AU2005202751B2 - Large conductance calcium-activated K channel opener - Google Patents

Description

S&F Ref: 650467D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Tanabe Seiyaku Co., Ltd., of 2-10 Dosho-Machi 3-chome Chuo-ku, Osaka, 541-8505, Japan Mitsuya Hongu Thoshihiro Hosaka Toshihiko Kashiwagi Hiroyuki Kobayashi Rikako Kono Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Large conductance calcium-activated K channel opener The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c 1

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 nitrogencontaining 5-membered heterocyclic compound as an active ingredient, which is useful for treatment of disorders or diseases such as pollakiuria, 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 -2 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 W096/40634, a furan derivative disclosed in Japanese Provisional Patent Publication No. 2000-351773, and a nitrogen-containing derivative in which the nitrogen atom is substituted by phenyl group or benzyl group disclosed in International Publication W098/04135.

Also, a compound having a similar structure to the nitrogencontaining 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 3 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

R

1

R

2 X N

(I)

R

3 wherein X represents N-R 4 0 or S, 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 or a substituted or unsubstituted lower alkyl group, or a pharmaceutically acceptable salt thereof as an active ingredient.

4 BEST MODE FOR CARRYING OUT THE INVENTION In the nitrogen-containing 5-membered heterocyclic compound 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, trihydrocyclopentathienyl 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 abovementioned 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 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.

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, 6 a lower alkylsulfonylamino group, a lower alkoxycarbamoyl group, a lower alkylsulfonylcarbamoyl group, sulfamoyl group, a monoor 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 alkyL3ulfonylamino 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 7 group and a mono- or di-lower alkylsulfamoyl group.

As a substituent on the heterocyclic group for the heterocyclic group-substituted carbonyl group, there maybe 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 monoor 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 R 3 there may be 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 8 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 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.

Of the compounds which are active ingredients of the present invention, 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, -9 a trif luoromethy--lower alkyl group, a cyclo-lower alkcyl 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 alkylheterocyclic group, a haogeno-heterocyclic group, or a heterocyclic group substituted by a halogen atom and a lower alkyl group; R 3 is an aryl group, a halogefloaryl group, a hydroxyaryl group, a cyanoaryl group', a nitroaryl group, a lower alkylaryl group, a lower alkoxyaryl group, a lower alkyithicaryl group, a heterocyclic group, a lower alkoxycarboflylheterocyclic group, a cyano- heterocyclic group, a halogeloheterocyclic group, a lower alkyl-heterocyclic group, a *di-lower alkyl-heterocycllc 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 alkcyl group; and R 4 is hydrogen atom.

In another preferred embodiment of the present invention,. X is N-10,F 0 or R' or R 2 is independently hydrogen atom, a lower alkcyl group, a lower alkyl group substituted by a heterocycl~ic group, a lower alkylamino group, a di-lower alkylainfo group, a cyano-lower alkcyl 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 alkylsulfonylamlifoarYl 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 3 .5 alkoxy group, an aryl group substituted by a halogen 10 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 3 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 alkylheterocyclic group, a hydroxy-lower alkyl-heterocyclic group, a di-lower aralkylamino-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 R 4 is hydrogen atom or a lower alkyl group.

Of these, particularly preferred compounds are compounds wherein X is 0 or S; 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 alkylthio-heterocyclic group, or a di-lower alkylaminoheterocyclic group.

Among the nitrogen-containing 5-membered heterocyclic compounds more preferred compounds in view of 11 pharmaceutical effects are compounds wherein R 1 is a lower alkyl group which may be substituted by carboxyl group, a lower alkoxycarbonyl group or a heterocyclic group, 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 a lower alkyl group which may be substituted by carboxyl group, a lower alkoxycarbonyl group or a heterocyclic group, a heterocyclic group which may be substituted by a halogen atom, or an aryl group which may be substituted by one or two halogen atoms; R 3 is 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 monoor di-lower alkylamino group and a lower alkylthio group, or 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

R

4 is hydrogen atom or a lower alkyl group.

Of these, more preferred compounds are compounds wherein R 1 is a carboxyl-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a lower alkyl group substituted by a tetrazolyl group, a phenyl group which may be substituted by one or two halogen atoms, or a thienyl group which may be substituted by a halogen atom; R 2 is a carboxyl-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a lower alkyl group substituted by a tetrazolyl group, a thienyl group which may be substituted by a halogen atom, or a phenyl group which may be substituted by one or two halogen atoms; and R 3 is 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 alkyl group, a lower alkoxy group or a di-lower alkylamino group, a pyrimidinyl group which may be substituted by a di-lower alkylamino group or a lower alkylthio group, a thienyl group which may be 12 substituted by one or two lower alkyl groupS, thieflopyridyl group, benzofuryl group, dihydrobenzofuryl group o Ir an indolyl group which may be substituted by a lower alkyl group.

these, particularly preferred compounds are compounds wherein X is 0 or S; e 1 is a carboCyl-lower alkcyl group, a lower alkoxycarbonYl-lower alkyl group, a phenlyl 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 a carboxyl-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a thienyl group which may be substituted by a halogen atom, or a phenyl group which may be substituted by one or two halogen atoms; and e 3 is 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 alkylain~fo group, a pyridyl group which may be substituted by a lower alkoxy group,. or a- di-lower alkylainfo group, a pyrimidinyl group which may be substituted by a di-lower allcylamnifo group, a thienyl group which may be substituted by two lower alkyl groups, thieno[3,2blpyridyl group, or an indolyl group which may be substituted by a lower alkyl group.

The most preferred compound in view of. pharmfaceutical ef fects is the compound selected- from the group consistinlg of! 4 (5-chlorothioPhel- 2 (2-benzo thienyl) acetic acid, 5- (4-chlorophelYl) -2 (2 oxazol-4-yl acetic acid, 4- (5-chlorothiophefl- 2 -y1) (4-methoxyphelYl) acetic acid, (5-chiorothiophen-2-yl) 5-d{methylth.ophel- 2 -yl)oxazol-4-yl acetic acid, 4- (5-chlorothiophen-2 -yl) (2-NN-dime thyl aminopyrimidin- 13 acetic acid, 4- (5-chlorothiophen-2-yl) N-dimethylaminopyridinacetic acid, (4-chiorophenyl) (4-fluorophenyl) oxazol-4-y. acetic acid, (4-chiorophenyl) (2-benzo~b] thienyl) oxazol-4-y. acetic acid, 4- (5-chlorothiophen-2-yl) (2-benzo (bithienyl) acetic acid,.

5- (5-chlorothiophen-2-yl) N-dimethylaminopyrimidin- 5-yl)oxazol-4-yl acetic acid, 4- (4-chiorophenyl) N-dimethylaminopyrimidin-5-yl) acetic acid, (5-chlorothiophen-2-yl) (2-benzo Eb] thienyl) oxazol-4-y.

acetic acid, 4- (4-chiorophenyl) (4-methoxyphenyl) thiazol-5-yl acetic acid, (5-chlorothiophen-2-yl) (4-fluorophenyl) oxazol-4-yl acetic acid, 5- (5-chlorothiophen-2-yl) (6-fluorobenzo [bi thiophene-2yl)oxazol-4-yl acetic acid, (3-thienyl) (2-benzo[b] thienyl) oxazol-4-yl acetic acid, (5-chlorothiophen-2-yl) (2-thieno[3,2-bjpyridyl) oxazol-4-yl acetic acid, 5- (3-fluoro-4-chlorophenyl)-2-(2-benzo~b~thienyl)oxazol-4yl acetic acid, (5-chlorothiophen-2-yl) (2-benzo Ib] thienyl) thiazol-4-yl acetic acid, (5-chlorothiophen-2-yl) (4-methyithiophenyl) oxazol-4-yl acetic acid, 4- (5-chlorothiophen-2-yl) (4-fluorophenyl) acetic acid, (5-chlorothiophen-2-yl) (4-chiorophenyl) oxazol-4-yl acetic acid, 4- (3-fluoro-4-chlorophenyl) (4-methoxyphenyl) acetic acid, 14 4-(5-chlorothiophen-2-yl)-2-(4,5-dimethylthiophen-2-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)acetic acid, 4-(5-chlorothiophen-2-yl)-2-(4-N,N-dimethylaminophenyl)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 R' and R 2 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 R 3 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group.

Of these, more preferred compounds are compounds wherein R 3 is 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 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 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 15 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 R 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 R 1 and R 2 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 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.

In a more preferred embodiment, 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 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, pyrimidinyl group, a benzothienyl group, and a thieno[3,2-b]pyridyl group.

In a further preferred embodiment, one of R 1 and R 2 is a thienyl 16 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.

In the compound 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 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 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 or pharmaceutically acceptable salts thereof includes its internal salts, addition products, solvates and hydrates.

The active ingredient 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.

17 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, GumArabic, 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 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 may generally be about 0.1 to 50 mg/kg per day, more preferably about 0.3 to 30 mg/kg per day.

'The compound 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 -incont-i-nen-e,-naoect-r-na-l-enu-rei-s,--nd-the 18 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) 19 V H Condensation N R cyclization

R

1 agent i

R

2

R

3 (I-a) wherein X 1 represents NH, O or S, and other symbols have the same meanings as defined above.

Among the nitrogen-containing 5-membered heterocyclic compound a compound 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

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, triphenylphosphinephosgene, sulfuric acid, polyphosphoric acid, p-toluenesulfonic 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.

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, 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 20 temperature to 120 0

C.

(Method B)

R

1

R

2 0 1

NH

R R HN N R2 NH 2 (IV)

R

(I-b) wherein Z 1 represents a reactive residue, and other symbols have the same meanings as defined above.

Also, among the compound 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 abovementioned solvents. The present reaction proceeds suitably at to 150°C, particularly at 60 to 120°C.

(Method C) 21

R

1 R2 R R

R

3

-B(OW')

2 VI X N or X N R-Sn(W) 3 VI I

R

3

(I)

wherein Z 2 represents a reactive residue, W 1 represents hydrogen atom or a lower alkyl group, W 2 represents a lower alkyl group, and other symbols have the same meanings as defined above.

The compound can be also prepared by reacting a compound represented by the formula 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 bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, etc.

When Method C is carried out by using the compound 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, tetrahydrofuran, dimethylformamide, methanol, ethanol, toluene, benzene, chloroform or a mixed solvent of the above-mentioned solvents. The present reaction proceeds suitably at 60 to 150 0

C,

22 m particularly at 80 to 120 0

C.

(Method D)

R

1

R

2 Ammonia or N= R

R

3 -CHO ammonium salt HN o (ix) CN

R

3 (I-b) wherein the symbols have the same meanings as defined above.

Also, among the compound a compound 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 to 120 0

C.

In the above-mentioned Methods A to D, the compounds (III), (VIII) or (IX) may be used as a salt of an inorganic acid such as hydrochloride, sulfate, etc., or a salt of an 23 inorganic base such as an alkali metal salt, an alkaline earth metal salt, etc.

As the reactive residue of Z 1 and Z 2 a halogen atom is suitably used.

The nitrogen-containing 5-membered heterocyclic compound (I) can be prepared by converting objective 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 to Method A compound wherein R 1 or R 2 is a halogen atom can be prepared by reacting a compound where corresponding R 1 or R 2 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 0

C.

Method A compound 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 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. 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 etc. Also this reaction proceeds 24 more suitably in the presence of a zinc salt such as zinc chloride, zinc bromide, zinc iodide, etc. This reaction proceeds suitably at 50 0 C to 120 0

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 A compound wherein R 1 or R 2 is a substituted or unsubstituted heterocyclic group-substituted carbonyl group can be prepared by reacting a compound 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.

Method A compound where X is N-R 4 and R 4 is a substituted or unsubstituted alkyl group can be prepared by reaction of a compound 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. 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 0 C to 80 0

C.

Method 25 A compound where R1 or R2 is a formylamino group or an N-lower alkyl-N-formylamino group can be prepared by reacting a compound 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.

Method A compound 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 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. 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 Method A compound where R or R 2 is a lower alkoxycarbonylamino group can be prepared by reacting a compound where corresponding R 1 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 Method A compound where R 1 or R 2 is a hydroxy-lower alkyl group can be prepared by reacting a compound where corresponding

R

1 or R 2 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 26 alkoxide, triethylamine, and the like. This reaction proceeds suitably at 60 0 C to 120 0

C.

Method (i) A compound where R 1 or R 2 is a halogeno-lower alkyl group can be prepared by reacting a compound where corresponding

R

1 or R 2 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 0

C.

Method A compound where R 1 or R 2 is a lower alkoxy-lower alkyl group can be prepared by reacting a compound where corresponding

R

1 or R 2 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 to 800C.

Method A compound where R 1 or R 2 is a lower alkylthio-lower alkyl group can be prepared by reacting a compound where corresponding R' or R 2 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 00C to 600C.

Method 27 A compound 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 where corresponding R 1 or R2 is a lower alkylthio-lower alkyl group with an oxidizing agent.

As the oxidizing agent, there may be suitably used metachloroperbenzoic acid, aqueous hydrogen peroxide solution and the like. This reaction proceeds suitably at -20°C to 30 0

C.

Method A compound 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 where corresponding R' 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. 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 0

C.

Method A compound where R 3 is a heterocyclic group substituted by a sulfo group can be prepared by reaction of a compound 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) This reaction proceeds suitably at 0°C to 50 0

C.

Method A compound where R 3 is a heterocyclic group substituted by sulfamoyl group can be prepared by treating a compound where corresponding R 3 is a heterocyclic group substituted by chlorosulfonyl group with ammonia. This reaction proceeds suitably at OOC to 60 0

C.

Method A compound where

R

1

R

2 or R 3 is a heterocyclic group substituted by a hydroxy-lower alkyl group or R I or R 2 is a hydroxy-lower alkyl group can be prepared by reacting a compound where corresponding

R

1 R2 or R 3 is a heterocyclic group substituted by a lower alkoxycarbonyllower alkyl group or corresponding

R

1 or R 2 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 0

C.

Method A compound where R 1 or R 2 is a substituted or unsubstituted carbamoyl group can be prepared by reaction of a compound where corresponding R' br R 2 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-dimethylamino propyl)-carbodiimide hydrochloride, diethylcycanophosphate and the like. This reaction proceeds suitably at 0 C to 0

C.

Method A'compound 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 dilower alkylamine. This reaction proceeds suitably at 30 0 C to 120 0

C.

29 u Method A compound where R 3 is a pyrimidinyl group substituted with amono- or di- lower alkylamino group can be prepared by reacting C 5 a compound where corresponding R is a pyrimidinyl group substituted with a lower alkylthio group with a oxidizing agent, followed by reacting the resulting compound with corresponding

C

N 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 Method A compound where R 1 or R 2 is a substituted or unsubstituted carbamoyl-lower alkyl group can be prepared by reacting a compound where corresponding R* or R 2 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-- (3-dimethylaminopropyl)carbodiimide hydrochloride, diethyl cyanophosphonate, and the like. This reaction proceeds suitably at 0*C to Method A compound where

R

1 or R 2 is a cyano-lower alkyl group can be prepared by reacting a compound where corresponding

R

1 or R 2 is a carbamoyl-lower alkyl 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 0 C to 1000C.

Method A compound where R 1 or R 2 is a tetrazolyl-lower alkyl group can be prepared by reacting a compound where corresponding

R

1 or R 2 is a cyano-lower alkyl group with an azide compound.

30 Examples of the azide compound may be sodium azide, a trialkyltin azide, a trialkylsilyl azide, and the like. This reaction proceeds suitably at 80 0 C to 120 0

C.

The reactions mentioned in the above Methods to 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 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. W095/04724 and No. W099/01128, 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 31 conventional method as mentioned below.

0 R R2 Bromination R^ Azidation

R!

Reduction 0

R

2 NH2

R

3

-COCI

0

H

O

RN

R

2 0 (n) wherein the symbols have the same meanings as defined above.

Also, among the compounds a compound wherein R 2 is a halogen atom can be prepared specifically by the conventional method as mentioned below.

Formylation 0 R 0

NHCHO

Condensationcyclization agent

R

1

R

2 x N Halogenation

ON

wherein symbols (V-a)

Z

3 represents a halogen atom, and the other have the same meaning as defined above.

The active ingredients of the present invention can be 32 exemplified by the following Preparation examples but they are not limited thereto.

Preparation example Preparation example 1 A crude product of 2- (6-methylnicotinoylamino) (3-pyridyl) 1-butanone (425 mg) was dissolved in acetic acid (5 ml), and ammoniumacetate (2.30 g) 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 removed under reduced pressure. The resulting residue was triturated with acetone to obtain 5-ethyl-2-(2-methylpyridin-5-yl)-4-(3-pyridyl)imidazole trihydrochloride (369 mg) as pale yellowish crystalline powder.

Melting point: 270 to 273°C (decomposed) MS-APCI 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.

33 Table 1 34 Table 1 (contd.) 35 Table 1 (contd.) 36 Table 1 (contd.) 37 Table 1 (contd.) Preparation Chemical structure salt Phy c.

example No.: constnec 2HCl Crystal Melting point: 250-253 0

C

MS -APCI (m/z) 293 19

I

2HCl Crystal Melting point: 2 14-2 160 C MS -APCI z) 334/336 r--H3 2HCl Crystal Melting point: 215-217 0

C

MS-APCI.(m/z): 256 Free material Powder MS-APCI(m/z): 308 38 Table 1 (contd.) 39 Table I (contd.) 40 Table 1 (contd.) 41 Table 1 (contd.) 42 Table 1 (contd.) Preparation Chemical Salt Physical constant, example No. structure etc.

C Ha lHCl Crystal Melting point: 185-188 0

C

38HN ,N MS-APCI(m/z): 303(M+H)+ 'PF H 1HCl Crystal Melting point: 39 H ,-N233-236 0

C

39 HSMS.APCI NO.308 (M-IH) \C HCl Crystal Melting point: 188-1900C H MS-APCI(m/z): 303 a /1HC1 Crystal Melting point: 41 H-250-2550C 41 MS.APCI(m/z): 1~1Ih1~~F239 43 Table 1 (contd.) Preparation Chemical Salt Physical constant, example No. structure etc.

1HC1 Crystal Melting point: >300 0

C

MS-APCI(m/z) :246(M+ HN 1N

H)+

42

CN

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 silica gel 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 293 (MH+) Preparation examples 44 to 62 The following compounds shown in Table 2 were prepared in a manner similartoPreparationexample43byusingcorrespondingstarting materials.

44 Table 2 45 Table 2 (contd.) 46 Table 2 (contd.) lE~i Crystal Melting point: 267-269"C.

MS-APCI 274 MS-APCI 275 Crystal Melting point: 198-201*C Crystal Melting point: 205-207 0

C

MS -APCI z): 290 47 Table 2 (contd.) 48 Table 2 (contd.) Preparation Chemical Salt Physical constant, example No. structure 3 Free Crystal -material Melting point: 147-149 0

C

EI-MS(M/z): HN N297/299(M+) 01 \Free Crystal -ti material Melting point: 169-170 0

C

HN ~NEI.MS(m/z): 266(M+) 61

F

QN Free Crystal material Melting point: 17 6-178 0

C

EI*MS(m/z): 291(M+) _2 H ~N

F

49 Preparation example 63 Under ice-cooling, phosphorus oxychloride (0.24 ml) was added dropwise to a solution of 2-(5-chlorothiophen-2-yl)amino-l- (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 and brine, and then, 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 ethyl acetate=2:l) and.treated with hydrogen chloride-ethanol solution to obtain chlorothiophen-2-yl)-4-ethyl-5-(3-pyridyl)oxazole hydrochloride (466 mg) as pale yellowish powder.

Melting point: 201 to 204 0

C

MS-APCI 291/293 (MH+) Preparation examples 64 and The following compounds shown in Table 3 were prepared in a manner similar to Preparation example 63 byusingcorresponding starting materials.

50 Table 3 Preparation Chemical Salt Physical example No. structure constant, etc.

S/ o 1HC 1 Powder o MS-APCI(m/z): 64 o0 343(M+H)+ I CH Free Powder S o material MSAPCI(m/z): N 349(M+H)+ a 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 dried over anhydrous sodiumsul fate, and the solvent was removed under reduced pressure. The resulting residue was recrystallized from methanol to obtain 2-(4-fluorophenyl)-4-(2methoxyphenyl)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) 51 Melting point: 245 to 248 0 C (hydrochloride) MS-APCI 269 (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 (58 mg) in an aqueous 2M sodiumcarbonate solution (1ml) and dimethoxyethane (3 ml) was stirred under argon atmosphere at 1000C for hours. After cooling, to the reaction mixture were added water 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 286 (MH+) Preparation examples 68 The following compounds shown in Table 4 were prepared in a manner similar to Preparation example 67byusingcorresponding starting materials.

52 Table 4 Preparation Chemical Salt Physical constant, example No. structure etc.

2HC1 Powder MS-APCI(m/z):

CH

3 257(M+H) 68 HN N Preparation example 69 A mixture of ethyl 2,3-diketovalerate (8.00 4-fluorobenzaldehyde (11.30 g) and ammonium acetate (35.00 g) in acetic acid (120 ml) was stirred under argon atmosphere at 70 to 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 solution andbrine, dried overanhydrous 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 263 (MH+) Preparation example A mixture of ethyl 5-ethyl-2-(4-fluorophenyl)imidazol-4carboxylate (2.81 4N aqueous sodium hydroxide solution (14 53 ml), ethanol (35 ml) and tetrahydrofuran (15 ml) was stirred at room temperature 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 neutralized by 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 purified by HP-20 resin (trade name, available fromNippon Rensui (solvent: water methanol) to give second crop of 5-ethyl-2-(4-fluorophenyl)imidazol-4-carboxylic acid (1.60 g).

ESI-MS 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 reaction mixture, 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-(Nmethoxy-N-methylcarbamoyl)imidazole (656 mg) as colorless powder.

MS-APCI 278 (MH+) 54 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 and after stirring the mixture at the same temperature for 30 minutes, a solution of 5-ethyl-2-(4-fluorophenyl)-4-(N-methoxy-N-methylcarbamoyl)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-(2pyridyl) 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 296 (MH+) Preparation example 73 The following compounds shown in Table 5 were prepared in a manner similartoPreparationexample 72byusingcorrespondingstarting materials.

55 Table Preparation Chemical structure Salt Physical example No. constant, etc.

CH

3 2HCl Solid MS*APCI(m/z): HN N 296(M+H)+ 73

F

Preparation example 74 Inacetonitrile (80ml) weredissolved 2, 2-dichlorobutanal (16.2 g) and 4-fluorobenzaldehyde (14.9 To the solution was added dropwise 28% aqueous ammonia (135 ml) under ice-cooling, and the resulting mixture 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-ethylfluorophenyl)imidazole (9.36 g).

MS-APCI 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.

56 Table 6 Preparation Chemical Physical example No. structure constant, etc.

CH

3 C 2HCl Solid MS-APCI(m/z): H N 188(M+H)+

N

CH

3

CH,

Free Crystal material Melting point: 168-170°C H N MS-APCI(m/z): 76 205(M+H)+

F

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 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) 57 MS-APCI :269/271 (MH+) Melting point: 219 to 221*C MS*APCI 269/271 (MH+) (Free material) (decomposed) (Hydrochloride) (Hydrochloride) Preparation examples 78 and 79 The f ollowing compounds shown in Table 7 were prepared in a manner similar to Preparation example 77 by using corresponding starting materials.

Table 7 Preparation Chemical Sat Physical constant, example No. structure Satetc.

Br CH 3 2H-Cl Solid rMS*APCI HN N 264/266(MIH)+ 78

'~N

CH 3 CH 3 lHCl Crystal Br Melting point: 178-180*C HN 14 N MS -APCI z): H~~J 283/285(M+H)+

F

58 Preparation example 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 acetatehexane 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 268 (MH+) Preparation examples 81 to 101 The following compounds shown in Table 8 were prepared in a manner similar to Preparation example 80by using corresponding starting materials.

59 Table 8 60 Table 8 (contd.) Preparation Chemical Salt Physical constant, example No. structure etc.

-N

h H lHCl Crystal Melting point: 287-289 0

C

MS-APCI(M/Z):

269(M+H)+

F

/S lHCl Crystal Melting point: 86 254-256 0

C

86 MS.APCI(m/z): 274(M+H)+

F

F

HCl Crystal CH3 Melting point: 233-2350C MS.APCI(m/z): 87 HN ~N 299(M+H)+ 1HCl Crystal Melting point: 224-226 0

C

88HN MS-APCI~m/z): 88 281

F

61 Table 8 (contd.) 62 Table 8 (contd.) 63 Table 8 (contd.) 64 Table 8 (contd.) Preparation Chemical structure Salt Physical constant, Chemical structure Salt e example No. etc.

C H, 1HC 1 Crystal Melting point: 186-189*C

H

2 N" MS-APCI(m/z): 101 OHN N 324(M+H)+

F

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 (79mg, 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 with 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: chloroform methanol=95:5), and treated with hydrogen chloride-methanol solution to obtain 5-ethyl-2-(4-fluorophenyl)-l-methyl-4- pyridyl) imidazole dihydrochloride (285 mg).

MS-APCI 282 (MH+) Preparation examples 103 and 104 65 The following compounds shown in Table 9 were prepared in a manner similar to Preparation example 102 by using corresponding starting materials.

Table 9 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 282 (MH+) 66 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 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 borane*dimethylsulfide complex (1.90 ml), and the mixture was stirred under argon atmosphere at room temperature 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=5:1) to obtain 5-methylamino-2-(4-fluorophenyl)-4phenylimidazole (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 0

C

MS-APCI 268 (MH+) Preparation example 108 To a solution of 5-formylmethylamino-2-(4-fluorophenyl)- 67 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 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-(4fluorophenyl)-4-phenylimidazole hydrochloride (174 mg) as colorless powder.

MS-APCI 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 chloridemethanol solution to obtain 5-methoxycarbonylamino-2-(4fluorophenyl)-4-phenylimidazole hydrochloride (67 mg) as colorless powder.

MS-APCI 312 (MH+) Preparation example 110 To a solution of 5-acetylamino-2-(4-fluorophenyl)-4-phenylimidazole (142 mg) in tetrahydrofuran (7 ml) was added C1 68 Cc 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 5 at 600C for 10 minutes. After cooling, the mixture was neutralized by adding a saturated aqueous sodium hydrogen CI carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Sanhydrous 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, treated with hydrogen chloride-methanol solution to obtain 5-ethylamino-2- (4-fluorophenyl) -4-phenylimidazole hydrochloride (89 mg) as colorless powder.

MS-APCI 282 (MH+) Preparation example 111 A mixture of 5-ethylamino-2-(4-fluorophenyl)-4-phenylimidazole (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 310 (MH+) Preparation example 112 Amixture of 2- (5-chlorothiophen-2-yl) (3-pyridyl) imidazole (1.07 35% formalin aqueous solution (35 ml), potassium carbonate (1.70 isopropanol (30 ml) and N,N-dimethylformamide (10ml) 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 69 removed under reduced pressure. The resulting residue was triturated with ethyl acetate to obtain phen-2-yl)-5-hydroxymethyl-4-(3-pyridyl)imidazole (519mg) as colorless powder.

MS-APCI 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 Preparation example No.

Chemical structure I Salt Physical constant, etc.

t *1- Free material Crystal Melting point: 225-228 0

C

MS-APCI(m/z): 270(M+H)+ 113 3HC1 Crystal Melting point: 266-269°C MS*APCI(m/z): 267(M+H)+ 114 70 Table 10 (contd.) Preparation Chemical Sat Physical constant, example No. structure Sat etc.

-Free Crystal /material Melting point: OH 232-234 0

C

MS -APCI z): 115 H269(M+H)+ Free Powder.

OH material MS-APCI(m/z): 277 H 116 Free Crystal OH material Melting point: 24 0-2 43 0

C

HN,-N MS.APCI(m/z): 117 269(MIH)+

F

71 Table 10 (contd.) Preparation Chemical Salt Physical constant, example No. structure etc.

Free Powder material MS-APCI(m/z): OH 276(M+H)+ HN N 118

CN

Preparation example 119 To a solution of 2-(5-chlorothiophen-2-yl)-5-hydroxymethyl-4-(3-pyridyl)imidazole (200 mg) inmethylene chloride ml) was added thionyl chloride (5ml), and the mixture was re fluxed 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 sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with a mixed solution of ethyl acetatetetrahydrofuran. The organic layer was washed with 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 72 and then, treated with hydrogen chloridedioxane 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 0 C (decomposed) MS-APCI 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.

73 Table 13.

Preparation Chemical Salt Physicaliproperty, etc.

-example No. structure H/ 1HC1 Crystal Melting point: 121- N 204-2070C 121 MS APCI(m/z): 283 1HCl Powder MS.APCI(m/z): 122 H 2 8 9 (M+Ii) h lC HCl Crystal 0 Melting point: 123 N_ f185-188 0

C

123 MS-APCI(m/z): HN 283 /3 1HC1 Powder 0 MS.APCI(m/z): Q __r290 124 H~N 74 Table 11 (contdl.) 75 Preparation example 129 To a solution of 2-(3-fluorophenyl)-5-hydroxymethyl-4- (3-pyridyl) imidazole (389 mg) in methylene chloride (10 ml) 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 mi) 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:l) to obtain 2-(3fluorophenyl)-5-methylthiomethyl-4-(3-pyridyl)imidazole (198 mg) as colorless powder.

MS*APCI 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.

76 Table 12 Preparation Chemical Sat Physical property, example No. structure Sat etc.

/,CHS 1HCl Crystal s Melting point: 218-220 0

C

131 HN AN MS *APCI 299 ,CH. lHCl Crystal S Melting point: H 256-259 0

C

132 H yN MS-APCI(m/z): 306(M+H)+

ON

h /l Free Crystal s material Melting point: 172-174 0

C

13 H N MS *APCI 133 300 SFree Crystal S material Melting point: 209-211 0

C

134 AMS-APCI(m/z): 307

CN

77 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)-5methylsulfinylmethyl-4-(3-pyridyl)imidazole hydrochloride (140 mg) as colorless powder.

MS-APCI 316 (MH+) Preparation examples 136 to 140 The following compounds shown in Table 13 were prepared in a manner similar to Preparation example 135 by using corresponding starting materials.

78 Table 13

I

79 Table 13 (contd.) Preparation Chemical structure Salt Pysica example No. constant, etc.

0^ 1HC1 Crystal CH, Melting point: -S 278-280 0

C

0 MS-APCI(m/z): 140 HN N 351(M+H)+

F

Preparation example 141 A mixture of ethyl 2-(5-chlorothiophen-2-yl)-5-(3-pyridyl)oxazole-4-yl acetate (68 mg), lithium hydroxide (9 mg), ethanol (4 ml) and water (4 ml) was stirred at room temperature for 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 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.

80 Table 14 Preparation Chemical structure Salt Physical example No. constant, etc.

-N 01HCl Powder MS -APCI z):

OH

142 0313

(M-H)

Preparation examples 143 and 144 A mixture of 2- (5-chlorothiophen-3-yl) -5-ethyl-4- (3-pyridyl) imidazole 00 g) in chiorosulf onic 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 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 4) and then, by NH silica gel f lush column chromatography (solvent: chloroform: methanol=l0:1 -4 4:1) to obtain. 2-(5-chloro-2-sulfothiophen-3-yl) -5-ethyl-4- (3-pyridyl) imidazole and 2- 2-sulfamoylthiophen-3-yl) -5-ethyl-4- (3-pyridyl) imidazole.

Each product was treated with hydrogen chloride-dioxane solution to obtain 2- (5-chloro-2-sulfothiophen-3-y.) -5--ethyl-4- (3pyridyl)imidazole dihydrochloride (741 mg) and 2-sulfamoylthiophen-3-yl) -5-ethyl-4- (3-pyridyl) imidazole dihydrochloride (105 mg) each as colorless powder.

2- C5-Chloro-2-sulfothiophen-3-yl) -5-ethyl-4- (3-pyridyl) 81 imidazole dihydrochloride (Preparation example 143) ESI-MS 368 (M-H) 2-(5-Chloro-2-sulfamoylthiophen-3-yl)-5-ethyl-4-(3-pyridyl) imidazole dihydrochloride (Preparation example 144) MS-APCI 369 (MH+) Preparation example 145 To a solution of 2-(2-ethoxycarbonylthiophen-3-yl)-5ethyl-4-(3-pyridyl)imidazole (879 mg) in tetrahydrofuran 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 sodium tartarate 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-(3pyridyl) imidazole dihydrochloride (788 mg) as colorless powder.

MS-APCI 286 (MH+) Preparation example 146 To a solution of ethyl 2-(5-chlorothiophen-2-yl)-4-(3pyridyl) imidazol-5-yl acetate (122 mg) in tetrahydrofuran ml) was added lithiumaluminumhydride (15 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 2.5 hours.

Underice-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 82 preparative thin-layer chromatography (TLC) (silica gel; solvent: chloroform methanol=20:l) to obtain 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 0 C (free material) MS*APCI 306 (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) (2-thienyl) oxazol-5-yl acetate mg) as pale yellowish powder.

MS'APCI 332 (MH+) Preparation example 148 To a solution of ethyl 2-(4-fluorophenyl)-4-(2-thienyl)acetate (94 mg) in tetrahydrofuran (3ml) and ethanol (3 ml) was added 1N 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 83 (556 pl, 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-ylacetate (90mg) as pale brownish powder.

ESI-MS 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 purified by silica gel flush column chromatography (solvent: n-hexane ethyl to obtain ethyl 5-bromo-2-(4-fluorophenyl)oxazol-4-yl acetate (3.57 g) as pale yellowish crystal.

Melting point: 84 to 85 0

C

MS-APCI 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 84 reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: n-hexane ethyl acetate=8:l) to obtain ethyl 2-(4-fluorophenyl)-5-iodoxazol- 4-yl acetate (300 mg) as colorless crystal.

Melting point: 120 to 122 0

C

MS*APCI 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 (1.5 ml) and dimethoxyethane 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:l) 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 1300C MS-APCI 366/368 (MH+) Preparation example 152 To a solution of ethyl 5-(5-chlorothiophen-2-yl)-2-(4fluorophenyl)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 pl, methanol solution) was added to the solution and the 85 solvent was removed under reduced pressure. The resulting residue was triturated with acetone to obtain thiophen-2-yl)-2-(4-fluorophenyl)oxazol-4-yl acetic acid sodium salt (100 mg) as pale yellowish powder.

ESI-MS 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.

86 Table Preparation Chemical Salt Physical property, exa-mple No. structure etc.

-Na Crystal Melting po-int: 0. Y >300 0

C

153 MS.APCI(m/z): 296 (M-Na) A 0 F'ree Crystal material Melting 0CH\ point:105-107*C 154 MSAC (m/z) y 344 Z Na. Powder ESI-MS (mlz): 0 314 (M-Na) 155 0' Na Powder 6' ESI.MS 0 -298 (M-Na) 156 87 Table 15 (contd.) Preparation Chemical structure Salt Physical example No. etc.

S

Free Powder material MS -APCI z): 157 382CM+H)+

F

0 Na Powder 0 0 MS*APCI(m/z): 158 0352(M-Na) pH.

Free Powder 0 material MS*APCI(m/z): 159 Z (386 f H, 0 HOG~ Na Powder 0 \/MS-APCI(m/z): 0 356(M-Na) 160 0 N0 88 Table 15 (contd.) 89 Table 15 (contd.) Preparation Chemical Salt Physical example No. structure property, etc.

F

F Free Powder ooi

H

material MS-APCI(m/z): 165 N 362(M+H)+

F

F /Na Powder o- MS-APCI(m/z): Y 332(M-Na) 166 0N 0 Preparation examples 167 to 202 The following compounds shown in Table 16 were prepared in a manner similar to one oftheabove-mentioned Preparationexamples, or conventionally known preparation processes as described in Japanese Provisional Patent Publications No. 5832/1972, No.

29771/1973 and the like.

90 Table 16 91 Table 16 (contd.) 92 Table 16 (contd.) Preparation Chemical Salt Physical example No. structure property, etc.

-CF

3 Free MS-EI(m/z): material 320(M,+) 175 OH Free N material 176 NBr Free MS*EI(m/z): HN Nmaterial 332/334/336(M+) 177

NH

2 2HC1 Powder MVS APCI(m/z): 178 HN .N 254(M+H)+ 93 Table 16 (contd.) Preparation Chemical structure Salt Physical example No. etc.

N) N CH, 1HCl Powder 0 MS APCI HN /N 296 179 h

OH

3 1HCl Powder Q -263 180 /CH 1HiCJ Powder MS APCI(m/z): HN 321(M+H)+ 181 SF lHCl Powder MS APCI 182 285(M+H)+ 94 Table 16 (contd.) PrepaationPhysical Peaparation Chemical structure Salt property, exampe No.etc.

0 1HCl Powder OW MS APCI 183 NN N329 IiiCl Powder O MS APCI (mlz): 184 HN ,N 343(Iv+H)+

F

lHCl Powder MS APCI 185 345 0 1HCl Powder HN MS APCI(m/z): 186 345(M+H)+ 95 Table 16 (contdi.) 96 Table 16 (contd.) Preparation Chemical structure Salt Physical example No. _____property, etc.

0 Free Crystal 0 material Melting point: 191 0109-111 0

C

MS.APCI(m/z): 3 32CMIH) 0 SFree Crystal OH material Melting point: 192 0 N214-215 0

C

Free H material 193 8 Free Powder 0 ~e H material ms Ei 194 319/321 97 Table 16 (contd.) Preparation Chemical structure Salt .Physical example No. etc.

S

Free MS EI(Iu/z):

H

2 material 334/336(M+) 195 A 0 Free Crystal

S

material Melting point: 196 0 H, 125-127 0

C

MS-APCI(m/z): 328

CH

S

/Na Powder 0 MS-ESI~m/z): 0 0 302 (M-Na) 197

F

98 Table 16 (contd.) Preparation Chemical structure Salt Physical example No. property, etc.

Na Powder 0 MS-ESI(m/z): 198 1I298 (N-Na)

CH,

/jI Na Powder 0 MS -ESI 199 X0314 (N-Na) OH0 s N OHFree Crystal 0 material Melt ing point: 200 198-199 0

C

ICH,

A 0 Na Powder MS -APCI z): 201 302 (N-Na)

CI

99 Table 16 (contd.) Preparation Chemical structure Salt Physical example No. property, etc.

Free Crystal S material Melting point: 202 ma t e r i a l 123-125 0

C

MS-APCI(m/z): 327(M+H)+

F

Preparation example 203 A mixture of ethyl 3-amino-4-(5-chlorothiophen-2-yl)- 4-oxobutyrate hydrochloride (300 mg), carboxylic acid (245 mg), 3-ethyl-l-(3-dimethylaminopropyl)carbodiimide hydrochloride (289 mg), 1-hydroxybenzotriazole (204 mg) and triethylamine (0.35ml) inmethylene chloride (4.5 ml) was stirred at room temperature for overnight.

A saturated aqueous sodium hydrogen 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 benzo[b]furoyl)amino-4-(5-chlorothiophen-2-yl)-4-oxobutyrate (352 mg) as colorless powder.

To a solution of the resulting ethyl 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 overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted 100 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 benzo[b]furyl)-5-(5-chlorothiophen-2-yl)oxazol-4-yl acetate (257 mg) as colorless powder.

MS-APCI 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.

101 Table 17 Preparation Ceiastuur Slt Physical property, example No. Ceiastcur Slt etc.

0 Free Powder Smaterial MS-APCI(m/z): 204 0 N344 0J' 3Free Powder /material MS*APCI(m/z): 205 356 W'C

CH

0 Free Powder

S

0 material MS-APCI(m/z): 206 0 N354 K~ Free Powder material MS-APCI(m/z):

N

207 0N370 s- 102 Table 17 (contd.) Preparation Ceiastuur Slt Physical property, example No. Ceiastuur Slt etc.

Free Powder C, material MS *APCI (m/z) 208 .365(M+H)+ 0 Free Powder 0 N material M S APCI 209 1354(M+H)+ 0 Free Powder 0 CH material MS*APCI(m/z): 210 "(334(M+H)+ AI~ Free Powder material MS.APCI(m/z): 00 CH 211 382/384(M4H)+ C1 103 Table 17 (contd.) 104 Table 17 (contd.) Preparation Chemical Sat Physical property, -example No. structure Sat etc.

Free Powder o- material MS*APCI 21 436/438(M+H)+ Free Powder 0 CH, material MS-APCI(m/z): 217 436/438 0," AFree Powder 21 o. CH material MS -APCI z): 218 390/392 cl 7 0 Free Powder 0 material MS.APCI(m/z):

CH~

219 406/408 105 Table 17 (contd.) Prep aration Chemical Salt Physical example No. structure property, etc.

CI Free Powder 22 CHO material MS-APCI(m/z): 220 399/401 /Free Powder material MS-APCI(m/z): 221 0 H, 5/5

HOC

S Free Powder 0- material MS-APCI(m/z): 0- CHO 222 1383/385 AI Free Powder material MS-APCI(m/z): 0 ~CHO 223 349/351 106 Table 17 (contd.) Preparation example 227 To a solution of 4-[(5-benzo[b]furoyl)aminoacetyl]-2chlorothiophene (543 mg) in N,N-dimethylformamide (10 ml) was added sodiumhydride (71.3 mg, 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 107 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 (5-benzob] 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)-4oxobutyrate (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:l), and then, triturated with diethyl ether to obtain ethyl 2-(5-benzo[b] furyl) thiophen-3-yl) oxazol-4-yl acetate (349mg) as colorless powder.

MS-APCI 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.

108 Table 18 109 Table 18 (contd.) 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.

110 Table 19 111 Table 19 (contd.) Preparation Chemical structure Salt Physical example No. property, etc.

h Na, Powder 0 237 0 ESI*MS(M/z): 237 312 (M-Na) /Na Powder 0 ESI*MS(M/z): 238BH 389 (M-Na)

F

Na Powder 0 ESI -MS (M/Z) 239 -347 (M-Na) 01

CI

Na Powder ESIN S (m/z) 240 N: 364 (M-Na) 112 Table 19 (contd.) Preparation Chemical structure Salt Physical property, example No. etc.

-Na Powder ESI-MS(m/z): 241 0 1 330 (M-Na) 0 Na Powder 0 ESI*MS(m/z): 242 0 ,N346(M-Na)

F

CI

Na' Powder 0 ESI MS 243 0~330 (M-Na)

F

F- Na Powder ESI'MS(m/z): 244 0364 (M-Na) 113 Table 19 (contd.) Preparation Chemical structure Salt Physicaliproperty, etc.

example A Na Powder 0 ESI*NS(M/z): 396(M-Na) 245 0

F

0Na Powder a ESI*MS(m/z): 344(M-Na) 246 P Na Powder ESI*MS(m/z): 326(M-Na) 247

HO

CH,

Na Powder h ESI.MS(m/z): 338(M-Na) 248 c-I. -114- Table 19 (contd.) 115 Table 19 (contd.) 253 ESI*MS(m/z): 348 (M-Na) Powder ESI -MS z) 3 36 (M-Na) 254 255 ESI*MS(m/z): 324 (M-Na) Powder ESI-MS(m/z): 382 (M-Na).

256 116 Table 19 (contd.) 117 Table 19 (contd.) Preparation Chemical structure Salt Physical property, -example No. etc.

0 Na Powder 0, ESI'MS(M/Z): 261 328 (M-Na) INa Powder 0 ESI'MS(M/z): 262 292 (M-Na)

OH

3 to Na Powder ESI.MS(m/z): 263 0 ,N 314(M-Na)

ICH

3 0 0 Na Powder 0 ESI'MS(M/z): 264 0 286(M-Na)

F

118 Table 19 (contd.) Powder ESI MS (M/z) 304 (M-Na) 265 ESI*MS(m/z): 324 (M-bNa) 266 267 ESI MS 3 40 (M-Na) 268 1 1 0

CHS

Powder ESI*MS(m/z): 304 (M-Na) 119 Table 19 (contd.) 120 Table 19 (contd.) Preparation Chemical Sl hsclpoetec example No. structure Sl hsclpoetec CINa Powder 0 ESI-MS(m/z): 360(M-Na) 273 A '0 Na Powder 0- ESI*MS(m/z): 325(M-Na) 274 0~ CI0 S Na Powder 275 ESI*MS(m/z): 275 352/354 CM-Na) 0 Na Powder 0 ESI'MS(m/z): 335(M-Na) 0 ~N 276

N.

121 Table 19 (contdl.) 122 Table 19 (contd.) 123 Table 19 (contd.) 124 Table 19 (contd.) 125 Table 19 (contd.) 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.

126 Table Preparation Physical Preparation Chemical structure Salt Physical example No. property, etc.

0 Br Free Powder C N material MS-APCI(m/z): 29 CH3 340/342(M+H)+ 294

H_,_C

CH,

I r Free Crystal material Melting point: 0 4N 120-122°C 295 MS-APCI(m/z): 376(MH)+

F

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- 127 phenyl)-5-phenyloxazol-4-yl acetate (144 mg) as colorless powder.

Melting point: 118 to 120°C MS-APCI 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.

128 Table 21 Preparation Chemical structure Salt Physical No.ampleNo._ constant, etc.

/Free Powder material MS'APCI (mlz): 297 344 F \/Free Powder material MS-APCI 298 N 0344

F

h Free Powder material MS-APCI (mlz): 299 CH, 419

F

Free Powder cb

ON_-CH

3 material MS-APCI 300 0 .0 377 129 Table 21 (contd.) 130 Table 21 (contd.) Preparation Chemical structure Salt Physical example No. etc.

J H- Free Powder /material MS-APCI(m/z): 305 394

CI

-I JH Free Powder 0 material MS-APCI(m/z): 306 0394/396(M+H)+

F

O /Free Powder 0 material MS-APCJI(m/ z) 307 360/362

F

F

Free Powder material MS-APCI z) 308 374 (H-IH) 131 Table 21 (contd.) 132 Table 21 (contd.) Preparation Chemical structure Salt Physical example No. _____constant, etc.

JH Free Powder material MS-APCI(m/z): 313 0, 374(M+H)+ Free Powder 0 material IvSAPCI(m/z): 314 418

CI

Free Powder material MS-APCI(m/z): 315 (378(M+H)+ S CH,

F

6 F nP, Free Powder h 0material MS-APCI(m/z): 316 362

F

133 Table 21 (contd.) 134 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 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 Preparation example 323 135 A mixed solution of ethyl 2-(4-fluorophenyl)-5-[3-(2methylpropyloxy)-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)-4hydroxyphenyl]oxazol-4-yl acetate (269 mg).

MS-APCI 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 Preparation Chemical structure Salt Physical example No. constant, etc.

HO ,0-0H HO -H H Free Powder 0 material MS-APCI(m/z):37

S

2 324 o

F

Preparation example 325 To a mixed solution of ethyl 2-(4-fluorophenyl)-5-(5formyl-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 136 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-2yl)oxazol-4-yl acetate (125 mg) as pale yellowish powder.

MS-APCI 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 Preparation Chemical structure Salt Physical example No. constant, etc.

H

3 C OH Free Powder material MS-APCI(m/z): o .CH 3 376(M+H)+ 326 0o -N 0

F

Preparation example 327 To a solution of ethyl 5-(3-benzyloxyphenyl)-2-(4-fluorophenyl) oxazol-4-yl acetate (349mg) inmethanol (20ml) was added 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 137 concentrated under reduced pressure. The resulting residue was crystallized from diisopropyl ether to obtain ethyl 2-(4fluorophenyl) (3-hydroxyphenyl) oxazol-4-yl acetate (195mg) as colorless crystal.

Melting point: 175 to 177 0

C

MS-APCI 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) under ice-cooling, and the mixture was allowed to warm to room temperature. To the mixture, another portion of boron tribromide (1.05 ml, 1.OM 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 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-methylpropionate (30 mg) as pale brownish powder.

MS-ESI 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) 138 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 (0.06 ml) in an ice bath, and the resulting mixture was stirred at room temperature for 14 hours. To the reaction mixture were addeda saturatedaqueous ammoniumchloride solution and ethyl acetate, 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 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 360 (MH+) Preparation example 330 A solution of ethyl 2-(6-chloropyridin-3-yl)-5-(5-chlorothiophen-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 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.

139 Table Preparation Chemical Salt Physical example No. structure constant, etc.

S 0 Free Powder material MS-APCI(m/z): 0 ;N OCH 358(M+H)+ 331

SNH

H

8

C/N'CH,

S

Free Powder material MS-APCI(m/z): H ~358(M+H)+ 332

-N

H C NCH, 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=20:1) to obtain methyl 2- (5-benzo[b] furyl)-5- (3-thienyl) oxazole-4-yl acetate (121 mg) as colorless powder.

140 MS-APCI 340 (MH+) Preparation examples 334 to 336 The following compounds shown in Table 26 were prepared in a manner similar to one of the above-mentioned Preparation examples, or conventionally known preparation processes as described in U.S. Patent No. 3,470,195 and the like.

141 Table 26 Preparation Chemical structure Salt consaec example No. constant,_e Br 01 0-CHS Free

S

0 material 01 334 0I Free r material

H

3

C

0 Free Powder material MS*APCI(m/z): 3364 CHS 250(M+H)+

F

Preparation example 337 To a solution of 2-[(4-fluorobenzoylamino)acetyljthiophene (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 142 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 ml), and phosphoryl chloride (240 pi) 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= 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 299 (MH+) Preparation example 338 A mixture of 4-(2-cyanoethyl)-2-(4-fluorophenyl)-5-(2thienyl)oxazole (95 mg), conc. hydrochloric acid (3 ml) and formic acid (4 ml) was stirred at 60 0 C overnight. After addition of conc. hydrochloric acid (1 ml), the mixture was stirred at 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), sodium methoxide (600 pl, 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 143 sodium salt (103 mg) as pale brownish powder.

MS-ESI 316 (M-Na) Preparation example 339 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 pl) 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 washedwith water 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.

To a solution of the product obtained in the above-mentioned (63 mg) in tetrahydrofuran (1 ml) and ethanol (2 ml) was added IN aqueous sodium hydroxide solution (170 pl) 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 350/352 (M-Na) 144 Preparation example 340 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-formyloxazole (943 mg) as colorless powder.

MS-APCI 308 (MH+) To a solution of ethyl diethylphosphonoacetate (740 pl) in tetrahydrofuran (12 ml) was added sodium hydride (153 mg, mineral oil) in an ice-acetone bath, and the resulting mixture was stirred at the same temperature for 15 minutes. 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 reaction mixture was neutralized by a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed withwater 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), and then, 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 378 (MH+) Preparation example 341 A mixture of 5- (5-chlorothiophen-2-yl) (4-fluorophenyl) -4methoxycarbonyloxazole (1.8 g) and lithium borohydride (580 mg) in tetrahydrofuran (40 ml) was stirred at room temperature for one hour, and then, refluxed for 1.5 hours. After cooling, water 145 and 10% hydrochloric acid were added to the reaction mixture, and the mixture was 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 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 310/312 (MH+) Preparation example 342 In a manner similar to Preparation example 341 by using the corresponding starting materials, 5-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)-4-hydroxymethyloxazole was obtained.

MS-APCI 322/324 (MH+) Preparation example 343 To a solution of ethyl 2- (4-fluorophenyl) oxazole-4-carboxylate (7.44 g) in chloroform (100ml) was addeddropwisebromine (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 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. 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 314/316 (MH+) Preparation example 344 146 To a solution of methyl 3-(5-chlorothiophen-2-yl)-2-(4fluorobenzoylamino)-3-oxopropionate (7.25 g) in N,N-dimethylformamide (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 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: 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 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-(4fluorophenyl)oxazol-4-carboxylate was obtained.

Preparation example 346 A mixture of ethyl 5-bromo-2-(4-fluorophenyl)oxazol-4carboxylate (600 mg), 0.05M (4-chloro-3-fluorophenyl) zinc bromide (6 ml, tetrahydrofuran solution), and tetrakis- (triphenylphosphine) palladium (231 mg) in tetrahydrofuran 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 solution andbrine, driedoveranhydrous sodiumsulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent: ethyl 147 acetate n-hexane=l:8) to obtain ethyl 5-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)oxazol-4-carboxylate (580 mg) as pale reddish solid.

MS.APCI 364/366 (MH+) Preparation example 347 A mixture of p-fluorobenzamide (5 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 and the filtrate was concentrated under 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 sodium hydrogen 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=1:9) to obtain ethyl 2-(4-fluorophenyl)oxazol-4carboxylate (7.44 g) as colorless solid.

MS-APCI 236 (MH+) Preparation example 348 Chlorine gas was bubbled through a suspension of 2-[5-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)oxazol-4yl]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 minutes. Water was added to the reactionmixture, and the mixture 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 148 product of 5-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)oxazol-4-yl methanesulfonyl chloride.

The product obtained in 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-ylmethanesulfonamide (164 mg) as pale yellowish solid.

MS-APCI 385/387 (MH+) To a solution of 5-(4-chloro-3-fluorophenyl)-2-(4-fluorophenyl)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 383/385 (MH+) Preparation example 349 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 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-fluorophenyl)oxazole (925 mg).

149 A solution of the crude product obtained in (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 chloro-3-fluorophenyl)-2-(4-fluorophenyl)-oxazol-4-yl]methylthiourea hydrochloride (954 mg).

MS-APCI 380/382 (MH+) Preparation example 350 To a solution of 5-(2-cyanoethyl)-2-(4-fluorophenyl)-4-(2methoxyphenyl)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 reduced pressure. The residue was purifiedbypreparative TLC (solvent: hexane ethyl acetate=l:l), and further purified by NH silica gel column chromatography (solvent: hexane ethyl acetate=l:l). To the product was added hydrogen chlorideethanol 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 308 (MH+) Preparation examples 351 to 355 The following compounds shown in Table 27 were prepared in a manner similarto Preparation examples 43 andPreparation example 152 by using the corresponding starting materials.

150 Table 27

I

151 Table 27 (contd.) Preparation Chemical structure Salt Physical constant, example No. etc.

1 0 Na Powder ESI.MS(m/z): N 0 367/369(M-H) 355 Preparation example 356 A mixture of ethyl 2- (6-aminopyridin-3-yl)-5-(5-chlorothiophen-2-yl)oxazol-4-yl acetate (70 mg) and 40% aqueous chloroacetoaldehyde solution (47 pl) in ethanol (2.1 ml) was refluxed for 3 hours, and 40% aqueous chloroacetoaldehyde solution (16 pl) wasaddedto 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= 49:1497:3) to obtain ethyl 5-(5-chlorothiophen-2-yl)oxazol-4-yl acetate (65 mg).

MS-APCI 388/390 (MH+) Preparation example 357 To a solution of ethyl 2-(6-chloropyridin-3-yl)-5- (5-chlorothiophen-2-yl)oxazol-4-yl acetate (1 g) in N,N-dimethylformaldehyde (10 ml) was added sodium azide (1.7 and the mixture was refluxed overnight. After cooling, water was added to the reaction mixture and the mixture was extracted with 152 ethyl acetate, 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: chloroform ethyl acetate=8:l) to obtain ethyl 2- (6-azidopyridin-3-yl)-5-(5-chlorothiophen- 2-yl)oxazol-4-yl acetate (401 mg) as yellowish powder.

A mixture of ethyl 2-(6-azidopyridin-3-yl)-5-(5chlorothiophen-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 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 ethyl acetate=5:122:341:2), and then, trituratedwith diethyl ether to obtain ethyl 2-(6-aminopyridin-3-yl)-5-(5-chlorothiophen-2-yl)oxazol-4-yl acetate (177 mg) as yellowish powder.

MS.APCI 364/366 (MH+) Preparation example 358 A mixture of ethyl 5-(5-chlorothiophen-2-yl)-2-(l-formylindolin-5-yl)oxazol-4-yl acetate (160 mg) and 6N hydrochloric acid (2 ml) in ethanol (4 ml) was stirred at 60 0 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:l) to obtain ethyl 5-(5-chlorothiophen-2-yl)-2-(5-indolinyl)oxazol-4-yl acetate (53 mg) as colorless powder.

MS.APCI 389/391 (MH+) 153 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, 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=8:1) to obtain ethyl 2-(2-dimethylaminopyrimidin-5-yl)-5-(5-chlorothiophen-2-yl) oxazol-4-yl acetate (139 mg) as colorless powder.

MS-APCI 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.

154 Table 28 Preparation Chemical Salt Physical example No. structure constant, etc.

o Free Powder material MS-APCI(m/z): 407/409(M+H)+ 360

NVN

cH Free Powder

CH

8 material MS-APCI(m/z): 405/407(M+H)+ 361

HCN'CH,

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.

155 Table 29 Preparation example 365 To a suspension of ethyl 2-(6--chloropyridin-3-yl)-5- (3thienyl) oxazol-4-yl acetate (150 mg) in ethanol (3 ml) was added aqueous sodiummethy. sulf ide solution (2 ml) and themixture was ref luxed for 3 days. After cooling, the reaction mixture 156 was neutralized by 10% hydrochloric acid, and extracted with 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 diethyl ether and dissolved inmethanol (5 ml), and 0.5M sodium methoxide (495 il, 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-(3thienyl)oxazol-4-yl acetic acid sodium salt (74 mg) as pale yellowish .powder.

MS-ESI 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 331 (M-Na) Preparation example 367 To a suspension of ethyl 2-(6-chloropyridin-3-yl)-5-(5chlorothiophen-2-yl) oxazol-4-yl acetate (192 mg) in ethanol 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 After cooling, the reactionmixture was neutralized by 10% hydrochloric acid, and extracted with 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 pl, methanol solution) was added to the solution and the solvent was removedunder reduced pressure.

The resulting residue was triturated with acetone to obtain 2-(6-ethoxypyridin-3-yl)-5-(5-chlorothiophen-2-yl)oxazol- 157 4-yl acetic acid sodium salt (169 mg) as pale yellowish powder.

MS-ESI 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 Preparation Chemical structure Salt Physical example No. constant, etc.

cI 0l Na Powder 0- ESI*MS(m/z): o/N 349/351(M-Na)- 368

HC"

S o Na Powder ESI-MS(m/z): o; 315(M-Na)- 369 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) 158 and 1, 8-diazabicyclo undecene (0.32 ml) were added to the mixture and the resulting mixture was stirred at 100 0 C overnight.

The reaction mixture was poured into 10% hydrochloric acid, 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 the reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane ethyl acetate= and then, the resulting product was dissolved in methanol (10 ml), and 0.5M sodium methoxide (68 pl, methanol solution) was added to the solution and the solvent was removed under reduced pressure to obtain N- (4-fluorophenyl) (3-thienyl) oxazol-4-yl acetyl]methanesulfonamide sodium salt (42 mg) as colorless powder.

MS-ESI 379 (M-Na) Preparation example 371 Corresponding starting compounds are treated in a manner similar to Preparation example 370 to obtain the compound shown in Table 31.

Table 31 Preparation Chemical structure Salt Physical constant, example No. etc.

S o Na Powder 3 o ESI MS(m/z): 371 442 (M-H)

F

159 Preparation example 372 To a mixture of ethyl 2-(4-fluorophenyl)-5-(5-chlorothiophen-2-yl)oxazol-4-yl acetate(1.01 g) in ethanol (5 ml), diethyl ether (5 ml) 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 reduced pressure. 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 381/383 (MH+) Preparation example 373 A mixture of 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 (95 mg), 1-hydroxybenzotriazole (67 mg) and triethylamine (0.14 ml) in N,N-dimethylformamide (3 ml) was stirred at room 160 temperature overnight. Water was added to the reaction mixture, the mixture was extracted with chloroform. The otganic 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=20:i'), and triturated with diethyl ether-hexane to obtain N-methoxy [2- (4-fluorophenyl)-5-(3-thienyl)oxazol-4-yl]acetamide (75 mg) as colorless powder.

1 MS-APCI 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.

161 Table 32 162 Preparation example 378 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 methanesulfonyl chloride (96 pl) and triethylamine (188 pl) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with methylene chloride. 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 2-(4-fluorophenyl)-4-(2-methanesulfonyloxyethyl)- 5-(3-thienyl)oxazole.

To a solution of methanesulfonamide (136 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (57 mg, 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 was added to the mixture and the resulting mixture was stirred at room temperature for one hour and then stirred at 60 0 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 reduced pressure. After the resulting residue was purified by silica gel column chromatography (solvent: hexane ethyl acetate=4:l), the obtained product was dissolved in methanol(5 ml), and 0.5M sodiummethoxide (562 pl, 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 365 (M-Na) 163 Preparation example 379 A mixture of 2-(4-fluorophenyl)-5-(3- thienyl)oxazol-4-yl acetic acid (1.5 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 and the mixture was extracted with chloroform. The organiclayer 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:9-1:7) to obtain 4- (t-butoxycarbonylamino) methyl- 2-(4-fluorophenyl-5-(3-thienyl)oxazole (501 mg).

MS-APCI 375 (MH+) A solution of 4-(t-butoxycarbonylamino)methyl-2-(4florophenyl)-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 275 (MH+) Preparation example 380 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 (0.15ml).

The reaction mixture was stirred at 0°C for one hour, and further 164 stirred at room temperature for 2 hours. To the reaction mixture 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).

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 concentratedunder reducedpressure andthe resulting residue was triturated with acetone to obtain fluorophenyl)-5-(3-thienyl)oxazol-4-yl]methanesulfonamide sodium salt (112 mg).

MS-APCI 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.

165 Table 3 3 166 Table 33 (contd.) Preparation Chemical Salt Physical constant, example No. structure etc.

ci

ZG

Free Powder 0 material MS-APCI(m/z): 385 X405/407 (M-iH)+ /Free Powder 0 material MS.APCI(m/z): 386 396/398 (14-H) Free Powder material MS.APCI(m/z): 387 06399/401 (M+H)

N

ci zFree Powder material MS-APCI(m/z): 0 0 ~N 391/393(M+H)+ 388

CH,

167 Table 33 (contd.) 168 Table 33 (contd.) Preparation Chemical SatPhysical example No. structure Sat constant, etc.

/Free Powder 0material MS*APCI(M/z): 393 387/389 0a--'CH Free Powder I, material MS'APCI(m/z): 394 368/370(M+H)i

CH,

0 Free Powder 0- material MS.APCI(m/z): 39535(MI)+ NyN CIFree Powder 0material MS.APCI(m/z): 372/374 396

O'CH.

169 Table 33 (contd.) 170 Table 33 (contd.) Preparation Chemical structure Salt Physical example No. _____constant, etc.

sFree Powder material MS'APCI(m/z): 401 403/405 Fre e Powder material ESI.MS 402 0333/335 (l-Na)- C3 Free Powder material MS-APCI(m/z): 403 393/395 (M-iH)+ a/l Free Powder omaterial MS*APCI(m/z): 404 aN c-I 171 Table 33 (contd.) Preparation Chemical structure Se example No.

C-I -matE c-I 405

F

172 Table 33 (contd.) Preparation Chemiical SatPhysical example No. structure Sat constant, etc.

's Free Crystal 0~ material Melting point: 409 77-78 0

C

K

1 MS.APCI(m/z) 360 a 0 Free Crystal material Melting point: 410 0H 84-86 0

C

MS-APCI(m/z): CH,358 Free Crystal -material Melting point: 411 130-133 0

C

~C H MS-APCI(m/z): 365(M+H)+

N

0 Free Oil material MS.APCI(m/z): 0 I& CH,370 412 173. Table 33 (contd.) 174 Table 33 (contd.) 175 Table 33 (contd.) Preparation Chemical SatPhysical ex!Mple No. structure aconstant, etc.

Free Powder material MS.APCI(m/z): 0 CH S/ 0 C4 1 Free Powder 0material MS.APCI(m/z): 422 359(M+H)+ 06 Free Powder S material MS-APCI(m/z): 423 0368/370 01 H, Free Powder -01 material MS-APCI(xn/z): 424N 417/419(M+H)+ 0

Z-/

176 Table 33 (contd.) Preparation Chemical srcue SatPhysical example No. stutr at constant, etc.

a ,,Free Powder

S

0 material MS.APCI(m/z): 425 0,384/386 0Free Crystal -material melting point: 426 112-113 0

C

MS-APCI(mlz): 420 (M-sH) z CH Free Crystal c material Melting point: 427 0 ,~80-81 0

C

MS.APCI(m/z): 6NCH 328

S

0 Free Crystal material Melting point: 428 MS-APCI(m/z): I365(H) 177 Table 33 (contd.) Preparation Chemical Salt Physical constant, example No. structure etc.

Free Crystal S 0 material Melting point: 145-146 0

C

429 0H' 429 C, MS-APCI(m/z): 389/391 0 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.

178 Table 34 Preparation Chemical struacture Salt Physical example No. etc.

0Na Powder ESI-MS(m/z): 352 430 (M-Na) h 0 Na Powder 0 ESI.MS(m/z): 332 0- 431 (M-Na) 0Na Powder

S

0 ESI*MS(m/z): 298 432 0 4 (M-Na) /Na Powder SESI -MS 298 0 (M-Na) 4330!:N

H,

179 Table 34 (contd.) Preparation Chemical structure Salt Physical example No. constant, etc.

CI aNa Powder .0 ESI*MS(M/Z): 369 434 (M-Na) 0Na Powder b- ESI*MS(m/z): 035 358/360 (M-Na) SNa Powder 0 ESI-MS(m/z): 348 436 (M-Na)

HO

S

0 Na Powder ESI-MS(m/z): 340 437, (M-Na)- 180 Table 34 (contd.) 181 Table 34 (contd.) Preparation Chemical structure Salt Physical constant, example No. etc.

0 Na Powder 0 ESI.MS(m/z): 335 442, (M-Na)

S

ONa Powder ESI*MS(m/z): 0 ,N 443 340(MN)

S

0ESI -MS z): 440 359/361 (M-Na)- 0' 01 v Na Powder 0- ESI.MS(m/z): 445 366/368 (M-Na)- 182 Table 34 (contd.) Preparation Chemical structure Salt Physical constant, example No. GI 0Na Powder

S

0 ESI*MS(m/z): 446 375/377 (M-Na)-

~S

F

cI/ 0 Na Powder 0- ESI.MS(m/z): 447 0386/388(M-Na)a' 0 Na Powder 0 ESI*MS(m/z): 448 378/380 (M-Na)ci Q 0 Na Powder 0- ESI-MS(m/z): 44 9 0 N378/380 (M-Na)- 183 Table 34 (contd.) 184 Table 34 (contd.) 185 Table 34 (contd.) Preparation Chemical structure Salt Physical example No. constant, etc.

0I /v 0 INa Powder 0 ESI.MS(m/z): 458 338/340 (M-Na)-

OH,

Na Powder 0l ESI*MS(m/z): 459 389/391 (M-Na) CI /Na Powder 0 ESI*MS(m/z): 460 il(370/372 (M-Na)- Na Powder

SI

0 ESI-MS(m/z): 461 362/364 (M-Na)- 461CH 186 Table 34 (contd.) 187 Table 34 (contd.) Preparation Chemical structure Salt Physical constant, example No. etc.

Zl 0 Na Powder

S

0 ESI-MS(m/z): 466 0 357/359 (M-Na)-

CI

S

0ESI*MS(m/z): 467 0N352/354 (M-Na) Cl 0Na Powder 0 o ESI -MS(n/ z): 468 375/377 (M-Na)- Cl/ 0v Na Powder 0 ESI.MS(m/z): 469 0371/373 (m-Na)- 188 Table 34 (contd.) Preparation Chemical structure Salt Physical example No. constant, etc.

a 'Na Powder 0 ESI*MS(m/z): 470 375/377 (M-Na)- A Na Powder 0 ESI.MS(m/z): 471 0361/363 (N-Na) a 0Na Powder 0 ESI.MS(m/z): 472 N371/373 (N-Na)- 0 Na Powder 0- ESI -MS 357/359 (M-Na)- 473a-L 189 Table 34 (contd.) Preparation Chemical structure Salt Physical constant, example No. etc.

01 aNa Powder ESI-MS(m/z): 474 346/348 (M-Na)- H0C CH, 0 Na Powder 0 ESI*MS(m/z): 475 342/344(M-Na)- \Na Powder 0 ~ESI-MS(n/z):- 329 476 (M-Na) I4'C CH, 0-Na Powder ESI*MS(m/z): 329 0 0"0 0 (M-Na) 477 HoN~ya* 190 Table 34 (contd.) Preparation Chemical structure Salt Physical constant, example No. etc.

S 0- Na Powder ESI-MS(m/z): 478 338/340 (M-Na)-

HC

0 Na Powder ESI*MS(m/z): 479 364/366(M-Na)- Preparation example 480 A mixture of ethyl 3-(4-chlorobenzoylamino)-4-phenyl-4oxobutyrate (25 g) in acetic acid (150 ml) was heated to 1300C, 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 311 191 Preparation example 481 To a solution of 2-(4-chlorophenyl)-4-phenylimidazol-5-yl acetamide (10.00g) in N,N-dimethylformamide (50 ml) was added dropwise 8.9 ml of phosphorus oxychloride (8.9 ml) below 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-cyanomethyl-4-phenylimidazole (6.85 g).

MS'EI 293 Preparation example 482 The corresponding starting materials were treated in a manner similar to Preparation example 112 to obtain thiophen-3-yl)-5-hydroxymethyl-4-(3-pyridyl)imidazole.

MS*APCI 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 298 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 299 192 Preparation example 485 A mixture of 2-(2-hydroxymethylthiophen-3-yl)-5-ethyl-4-(3pyridyl) imidazole dihydrochloride (212 mg) and manganese oxide (2 g) in tetrahydrofuran (15ml) was refluxed for one hour. The reaction mixture was filtered and washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform methanol=30:120:1) to obtain 2-(2-formylthiophen-3-yl)-5-ethyl-4-(3-pyridyl)imidazole (93 mg) as orange crystal.

MS*APCI 284 (MH+) Preparation example 486 To a solution of 2-(2-formylthiophen-3-yl)-5-ethyl-4-(3pyridyl)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 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 magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform methanol=20:l) to obtain 2-[2-(1-hydroxyethyl)thiophen-3-yl]-5-ethyl-4-(3-pyridyl)imidazole dihydrochloride (60 mg) as orange brownish powder.

MS-APCI 300 (MH+) Preparation example 487 Amixture of ethyl 4- (2-thienyl) (4-fluorophenyl) oxazolacetate (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

I

193 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)oxazolacetate (39.6 mg) as colorless powder.

MS-APCI 366/368 (MH+) The compound obtained in the above was hydrolyzed according to the conventional manner to obtain thiophen-2-yl)-2-(4-fluorophenyl)oxazol-5-yl acetic acid sodium salt.

ESI-MS 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.

194 Table Preparation Chemical structure Salt Physical example No. constant, etc.

Free Powder 0material MS-APCI(m/z): 488 392/39 4(M+H)

N

A H, Free Powder material 1S.APCI(m/z): 489 359(M+H)+

N

H

2

NONH,

Free Oil 0 material MS-APCI(in/z): 490 N~1358

H

8

ICH,

A 0Free Powder material MS-APCI(m/z): o 370 491 0~ 195 Table 35 (contd.) Preparation Chemical SatPhysical example No. structure Sat constant, etc.

0 Free Oil -material MS*APCI(m/z): 492 344 H.0H h f/0- Free Powder ob material MS-APCI(mlz): 493 370 Free Oil material MS-APCI(m/z): 494 372/374 Ai /H3 Free Oil 0 C material MS-APCI(m/z): 495 s 0378/380(M+H)+ 495C 196 Table 35 (contd.) Preparation Chemical Salt Physical example No. structure constant, etc.

/Free Powder 0material MS-APCI(m/z): 496 3 9 3/3 95

~CH

8 Free Powder -material MS-APCI(m/z): 497 386/388(M+H)+ K~i CH~ Free Powder -material MS-APCI(m/z): 498 387/389(M+H)+

CI

-H Free Powder /material MS.APCI(m/z): 398/400

I

197 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.

198 Table 36 199 Table 36. (contd.) 200- Table 36 (contd.) 201 Table 36 (contd.) 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.

202 Table 3 7 Preparation Ceia stuur SltPhysical example No. Ceiastu ur Slt constant, etc.

Free Powder 518 omaterial MS*APcI(M/z): 351 (M+H)

F

1 Free Powder 0 0 material MS-APCJIm/z): 519 0".415

(M+H)

/Free Powder material MS*APCI(m/z): 520 378 (M+H) ciFree Powder 0 material MS-APCI(m/z): 521 o7 ~390/392 Preparation examples 522 to 525 The corresponding starting materials were treated in a manner similar to Preparation example 152 to obtain the compounds shown 203 in Table 38 below.

Table 38 Preparation Chemical structure example No.II Salt Physical constant, N~ /Na Powder ESI.MS(m/z): 522 0321 (M-Na) Na Powder 0 ESI -MS 523 348 (M-Na) /Na Powder 0 ESI-MS(m/z): 524 0 285 (N-Na)

F

Na Powder 0ESI*MS(M/z) 525 0 360/362 (M-Na) 204 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 Preparation Chemical structure Salt Physical example No. constant, etc.

Free Powder material MS-APCI(m/z): 526 402(M+H)+ o Free Powder o material MS-APCI(m/z): o52 386(M+H)+ 527

N

CH,

ci Free Powder S 0 material MS APCI(m/z) SN 418/420(M+H)+ 528

H

N.,

a' w 205 Preparation examples 529 to 531 The corresponding starting materials were hydrolyzed in the conventional method to obtain the compounds shown in Table below.

Table

I

206 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 41 207 Table 41 (contd.) Preparation Chemical Salt Physical example No. structure constant, etc.

FFree Powder a 0 maerialMS*APCI(m/z): 416/418(M+H) 535 aFree Powder 0 material MS.APCI(m/z): 408/410(M+H-)+ 536 0- N N Preparation example 537 A mixture of ethyl 3-bromo--4- (5-chlorothiophen-2-yl) -4-oxobutyrate(651 mg) and 4-fluorothiobenzamide (310 mg) in IN,N-dimethylformamide (10 ml) was stirred at 70 0 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.1NH silica gel column chromatography (solvent: hexane :ethyl acetate=l0:l) to obtain ethyl 4- (5-chlorothiophen-2-yl)-2- (4-fluorophenyl) acetate (471 mg).

MS-APCI 382/284 (NH+) 208 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 Preparation Chemical Salt Physical constant, example structure etc.

No. P Free Powder Fr e 1 -NR 300M~z (DMSO-d) material 8 3.l1(6H,s), 3.70 538 4.05(2H,'s), 538 6.74(1H,dd), 7.52- 7.58 7.64-7.77 8.00'(1H,dd), qc"N'cf 8. 63-8. 65 (2H, m) /Free Powder ocI material MS-APCI(m/z): 0 /Free Powder CC material MS-APCI(m/z): 0 540 NS 400/402(M+H)+

A

209 Table 42 (contd.) Preparation Chemical structure Salt Physical example No. constant, etc.

CI

O-CH, Free Powder I material MS-APCI(m/z): 0 541 362/364(MIH)+

F

Al 0-/jH Free Powder 0material MS-APCI(M/z): 542 410/412 o-JFree Powder 0 material MS-APCI(m/z): 543 N S407/409

H

3 GN CH, aFree Powder 0material MS*APCI(m/z): 544 S398/400 210 Table 42 (contd.) Preparation Chemical salt Physical constant, example No. structure etc.

-I Free Powder -material MS -APCI z): 545 398/400(MiH)± 0-6a A4 Free Powder material KS -APCI 546 409/411(M+H)+ A Free Powder material MS.APCI(m/z): 547 395/397(M+H)+ H'q Free Oil 0 material MS-APCI(m/z): 548 374 (MiH)

N.

%NO NCH 3 211 Table 42 (contd.) Preparation Chemical Salt Physical example No. structure constant, etc.

SCH

Free Powder S material MS-APCI(m/z): 549 375(M+H)+ Free Oil -material MS'APCI(m/z): 550* S 348 SN/ H, Free Powder amaterial MS.APCI(m/z): 551 N386(M+H)+

S

/Free Powder -material MS-APCI(m/z): 552 S360 I.61c-0 212 Table 42 (contd.) Preparation chemical Salt Physical example No. structure constant, etc.

sFree Oil 0material MS-APCI(M/z): 553360 (M-iH) Free Powder material MS-APCI(m/z): 554 420/422(MIH)+ 0- Free Powder 0I material MS-APCI(m/z): 555421/423 (N-iH) a1

F

/CH Free Powder material MS-APCI(M/z): 556 394/396(M+H)i 213 Table 42 (contd.) Preparation Chemical structure Salt Physical example No. constant, etc.

Free Powder material MS.APCI(m/z): 550 N 432/434(M+H)+ 0-/C Free Powder 'b material MS-APCI(m/z): 558 406/408(M+H)+ Free Powder 559 N material MS.AC~/) ~s Free Powder material, MS -APCI 560 412 /414

NYC

214 Table 42 (contd.) Preparation Chem'ical SatPhysical example No. structure Sat constant, etc.

a-i6 /Free Powder -material MS.APCI(m/z): 561 374 IFree Powder -material MS*APCI(m/z): 562 375 N-y -/Free Powder -material MS-APCI(m/z): 563 348(M+H)+ A Free Powder material MS.APCI(m/z): 564 N386(M+H)+

I

215 Table 42 (contd.) Preparation Chemical Salt Physical constant, example No. structure etc.

a Free Powder 4 material MS-APCI(m/z): S0 392/394(M+H)+ 565 cI Free Powder material MS-APCI(m/z): Ns 394/396(M+H)+ 566 Free Powder I O-/

H

material MS-APCI(m/z): 408/410 567 Hp ^H.

Preparation examples 568 to 597 The corresponding starting materials were hydrolyzed in the conventional manner to obtain the compounds shown in Table 43 below.

216 Table 43 Preparation Ceia stctr Slt Physical constant, example No. Sl etc.

AI Na Powder 0 ESI-MS(m/z): 568 352/354 (M-Na)

F

a, 0 Na Powder 0 ESI.MS(m/z): 569 390/392 (M-Na) h CF- Na Powder ESI -MS 570 364/366(M-Na)- 0Na Powder -ESI*MS(m/z): S 378/380(M-Na)- 571 NCG~ CH.

217 Table 43 (contd.) Preparation Chmclstructure Salt Physical constant, example N~o. Chmcletc.

Na Powder

S

N ESI -MS 572 384/386 (N-Na)

Y

a3 o Na Powder ESI-MS(m/z): 573 346(M-Na)-

F

'0 Na Powder 574 ESI*MS(m/z): .54 384/386(M-Na)a C Na Powder ESI*MS(in/z): 0 57 S 358/360 (I-Na) 575 1 218 Table 43 (contd.) 219 Table 43 (contd.) Preparation Chemical Sl hsclcntnec example No. structure Sl hsclcntnec Na Powder N~S ESI-MS(m/z): 345(14-Na)- 580

N

P- Na Powder ESI*MS(m/z): 581 N391/393(14-Na)a 6- Na Powder ESI*MS(m/z): 582 376/378 (M-Na)- -Na Powder 0ESI -MS z): 358/360 (N-Na) 583 220 Table 43 (contd.) Preparation Chemical sl hsclcntnec example No. structure Sl hsclcntn 1 ec a Na Powder ESI*MS(m/z): 0 584 N364/366(M-Na)- Na Powder ESI*TMS(m/z): 585 NS 390/392(M-Na)-

N

0 Na Powder S 0ESI.MS(m/z): 586 379/381(M-Na)-

N

S/I0 Na Powder S ESI.MS(m/z): s 368/370(M-Na)- 587 HC H, 221 Table 43 (contd.) 222 Table 43 (contd.) Preparation Chemical structure Salt Physical constant, example No. h 0 Na Powder ESI -MS 592 356(M-Na)h Na Powder 0 ESI -MS 593 356 (M-Na)- 0Na Powder ESI.MS(m/z): 594N S 318 (M-Na)-

S

Na Powder ESI -MS z): 595 345 (M-Na) 595 01 223 Table 43 (contd.) Preparation Chemical structure Salt Physical example No. constant, etc.

Na Powder 0 ESI-MS(m/z): 596 344(M-Na)- 1 0- Na Powder I ESI-MS(m/z): 597 330(M-Na)- 597 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.

224 Table 44 Preparation Chemical SatPhysical example No. structure Sat constant, etc.

aFree Powder material MS.APCI(m/z): 3 89/391 598 8 CI h 0Free Powder material MS-APCI(m/z): S CH 8 409/411 599 T~ C4 Preparation examples 600 to 601 The corresponding starting materials were hydrolyzed in the conventional manner to obtain the compounds shown in Table below.

225 Table Preparation Chemical tructure Salt Physical constant, example No. etc.

CI 0 o Na Powder S ESI.MS(m/z): 0 0 379/381(M-Na) 600 N N

HC.N'ACH

CI

Na Powder ESI-MS(m/z): N 0" 373/375(M-Na)- 601

H

l CN' CH, Preparation example 602 A mixture of ethyl 3-amino-4-(5-chlorothiophen-2-yl)-4oxobutyrate hydrochloride(596 mg), 4-fluorobenzoyl chloride (380 mg) and sodium hydrogen carbonate (1.0 g) in ethyl acetate ml) and water (10 ml) was stirred at room temperature for 2 hours. To the reaction mixture were added ethyl acetate 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 2-yl)-3-[(4-fluorobenzoyl)amino]-4-oxobutyrate (732 mg) as colorless powder.

226 A mixture of ethyl 4-(5-chlorothiophen-2-yl)-3-[(4-fluorobenzoyl)amino]-4-oxobutyrate (720 mg) and 2,4-bis(4methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide (1.14 g) in tetrahydrofuran (20 ml) was refluxed for 2.5 hours.

The reaction mixture was cooled and purified by silica gel column chromatography (solvent: hexane ethyl acetate= 20:1), and triturated with hexane to obtain ethyl 2-yl)-2-(4-fluorophenyl)thiazol-4-yl acetate (667 mg) as yellowish powder.

MS*APCI 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.

227 Table 46 228 Table 46 (contd.) Preparation Chemical Salt Physical example No. structure constant, etc.

a Free Powder So-\ material MS-APCI(m/z): 607 408/410(M+H)+

JLO

HC-^,CH

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 47 229 Table 47 (contd.) Preparation Chemical-structure Salt Physical example constant, etc.

01 0 Na Powder 0 ESI -MS 610 390/392(M-Na)a0 Na Powder ESI-MS(m/z): 611 379/381 (M-Na) 0 Na Powder 0 ESI.MS(m/z): 612 368/370 (M-Na)- I CF6- 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.

230 Table 48 231 Table 48 (contd.) 232 Table 48 (contd.) 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.

233 Table 49 Preparation chemical SatPhysical example No. structure Sat constant, etc.

S-

68 material Melting point: 623 0 N208-210 0

C

MS-APCI(m/z): 338 (M+H)

F

0 Free Crystal material Melting point: CHS 173-174.5 0

C

0 14N 624 MS.APCI(m/z): 322

(M+H)

Free Crystal S material Melting point: 0 CHO 111-112 0

C

625 MS*APCI(m/z): 486

(M+H)

F

234 Table 49 (contd.) 235 Table 49 (contd.) Preparation Chemical structure Salt Physical example No. _____constant, etc.

/N Free Solid A material MS-APCI(m/z): 0 Ao" 393/395 (M+H) 62-9 CI 7oNa Powder S ESI*MS(m/z): o 0, 3581360 (M-Na) 630 ao1 Na. Powder b ESI*MS(m/z): 631359/3 61 (M-Na) Preparation example 632 Ethyl 2- (4-chlorophenyl) -5-phenylthiazol-4-yl acetate g) was dissolved in methanol (50 ml) and ammonia was saturated in the solution at 0 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 236 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 328 To a solution of 2-(4-chlorophenyl)-5-phenylthiazol-4-yl acetamide (3.4g) andphosphorus oxychloride (3 ml) in chloroform wasaddedonedropofpyridine, 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 310 To a solution of 2-(4-chlorophenyl)-5-phenylthiazol-4-yl acetonitrile (2.33g) inN,N-dimethylformamide (30ml) wereadded sodium azide (1.40 g) and ammonium chloride (1.3 and the mixture was stirred at 90 0 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 353 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.

237 Table Preparation Chemical structure Salt Physical .example No. constant, etc.

ciFree Solid material MS*APCI(m/z): 0 397/399 (MIH) 633 Free Powder S material MS*APCI(m/z): 634C 0392/394(M-H)+ Ny aI0/C Free Powder C- material MtS*APCI(m/z): 635 N377/379 -23R Table 50 (contd.) Preparation Chemical structure Salt Physical example No. constant, etc.

0IFree Powder s material MS-APCI(M/z): 636 391/393 Free Powder A P material MS-APCI(m/z): 637 '402 /404 (MtH)

S

/A Free Powder /material MS-APCI(m/z): 638 308 (MH+)

F

239 Table 50 (contd.) Preparation Chemical structure SatPhysical example No. _____constant, etc.

A 1HCl Crystal I/ Melting point: H 203-204 0

C

639 I EI.MS(m/z): 298 (14-16) 0 Na Powder ESI.MS S- 352 (M-Na) 640

F

Free material 0 641 Reference Examples 642 to 644 The following compounds listed in Table 50a were prepared in amanner similar to Example 608or 632, or similar to that described in Japanese Provisional Patent Publication No. 167685/1986.

240 Table Preparation Chemical structure Salt Physical examnple No. constant, etc.

N, Free Powder S \llESI-MS(M/z): S ~N 414/416 642 Na Powder ESI*MS(m/z): 0 334(M-Na)- 643

CI

S

0 Free 644 14CH., 241 Reference example 1 A mixture of 2-acetylpyrimidine (2.90 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 and brine, 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 128 (MH+) 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 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.

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 (4.51g) in ethanol (16ml) 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 242 acetone-ethanol to obtain 2-(2-axninoacetyl)pyrimidine hydrochloride (2.87 g) as pale brownish powder.

MS-APCI 138 (MH+) Reference examples 2 to 4 Corresponding starting compounds were treatedinamanner similar to Reference example 1 to obtain the compounds shown in Table 51 below.

Table 51 Reference Chemical structure Salt Physical constant, example No. NH lHCl Powder 2 S,'N 2 MS*APCI(m/z): 0 143(M+H)+ lHCl Powder 3 CSNH 2 MS*APCI(m/z): 0 143(M+H)+ 1HC1 Powder 4NH 2 MS*APCI(m/z): (N 138(M+H)+ 243 Reference example To a solution of 1-(3-pyridyl)-l-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 for 30 minutes. The reaction mixture was poured into ice-water, andafter adding a saturated aqueous sodiumthiosulfate solution, potassium carbonate was added to the mixture to adjust pH to 4. The reaction mixture 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.

The crude product obtained in the above 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 191 (MH+) A mixture of 2-azido-l-(3-pyridyl)-l-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 reducedpressure and the residue was purifiedby silica gel flush column chromatography (solvent: hexane ethyl acetate= 2:1-1:1) to obtain 2-(t-butoxycarbonylamino)-l-(3-pyridyl)- 244 1-butanone (20.53 g) as yellowish red oil.

A mixture of 2-(t-butoxycarbonylamino)-l-(3-pyridyl)-1butanone (20.50 g) and 6N hydrochloric acid (38.8 ml) in ethanol (100 ml) was refluxed for one hour. After cooling, the reaction mixture was concentrated under reduced pressure and the resulting residue was trituratedwithethanol-ethyl acetate to obtain 2-amino-l- (3-pyridyl) -1-butanone dihydrochloride (13.40 g) as pale reddish purple crystalline powder.

Melting point: 199 to 201 0 C (decomposed) Reference examples 6 to 8 Corresponding starting compounds were treatedin amanner similar to Reference example 5 to obtain the compounds shown in Table 52 below.

245 Table 52 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) -l-butanone dihydrochloride (356 mg) and triethylamine (1.05 ml), and the mixture was stirred for minutes. The mixture was poured into water and extracted with ethyl acetate. The organic layer was collected, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a crude product of 246 2-(6-methylnicotynoylamino)-1-(3-pyridyl)-1-butanone (425 mg).

Reference example A mixture of 3-(2-aminoacetyl)pyridine dihydrochloride (50.00g), 4-fluorobenzoylchloride (41.71g) andsodiumhydrogen carbonate (100.44 g) in ethyl acetate (1 liter) and water (0.6 liter) was stirred at room temperature for 2 hours. To the reactionmixture were added tetrahydrofuran (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 259 (MH+) To a solution of 3-[2-(4-fluorobenzoyl)aminoacetyl]pyridine (500 mg) in N, N-dimethylformamide (10 ml) were added sodiumhydride (81.3mg, 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 To acetic anhydride (2.39 ml) was added dropwise formic 247 acid (0.97 ml) under ice-cooling, and the mixture was stirred at 50 0 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)-l-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 residue was trituratedwith ethyl acetate-diethyl ether to obtain 2-formylamino-l-(3-pyridyl)-l-butanone (440 mg) as colorless powder.

MS-APCI 193 (MH+) A mixture of 2-formylamino-l- pyridyl) -1-butanone (640 mg) and ammonium acetate (5.13 g) in acetic acid (5ml) 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 with brine, 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-(3pyridyl)imidazole (520 mg) as colorless powder.

MS-APCI 174 (MH+) 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 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 saturated aqueous sodiumthiosulfate solution andbrine 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).

248 MS-APCI 300 (MH+) Reference example 12 A mixture of methyl a-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 a-(4-fluorobenzoylamino)-2-thiophene acetate (2.40 g) as colorless powder.

MS.APCI 294 (MH+) Toa solution of diisopropylamine (2.48 g) intetrahydrofuran 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 a-(4fluorobenzoylamino)-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 ethylacetate. The organiclayerwas 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:l) to obtain ethyl 4-(4-fluorobenzoylamino)-4- (2-thienyl)acetacetate (2.53 g) as yellowish oil.

MS'APCI 350 (MH+) 249 Reference example 13 To a solution of benzo[b]furan-5-carboxylic acid (1.30 g) and of methyl isocyanoacetate (834 mg) in N, N-dimethylformamide (10 ml) were added diethyl cyanophosphate (1.33 ml) and triethylamine (3.6ml) 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 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: n-hexane ethyl acetate=l:l) to obtain a crude product of methyl 5-(5-benzo[b]furyl)oxazol-4-carboxylate (1.14 g).

To a solution of the crudeproduct of methyl benzo[b] furyl)oxazol-4-carboxylate (1.14 g) inmethanol and tetrahydrofuran (5 ml) was added conc. hydrochloric acid (8 ml), and the mixture was stirred overnight. The reaction mixturewas concentratedunder reducedpressure and the resulting residue was triturated with methanol-diethyl ether-acetone to obtain 5-(aminoacetyl)benzo[b]furan hydrochloride (600 mg).

MS-APCI 176 (MH+) Reference example 14 Corresponding starting compounds were treated in a manner similar to Reference example 13 and to obtain the compounds shown in Table 53 below.

250 Table 53 Reference example Chemical structure Salt Physical No. constant, etc.

Free Solid 0 C H material MS*APCI(m/z): 14(1) 0 244(M+H)+ 0 N CI 1HC1 Powder MS APCI(m/z): 14 1 \176(M+H)+ S

NH

2 0 Reference examples 15 to 19 Corresponding starting compounds were treated in amanner similar to Reference example 10 to obtain the compounds shown in Table 54 below.

251 Table 54 Reference example To a solution of 2-chloro-5- (bromoacetyl) thiophene, (28. 04 g) in acetonitrile (150 mal) was added sodiumdif ormylimide (13.35 g) and the mixture was stirred at room temperature f or 45 minutes 252 followedby 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 (20.63 g).

To the crude crystal of thiophene were added potassium hydroxide (0.60 ethanol ml) and tetrahydrofuran (40 ml), and the mixture was stirred at room temperature for one hour. After removing the solvent under reduced pressure, tetrahydrofuran (150ml) 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 (14.81 g) as pale brownish crystal.

Melting point: 111 to 113°C MS-APCI 204 (MH+) To a solution of (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 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 :ethylacetate=6:1) to obtain 253 ethyl 4-(5-chlorothiophen-2-yl)-3-formylamino-4-oxobutyrate (17.8 g) as yellowish oil.

MS-APCI 290/292 (MH+) To a solution of 4-(5-chlorothiophen-2-yl)-3-formylamino-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)-3amino-4-oxobutyrate hydrochloride (14.2 g) as colorless powder.

MS-APCI 262/264 (MH+) Reference example 21 Corresponding starting compounds were treated in amanner similar to Reference example 20 to to obtain the compounds shown in Table 55 below.

254 Table Reference Physical example Chemical structure Salt constant, etc.

No.constant, etc.

No.

Free Powder 21(1) /N H material MS-APCI 0 170(M+H)+ g Free Powder 0 material MS-APCI 21(2) 0 256(M+H)+ 0

H

3

C

0 S 1HC1 Powder S/ NH MS-APCI(m/z): 21(3) 0 228(M+H)+ 0

HC

Reference example 22 A mixed solution of P-methyl N-(5-benzo [b]furoyl)aspartate g) and acetic anhydride (10 ml) was stirred at 85 0 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-5oxo-2-oxazoline (751 mg) as colorless powder.

255 To a mixture of 2-(5-benzo[b]furyl)-4-methoxycarbonylmethyl-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 acetate was added to the mixture, the mixture was filtered and the resulting filtrate was concentrated under 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 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)-4oxobutyrate (253 mg) as colorless powder.

MS-APCI 358 (MH+) Reference example 23 Corresponding starting compounds were treated in a manner similar to Reference example 10(1) to obtain 2-[2-(4-fluorobenzoylamino)acetyl]thiophene.

Reference example 24 To a solution of methyl 5-(5-chlorothiophen-2-yl)oxazol- 4-carboxylate (12.6 g) in methanol (150ml) was added 4N hydrogen chloride-dioxane solution (100 ml) under argon atmosphere, and the mixture was stirred at 70 0 C for overnight. The reaction mixture was cooled and the solvent was removed under reduced pressure, and the resulting residue was triturated with acetone 256 to obtain methyl 2-amino-3-(5-chlorothiophen-2-yl)-3-oxopropionate hydrochloride (13.9 g) as colorless powder.

MS-APCI 234 (MH+) A mixture of methyl 2-amino-3-(5-chlorothiophen-2-yl)- 3-oxopropionate hydrochloride (6.0 4-fluorobenzoyl chloride (4.23 g) and sodium hydrogen carbonate (11.2 g) in ethyl acetate (100 ml) and water (10 ml) was stirred at room temperature for 2 hours. The organic layer was collected, washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with diethyl ether to obtain methyl chlorothiophen-2-yl)-2-(4-fluorobenzoylamino)-3-oxopropionate (7.3 g) as colorless powder.

MS-APCI 356/358 (MH+) Reference example A mixture of 1,2,3, 4-tetrahydroquinolin-6- carboxylic acid (2 32% aqueous formalin solution (2ml) 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-1,2,3,4tetrahydroquinolin-6-carboxylic acid (1.98 g) as yellowish powder.

ESI-MS 190 Reference example 26 Corresponding starting compounds were treated in amanner similar to Reference example 25 to obtain 1-methylindolin-5- carboxylic acid.

ESI-MS 176 257 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 166 (M-Na) Reference example 28 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 195 (MH+) A mixture of methyl 6- (dimethylamino)methylnicotinate (256 mg) and 10N 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 181 (MH+) 258 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 washed with water and brine, dried over anhydrous sodium sulfate, and active charcoal was added thereto and insoluble material was removed by filtration. The filtrate was concentrated under reducedpressure, and the residue was purifiedbymediumpressure column chromatography (solvent: chloroform methanol=30:1and triturated with diisopropyl ether to obtain 3-(2-t-butoxycarbonylaminoacetyl)pyridine (3.20 g).

Melting point: 98 to 99 0

C

MS*APCI 237 (MH+) Reference example Amixtureof (2-methoxy)phenacyl bromide (550mg) and sodium diformylimide (274 mg) in acetonitrile (2.5 ml) was stirred at room temperature for 30 minutes, and then, stirred at 70 0 C for 24 hours. Insoluble material was removed by filtration, washed with acetonitrile and the filtrate was concentrated under 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-(diformylamino)-2'-methoxyacetophenone(4.40 g) as colorless powder.

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 and the mixture was stirred at room temperature for one day, and the mixture was concentrated 259 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 166 (MH+) Reference example 31 A mixture of methyl dl-a-amino-2-thiophene acetate (5.59 g), N-chlorosuccinimide (4.67g) and acetic acid (60ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, to the residue obtained was addedwater, 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. To the resulting residue were added methanol ml) and 4N hydrogen chloride-dioxane solution (30 ml), the solvent was removed under reduced pressure and the residue was triturated with using diethyl ether and methanol to obtain methyl hydrochloride (4.24 g) as pale brownish powder.

MS-APCI 206/208 (MH+) Reference examples 32 to 46 Corresponding starting compounds were treated inamanner similar to Reference example 12 to obtain the compounds shown in Table 56 below.

260 Table 56 Reference Pyia example Chemical structure Salt consa lec No. constant,_etc.

oS Free Powder 32 material MS*APCI(m/z): CI 360/362CM+H)+ 0 Free Powder 33 'NXH material MS.APCI(m/z): 01 t, I I 349/351

CH,

H

3 Free Powder 34 N material MS -APCI CI NH,, 348/350 01 Free Powder material MS -APCI CI 360/362 0 0 Free Powder 36N Nmaterial MS-APCI.(m/z): NI N4 NCH 355/357 261 Table 56 (contd.) Reference Pyia example Chemical structure Salt Pysatc HFree Powder 37 CIS N material MS-APCI 1- H 340/342

OH,

o0 Free Powder 38 material MS -APCI z):

NN

I I 335/336(M+H)+ oFree Powder 39 N material Ms-APCI~m/z): S WH 321

N,

a0 Free Powder S material MS-APCI z) N1 N s6 332(M+H)+ oFree Powder 41 Nmaterial MS-APCI(m/z): I'lJJH 321 262 Table 56 (contd.) Reference Physical example Chemical structure Salt constant, etc.

No.

H,

0 0Free Powder 42 material MS-APCI~m/z): N N CH3 306 0 Free Powder 43 N N material MS-APCI(m/z): 1! I I 320

CH,

0 Free Powder 44 Nmaterial MS -APCI I ~332(M+H)+ 00 Free Powder J N Smaterial MS-APCI(m/z): 'j36 3 8(MH 0Free Oil ci Nmaterial MS*APCI(m/z): 354/356

CH,

263 Reference examples 47 to 61 Corresponding starting compounds were treated in a manner similar to Reference example 12 to obtain the compounds shown in Table 57 below.

264 Table 57 265 Table 57 (contd.) 266 Table 57 (contd.) Reference Physical example Chemical structure Salt constant, etc.

Nqo.

CH.

Free Powder 57 Nj material MS*APCI(m/z): /N 416/418 (MIH) Free Powder 58 material MS-APCI(m/z): 41 1/4 13 0Free Powder 590 material MS-APCI(m/z): aN 405/407 0 Free Powder 0 0material MS*APCI(m/z): W' 'N 404/406(M+H)+ 0 0 Free Powder 61 0material MS*APCI(M/z): IRNS, 378/380 CI F 267 Reference examples 62 to 66 Corresponding starting compounds we re treated in amanner similar to Reference example 10 to obtain the compounds shown in Table 58 below.

Table 58 Reference Physical example chemical structure Salt constant, No. etc.

IFree Powder 62 N material MS*APCI(m/z): 0 259(M+H) S"H3 Free Powder 63 F N N material MS -APCI z): CI 3 40/3 42 F 0 Free Powder 64 c~\I N material MS*APCI(m/z): 0 348/350 NC Free Powder material MS*APCI(m/z): CI 320/322 0 Free Powder 66 N S material MS-APCI~m/z): 330/332 268 Reference example 67 Under argon atmosphere, to a solution of 4-chloro-3-fluorobenzaldehyde (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 columnchromatography (solvent: hexane ethyl acetate=20:1) toobtainethyl 4-(4-chloro-3-fluorophenyl)-4-oxobutyrate (9.4 g) as pale yellowish powder.

MS*APCI 259/261 (MH+) Reference example 68 Under argon atmosphere, a mixture of succinic acid monoethyl estermonochloride (2.0 tributyl(3-thienyl)tin (5.44 g) and bis (triphenylphosphine) palladium chloride (853 mg) in dioxane ml) was refluxed for 3 hours. After cooling, to the residue was added a saturated aqueous sodiumhydrogen 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 residue was purified by silica gel column chromatography (solvent: hexane ethyl acetate and recrystallized from ethyl acetate-hexane to obtain ethyl 4-(3-thienyl)-4-oxobutyrate (1.4 g) as pale yellowish powder.

MS*APCI 213 (MH+) 269 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 pl) 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 reduced pressure to obtain ethyl 3-bromo-4-(5-chlorothiophen-2-yl)-4-oxobutyrate (1.22 g) as pale brownish liquid.

MS-APCI 326/328 (MH+) Reference examples 70 and 71 Corresponding startingcompounds were treatedinamannersimilar to Reference example 69 to obtain the compounds shown in Table 59 below.

270 Table 59 Reference Physical example Chemical structure Salt constant, No. etc.

Free Oil F material MS*APCI(m/z): Br O CH 337/339 Free Oil 71 0 CH, material MSAPCI(m/z): B r 0 291/293(M+H)+ Reference example 72 to a mixture of (2-methylthio)pyrimidin-5-carboxylic acid sodium salt (1.50 ammonium chloride (2.09 g) and 1-hydroxybenzotriazole (1.27 g) in N,N-dimethylformamide ml) were successively added 3-ethyl-l-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.80 g) and triethylamine 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 oxamide (927 mg).

MS-APCI 170 (MH+) 271 Reference example 73 Corresponding starting compounds were treated in amanner similar to Reference example 72 to obtain 2-carboxamide.

MS-APCI 156 (MH+) Reference example 74 To a suspension of 6-chloronicotinamide (1.50 g) in ethanol 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 167 (MH+) Reference example 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 (247 mg) as yellowish powder.

MS-APCI 186 (MH+) Reference examples 76 to 272 Corresponding starting compounds were treated in amanner similar to Reference example 75 to obtain the compounds shown in Table below.

Table Reference Physical Reference Chemical structure Salt Physical example No. constant, etc.

Free Crystal N NH 2 material Melting point: 76 H 1CN 227.5-228.5 0

C

I MS-APCI(m/z):

CH,

OH

3 183(M+H)+ Free Powder 77 NH material MS-APCI(m/z): HaC,

N

I 182(M+H)+

CH

3

SNH

2 Free Powder 78 material MS-APCI(m/z):

N

HCI 183(M+H)+

H

3

C

S S Free Powder 79 material MS-APCI(m/z):

NH

2 194(M+H)+ H3C S Free Powder

NH

2 material ESI-MS HaC 170(M-H) Hf 273 Reference example 81 Corresponding starting compounds were treated in amanner similar to Reference example 13(1) to obtain methyl 5-(3-chloro- 4-fluorphenyl)oxazol-4-yl carboxylate.

MS-APCI 256/258 (MH+) Reference examples 82 and 83 Corresponding starting compounds were treated in amanner similar to Reference example 13 to obtain the compounds shown in Table 61 below.

Table 61 Reference Physical example Chemical structure Salt constant, No. ___etc.

0 HCl Powder

NH

2 MS*APCI(m/z): 82 136(M+H)+ F HC1 Powder CI MS-APCI 83 188/190(M+H)+

NH,

0 Reference examples 84 to 87 Corresponding starting compounds were treated in amanner similar 274 to Reference example 10 or Reference example 20 to obtain the compounds shown in Table 62 below.

Table 62 Reference examples 88 to Corresponding starting compounds were treatedin amanner similar to Reference example 20 to obtain the compounds shown in Table 63 below.

275 Table 63 Reference example Chemical structure Salt Physical No. constant, etc.

o o Free Oily state 88 0 material MS*APCI(m/z): 88 a 284/286 Free Oily state 89 0 _CH 3 material MS-APCI(m/z): 89 S N 0 256(M+H)+ 0 NFree Oily state N material MS APCI H0, N 323(M+H) H

-CH,

H

3 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 (in mM: 118 NaC1, 4.7 KC1, 1.2, 2.5 CaCl 2 MgSO 4 1.2 KH 2

PO

4 11 glucose, 25NaHC03). The urinary bladder was cut into longitudinal strips 276 length, 3-4mm width) after mucosal layer was removed.

Preparations were mounted in organ baths containing 10ml of Krebs solution maintained at 37 0 C and gassed with 95% 02 CO z Accordingly, preparations were stretchedwithan 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 Krebs solution (in mM: 92.7 NaCl, 30 KC1, 1.2, 2.5 CaCl 2 MgSO 4 1.2 KH 2

PO

4 11 glucose, 25 NaHCO 3 After stable tension was obtained, compounds were added into organ baths cumulatively (10-'M-10-M) The effects of compounds were expressed as a percentage of the maximum relaxation produced by 0.1mM papaverine. 50% relaxation concentration (EC5s) was calculated and ECso value range (pM) 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.

3C>1B>0. 277 Table 64 Preparation ECso value Preparation ECso value example No. range example No. range C 95 C C 96 C 13 A 97 B 14 C 99 B 16 C 104 B 19 A 108 C A 120 A C 121 C 33 A 131 C 34 C 132 B C 136 B 36 C 140 C 38 C 152 C 39 C 155 C 49 B 158 C C 168 B 51 A 169 C 52 A 1-70 C 53 B 171 C 54 C 172 C C 173 C 56 B 180 C 57 C 181 B 59 C 182 A C 187 B 61 C 197 C 81 C 235 B 84 A 240 B 86 B 243 A 87 C 244 C 88 C 245 C C 246 B 278 Table 64 (Contd.) Preparation EC50 value Preparation EC50 value example No. range example No. range 247 C 362 C 248 C 363 C 249 C 364 C 252 B 365 C 253 B 366 A 255 C 367 B 256 A 372 C 257 A 373 C 262 C 374 C 265 C 377 C 267 A 378 C 268 A 431 B 269 A 432 A 271 B 434 B 272 A 435 B 273 C 437 A 275 A 438 C 277 B 441 C 278 B 444 C 279 A 445 C 280 A 446 A 281 A 451 C 282 B 452 A 283 A 453 B 284 C 454 C 285 C 455 C 286 A 458 A 287 A 459 C 288 A 462 B 339 C 464 C 350 C 469 C 355 A 473 B 279 Table 64 (Contd.) Preparation ECso value Preparation ECso value example No. range example No. range 478 A 578 B 479 A 579 B 486 C. 584 C 487 B 586 A 503 C 587 B 504 C 590 A 506 B 594 A 507 A 596 C 511 A 597 A 512 B 600 A 514 B 601 B 517 A 609 B 524 C 610 A 531 C 612 A 572 C 616 C 574 C 623' C 575 A 626 C 576 B 639 C Experimental example 2 Inhibitory effect on the rhythmic bladder by substance P in anesthetized rats contractions induced 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 for administration of compounds, and the other was for the substance P (0.33 pg/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 280 inserted into the bladder through the urethra and tied in place by a ligature around the urethral orifice. One end of the catheterwas attachedtoapressure transducer inorder 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 the bladder was emptied, cystometry was performedby filling the bladder slowly with about 0.6 ml of saline. After about 10 minutes, intravenous infusion of substance P (0.33pg/kg/min) was started for stabilization of the micturition reflex. Compounds were administered after stable rhythmic bladder contractionwas obtained over 15 minutes.

All compounds were dissolved or suspended in saline containing Tween 80 for intravenous administration (0.1ml/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) 281 Table Preparation 100% Preparation 100% example No. inhibition example No. inhibition time range time range 13 C 90 B 14 A 93 B 16 B 99 B 24 C 102 C B 104 A 27 B 107 B 28 B 108 B B 120 C 31 A 122 B 34 A 123 C 43 C 124 B 46 B 125 C 47 B 132 B 48 C 133 C C 136 C 53 C 137 C 54 B 142 C B 143 C 56 B 144 C 59 B 152 B 61 A 153 B 62 C 155 B 63 C 156 B 67 B 158 C 72 C 160 C B 162 C 83 B 164 B C 166 B 86 B 168 B 87 B 171 B 88 B 172 C 282 Table 65 (contd.) Preparation 100% Preparation 100% example No. inhibition example No. inhibition time range time range 176 C 256 C 181 B 257 B 182 B 258 C 187 B 259 B 189 C 260 A 197 C 262 C 198 C 263 C 201 C 267 C 233 C 268 C 234 C 269 B 235 B 270 B 236 C 271 C 237 C 272 B 238 C 273 C 239 C 274 B 240 C 275 A 241 C 276 C 242 C 277 C 243 A 278 B 244 B 279 C 245 C 280 C 246 B 281 C 247 C 282 B 248 B 283 C 249 B 284 B 250 B 285 B 251 C 286 C 252 C 287 B 253 A 288 C 254 C 289 B 255 B 290 B 283 Table 65 (contd.) Preparation 100% Preparation 100% example No. inhibition example No. inhibition time range time range 291 C 433 C 292 C 434 B 293 C 435 B -295 B 436 C 296 C 437 B 331 A 438 C 337 C 439 C 338 C 440 C 348 C 441 B 350 B 442 C 351 C 443 C 362 A 444 B 363 C 445 A 364 B 446 C 365 B 447 B 366 C 448 C 367 A 449 B 368 B 450 B 369 B 451 B 370 C 452 B 371 C 453 C 373 C 454 A 374 C 455 B 375 C 456 C 376 C 457 B 377 C 458 B 378 C 459 C 380 C 462 C 430 B 464 C 431 B 466 B 432 C 467 A 284 Table 65 (contd.) Preparation 100% Preparation 100% example No. inhibition example No. inhibition time range time range 469 B 569 A 470 B 570 A 472 A 571 A 473 A 572 C 474 C 573 B 475 B 574 B 476 B 575 B 478 B 576 A 479 C 577 B 482 C 578 B 484 B 579 C 486 B 580 C 487 C 582 A 503 A 583 B 504 C 584 A 505 B 585 C 511 C 586 B 512 B 587 A 513 C 588 C 514 B 589 A 516 B 590 B 517 C 591 B 522 B 594 C 523 B 596 B 524 B 600 A 525 A 601 A 529 B 608 B 530 C 609 B 531 C 610 B 532 C 611 B 568 A 612 A 285 Table 65 (contd.) Preparation 100% Preparation 100% example No. inhibition example No. inhibition time range time range 613 C 624 C 614 C 626 C 615 B 627 C 616 B 628 C ,617 B 630 C 622 B 639 C 623

C

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-cold Krebs-bicarbonate solution, andmountedin organ baths.

The initial tension was 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 286 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, 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.

Also, the nitrogen-containing 5-membered heterocyclic compound or a pharmaceutically acceptable salt has a low toxicity, so that it has high safety as a medicine.

Claims (11)

1. A compound of formula (I) R 1 R 2 S N R3 R 3 (I) wherein R 1 is a carboxyl-lower alkyl group or a lower alkoxycarbonyl-lower alkyl group, R 2 is a phenyl group substituted by two halogen atoms, and R 3 is a phenyl group substituted by a lower alkoxy, or a pharmaceutically acceptable salt thereof.

2. The compound of formula according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R' is carboxymethyl or an alkoxycarbonylmethyl, R 2 is 4- chloro-3-fluorophenyl, and R 3 is 4-alkoxyphenyl.

3. A compound of formula or a pharmaceutically acceptable salt thereof substantially as hereinbefore described with reference to any one of the examples.

4. A method for prophylaxis or treatment of a disease against which a large conductance calcium-activated K channel opening activity is efficacious, which comprises administering an effective amount of a compound according to claim 1, 2 or 3 or a pharmaceutically acceptable salt thereof.

The method according to claim 4, wherein the disease is 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, nocturnal enuresis, pollakiuria or urinary incontinence.

6. The method according to claim 4 or 5, wherein the disease is pollakiuria or urinary incontinence.

7. Use of a compound according to claim 1, 2 or 3, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in the treatment or prophylaxis of a disease against which a large conductance calcium-activated K channel opening activity is efficacious. [R:\LIBZZ]06086.doc:aak 288

8. The use according to claim 7, wherein the disease is 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, nocturnal enuresis, pollakiuria or urinary incontinence.

9. The use according to claim 7 or 8, wherein the disease is pollakiuria or urinary incontinence.

10. A method for prophylaxis or treatment of a disease against which a large conductance calcium-activated K channel opening activity is efficacious comprising the steps substantially as hereinbefore described with reference to any one of the examples.

11. Use of a compound of formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament substantially as hereinbefore described with reference to any one of the examples. Dated 14 August, 2006 Tanabe Seiyaku Co., Ltd. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [R:\LIZZ]06086.doc:aak