl acetate (160 mg) and 6N hydrochloric acid (2 ml) in ethanol (4 ml) was stirred at 60°C for 4 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (solvent: chloroform : methanol=20 : 1) to obtain ethyl 5- (5-chlorothiophen-2-yl) -2- (5-indolinyl) oxazol-4-yl acetate (53 mg) as colorless powder. MS-APCI (m/z): 389/391 (MH+) Preparation example 359
To a suspension of ethyl 2- (2-methylthiopyrimidin-5-yl) - 5- (5-chlorothiophen-2-yl) oxazol-4-yl acetate (156 mg) in tetrahydrofuran (3.12 ml) was added metachloroperbenzoic acid (88mg, 70%purity) under ice-cooling, and themixture was stirred at room temperature for one hour. After ice-cooling again, 70% metachloroperbenzoic acid (40 mg) was added to the mixture and the resulting mixture was stirred at room temperature for one hour. To the mixture was added 50% aqueous dimethylamine solution (1 ml) and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform : ethyl acetate=8:l) to obtain ethyl 2- (2-dimethylaminopyrimidin-5-yl) -5- (5-chlorothiophen-2-yl) oxazol-4-yl acetate (139 mg) as colorless powder. MS-APCI (m/z): 393/395 (MH+)
Preparation examples 360 and 361
The following compounds shown in Table 28 were prepared in a manner similar to Preparation examples 359 by using the corresponding starting materials.
Table 28
Preparation examples 362 to 364
The compounds obtained in Preparation examples 359 to 361 were subjected to hydrolysis according to the conventional manner to obtain the compounds shown in Table 29.
Table 29
Figure imgf000156_0001
Preparation example 365
To a suspension of ethyl 2- (6-chloropyridin-3-yl) -5- (3- thienyl) oxazol-4-yl acetate (150 mg) in ethanol (3 ml) was added 15% aqueous sodiummethyl sulfide solution (2ml) , andthemixture was refluxed for 3 days. After cooling, the reaction mixture was neutralized by 10% hydrochloric acid, and extracted with ethyl acetate . The organic layerwas driedover anhydrous sodium sulfate and the solvent was removedunder reducedpressure. The resulting residue was washed with diethyl ether and dissolved in methanol (5 ml) , and 0.5M sodium methoxide (495 μl, methanol solution) was added to the solution and the solvent was removed under reduced pressure. The resulting residue was triturated with acetone to obtain 2- (6-methylthiopyridin-3-yl) -5- (3- thienyl)oxazol-4-yl acetic acid sodium salt (74 mg) as pale yellowish powder.
MS-ESI (m/z): 331 (M-Na)
Preparation example 366
In a manner similar to Preparation example 365 and using corresponding starting materials, 2- (6-methylthiopyridin- 3-yl) -5- (2-thienyl) oxazol-4-yl acetic acid sodium salt was obtained. MS-ESI (m/z): 331 (M-Na)
Preparation example 367
To a suspension of ethyl 2- (6-chloropyridin-3-yl) -5- (5- chlorothiophen-2-yl) oxazol-4-yl acetate (192 mg) in ethanol (5 ml) was added sodium hydride (100 mg, 60% mineral oil) , and the mixture was refluxed for 6 hours, and then, water (1 ml) was added to the mixture and the mixture was further refluxed for 30 minutes. After cooling, the reactionmixturewas neutralized by 10% hydrochloric acid, and extractedwith ethyl acetate . The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was washed with hexane and dissolved in methanol (5 ml) , and 0.5M sodium methoxide (867 μl, methanol solution) was added to the solutionandthe solvent as removedunder reducedpressure . The resulting residue was triturated with acetone to obtain 2- (6-ethoxypyridin-3-yl) -5- (5-chlorothiophen-2-yl) oxazol- 4-yl acetic acid sodium salt (169 mg) as pale yellowish powder. MS-ESI (m/z): 363/365 (M-Na)
Preparation examples 368 and 369
The following compounds shown in Table 30 were prepared in a manner similar to Preparation examples 367 by using the corresponding starting materials.
Table 30
Figure imgf000158_0001
Preparation example 370
To a mixture of 2- (4-fluorophenyl) -5- (3-thienyl) oxazol-4-yl acetic acid (130 mg) in N,N-dimethylformamide (5 ml) was added N,N-carbonyldiimidazole (347 mg) , and the mixture was stirred at room temperature for 2 hours. Methanesulfonamide (204 mg) and 1, 8-diazabicyclo [5.4.0]undecene ( 0.32 ml) were added to the mixture and the resultingmixture as stirredat 100°C overnight . The reaction mixture was poured into 10% hydrochloric acid, and extractedwith ethyl acetate . The organic layer was washedwith water and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under the reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane : ethyl acetate= 1:1) , and then, the resulting product was dissolved in methanol (10 ml) , and 0.5M sodium methoxide (68 μl, methanol solution) was added to the solution and the solvent was removed under reduced pressure to obtain N- [2- (4-fluorophenyl) -5- (3-thienyl) oxazol-4-yl acetyl]methanesulfonamide sodium salt (42 mg) as colorless powder . MS-ESI (m/z): 379 (M-Na)
Preparation example 371
Corresponding starting compounds are treated in amanner similar to Preparation example 370 to obtain the compound shown in Table 31.
Table 31
Figure imgf000159_0001
Preparation example 372
To a mixture of ethyl 2- (4-fluorophenyl) -5- (5-chloro- thiophen-2-yl) oxazol-4-yl acetate (1.01 g) in ethanol (5 ml), diethyl ether (5ml) and tetrahydrofuran (6ml) was added sodium hydride (110 mg, 60% mineral oil) under argon atmosphere, and the mixture was stirred for 10 minutes under ice-cooling . After addition of isoamyl nitrite (647 mg) , the mixture was stirred at room temperature for 1.5 hours. 10% Hydrochloric acid was added to the mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reducedpressure. The resulting crude product
(395 mg) was taken up into formic acid (4 ml) and ethanol (3 ml) . To the mixture zinc powder (291 mg) was added at room temperature, and the mixture was stirred for 10 minutes followed by stirring at 70°C for 20 minutes . After cooling, the reaction mixture was filtered through glass filter, the residue was washed with ethanol and the filtrate was concentrated under reduced pressure. To the resulting residue was added a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was triturated with diethyl ether-hexane to obtain ethyl
2-amino-2- [5- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) - oxazol-4-yl] acetate (307 mg) as colorless powder. MS-APCI (m/z): 381/383 (MH+)
Preparation example 373
A mixture 2- (4-fluorophenyl) -5- (3-thienyl) oxazol-4-yl acetic acid (100 mg) , methoxyamine hydrochloride (37.6 mg) , 3-ethyl-l- (3-dimethylaminopropyl) carbodiimide hydrochloride (95mg), 1-hydroxybenzotriazole (67 mg) and triethylamine (0.14 ml) in N,N-dimethylformamide (3 ml) was stirred at room temperature overnight . Waterwas added to the reactionmixture, the mixture was extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removedunder reducedpressure . The resulting residue was purified by silica gel column chromatography (solvent: chloroform : methanol=20: 1) , and triturated with diethyl ether-hexane to obtain [2- (4- fluorophenyl) -5- (3-thienyl) oxazol-4-yl acetyl] N-methoxy- amide (75 mg) as colorless powder. MS-APCI (m/z) : 333 (MH+)
Preparation examples 374 to 377
The corresponding starting materials were treated in a manner similar to Preparation example 373 to obtain the compounds shown in Table 32 below.
Table 32
Figure imgf000162_0001
Preparation example 378
(1) Under argon atmosphere, to a solution of 2- (4-fluorophenyl) -4- (2-hydroxyethyl) -5- (3-thienyl) oxazole (300 mg) in methylene chloride (10 ml) were successively added methane- sulfonyl chloride (96 μl) and triethylamine (188 μl) under ice-cooling, and the mixture was stirred at room temperature for 3 hours . The reaction mixture was poured into water and extractedwithmethylene chloride . The organic layerwas washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product of 2- (4-fluorophenyl) -4- (2-methanesulfonyloxyethyl) - 5- (3-thienyl) oxazole .
(2) To a solution of methanesulfonamide (136 mg) in N,N-di- methylformamide (10 ml) was added sodium hydride (57 mg, 60% mineral oil) under ice-cooling, and the mixture was stirred at room temperature for one hour. After the mixture was ice-cooled again, an N,N-dimethylformamide solution of the crude product obtained in (1) was added to the mixture and the resultingmixture was stirred at room temperature for one hour and then stirred at 60°C overnight. The reaction mixture was ice-cooled, and then, poured into an aqueous ammonium chloride solution and extracted with ethyl acetate . The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reducedpressure . After the resulting residue was purified by silica gel column chromatography (solvent: hexane : ethyl acetate=4 : 1) , the obtained product was dissolved in methanol (5 ml) , and 0.5M sodium methoxide (562 μl, methanol solution) was added to the solution and the solvent was removed under reduced pressure to obtain 2- (4-fluorophenyl) -4-methanesulfonylaminoethyl-5- (3-thienyl) oxazole sodium salt (143 mg) as colorless powder. MS-ESI (m/z) : 365 (M-Na) Preparation example 379
(1) A mixture of 2- (4-fluorophenyl) -5- (3- thienyl) oxazol-4-yl acetic acid (1.5 g) , diphenylphosphoryl azide (1.28 ml) and triethylamine (0.83 ml) in t-butanol (30 ml) was refluxed for one day. After cooling the reaction mixture, the solvent was removed under reduced pressure. Water was added to the residue andthemixture was extractedwith chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure . Chloroform was added to the residue, the mixture was heated and insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: ethyl acetate : n-hexane=l : 9->l : 7) to obtain 4- (t-butoxycarbonylamino) methyl- 2- (4-fluoroρhenyl-5- (3-thienyl) oxazole (501 mg) . MS-APCI (m/z): 375 (MH+)
(2) A solution of 4- (t-butoxycarbonylamino)methyl-2- (4- florophenyl) -5- (3-thienyl) oxazole (455 mg) in 4N hydrogen chloride-dioxane solution was stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure and the remaining volatiles were removed by evaporation with toluene, and the resulting residue was triturated with diethyl ether to obtain 4-aminomethyl-2- (4-fluorophenyl) -5- (3-thienyl) oxazole hydrochloride (288 mg) as colorless powder . MS-APCI (m/z): 275 (MH+)
Preparation example 380
(1) To a suspension of 4-aminomethyl-2- (4-fluorophenyl) -5- (3-thienyl) oxazole (110 mg) in dichloromethane (5 ml) were successively added dropwise under acetone-ice cooling methanesulfonyl chloride (0.036ml) and triethylamine (0.15 ml) . The reaction mixture was stirred at 0°C for one hour, and further stirred at roomtemperature for 2 hours . To the reactionmixture was added a saturated aqueous ammonium chloride solution and extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform : methanol=100 : 0~>95 :5) to obtain a crude product of N- [2- (4-fluorophenyl) -5- (3-thienyl) oxazol-4-yl] - methanesulfonamide (140 mg) .
(2) Crude N- [2- (4-fluorophenyl) -5- (3-thienyl) oxazol-4-yl] - methanesulfonamide (133 mg) was dissolved in methanol (5 ml) and tetrahydrofuran (5 ml), and 0.5M sodium methoxide (0.72 ml, methanol solution) was added to the solution and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentratedunderreducedpressure andthe resulting residue was triturated with acetone to obtain N-[2-(4- fluorophenyl) -5- (3-thienyl) oxazol-4-yl]methanesulfonamide sodium salt (112 mg) . MS-APCI (m/z): 353 (MH+)
Preparation examples 381 to 429
The following compounds shown in Table 33 were prepared in a manner similar to Preparation example 63 by using corresponding starting materials.
Table 33
Figure imgf000166_0001
Table 33 (contd. )
Figure imgf000167_0001
Table 33 (contd.)
Figure imgf000168_0001
Table 33 (contd.)
Figure imgf000169_0001
Table 33 (contd.)
Figure imgf000170_0001
Table 33 (contd. )
Figure imgf000171_0001
Table 33 (contd.)
Figure imgf000172_0001
Table 33 (contd. )
Figure imgf000173_0001
Table 33 (contd.)
Figure imgf000174_0001
Table 33 (contd.)
Figure imgf000175_0001
Table 33 (contd. )
Figure imgf000176_0001
Table 33 (contd. )
Figure imgf000177_0001
Table 33 (contd.)
Figure imgf000178_0001
Preparation examples 430 to 479
The following compounds shown in Table 34 were prepared in a manner similar to Preparation example 148 or 152 by using corresponding starting materials.
Table 34
Figure imgf000179_0001
Table 34 (contd. )
Figure imgf000180_0001
Table 34 (contd. )
Figure imgf000181_0001
Table 34 (contd.)
Figure imgf000182_0001
Table 34 (contd.)
Figure imgf000183_0001
Table 34 (contd.)
Figure imgf000184_0001
Table 34 (contd. )
Table 34 (contd. )
Figure imgf000186_0001
Table 34 (contd. )
Figure imgf000187_0001
Table 34 (contd.)
Figure imgf000188_0001
Table 34 (contd.)
Figure imgf000189_0001
Table 34 (contd. )
Figure imgf000190_0001
Table 34 (contd.)
Figure imgf000191_0001
Preparation example 480
A mixture of ethyl 3- (4-chlorobenzoylamino) -4-phenyl-4- oxobutyrate (25 g) in acetic acid (150 ml) was heated to 130°C, and a largely excessive amount of ammonium acetate was added to the mixture. After confirming completion of the reaction by TLC, the reaction mixture was cooled. Ice-water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized from diisopropyl ether to obtain 2- (4-chlorophenyl) -4-phenylimidazol-5-yl acetamide (10.42 g) . MS-EI (m/z) : 311 (M+) Preparation example 481
To a solution of 2- (4-chlorophenyl) -4-phenylimidazol-5-yl acetamide (lO.OOg) in N,N-dimethylformamide (50ml) was added dropwise 8.9 ml of phosphorus oxychloride (8.9 ml) below 20°C, and the mixture was stirred at room temperature for one hour. To the reaction mixture were added ice-water and ethyl acetate, and the mixture was neutralized by sodium hydrogen carbonate. The organic layer was collected, washed with brine, and dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was crystallized from diisopropyl ether to obtain 2- (4-chlorophenyl) -5-cyano- methyl-4-phenylimidazole (6.85 g) . MS-EI (m/z) : 293 (M+)
Preparation example 482
The corresponding starting materials were treated in a manner similar to Preparation example 112 to obtain 2-(5-chloro- thiophen-3-yl) -5-hydroxymethyl-4- (3-pyridyl) imidazole . MS-APCI (m/z): 292 (MH+)
Preparation example 483
The corresponding starting materials were treated in a manner similar to Preparation example 130 to obtain 2- (4-fluorophenyl) -5-methylthiomethyl-4-phenylimidazole hydrochloride. MS-APCI (m/z) : 298 (M+)
Preparation example 484
The corresponding starting materials were treated in a manner similar to Preparation example 141 to obtain 2- (4-fluorophenyl) -5- (3-pyridyl) oxazol-4-yl acetic acid hydrochloride. MS-APCI (m/z): 299 (M+) Preparation example 485
A mixture of 2- (2-hydroxymethylthiophen-3-yl) -5-ethyl-4- (3- pyridyl) imidazole dihydrochloride (212 mg) and manganese oxide (2 g) in tetrahydrofuran (15 ml) was refluxed for one hour. The reaction mixture was iltered and washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform : methanol=30: 1-^20 : 1) to obtain 2- (2-formylthiophen-3-yl) -5-ethyl-4- (3-pyridyl) imidazole (93 mg) as orange crystal. MS-APCI (m/z): 284 (MH+)
Preparation example 486
To a solution of 2- (2-formylthiophen-3-yl) -5-ethyl-4- (3- pyridyl) imidazole (68 mg) in tetrahydrofuran (5 ml) was added dropwise 3M methyl magnesium bromide (0.24 ml, diethyl ether solution) under argon atmosphere in an ice bath, and the mixture was stirred at the same temperature for 30 minutes. To the reactionmixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate . The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform : methanol=20 : 1) to obtain 2- [2- (1-hydroxyethyl) thiophen-3-yl] -5-ethyl-4- (3-pyridyl) - imidazole dihydrochloride (60 mg) as orange brownish powder. MS-APCI (m/z): 300 (MH+)
Preparation example 487
(1) Amixture of ethyl 4- (2-thienyl) -2- (4-fluorophenyl) oxazol- 5-yl acetate (140 mg) , N-chlorosuccinic imide(62 mg) and a catalytic amount of 70% aqueous perchloric acid solution in carbon tetrachloride (7 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, neutralized by a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane : ethyl acetate=95 :5) to obtain ethyl 4- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) oxazol- 5-yl acetate (39.6 mg) as colorless powder. MS-APCI (m/z): 366/368 (MH+)
(2) The compound obtained in the above (1) was hydrolyzed according to the conventional manner to obtain 4-(5-chloro- thiophen-2-yl) -2- (4-fluorophenyl) oxazol-5-yl acetic acid sodium salt.
ESI-MS (m/z): 336/338 (M-Na)-
Preparation examples 488 to 502
The corresponding starting materials were treated in a manner similar to Preparation example 147 to obtain the compounds shown in Table 35 below.
Table 35
Figure imgf000195_0001
Table 35 (contd.
Figure imgf000196_0001
Table 35 (contd. )
Figure imgf000197_0001
Table 35 (contd. )
Preparation examples 503 to 517
The corresponding starting materials were treated in a manner similar to Preparation example 148 to obtain the compounds shown in Table 36 below. Table 36
Figure imgf000199_0001
Table 36 (contd.)
Figure imgf000200_0001
Table 36 (contd. )
Figure imgf000201_0001
Table 36 (contd. )
Figure imgf000202_0001
Preparation examples 518 to 521
The corresponding starting materials were treated in a manner similar to Preparation example 151 or 296 to obtain the compounds shown in Table 37 below. Table 37
Figure imgf000203_0001
Preparation examples 522 to 525
The corresponding starting materials were treated in a manner similar to Preparation example 152 to obtain the compounds shown Table 38 below.
Table 38
Figure imgf000204_0001
Preparation examples 526 to 528
The corresponding starting materials were treated in a manner similar to Preparation example 330 to obtain the compounds shown in Table 39 below.
Table 39
Figure imgf000205_0001
Preparation examples 529 to 531
The corresponding starting materials were hydrolyzed in the conventional method to obtain the compounds shown in Table 40 below.
Table 40
Figure imgf000206_0001
Preparation examples 532 to 536
The corresponding starting materials were treated in a manner similar to Preparation example 227 to obtain the compounds shown in Table 41 below.
Table 41
Figure imgf000207_0001
Table 41 (contd. )
Figure imgf000208_0001
Preparation example 537
A mixture of ethyl 3-bromo-4- (5-chlorothiophen-2-yl) -4-oxobutyrate (651 mg) and 4-fluorothiobenzamide (310 mg) in N,N-dimethylformamide (10 ml) was stirred at 70°C for 2 hours. After cooling, water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (solvent: hexane : ethyl acetate=10:l) to obtain ethyl 4- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) thiazol-5-yl acetate (471 mg) . MS-APCI (m/z): 382/284 (MH+) Preparation examples 538 to 567
The corresponding starting materials were treated in a manner similar to Preparation example 537 to obtain the compounds shown in Table 42 below.
Table 42
Figure imgf000209_0001
Table 42 (contd.)
Figure imgf000210_0001
Table 42 (contd. )
Figure imgf000211_0001
Table 42 (contd. )
Figure imgf000212_0001
Table 42 (contd.)
Table 42 (contd. )
Figure imgf000214_0001
Table 42 (contd.)
Figure imgf000215_0001
Table 42 (contd.)
Figure imgf000216_0001
Preparation examples 568 to 597
The corresponding starting materials were hydrolyzed in the conventional manner to obtain the compounds shown in Table 43 below. Table 43
Figure imgf000217_0001
Table 43 (contd. )
Figure imgf000218_0001
Table 43 (contd. )
Figure imgf000219_0001
Table 43 (contd.)
Figure imgf000220_0001
Table 43 (contd. )
Figure imgf000221_0001
Table 43 (contd. )
Figure imgf000222_0001
Table 43 (contd. )
Figure imgf000223_0001
Table 43 (contd.)
Figure imgf000224_0001
Preparation examples 598 to 599
The corresponding starting materials were treated in a manner similar to Preparation example 359 to obtain the compounds shown in Table 44 below.
Table 44
Figure imgf000225_0001
Preparation examples 600 to 601
The corresponding starting materials were hydrolyzed in the conventional manner to obtain the compounds shown in Table 45 below.
Table 45
Figure imgf000226_0001
Preparation example 602
A mixture of ethyl 3-amino-4- (5-chlorothiophen-2-yl) -4- oxobutyrate hydrochloride (596 mg) , 4-fluorobenzoyl chloride (380 mg) and sodium hydrogen carbonate (l.Og) in ethyl acetate (10 ml) and water (10 ml) was stirred at room temperature for 2 hours. To the reaction mixture were added ethyl acetate (30 ml) and water (30 ml) , and the organic layer was collected. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with hexane to obtain a crude product of ethyl 4- (5-chlorothiophen- 2-yl) -3- [ (4-fluorobenzoyl) amino] -4-oxobutyrate (732 mg) as colorless powder. A mixture of ethyl 4- (5-chlorothiophen-2-yl) -3- [ (4-fluorobenzoyl) amino] -4-oxobutyrate (720 mg) and 2,4-bis(4- methoxyphenyl) -1, 3-dithia-2, 4-diphosphetan-2, 4-disulfide (1.14 g) in tetrahydrofuran (20 ml) was refluxed for 2.5 hours. The reactionmixture was cooled and purified by silica gel column chromatography (solvent: hexane : ethyl acetate= 20:1), and triturated with hexane to obtain ethyl 5- (5-chlorothiophen- 2-yl) -2- (4-fluorophenyl) thiazol-4-yl acetate (667 mg) as yellowish powder. MS-APCI (m/z): 382/284 (MH+)
Preparation examples 603 to 607
The corresponding starting materials were treated in a manner similar to Preparation example 602 to obtain the compounds shown in Table 46 below.
Table 46
Figure imgf000228_0001
Table 46 (contd.)
Figure imgf000229_0001
Preparation examples 608 to 612
The corresponding starting materials were hydrolyzed in the conventional manner to obtain the compounds shown in Table 47 below.
Table 47
Figure imgf000229_0002
Table 47 (contd.)
Figure imgf000230_0001
Preparation examples 613 to 622
In accordance with the above-mentioned preparation examples or the conventionally known preparation processes, the compounds shown in Table 48 below were obtained. Table 48
Figure imgf000231_0001
Table 48 (contd.)
Figure imgf000232_0001
Table 48 (contd. )
Figure imgf000233_0001
Preparation examples 623 to 631
According to the preparation example 129, 130, 135, 148, 152 or 330 mentioned above, the compounds shown in Table 49 below were obtained.
Table 49
Figure imgf000234_0001
Table 49 (contd. )
Figure imgf000235_0001
Table 49 (contd. )
Figure imgf000236_0001
Preparation example 632
(1) Ethyl 2- (4-chlorophenyl) -5-phenylthiazol-4-yl acetate (4.5 g) was dissolved in methanol (50 ml) , and ammonia was saturated in the solution at 0°C and the resulting mixture was allowed to stand at room temperature for 3 days . After removing the solvent, methanol was added to the residue. The resulting precipitate was collected and dried to obtain 2- (4-chlorophenyl) -5-phenylthiazol-4-yl acetamide (4.2 g) . Melting point: 202-203°C MS-EI (m/z) : 328 (M+)
(2) To a solution of 2- (4-chlorophenyl) -5-phenylthiazol-4-yl acetamide (3.4 g) andphosphorus oxychloride (3ml) in chloroform
(50ml) was addedone drop ofpyridine, andthemixturewas refluxed for 8 hours . Cold diluted aqueous ammonia was poured into the mixture and the organic layer was collected. After removing the solvent under reduced pressure, ethanol was added to the residue and crystal was collected by filtration to obtain 2- (4-chlorophenyl) -5-phenylthiazol-4-yl acetonitrile (3.1 g) . Melting point: 118-120°C MS-EI (m/z) : 310 (M+)
(3) To a solution of 2- (4-chlorophenyl) -5-phenylthiazol-4-yl acetonitrile (2.33g) inN,N-dimethylformamide (30ml) were added sodium azide (1.40 g) and ammonium chloride (1.3 g) , and the mixture was stirred at 90°C for 12 hours. After removing the solvent under reduced pressure, ethyl acetate and water were added to the residue. The organic layer was collected, dried and the solvent was removed under reduced pressure . The residue was recrystallized from chloroform and methanol to obtain 5- [2- (4-chlorophenyl) -5-phenyl-thiazol-4-ylmethyl] tetrazole (1.75 g) .
Melting point: 213-214°C MS-EI (m/z) : 353 (M+)
Preparation examples 633 to 641
The corresponding starting materials were treated in a manner similar to Preparation example 43, 135, 608 or the conventionally known processes to obtain the compounds shown in Table 50 below. Table 50
Figure imgf000238_0001
Table 50 (contd. )
Figure imgf000239_0001
Table 50 (contd. )
Figure imgf000240_0001
Reference Examples 642 to 644
The following compounds listed in Table 50a were prepared in amanner similar to Example 608 or 632 , or similar to thatdescribed in Japanese Provisional Patent Publication No. 167685/1986. Table 50a
Figure imgf000241_0001
Reference example 1
(1) A mixture of 2-acetylpyrimidine (2.90 g) , hydroxylamine hydrochloride (2.48 g) and triethylamine (5.3 ml) in ethanol (40 ml) was stirred at room temperature overnight . The reaction mixture was poured into water, and extracted with methylene chloride . The organic layer was washed with a saturated aqueous ammonium sulfate solution andbrine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 2-acetylpyrimidine oxime (4.44 g) as colorless powder. MS-APCI (m/z): 138 (MH+)
(2) A mixture of 2-acetylpyrimidine oxime (4.40 g) and p-toluenesulfonyl chloride (6.79 g) in pyridine (40 ml) was stirred at room temperature overnight. The reaction mixture was poured into ice-water and precipitated crude product was collected by filtration. The filtrate was neutralized by 10% hydrochloric acid and extracted with ethyl acetate . The organic layer was washedwithwater andbrine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure . The resulting residue and the crude product previously obtained were combined and triturated with diethyl ether to obtain O-p-toluenesulfonyl-2-acetylpyrimidine oxime (4.53 g) as colorless powder.
(3) To ice-cooled ethanol (19 ml) was added sodium hydride (681 mg, 60% mineral oil) and the mixture was stirred at room temperature for 30 minutes. To the solution was added dropwise a solution of O-p-toluenesulfonyl-2-acetylpyrimidine oxime (4.51 g) in ethanol (16 ml) and of tetrahydrofuran (10 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 1.5 hours . To the reaction mixture was added diethyl ether (150 ml) and precipitated insoluble material was removed by filtration. The filtrate was extracted with 2N hydrochloric acid and the aqueous layer was concentrated under reduced pressure. The resulting residue was triturated with acetone-ethanol to obtain 2- (2-aminoacetyl)pyrimidine hydrochloride (2.87 g) as pale brownish powder. MS-APCI (m/z): 138 (MH+)
Reference examples 2 to 4
Correspondingstartingcompounds were treatedinamanner similar to Reference example 1 to obtain the compounds shown in Table 51 below.
Table 51
Figure imgf000243_0001
Reference example 5
(1) To a solution of 1- (3-pyridyl) -1-butanone (20.0 g) in 47% aqueous hydrobromic acid (40 ml) and acetic acid (40 ml) was added bromine (15.2 ml), and the mixture was stirred at 60°C for 30 minutes . The reaction mixture was poured into ice-water, and after adding a saturated aqueous sodiumthiosulfate solution, potassium carbonate was added to the mixture to adjust pH to 4. The reactionmixture was extractedwith ethyl acetate, washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a crude product of 2-bromo-l- (3-pyridyl) -1-butanone (30.15 g) as brownish oil.
(2) The crude product obtained in the above (1) was dissolved in N,N-dimethylformamide (100 ml), and sodium azide (9.50 g) was added to the solution under ice-cooling and the resulting mixture was stirred at room temperature for one hour. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate three times, and combined organic layers was washed with brine, and dried over anhydrous sodium sulfate . The solvent was removed under reduced pressure and the residue was purified by silica gel flush column chromatography (solvent: n-hexane : ethyl acetate=2 : 1) to obtain 2-azido-l- (3-pyridyl) - 1-butanone (18.65 g) as yellowish oil. MS-APCI (m/z): 191 (MH+)
(3) A mixture of 2-azido-l- (3-pyridyl) -1-butanone (18.60 g) , di-t-butyl dicarbonate (23.50 g) and 10% palladium-carbon (2.70 g) in methanol (200 ml) was stirred under hydrogen atmosphere at room temperature for one hour. After removing the palladium-carbon by filtration, the solvent was removed under reduced pressure and the residue was purified by silica gel flush column chromatography (solvent: hexane : ethyl acetate=
2:1->1:1) to obtain 2- (t-butoxycarbonylamino) -1- (3-pyridyl) - 1-butanone (20.53 g) as yellowish red oil.
(4) A mixture of 2- (t-butoxycarbonylamino) -1- (3-pyridyl) -1- butanone (20.50 g) and 6N hydrochloric acid (38.8 ml) in ethanol (100 ml) was refluxed for one hour. After cooling, the reaction mixturewas concentratedunder reducedpressure andthe resulting residuewas trituratedwith ethanol-ethyl acetate (1:1) to obtain 2-amino-l- (3-pyridyl) -1-butanone dihydrochloride (13.40 g) as pale reddish purple crystalline powder. Melting point: 199 to 201°C (decomposed)
Reference examples 6 to 8
Corresponding starting compounds were treatedinamanner similar to Reference example 5 to obtain the compounds shown in Table 52 below.
Table 52
Figure imgf000246_0001
Reference example 9
To a solution of an acid chloride product prepared from 6-methyl nicotinic acid (245 mg) in chloroform (10 ml) were added 2-amino-l- (3-pyridyl) -1-butanone dihydrochloride (356 mg) and triethylamine (1.05 ml), and the mixture was stirred for 30 minutes . The mixture was poured into water and extracted with ethyl acetate. The organic layer was collected, washedwith brine anddried over anhydrous sodiumsulfate . The solventwas removed under reduced pressure to obtain a crude product of 2- (6-methylnicotynoylami.no) -1- (3-pyridyl) -1-butanone (425 mg) .
Reference example 10
(1) A mixture of 3- (2-aminoacetyl) pyridine dihydrochloride
(50.00g), 4-fluorobenzoyl chloride (41.71g) andsodiumhydrogen carbonate (100.44 g) in ethyl acetate (1 liter) andwater (0.6 liter) was stirred at room temperature for 2 hours. To the reactionmixturewere addedtetrahydrofuran (0.51iter) andwater
(1 liter) , and the organic layer was collected. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with ethyl acetate to obtain 3- [2- (4-fluorobenzoyl) aminoacetyl] pyridine
(40.87 g) as pale yellowish powder. Melting point: 164.5 to 165.5°C MS-APCI (m/z): 259 (MH+)
(2) To a solution of 3- [2- (4-fluorobenzoyl) aminoacetyl] - pyridine (500 mg) in N,N-dimethylformamide (10 ml) were added sodium hydride (81.3 mg, 60% mineral oil) and acrylonitrile (113 mg) under dry ice-acetone cooling, and the mixture was stirred at the same temperature under argon atmosphere for 10 minutes . The mixture was warmed slowly to 0°C and stirred at the same temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product of 4-cyano-2- (4-fluorobenzoylamino) -1- (3-pyridyl) -1- butanone (500 mg) .
Reference example 11
(1) To acetic anhydride (2.39 ml) was added dropwise formic acid (0.97 ml) under ice-cooling, and the mixture was stirred at 50°C for 30 minutes. The mixture was ice-cooled again, and diluted with tetrahydrofuran (9 ml) . To the mixture were added 2-amino-l- (3-pyridyl) -1-butanone dihydrochloride (600 mg) and triethylamine (1.41 ml), and the mixture was stirred under ice-cooling for 1.5 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residuewas trituratedwithethyl acetate-diethyl ether to obtain 2-formylamino-l- (3-pyridyl) -1-butanone (440 mg) as colorless powder . MS-APCI (m/z) : 193 (MH+)
(2) A mixture of 2-formylamino-l- (3- pyridyl) -1-butanone (640 mg) and ammoniumacetate (5.13g) in acetic acid (5 ml) was stirred at 100°C for 1.5 hours. After cooling, 28% aqueous ammonia was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed withbrine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with ethyl acetate-diethyl ether to obtain 5-ethyl-4- (3- pyridyl) imidazole (520 mg) as colorless powder. MS-APCI (m/z): 174 (MH+)
(3) To a solution of 5-ethyl-4- (3-pyridyl) imidazole (1.50 g) and potassium acetate (2.55 g ) in methanol (40 ml) was added iodine (2.86 g), and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and ethyl acetate, and the organic layer was collected, washed with a saturatedaqueous sodiumthiosulfate solutionandbrine anddried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by NH silica gel flush column chromatography (solvent: ethyl acetate) to obtain 5-ethyl-2-iodo-4- (3-pyridyl) imidazole (1.75 g) . MS-APCI (m/z) : 300 (MH+)
Reference example 12
(1) A mixture of methyl o.-amino-2-thiophene acetate (1.48 g) , 4-fluorobenzoyl chloride (1.64 g) and sodium hydrogen carbonate (2.89 g) in methylene chloride (20 ml) and water (20 ml) was stirred at room temperature overnight. The organic layer was collected, washed with water and brine, and the solvent was removed under reduced pressure. The resulting residue was triturated with ethyl acetate-hexane to obtain methyl α- (4-fluorobenzoylamino) -2-thiophene acetate (2.40 g) as colorless powder. MS-APCI (m/z) : 294 (MH+)
(2) To a solution of diisopropylamine (2.48 g) in tetrahydrofuran (45 ml) was added dropwise 1.6M n-butyl lithium (15.71 ml, n-hexane solution) under argon atmosphere at -78 °C, and after stirring for 30 minutes, a solution of ethyl acetate (2.16 g) in tetrahydrofuran (5 ml) was added dropwise to the mixture and the resulting mixture was further stirred for 30 minutes. To the mixture was slowly added a solution of methyl α-(4- fluorobenzoylamino) -2- thiophene acetate (2.40 g) in tetrahydrofuran (15 ml) , and the mixture was stirred for one hour. To the reaction mixture were added a saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic layerwas washedwithwater andbrine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: chloroform : ethanol=100: 1) to obtain ethyl 4- (4-fluorobenzoylamino) -4- (2-thienyl) acetacetate (2.53 g) as yellowish oil. MS-APCI (m/z): 350 (MH+) Reference example 13
(1) To a solution of benzo [b] furan-5-carboxylic acid (1.30 g) and of methyl isocyanoacetate (834mg) in N,N-dimethylformamide (10 ml) were added diethyl cyanophosphate (1.33 ml) and triethylamine (3.6 ml) at room temperature, and the mixture was stirred overnight. After removing the solvent under reduced pressure, an aqueous citric acid solution and ethyl acetate were added to the residue, the organic layer was collected, washed successively with an aqueous citric acid solution, water, a saturated aqueous sodiumhydrogen carbonate solution andbrine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane : ethyl acetate=l: 1) to obtain a crude product of methyl 5- (5-benzo [b] furyl) oxazol-4-carboxylate (1.14 g) .
(2) To a solution of the crude product of methyl 5- (5- benzo [b] furyl) oxazol-4-carboxylate (1.14 g) inmethanol (20 ml) and tetrahydrofuran (5 ml) was added cone, hydrochloric acid
(8 ml), and the mixture was stirred overnight. The reaction mixturewas concentratedunder reducedpressure andthe resulting residue was triturated with methanol-diethyl ether-acetone to obtain 5- (aminoacetyl) benzo [b] furan hydrochloride (600 mg) . MS-APCI (m/z): 176 (MH+)
Reference example 14
Corresponding startingcompounds were treatedinamanner similar to Reference example 13 (1) and (2) to obtain the compounds shown in Table 53 below. Table 53
Figure imgf000251_0001
Reference examples 15 to 19
Corresponding startingcompounds were treatedin amanner similar to Reference example 10(1) to obtain the compounds shown in Table 54 below.
Table 54
Figure imgf000252_0001
Reference example 20
(1) To a solution of 2-chloro-5- (bromoacetyl) thiophene (28.04 g) in acetonitrile (150 ml) was added sodiumdiformylimide (13.35 g) , and the mixture was stirred at roomtemperature for 45 minutes followed by stirring at 50 °C for 2.5 hours . The reaction mixture was filtered through Celite, insoluble material was washed with tetrahydrofuran, the filtrate and the washed solution were combined and the solvent was removed under reduced pressure. The residue was crystallized from diisopropyl ether to obtain a crude crystal of 2-chloro-5- (diformylaminoacetyl) thiophene (20.63 g) .
(2) To the crude crystal of 2-chloro-5- (diformylaminoacetyl) - thiophene were added potassium hydroxide (0.60 g), ethanol (70 ml) and tetrahydrofuran (40 ml), and the mixture was stirred at room temperature for one hour. After removing the solvent under reduced pressure, tetrahydrofuran (150 ml) and anhydrous magnesium sulfate were added to the residue, and insoluble material was removed by filtration and washed with tetrahydrofuran. The filtrate and the washed solution were combined and the solvent was removed under reduced pressure . The residue was crystallized from diisopropyl ether-ethyl acetate to obtain 2-chloro-5- (formylaminoacetyl) thiophene (14.81 g) as pale brownish crystal.
Melting point: 111 to 113°C MS-APCI (m/z): 204 (MH+)
(3) To a solution of 2-chloro-5- (formylaminoacetyl) thiophene (20.1 g) in N,N-dimethylformamide (400 ml) was added sodium hydride (4.44 g, 60% mineral oil) under ice-cooling, and the mixture was stirred under argon atmosphere at room temperature for one hour. After ice-cooling, to the mixture was added dropwise ethyl bromoacetate (20.8 g), and the mixture was stirred at room temperature for 2 hours. After cooling, ice was added to the reaction mixture, and then water and ethyl acetate were also added to the mixture. The organic layer was collected , washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane : ethyl acetate=6:l) to obtain ethyl 4- (5-chlorothiophen-2-yl) -3-formylamino-4-oxobutyrate (17.8 g) as yellowish oil. MS-APCI (m/z) : 290/292 (MH+)
(4) To a solution of 4- (5-chlorothiophen-2-yl) -3-formyl- amino-4-oxobutyrate (17.8 g) in ethanol (178 ml) was added 4N hydrogen chloride-dioxane solution (178 ml) under ice-cooling, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the resulting residue was triturated with ethyl acetate to obtain ethyl 4- (5-chlorothiophen-2-yl) -3- amino-4-oxobutyrate hydrochloride (14.2 g) as colorless powder . MS-APCI (m/z) : 262/264 (MH+)
Reference example 21
Corresponding startingcompounds were treatedinamanner similar to Reference example 20(1) to (4) to obtain the compounds shown in Table 55 below.
Table 55
Figure imgf000255_0001
Reference example 22
(1) A mixed solution of β-methyl N- (5-benzo [b] furoyl) aspartate (1.0 g) and acetic anhydride (10 ml) was stirred at 85°C for one hour. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The resulting residue was crystallized from n-hexane-diethyl ether to obtain 2- (5-benzo [b] furyl) -4-methoxycarbonylmethyl-5- oxo-2-oxazoline (751 mg) as colorless powder. (2) To a mixture of 2- (5-benzo [b] furyl) -4-methoxycarbonyl- methyl-5-oxo-2-oxazoline (410 mg) and 3-thenoyl chloride (242 mg) in ethyl acetate (8 ml) was added triethyl amine (0.23 ml) under ice-cooling, and the mixture was stirred at room temperature for 0.5 hour. Ethyl acetatewas addedtothemixture, the mixture was filtered and the resulting filtrate was concentratedunder reducedpressure . Amixture of the resulting residue and pyridine (3.6 ml) was stirred at room temperature for 10 minutes followed by stirring at 60 °C for 2 hours. Then, acetic acid (1.35 ml) was added to the mixture and the resulting mixture was stirred at 80 °C for 1.5 hours. After cooling, to the reaction mixture were added water and ethyl acetate, the organic layer was collected, washed successively with a 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane : ethyl acetate=5:l) to obtain methyl 3- (5-benzo [b] furoylamino) -4- (3-thienyl) -4- oxobutyrate (253 mg) as colorless powder. MS-APCI (m/z) : 358 (MH+)
Reference example 23
Corresponding starting compounds were treatedin amanner similar to Reference example 10(1) to obtain 2- [2- (4-fluorobenzoylamino) acetyl] thiophene .
Reference example 24
(1) To a solution of methyl 5- (5-chlorothiophen-2-yl) oxazol- 4-carboxylate (12.6 g) in methanol (150 ml) was added 4N hydrogen chloride-dioxane solution (100 ml) under argon atmosphere, and the mixture was stirred at 70°C for overnight. The reaction mixture was cooled and the solvent was removed under reduced pressure, and the resulting residue was triturated with acetone to obtain methyl 2-amino-3- (5-chlorothiophen-2-yl) -3-oxo- propionate hydrochloride (13.9 g) as colorless powder. MS-APCI (m/z): 234 (MH+)
(2) A mixture of methyl 2-amino-3- (5-chlorothiophen-2-yl) - 3-oxopropionate hydrochloride (6.0 g) , 4-fluorobenzoyl chloride (4.23 g) and sodiumhydrogen carbonate (11.2 g) in ethyl acetate (100ml) andwater (10ml) was stirred at roomtemperature for 2 hours . The organic layer was collected, washed with water andbrine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with diethyl ether to obtain methyl 3- (5- chlorothiophen-2-yl) -2- (4-fluorobenzoylamino) -3-oxopropionate (7.3 g) as colorless powder. MS-APCI (m/z): 356/358 (MH+)
Reference example 25
A mixture of 1, 2, 3, 4-tetrahydroquinolin-6- carboxylic acid (2 g) , 32% aqueous formalin solution (2 ml) and 10% palladium-carbon (400 mg) in N,N-dimethylformamide (10 ml) was stirred under hydrogen atmosphere at room temperature for one hour. After removing the palladium-carbon by filtration, the solvent was removed under reduced pressure and the resulting residue was triturated with diethyl ether to obtain 1-methyl-l, 2, 3, 4- tetrahydroquinolin-6-carboxylic acid (1.98 g) as yellowish powder. ESI-MS (m/z): 190 (M-H) -
Reference example 26
Corresponding startingcompounds were treatedin amanner similar to Reference example 25 to obtain l-methylindolin-5- carboxylic acid. ESI-MS (m/z): 176 (M-H)- Reference example 27
A mixture of methyl 6-methoxymethylnicotinate (737 mg) in a 2N aqueous sodium hydroxide solution (2 ml) and methanol (15 ml) was refluxed overnight. After cooling, the reaction mixture was concentrated under reduced pressure, and the resulting residue was triturated with diethyl ether to obtain 6-methoxymethylnicotinic acid sodium salt (754 mg) as colorless powder . ESI-MS (m/z): 166 (M-Na)
Reference example 28
(1) To a solution of methyl 6-bromomethylnicotinate (350 mg) in tetrahydrofuran (5 ml) was added a 50% aqueous dimethylamine solution (3 ml) , and the mixture was vigorously stirred at room temperature for 10 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure . The resulting residue was purified by silica gel column chromatography (solvent: chloroform : methanol= 100:1) to obtain methyl 6- (dimethylamino) methylnicotinate (276 mg) as brownish powder. MS-APCI (m/z): 195 (MH+)
(2) A mixture of methyl 6- (dimethylamino) methylnicotinate (256 mg) and ION hydrochloric acid was refluxed overnight. After cooling, the reaction mixture was concentrated under reduced pressure to obtain 6- (dimethylamino) methylnicotinic acid hydrochloride (329 mg) as colorless powder. MS-APCI (m/z): 181 (MH+) Reference example 29
To a suspension of 3- (2-aminoacetyl) pyridine dihydrochloride (5.23 g) in chloroform (50 ml) were added di-t-butyl dicarbonate (5.73 g) and triethylamine (10.5ml), and the mixture was stirred for one hour. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washedwith water andbrine, dried over anhydrous sodium sulfate, and active charcoal was added thereto and insoluble material was removed by filtration. The filtrate was concentratedunder reducedpressure, and the residue was purifiedbymediumpressure column chromatography (solvent: chloroform : methanol=30 : l-> 20:1), and triturated with diisopropyl ether to obtain 3- (2-t-butoxycarbonylaminoacetyl) pyridine (3.20 g) . Melting point: 98 to 99°C MS-APCI (m/z): 237 (MH+)
Reference example 30
(1) Amixtureof (2-methoxy) phenacyl bromide (550 mg) and sodium diformylimide (274 mg) in acetonitrile (2.5 ml) was stirred at room temperature for 30 minutes, and then, stirred at 70°C for 24 hours . Insoluble material was removed by filtration, washed withacetonitrile andthe filtrate was concentratedunder reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane : ethyl acetate=2:l) , and triturated with hexane-ethyl acetate to obtain 2-(diformyl- amino) -2' -methoxyacetophenone (4.40 g) as colorless powder.
(2) A mixture of 2-(diformyl -amino) -2 ' -methoxyacetophenone
(3.28 g) and 5% hydrogen chloride-ethanol solution (37 ml) was stirred at room temperature for 17 hours . The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether. To the powder was again added 5%hydrogen chloride-ethanol solution andthemixturewas stirred at room temperature for one day, and the mixture was concentrated under reduced pressure. The residue was washed with diethyl ether and ethyl acetate to obtain 2-amino-2' -methoxyacetophenone hydrochloride (2.91 g) as colorless solid. MS-APCI (m/z): 166 (MH+)
Reference example 31
A mixture of methyl dl- -amino-2-thiophene acetate (5.59 g) , N-chlorosuccinimide (4.67 g) and acetic acid (60 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, to the residue obtained was addedwater, andthemixture was extractedwith ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure . To the resulting residue were added methanol (40 ml) and 4N hydrogen chloride-dioxane solution (30 ml) , the solvent was removed under reduced pressure and the residue was trituratedwith using diethyl ether andmethanol to obtainmethyl dl-α-amino-2- (5-chlorothiophene) acetate hydrochloride (4.24 g) as pale brownish powder. MS-APCI (m/z) : 206/208 (MH+)
Reference examples 32 to 46
Corresponding startingcompounds were treatedinamanner similar to Reference example 12 (1) to obtain the compounds shown in Table 56 below.
Table 56
Figure imgf000261_0001
Table 56 (contd.
Figure imgf000262_0001
Table 56 (contd.)
Figure imgf000263_0001
Reference examples 47 to 61
Corresponding startingcompoundswere treatedin amanner similar to Reference example 12 (2) to obtain the compounds shown in Table 57 below.
Table 57
Figure imgf000265_0001
Table 57 (contd.)
Figure imgf000266_0001
Table 57 (contd.)
Figure imgf000267_0001
Reference examples 62 to 66
Corresponding startingcompounds were treatedinamanner similar to Reference example 10(1) to obtain the compounds shown in Table 58 below.
Table 58
Figure imgf000268_0001
Reference example 67
Under argon atmosphere, to a solution of 4-chloro-3-fluoro- benzaldehyde (10 g) in N,N-dimethylformamide (50 ml) was added sodium cyanide (620 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hours. Then, to the mixture was added dropwise a solution of ethyl acrylate (5.2 ml) in N,N-dimethylformamide (25 ml), and the resulting mixture was stirred at the room temperature for 3 hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure . The resulting residue was purified by silica gel column chromatography (solvent: hexane : ethyl acetate=20 : 1) to obtainethyl 4- (4-chloro-3-fluorophenyl) -4-oxobutyrate (9.4 g) as pale yellowish powder. MS-APCI (m/z): 259/261 (MH+)
Reference example 68
Under argon atmosphere, a mixture of succinic acid monoethyl ester monochloride (2.0 g), tributyl (3-thienyl) tin (5.44 g) and bis (triphenylphosphine) palladium chloride (853 mg) in dioxane
(40 ml) was refluxed for 3 hours. After cooling, to the residue was addeda saturatedaqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane : ethyl acetate =6:1), and recrystallized from ethyl acetate-hexane to obtain ethyl 4- (3-thienyl) -4-oxobutyrate (1.4 g) as pale yellowish powder. MS-APCI (m/z): 213 (MH+) Reference example 69
To a solution of ethyl 4- (5-chlorothiophen-2-yl) -4-oxobutyrate (900 mg) in dichloromethane (9 ml) was added bromine (200 μl) under ice-cooling, and after stirring at the same temperature for 30 minutes, the reaction mixture was warmed to room temperature and the mixture was stirred for one hour. The reaction mixture was poured into ice-water, and ethyl acetate and diethyl ether were added thereto. The organic layer was collected, washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reducedpressure to obtain ethyl 3-bromo-4- (5-chlorothiophen-2-yl) -4-oxobutyrate (1.22 g) as pale brownish liquid. MS-APCI (m/z): 326/328 (MH+)
Reference examples 70 and 71
Corresponding startingcompoundswere treatedinamanner similar to Reference example 69 to obtain the compounds shown in Table 59 below.
Table 59
Figure imgf000271_0001
Reference example 72
to a mixture of (2-methylthio)pyrimidin-5-carboxylic acid sodium salt (1.50 g) , ammonium chloride (2.09 g) and 1-hydroxybenzotriazole (1.27 g) in N,N-dimethylformamide (20 ml) were successively added 3-ethyl-l- (3-dimethylamino- propyl) carbodiimide hydrochloride (1.80 g) and triethylamine (6.5 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was digested with diethyl ether-ethyl acetate. Then, the suspension was cooled and the precipitate was filtered, and washed with diethyl ether-n-hexane to obtain (2-methylthio)pyrimidin-5-carb- oxamide (927 mg) .
MS-APCI (m/z) : 170 (MH+) Reference example 73
Corresponding startingcompounds were treatedinamanner similar to Reference example 72 to obtain 4, 5-dimethylthiophen- 2-carboxamide .
MS-APCI (m/z): 156 (MH+)
Reference example 74
To a suspension of 6-chloronicotinamide (1.50 g) in ethanol (30 ml) was added sodium hydride (1.88 g, 60% mineral oil), and the mixture was stirred at room temperature for 24 hours. Another portion of sodium hydride (940 mg, 60% mineral oil) was added to the mixture, and the resulting mixture was stirred at room temperature for 24 hours followed by refluxing for 4.5 hours. Then, the reaction mixture was cooled, a saturated aqueous ammonium chloride solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure . The residue was triturated with diethyl ether to obtain 6-ethoxynicotinamide (1.05 g) as colorless powder. MS-APCI (m/z): 167 (MH+)
Reference example 75
Amixtureof (2-methylthio)pyrimidin-5-carboxamide (569mg) and Lawesson' s reagent (2.72 g) in chloroform (20 ml) was refluxed overnight. After cooling the reaction mixture, it was purified by NH silica gel column chromatography (solvent: ethyl acetate) . The residue was triturated with diethyl ether and washed with n-hexane to obtain (2-methylthio) pyrimidin-5-carbothioamide (247 mg) as yellowish powder. MS-APCI (m/z): 186 (MH+)
Reference examples 76 to 80 Corresponding starting compounds were treatedin amanner similar to Reference example 75 to obtain the compounds shown in Table 60 below.
Table 60
Figure imgf000273_0001
Reference example 81
Corresponding startingcompounds were treatedinamanner similar to Reference example 13(1) to obtain methyl 5-(3-chloro- 4-fluorphenyl) oxazol-4-yl carboxylate. MS-APCI (m/z): 256/258 (MH+)
Reference examples 82 and 83
Corresponding startingcompounds were treatedinamanner similar to Reference example 13 (2) to obtain the compounds shown in Table 61 below.
Table 61
Figure imgf000274_0001
Reference examples 84 to 87
Corresponding startingcompounds were treatedinamanner similar to Reference example 10 (1) or Reference example 20 (4) to obtain the compounds shown in Table 62 below.
Table 62
Figure imgf000275_0001
Reference examples 88 to 90
Corresponding starting compounds were treatedinamanner similar to Reference example 20(3) to obtain the compounds shown in Table 63 below. Table 63
Figure imgf000276_0001
Experimental example 1
Relaxation effect on potassium-induced contraction of isolated rabbit urinary bladder
Urinary bladder was isolated from Male NZW rabbits (2.0-3.5kg) and immersed in ice-cold Krebs-bicarbonate solution (inmM: 118
NaCl, 4.7 KCl, 1.2, 2.5 CaCl2, MgS04, 1.2 KH2P04, 11 glucose,
25 NaHC03 ) . The urinarybladder was cut into longitudinal strips (5mm length, 3-4mm width) after mucosal layer was removed. Preparations were mounted in organbaths containing 10ml of Krebs solution maintained at 37 °C and gassed with 95% 02 /5% C02. Accordingly, preparations were stretchedwith an initial tension of 2.0+1.0g, and changes in isometric tension were measured by force-displacement transducer. The preparations were pre-contracted by changing organ-bath solution into high-K+ (30mM) Krebs solution (inmM: 92.7 NaCl, 30 KCl, 1.2, 2.5 CaCl2, MgS0, 1.2 KH2P04, 11 glucose, 25 NaHC03) .
After stable tension was obtained, compounds were added into organ baths cumulatively (10"8M-10"M) . The effects of compounds were expressed as a percentage of the maximumrelaxationproduced by 0. ImM papaverine . 50% relaxation concentration (EC50) was calculated and EC5o value range (μM) of the compounds of the present invention was shown in the following Table 64 with a rank of A, B or C. These ranges are as mentioned below. 3>C>1>B>0.5>A
Table 64
Figure imgf000278_0001
Table 64 (Contd.)
Figure imgf000279_0001
Table 64 (Contd . )
Figure imgf000280_0001
Experimental example 2
Inhibitory effect on the rhythmic bladder contractions induced by substance P in anesthetized rats
For the experiments, Sprague-Dawley female rats (9 to 12 weeks old) weighing between 200 to 300 g were used. After urethane anesthetization (subcutaneously administered with a dose of 1.2 g/kg) , cannulae were placed in both right and left femoral veins . One intravenous catheterwas used foradministrationofcompounds, and the other was for the substance P (0.33 μg/kg/min) infusion. We also cannulated into ureter to pass urine. Polyethylene catheters were inserted into carotid artery for continuous monitoring of arterial blood pressure and heart rate. For continuous infusion, transurethral bladder catheter was inserted into the bladder through the urethra and tied in place by a ligature around the urethral orifice. One end of the catheterwas attachedto apressure transducer in order tomeasure intravesical pressure. The other end of the catheter was used for infusion of saline into the bladder. After stabilization ofbloodpressure andheart rate and after thebladderwas emptied, cystometrywas performedby filling the bladder slowlywith about 0.6ml of saline. After about 10 minutes, intravenous infusion of substance P (0.33μg/kg/min) was started for stabilization of the micturition reflex. Compounds were administered after stable rhythmicbladder contractionwas obtainedover 15minutes . All compounds were dissolved or suspended in saline containing 0.5% Tween 80 for intravenous administration (0.1 ml/kg) . The rhythmic contraction frequency and the intravesical pressure were observed for 35 minutes after administration of the test compound.
As a result, the compounds of the present invention decreased the frequency of bladder rhythmic contraction without changing the amplitude of contraction. Also, we determined a time
(minute) during which the frequency of the rhythmic contraction had been completely inhibited by administering 0.25 mg/kg of the compound. A 100% inhibition time (minute) of the selected compounds of the present invention is shown in the following Table 65 with a rank of A, B or C. These ranges are as mentioned below. A>20>B>10>C (minute)
Table 65
Figure imgf000282_0001
Table 65 (contd.)
Figure imgf000283_0001
Table 65 (contd.)
Figure imgf000284_0001
Table 65 (contd.
Figure imgf000285_0001
Table 65 (contd.)
Figure imgf000286_0001
Experimental example 3
Large conductance calcium-activated K channel opening action in isolated rabbit bladder
The urinary bladder strips were prepared according to the same manner as described in Experimental example 1. Briefly, the isolated urinary bladder was cut into longitudinal strips in ice-coldKrebs-bicarbonate solution, andmountedin organbaths . The initial tension was 2.0+/-1.0g. The preparations were contracted by high-K+(20mM or 60mM) Krebs solution.
Active ingredients of the present invention showed relaxation effect on 20mM K+-contracted preparation and the effect was blocked by iberiotoxin, a selective large conductance calcium-activated K channel blocker.
Also in in vivo animal study, pre-administration of iberiotoxin (0.15 mg/kg, intravenous administration) reduced inhibitory effect of active ingredients in the present invention on the rhythmic bladder contraction.
It is suggested from the results that the active ingredients of the present invention have a detrusor relaxing activity through the large conductance calcium-activated K channel .
Thus, it was shown that the compounds which are active ingredients of the present invention were effective for prophylaxis and treatment of diseases such as pollakiuria, urinary incontinence and the like through the large conductance calcium-activated K channel opening activity.
The nitrogen-containing 5-membered heterocyclic compound (I) or a pharmaceutically acceptable salt which is an active ingredient of the present invention has an excellent large conductance calcium-activated K channel opening activity and hyperpolarizes a membrane electric potential of cells, so that it is useful for a prophylactic, relief and/or treatment agent of, for example, hypertension, asthma, premature birth, irritable bowel syndrome, chronicheart failure, angina, cardiac infarction, cerebral infarction, subarachnoid hemorrhage, cerebral vasospasm, cerebral hypoxia, peripheral blood vessel disorder, anxiety, male-pattern baldness, erectile dysfunction, diabetes, diabetic peripheral nerve disorder, other diabetic complication, sterility, urolithiasis and pain accompanied thereby, pollakiuria, urinary incontinence, nocturnal enuresis, and the like.
Also, the nitrogen-containing 5-membered heterocyclic compound (I) or a pharmaceutically acceptable salt has a low toxicity, so that it has high safety as a medicine.

Claims

Claims :
1. A large conductance calcium-activated K channel opener comprising as an active ingredient a nitrogen-containing 5-membered heterocyclic compound represented by the following formula (I) :
Figure imgf000288_0001
wherein X represents N-R4, 0 or S, R1 and R2 are different from each other and each independently represents hydrogen atom, a halogen atom, carboxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted lower alkyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted lower alkenyl group, a cyclo-lower alkyl group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted heterocyclic group-substi- tuted carbonyl group, R3 represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted lower alkyl group, and R4 represents hydrogen atom or a substituted or unsubstituted lower alkyl group, or a pharmaceutically acceptable salt thereof.
2. The large conductance calcium-activated K channel opener according to Claim 1, wherein R1 and R2 each independently represent (1) hydrogen atom, (2) a halogen atom, (3) a carboxyl group, (4) an amino group which may be substituted by at least one selected from formyl group, a lower alkyl group, a lower alkanoyl group, a lower alkylsulfonyl group and a lower alkoxycarbonyl group, (5) a lower alkyl group which may be substituted by at least one selected from a halogen atom, hydroxyl group, cyano group, carboxyl group, carbamoyl group, amino group, aminosulfonyl group, a halogenosulfonyl group, amidinothio group, a mono- or di-lower alkylamino group, a lower alkanoylamino group, a lower alkylsulfonylami.no group, hydroxyami.no group, a mono- or di-lower alkylcarbamoyl group, trifluoromethyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a lower alkoxycarbamoyl group, a lower alkylsulfonylcarbamoyl group, sulfamoyl group, a mono- or di-lower alkylsulfamoyl group, a lower alkoxycarbonyl group, a heterocyclic group, a heterocyclic group-substituted carbamoyl group, a heterocyclic group-substituted lower alkylcarbamoyl group and a heterocyclic group-substituted sulfonylcarbamoyl group, (6) a lower alkoxycarbonyl group, (7) a lower alkenyl group which may be substituted by carboxyl group or a lower alkoxycarbonyl group, (8) a cyclo-lower alkyl group, (9) a carbamoyl group which may be substituted by at least one selected from a lower alkyl group, a lower alkoxy group and a lower alkylsulfonyl group, (10) an aryl group which may be substituted by at least one selected from nitro group, amino group, hydroxyl group, carbamoyl group, cyano group, carboxyl group, trifluoromethyl group, a lower alkoxycarbonyl group, a halogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkoxy-lower alkoxy group, a mono- or di-lower alkylamino group, a mono- or di-lower alkanoylamino group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, sulfamoyl group, a mono- or di-lower alkylsulfamoyl group, a lower alkylsulfonylamino group and a phenyl-lower alkoxy group, (11) a heterocyclic group which may be substituted by at least one selected from nitro group, hydroxyl group, formyl group, carbamoyl group, cyano group, amino group, carboxyl group, a lower alkoxycarbonyl group, a halogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a mono- or di-lower alkylamino group, a mono- or di-lower alkanoylamino group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, sulfamoyl group and a mono- or di-lower alkylsulfamoyl group, or (12) a heterocyclic group-substituted carbonyl group which may be substituted by at least one selected from nitro group, hydroxyl group, carbamoyl group, cyano group, carboxyl group, a lower alkoxycarbonyl group, a halogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a mono- or di-lower alkylamino group, a mono- or di-lower alkanoylamino group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, sulfamoyl group and a mono- or di-lower alkylsulfamoyl group; R3 is (1) an aryl group which may be substituted by at least one selected from cyano group, nitro group, amino group, a halogen atom, trifluoromethyl group, carboxyl group, hydroxyl group, carbamoyl group, a mono- or di-lower alkylamino group, a mono- or di-lower alkylamino-lower alkyl group, a mono- or di-lower alkylcarbamoyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkanoyloxy-lower alkyl group, sulfo group, a lower alkylthio group, a lower alkylthio-lower alkyl group, a lower alkylsulfonyl group, a lower alkylsulfamoyl group and a lower alkylsulfinyl group, (2) a heterocyclic group which may be substituted by at least one selected from oxo group, cyano group, nitro group, amino group, a halogen atom, carboxyl group, hydroxyl group, formyl group, carbamoyl group, a mono- or di-lower alkylamino group, a N-lower alkyl-N-cyclo-lower alkylamino group, a mono- or di-lower alkylamino-lower alkyl group, a mono- or di-lower alkylcarbamoyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkoxy-lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, sulfo group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfamoyl group, a lower alkylsulfinyl group and a heterocyclic group, or (3) a alkyl group which may be substituted by at least one selected from hydroxyl group, cyano group, carboxyl group, carbamoyl group, amino group, a mono- or di-lower alkylamino group, a lower alkanoylamino group, a lower alkylsulfonylamino group, hydroxyamino group, a mono- or di-lower alkylcarbamoyl group, trifluoromethyl group, a halogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, sulfamoyl group, a mono- or di-lower alkylsulfamoyl group, a lower alkoxycarbonyl group and a heterocyclic group; and R4 is (1) hydrogen atom, or (2) a lower alkyl group which may be substituted by a mono- or di-lower alkylamino group.
3. The large conductance calcium-activated K channel opener according to Claim 1 or 2, wherein R1 is (1) a lower alkyl group which may be substituted by carboxyl group, a lower alkoxycarbonyl group or a heterocyclic group, (2) an aryl group which may be substituted by one or two halogen atoms, or (3) a heterocyclic group which may be substituted by a halogen atom, R2 is (1) a lower alkyl group which may be substituted by carboxyl group, a lower alkoxycarbonyl group or a heterocyclic group, (2) a heterocyclic group which may be substituted by a halogen atom, or (3) an aryl group which may be substituted by one or two halogen atoms; R3 is (1) a heterocyclic group which may be substituted by one or two groups selected from amino group, a halogen atom, a lower alkyl group, a lower alkoxy group, a mono- or di-lower alkylamino group and a lower alkylthio group, or (2) an aryl group which may be substituted by amino group, a halogen atom, a lower alkyl group, a lower alkylthio group, a lower alkoxy group or a mono- or di-lower alkylamino group; and R4 is hydrogen atom or a lower alkyl group.
4. The large conductance calcium-activated K channel opener according to Claim 3, wherein R1 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxycarbonyl-lower alkyl group, (3) a lower alkyl group substituted by a tetrazolyl group, (4) a phenyl group which may be substituted by one or two halogen atoms, or (5) a thienyl group which may be substituted by a halogen atom; R2 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxy- carbonyl-lower alkyl group, (3) a lower alkyl group substituted by a tetrazolyl group, (4) a thienyl group which may be substituted by a halogen atom, or (5) a phenyl group which may be substituted by one or two halogen atoms; and R3 is (1) a benzothienyl group which may be substituted by a halogen atom, (2) a phenyl group which may be substituted by a halogen atom, a lower alkylthio group, a lower alkoxy group or a di-lower alkylamino group, (3) a pyridyl group which may be substituted by a lower alkyl group, a lower alkoxy group or a di-lower alkylamino group, (4) a pyrimidinyl group which may be substituted by a di-lower alkylamino group or a lower alkylthio group, (5) a thienyl group which may be substituted by one or two lower alkyl groups, (6) thieno [3, 2-b] pyridyl group, (7) benzofuryl group, (8) dihydrobenzofuryl group or (9) an indolyl group which may be substituted by a lower alkyl group.
5. The large conductance calcium-activated K channel opener according to Claim 4, wherein X is 0 or S; R1 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxycarbonyl-lower alkyl group, (3) a phenyl group which may be substituted by one or two halogen atoms, or (4) a thienyl group which may be substituted by a halogen atom; R2 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxycarbonyl-lower alkyl group, (3) a thienyl group which may be substituted by a halogen atom, or (4) a phenyl group which may be substituted by one or two halogen atoms; and R3 is (1) a benzothienyl group which may be substituted by a halogen atom, (2) a phenyl group which may be substituted by a halogen atom, a lower alkylthio group, a lower alkoxy group or a di-lower alkylamino group, (3) a pyridyl group which may be substituted by a lower alkoxy group or a di-lower alkylamino group, (4) a pyrimidinyl group which may be substituted by a di-lower alkylamino group, (5) a thienyl group which may be substituted by a di-lower alkyl group, (6) thieno [3, 2-b] pyridyl group, or (7) an indolyl group which may be substituted by a lower alkyl group.
6. Use of the large conductance calcium-activated K channel opener as set foth in any one of Claims 1 to 5 for manufacture of a medicament for use in the treatment or prophylaxis of pollakiuria or urinary incontinence.
7. A method for prophylaxis and/or treatment of pollakiuria or urinary incontinence which comprises administering an effective amount of the large conductance calcium-activated K channel opener as set forth in any one of Claims 1 to 5 to a patient of pollakiuria or urinary incontinence or a patient who has a possibility of causing pollakiuria or urinary incontinence.
8. Use of a compound of formula (I)
R1 R2
Figure imgf000293_0001
wherein X represents N-R4, 0 or S, R1 and R2 are different from each other and each independently represents hydrogen atom, a halogen atom, carboxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted lower alkyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted lower alkenyl group, a cyclo-lower alkyl group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted heterocyclic group-substi- tuted carbonyl group, R3 represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted lower alkyl group, and R4 represents hydrogen atom or a substituted or unsubstituted lower alkyl group, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in the treatment or prophylaxis of pollakiuria or urinary incontinence.
9. The use according to Claim 8, wherein R1 and R2 each independently represent (1) hydrogen atom, (2) a halogen atom, (3) a carboxyl group, (4) an amino group which may be substituted by at least one selected from formyl group, a lower alkyl group, a lower alkanoyl group, a lower alkylsulfonyl group and a lower alkoxycarbonyl group, (5) a lower alkyl group which may be substituted by at least one selected from a halogen atom, hydroxyl group, cyano group, carboxyl group, carbamoyl group, amino group, aminosulfonyl group, a halogenosulfonyl group, amidinothio group, a mono- or di-lower alkylamino group, a lower alkanoylamino group, a lower alkylsulfonylamino group, hydroxyamino group, a mono- or di-lower alkylcarbamoyl group, trifluoromethyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a lower alkoxycarbamoyl group, a lower alkylsulfonylcarbamoyl group, sulfamoyl group, a mono- or di-lower alkylsulfamoyl group, a lower alkoxycarbonyl group, a heterocyclic group, a heterocyclic group-substituted carbamoyl group, a heterocyclic group-substituted lower alkylcarbamoyl group and a heterocyclic group-substituted sulfonylcarbamoyl group, (6) a lower alkoxycarbonyl group, (7) a lower alkenyl group which may be substituted by carboxyl group or a lower alkoxycarbonyl group, (8) a cyclo-lower alkyl group, (9) a carbamoyl group which may be substituted by at least one selected from a lower alkyl group, a lower alkoxy group and a lower alkylsulfonyl group,
(10) an aryl group which may be substituted by at least one selected from nitro group, amino group, hydroxyl group, carbamoyl group, cyano group, carboxyl group, trifluoromethyl group, a lower alkoxycarbonyl group, a halogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkoxy-lower alkoxy group, a mono- or di-lower alkylamino group, a mono- or di-lower alkanoylamino group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, sulfamoyl group, a mono- or di-lower alkylsulfamoyl group, a lower alkylsulfonylamino group and a phenyl-lower alkoxy group, (11) a heterocyclic group which may be substituted by at least one selected from nitro group, hydroxyl group, formyl group, carbamoyl group, cyano group, amino group, carboxyl group, a lower alkoxycarbonyl group, a halogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a mono- or di-lower alkylamino group, a mono- or di-lower alkanoylamino group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, sulfamoyl group and a mono- or di-lower alkylsulfamoyl group, or (12) a heterocyclic group-substituted carbonyl group which may be substituted by at least one selected from nitro group, hydroxyl group, carbamoyl group, cyano group, carboxyl group, a lower alkoxycarbonyl group, a halogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a mono- or di-lower alkylamino group, a mono- or di-lower alkanoylamino group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, sulfamoyl group and a mono- or di-lower alkylsulfamoyl group; R3 is (1) an aryl group which may be substituted by at least one selected from cyano group, nitro group, amino group, a halogen atom, trifluoromethyl group, carboxyl group, hydroxyl group, carbamoyl group, a mono- or di-lower alkylamino group, a mono- or di-lower alkylamino-lower alkyl group, a mono- or di-lower alkylcarbamoyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkanoyloxy-lower alkyl group, sulfo group, a lower alkylthio group, a lower alkylthio-lower alkyl ω ω t cn o 01 o o cπ
Figure imgf000296_0001
substituted by one or two groups selected from amino group, a halogen atom, a lower alkyl group, a lower alkoxy group, a mono- or di-lower alkylamino group and a lower alkylthio group, or (2) an aryl group which may be substituted by amino group, a halogen atom, a lower alkyl group, a lower alkylthio group, a lower alkoxy group or a mono- or di-lower alkylamino group; and R4 is hydrogen atom or a lower alkyl group.
11. The use according to Claim 10, wherein R1 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxycarbonyl-lower alkyl group, (3) a lower alkyl group substituted by a tetrazolyl group, (4) a phenyl group which may be substituted by one or two halogen atoms, or (5) a thienyl group which may be substituted by a halogen atom; R2 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxycarbonyl-lower alkyl group, (3) a lower alkyl group substituted by a tetrazolyl group, (4) a thienyl group which may be substituted by a halogen atom, or (5 ) a phenyl group which may be substituted by one or two halogen atoms; and R3 is (1) a benzothienyl group which may be substituted by a halogen atom, (2) a phenyl group which may be substituted by a halogen atom, a lower alkylthio group, a lower alkoxy group or a di-lower alkylamino group, (3) a pyridyl group which may be substituted by a lower alkyl group, a lower alkoxy group or a di-lower alkylamino group, (4) a pyrimidinyl group which may be substituted by a di-lower alkylamino group or a lower alkylthio group, (5) a thienyl group which may be substituted by one or two lower alkyl groups, (6) thiopheno [3, 2-b] pyridyl group, (7) benzofuryl group, (8) dihydrobenzofuryl group or (9) an indolyl group which may be substituted by a lower alkyl group .
12. The use according to Claim 11, wherein X is 0 or S; R1 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxycarbonyl- lower alkyl group, (3) a phenyl group which may be substituted by one or two halogen atoms, or (4) a thienyl group which may be substituted by a halogen atom; R2 is (1) a carboxyl-lower alkyl group, (2) a lower alkoxycarbonyl-lower alkyl group, (3) a thienyl group which may be substituted by a halogen atom, or (4) a phenyl group which may be substituted by one or two halogen atoms; and R3 is (1) a benzothienyl group which may be substituted by a halogen atom, (2) a phenyl group which may be substituted by a halogen atom, a lower alkylthio group, a lower alkoxy group or a di-lower alkylamino group, (3) a pyridyl group which may be substituted by a lower alkoxy group or a di-lower alkylamino group, (4) a pyrimidinyl group which may be substituted by a di-lower alkylamino group, (5) a thienyl group which may be substituted by a di-lower alkyl group, (6) thiopheno [3, 2-b] pyridyl group, or (7) an indolyl group which may be substituted by a lower alkyl group.
13. A compound represented by the formula (I) wherein X is 0, one of R1 and R2 is a thienyl group substituted by a chlorine atom, and the other is a carboxyl-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group or a lower alkyl group substituted by a tetrazolyl group, and R3 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, or a pharmaceutically acceptable salt thereof.
14. The compound according to Claim 13, wherein R3 is (1) an aryl group which may be substituted by one or two substituents selected from a halogen atom, a di-lower alkylamino group, a lower alkylthio group and a lower alkoxy group, or (2) a heterocyclic group which may be substituted by one or two substituents selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group and a mono- or di-lower alkylamino group.
15. The compound according to Claim 14, wherein one of R1 and R2 is a thienyl group substituted by a chlorine atom, and the other is a carboxyl-lower alkyl group or a lower alkoxy- carbonyl-lower alkyl group; the aryl group is phenyl group; and the heterocyclic group is a thienyl group, a pyridyl group, a pyrimidinyl group, a benzothienyl group, a benzofuryl group, a dihydrobenzofuryl group, an indolyl group or a thieno- [3, 2-b] pyridyl group.
16. The compound according to Claim 14, wherein R3 is a phenyl group which is substituted by a halogen atom or a lower alkylthio group; a thienyl group which is substituted by one or two lower alkyl groups; a pyrimidinyl group which is substituted by di-lower alkylamino group; a benzothienyl group which may be substituted by a halogen atom; an indolyl group which may be substituted by a lower alkyl group; or a thieno [3, 2-b] pyridyl group .
17. A compound represented by the formula (I) wherein X is S, one of R1 and R2 is a thienyl group substituted by a chlorine atom, and the other is a carboxyl-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group or a lower alkyl group substituted by a tetrazolyl group, and R3 is a substituted or unsubstituted heterocyclic group, where said heterocyclic group is selected from a pyridyl group, a pyrimidinyl group, a benzothienyl group, an indolyl group and a thieno [3, 2-b] - pyridyl group, or a pharmaceutically acceptable salt thereof.
18. The compound according to Claim 17, wherein R3 is a heterocyclic group which may be substituted by one or two substituents selected from a halogen atom, a lower alkoxy group, a mono- or di- lower alkyl group, a lower alkylthio group and a mono- or di-lower alkylamino group, where said heterocyclic group is selected from a pyridyl group, a pyrimidinyl group, a benzothienyl group, and a thieno [3, 2-b] pyridyl group.
19. The compound according to Claim 18, wherein one of R1 and R2 is a thienyl group substituted by a chlorine atom, and the other is a carboxyl-lower alkyl group or a lower alkoxy- carbonyl-lower alkyl group; R3 is a pyridyl group which may be substituted by a di-lower alkylamino group; a pyrimidinyl group which may be substituted by a mono- or di-lower alkylamino group; or a benzothienyl group which may be substituted by a halogen atom.
20. 4- (5-Chlorothiophen-2-yl) -2- (2-benzo [b] thienyl) - thiazol-5-yl acetic acid,
5- (4-chlorophenyl) -2- (2-N,N-dimethylaminopyrimidin-5-yl) - oxazol-4-yl acetic acid,
4- (5-chlorothiophen-2-yl) -2- (4-methoxyphenyl) thiazol-5-yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (4, 5-dimethylthiophen-2-yl) - oxazol-4-yl acetic acid,
4- (5-chlorothiophen-2-yl) -2- (2-N,N-dimethylaminopyrimidin-
5-yl) thiazol-5-yl acetic acid, 4- (5-chlorothiophen-2-yl) -2- (2-N,N-dimethylaminopyridin-
5-yl) thiazol-5-yl acetic acid,
5- (4-chlorophenyl) -2- (4-fluorophenyl) oxazol-4-yl acetic acid,
5- (4-chloroρhenyl) -2- (2-benzo [b] thienyl) oxazol-4-yl acetic acid,
4- (5-chlorothiophen-2-yl) -2- (2-benzo [b] thienyl) oxazol-5-yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (2-N,N-dimethylaminopyrimidin-
5-yl) oxazol-4-yl acetic acid, 4- (4-chlorophenyl) -2- (2-N,N-dimethylaminopyrimidin-5-yl) - thiazol-5-yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (2-benzo [b] thienyl) oxazol-4-yl acetic acid,
4- (4-chloroρhenyl) -2- (4-methoxyphenyl) thiazol-5-yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) oxazol-4-yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (6-fluorobenzo [b] thiophene-2- yl) oxazol-4-yl acetic acid, 5- (3-thienyl) -2- (2-benzo [b] thienyl) oxazol-4-yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (2-thieno [3, 2-b] pyridyl) - oxazol-4-yl acetic acid,
5- (3-fluoro-4-chlorophenyl) -2- (2-benzo [b] thienyl) oxazol-4- yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (2-benzo [b] thienyl) thiazol-4-yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (4-methylthiophenyl) oxazol-4-yl acetic acid,
4- (5-chlorothiophen-2-yl) -2- (4-fluorophenyl) oxazol-5-yl acetic acid, 5- (5-chlorothiophen-2-yl) -2- (4-chlorophenyl) oxazol-4-yl acetic acid,
4- (3-fluoro-4-chlorophenyl) -2- (4-methoxyphenyl) thiazol-5-yl acetic acid,
4- (5-chlorothiophen-2-yl) -2- (4, 5-dimethylthiophen-2-yl) - thiazol-5-yl acetic acid,
4- (3-fluoro-4-chlorophenyl) -2- (4-fluorophenyl) thiazol-5-yl acetic acid,
4- (4-chlorophenyl) -2- (2-N,N-dimethylaminopyridin-5-yl) - thiazol-5-yl acetic acid, 4- (5-chlorothioρhen-2-yl) -2- (4-N,N-dimethylaminophenyl) - thiazol-5-yl acetic acid,
5- (5-chlorothioρhen-2-yl) -2- (N-methylindol-2-yl) oxazol-4-yl acetic acid,
5- (5-chlorothiophen-2-yl) -2- (4, 5-dimethylthiophen-2-yl) - thiazol-4-yl acetic acid; or a lower alkyl ester thereof; or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a therapeutically effective amount of a compound as set forth in any one of Claims
13 to 20 in admixture with a therapeutically acceptable carrier or diluent.
22. Use of the compound as set forth in any one of Claims 13 to 20 for manufacture of a medicament for use in the prophylaxis and/or treatment for pollakiuria or urinary incontinence.
23. The use according to Claim 22, wherein the compound is as set forth in Claim 20.
24. Use of a compound as set forth in any one of Claims 13 to 20 for manufacture of a large conductance calcium-activated K channel opener.
25. The use according to Claim 24, wherein the compound is as set forth in Claim 20.
26. A large conductance calcium-activated K cannel opener comprising as an active ingredient the compound as set forth in any one of Claims 13 to 20.
27. The large conductance calcium activated K channel opener according to Claim 26, wherein the compound is as set forth in Claim 20.
28. A method for prophylaxis and/or treatment of pollakiuria or urinary incontinence which comprises administering an effective amount of the compound as set forth in any one of Claims 13 to 20 to a patient of pollakiuria or urinary incontinence or a patient who has a possibility of causing pollakiuria or urinary incontinence.
29. The method according to Claim 28, wherein the compound is as set forth in Claim 20.
PCT/JP2002/003723 2001-04-16 2002-04-15 Imidazole, thiazole and oxazole derivatives and their use for the manufacture of a medicament for the treatment and/or prevention of pollakiuria or urinary incontinence WO2002083111A2 (en)

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IL15816802A IL158168A0 (en) 2001-04-16 2002-04-15 5-membered, nitrogen-containing heterocyclic compounds and pharmaceutical compositions containing the same
KR1020037013493A KR100863659B1 (en) 2001-04-16 2002-04-15 Nitrogen-Containing Heterocyclic Compound and Pharmaceutical Composition Thereof
NZ529043A NZ529043A (en) 2001-04-16 2002-04-15 Large conductance calcium-activated K channel opener
JP2002580915A JP4073786B2 (en) 2001-04-16 2002-04-15 High conductance calcium-sensitive K channel opener
AU2002246397A AU2002246397B2 (en) 2001-04-16 2002-04-15 Imidazole, thiazole and oxazole derivatives and their use for the manufacture of a medicament for the treatment and/or prevention of pollakiuria or urinary incontinence
EP02714577A EP1432690A2 (en) 2001-04-16 2002-04-15 Imidazole, thiazole and oxazole derivatives and their use for the manufacture of a medicament for the treatment and/or prevention of pollakiuria or urinary incontinence
CA002444596A CA2444596A1 (en) 2001-04-16 2002-04-15 Large conductance calcium-activated k channel opener
US10/474,850 US7759373B2 (en) 2001-04-16 2002-04-15 Large conductance calcium-activated K channel opener
US12/795,323 US20100256165A1 (en) 2001-04-16 2010-06-07 Large conductance calcium-activated k channel opener

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