WO1997010214A1

WO1997010214A1 - Novel phenylacetic acid derivatives and medicinal composition containing the same

Info

Publication number: WO1997010214A1
Application number: PCT/JP1996/002607
Authority: WO
Inventors: Kunio Hayashi; Teruo Yamamori; Yasuhiko Kanda
Original assignee: Shionogi & Co., Ltd.
Priority date: 1995-09-14
Filing date: 1996-09-12
Publication date: 1997-03-20
Also published as: AU6944696A

Abstract

Compounds represented by general formula (I), amine oxides thereof, pharmaceutically acceptable salts thereof, or hydrates thereof, and medicinal compositions comprising the same, wherein R1 to R7 represent each hydrogen, halogeno, optionally substituted lower alkyl, etc; and X represents -O-, -S- or -NR15 wherein R15 represents hydrogen or optionally substituted lower alkyl. The compounds are a potent endothelin receptor antagonist and thus highly useful in the treatment or prevention of diseases caused by endothelin.

Description

TECHNICAL FIELD The present invention relates to a novel phenylacetic acid derivative and a pharmaceutical composition containing the same.

The present invention relates to compounds useful as medicaments and uses thereof. More specifically, the present invention relates to a novel phenylsulfonic acid derivative and an intermediate thereof useful for the prevention and treatment of a disease involving endoselin. Background art

Endoselin is a vasoconstrictor peptide derived from vascular endothelial cells consisting of 21 amino acids, and is involved in vascular homeostasis. For example, endoserine has high blood pressure, cerebral vasoconstriction, acute renal failure, acute proliferative nephropathy, acute myocardial infarction, cerebral infarction, renal ischemia, myocardial ischemia, cerebral ischemia, intimal hyperplasia, subarachnoid Operates via endoselin receptors as a worsening factor for circulatory diseases such as bleeding. It is also known to have some effects on the central nervous system and endocrine tissues such as the pituitary gland and adrenal gland in addition to the circulatory system.

Several compounds having a similar structure are known among the compounds having an endothelin receptor antagonistic action (Japanese Patent Application Laid-Open Nos. Hei 6-21810, WO 94/21590, W 095/03295, W095 / 26710, etc.). However, it has been desired to develop a clinically useful endoselin receptor antagonist having even higher activity. Disclosure of the invention

Means for Solving the Problems The present inventors have conducted intensive studies to develop a potent endoselin receptor antagonist, and as a result, have found that a compound represented by the following formula (I) achieves the object, and completed the present invention. did. That is, the present invention provides a compound represented by the formula (I):

(In the formula, R ¹ is hydrogen, halogen, lower alkyl optionally having substituent (s), lower alkenyl optionally having substituent (s), cycloalkyl optionally having substituent (s), Aryl which may be substituted, heteroaryl which may have a substituent, lower alkoxy which may have a substituent, lower alkylthio which may have a substituent, Lower alkoxycarbonyl, carboxy, optionally substituted lower acyl, optionally substituted amino, hydrazono lower alkyl, hydroxymino lower alkyl, Lower alkoxyimino lower alkyl, optionally substituted rubamoyl, optionally substituted rubamoyl lower alkyl, optionally substituted rubamoyl Shi-lower alkyl, - NHCOR ⁸ or _{^{- NHS 0 2 R 8 (R}} 8 in here which may have an optionally substituted lower alkyl or a substituent § reel) der O,

R ² and R ³ are each independently hydrogen, halogen, lower alkyl which may have a substituent or aryl which may have a substituent,

R ⁴ is hydrogen, halogen, lower alkyl optionally having substituent (s), — NHCOR ⁸ ′ (where R ⁸ ′ is lower alkyl optionally having substituent (s) or having substituent (s)) Aryl), optionally substituted lower alkoxycarbonyl, optionally substituted acyl, carboxy, nitrile, hydrazono lower alkyl, hydroxymino lower alkyl, lower alkoxy Imino lower alkyl, optionally substituted rubamoyl, optionally substituted rubamoyl lower alkyl, optionally substituted labamoyloxy lower alkyl or substituted Are reels that may have R ⁵ , R ⁶ and R ⁷ are each independently hydrogen, halogen, lower alkyl optionally having substituent (s), lower alkenyl optionally having substituent (s), optionally having substituent (s) Lower alkoxy, optionally substituted aryl, carboxy, optionally substituted lower alkoxycarbonyl, hydroxy, nitro, optionally substituted amino, substituent -NHCOR ⁸ ".-NHSO ₂ R ⁸ " (where R ⁸ '' is an optionally substituted lower alkyl or an optionally substituted substituent) A good aryl) or one SO n R ⁹ (where n is an integer from 0 to 2 and R ⁹ is lower alkyl), R ⁵ and R ⁶ are adjacent to each other and are joined together—W- CRCR ^{1 1} —, — W— CR ^{1 0} = N—, — W 1 N = CR ^{1 0} —,-W-(CR ^{1 2} R ^{1 2} ) m-W '1, — W_ CR ^{1 2} R ^{1 2} _ CR ^{1 2} R ^{1 2} -,-CR ^{1 0} = CR ^1] -W-, one N = CR ^{1 0} —W—,-CR ^{1 2} R ¹ ² — CR ^{1 2} ^{R 1 2 - W-, - CR} '^ CR ^ CR ^ - CR 1 1 - ( wherein W and W' each independently an O-, - SO p -, or - NR ^{1 3} - in R ¹⁰ and R ¹¹ are each independently hydrogen, lower alkyl optionally having substituent (s), lower alkenyl optionally having substituent (s), optionally having substituent (s) Cycloalkyl, halogen, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted rubamoyl, optionally substituted amino, --NHCOR ⁸ '' Or — NHS〇 ₂ R ⁸ ″ (where R ⁸ ″ is as defined above), lower alkoxy which may have a substituent, — S〇 n R ⁹ (where n and R ⁹ are as defined above) or - S 0 a _{^{^{2 NR 1 3 R 1 4,}}} R 1 2 is water A lower alkyl optionally having a substituent, a lower alkenyl optionally having a substituent, hydroxy, an amino which may have a substituent, carboxy, and a substituent which may be lower § alkoxycarbonyl or a NHCOR ⁸ '' (R ⁸ in here '' is as defined above) and, R ^{1 3} is hydrogen, optionally substituted lower alkyl, substituent R ¹⁴ is a cycloalkyl optionally having a substituent or a cycloalkyl optionally having a substituent, and R ¹⁴ is a lower alkyl optionally having a substituent, optionally having a substituent. Aryl, an optionally substituted cycloalkyl or an optionally substituted tetrazolyl, m is 1 or 2, and p is an integer of 0 to 2.) May <,

X is ¹⁰⁰ _, 1 S — or 1 NR ¹⁵ — (where R ¹⁵ is hydrogen or lower alkyl optionally having substituent (s));

Y is arsenic Dorokishi or single NHS 0 ₂ - a Z (heteroaryl where Z is the optionally having also good Ariru or substituent be substituted),

Wavy lines indicate that the X substituted at the benzyl position is in the R configuration, the S configuration, or a mixed configuration thereof.)

Or a pharmaceutically acceptable salt thereof or a hydrate thereof. In addition, the present invention provides a pharmaceutical composition containing the compound (I), specifically, an endoselin receptor antagonist.

In another aspect, the present invention relates to a method for preventing and / or treating endoserine-related diseases, which comprises administering compound (I). Furthermore, the present invention relates to the use of the compound (I) for the manufacture of a medicament for preventing and / or treating a disease involving endoselin. BEST MODE FOR CARRYING OUT THE INVENTION

As used herein, "halogen" refers to fluorine, chlorine, bromine, and iodine. The “lower alkyl” in the “lower alkyl optionally having substituent (s)” means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, methyl, ethyl, n —Propyl, isopropyl, n-butyl, isoptyl, sec —butyl, tert-butyl, n_pentyl, isopentyl, neopentyl, hexyl, etc. Among them, alkyl having 1 to 4 carbon atoms is preferable, and methyl, ethyl and propyl are particularly preferable. These groups may have one or more substituents such as halogen, hydroxy, carboxy, lower alkoxycarbonyl, lower alkoxy, lower acyl, lower acyloxy, amino, and trialkylsilyloxy at any position. The term "lower alkenyl" in "lower alkenyl J optionally having substituent (s)" means a straight-chain or branched alkenyl having 2 to 7 carbon atoms, for example, vinyl, aryl, probenyl , Isoprobenyl, butenyl, buyugenil, pentenyl, Pennenyl, hexenyl, hexenyl, heptynyl and heptenyl, and the like. These may have one or more double bonds at any position, and they may have one or more substituents at any position. The substituent is the same as that of the lower alkyl.

“Cycloalkyl” in “cycloalkyl optionally having substituent (s)” means cyclic alkyl having 3 to 8 carbon atoms, and is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Includes cyclooctyl. These may have one or more substituents such as lower alkyl, halogen, hydroxy, carboxy, lower alkoxyl propyl, lower alkoxy, lower acyl, lower acyloxy and amino at any position. Particularly, cyclopropyl, cyclobutyl and cyclopentyl are preferred.

The "aryl" in the "aryl which may have a substituent" specifically includes phenyl, naphthyl, 1,2,3,4-tetrahydridonaphthyl, indanyl and the like. These may be substituted at any position with lower alkyl, halogen, hydroxy, carboxy, lower alkoxycarbonyl, lower alkoxy, lower acyl, lower acyloxy, amino, lower alkylamino, lower alkoxycarbonyl, cycloalkyl, phenyl, etc. It may have one or more substituents. Preferable is phenyl which may have a substituent.

The "heteroaryl" in the "heteroaryl optionally having substituent (s)" refers to a heteroaryl having at least one heteroatom in the ring arbitrarily selected from 0, S and N. means. Specifically, 5 such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and chenyl 6-membered heteroaryl, indril, benzimidazolyl, indazolyl, indolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pterinyl Zinyl, Benzisoxazolyl, Benzoxazolyl, Oxaziazolyl, Benzisothiazolyl, Benzthiazolyl, Benzthiaziazolyl, Benzofuri And condensed heteroaryls such as benzothenyl. Chenil is particularly preferred. All of these may have one or more substituents at arbitrary positions, and the substituents are the same as those of the above aryl, but lower alkoxycarbonyl is particularly preferred.

The term "lower acyl" in the "optionally substituted lower acyl" refers to a linear or branched C1-C6 chain having a double bond and a hydrogen atom or a substituent at any position. Includes an optional file. Specific examples include formyl, acetyl, propionyl, petyryl, isoptyryl, benzoyl, 'relyl, isovaleryl, vivaloyl, acryloyl, methacryloyl, crotonyl and the like. These may have one or more substituents at any positions, and the substituents are the same as the above-mentioned "lower alkyl optionally having substituent (s)".

The definition of the "lower acyl" portion in the "lower acyloxy" is the same as the definition of the "lower acyl J" in the above "optionally substituted lower acyl".

“Amino optionally having a substituent” includes unsubstituted and substituted amino. Examples of the substituent include lower alkyl which may have a substituent, aryl which may have a substituent, and heteroaryl which may have a substituent.

The substituents of the "optionally substituted rubamoyl" and the "optionally substituted rubamoyloxy" are the substituents of the above-mentioned "optionally substituted amino" Is the same as

"Lower alkoxy optionally having substituent (s)", "lower alkylthio optionally having substituent (s)", "lower alkoxycarbonyl optionally having substituent (s)", "hydrazono lower alkyl", The lower alkyl part and the substituent of each of "hydroxy lower amino" and "lower alkoxy lower alkyl" are the same as defined in the above "lower alkyl optionally having substituent (s)". The compounds represented by the above formula (I) all have an endoserine receptor antagonistic action, and preferably have the formulas (II) and (III):

(Where, shaku ¹ ~! ⁷ , X, Z and wavy line are as defined above)

Or a pharmaceutically acceptable salt thereof or a hydrate thereof. Further, in the above formulas (II) and (III),

(1) R ¹ is hydrogen, lower alkyl optionally having substituent (s), cycloalkyl optionally having substituent (s), aryl which may have substituent (s), Lower alkoxy which may be substituted, lower alkylthio which may have a substituent, lower acyl which may have a substituent, amino which may have a substituent, and a substituent A compound which is also a good Lumbamoyl or one NH S〇 ₂ R ⁸ ;

More preferably, they have hydrogen, lower alkyl which may have a substituent, cycloalkyl which may have a substituent, aryl which may have a substituent, and a substituent. A compound which is an optionally substituted lower alkoxy or an optionally substituted lower alkylthio,

More preferably, a lower alkyl which may have a substituent, a cycloalkyl which may have a substituent, a aryl which may have a substituent or a tough group may be used. A compound which is a lower alkylthio which may have

Most preferably a compound which is an optionally substituted lower alkyl,

(2) a compound wherein R ² and R ³ are each independently hydrogen or a lower alkyl optionally having a substituent,

More preferably compounds each being hydrogen,

(3) R ⁴ is hydrogen, lower alkyl which may have a substituent group, optionally substituted lower alkoxycarbonyl may have a substituent, which may have a substituent Ashiru, di- Application Benefits Le, human Drazono lower alkyl, hydroxymino lower alkyl, lower alkoxymino lower alkyl, optionally substituted rubamoyl, A compound which is an optionally substituted lower alkyl or a substituted or unsubstituted aryl;

More preferably, a compound which is hydrogen, lower alkyl which may have a substituent or aryl which may have a substituent,

Most preferably, a compound which is hydrogen or lower alkyl optionally having substituent (s)

(4) R ⁵ , R ⁶ and R ⁷ each independently represent hydrogen, halogen, lower alkyl optionally having substituent (s), lower alkenyl optionally having substituent (s), or substituent Optionally substituted lower alkoxy, carboxy, optionally substituted lower alkoxycarbonyl, hydroxy, nitro, or optionally substituted amino, or adjacent R ⁵ And R ⁶ together form —W— (CR ^{1 2} R ^{1 2} ) m -W 1,

More preferably, R ⁵ , R ⁶ and R ⁷ are each independently hydrogen, halogen, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s) or nitro. A compound in which R ⁵ and R ⁶ are present or adjacent to each other to form —W— (CR ¹ ² R ^{1 2} ) m -W 1,

(5) a compound wherein X is -O-,

(6) Z is phenyl which may have a substituent, naphthyl which may have a substituent, 1.2, 3, 4 which may have a substituent. A compound which is indanyl which may have a substituent or chenyl which may have a substituent,

More preferably, a compound that is an aryl optionally substituted with lower alkyl, halogen, lower alkoxy, lower alkylamino, lower alkoxycarbonyl or cycloalkyl,

Most preferably a compound which is phenyl optionally substituted with lower alkyl,

(7) R ² and R ³ are each independently hydrogen or lower alkyl optionally having substituent (s), and R ⁴ is hydrogen, lower alkyl optionally having substituent (s), Optionally substituted lower alkoxycarbonyl, optionally substituted acyl, nitryl, hydrazono lower alkyl, hydroxymino lower alkyl, lower alkyl A compound which is a coxymino lower alkyl, an optionally substituted rubamoyl, an optionally substituted rubamoyloxy lower alkyl or an optionally substituted aryl.

(8) R ¹ is hydrogen, lower alkyl which may have a substituent, cycloalkyl which may have a substituent, aryl which may have a substituent, Lower alkoxy which may be substituted, lower alkylthio which may have a substituent, lower acyl which may have a substituent, amino which may have a substituent, and a substituent good force Rubamoiru or even - a NHS 〇 ₂ R ^8, have a hydrogen or a substituent independently R ² and R ³ each is also lower alkyl, R ⁴ is hydrogen, a substituent Yes Lower alkyl which may be substituted, lower alkoxycarbonyl which may have a substituent, acyl which may have a substituent, nitril, hydrazono lower alkyl, hydroxymino lower alkyl, lower Alkoxy mino lower alkyl Which may have a substituent force Rubamoiru, compounds which are good Ariru have a good force Rubamoiruokishi optionally substituted lower alkyl or a substituent,

(9) R ¹ is hydrogen, lower alkyl optionally having substituent (s), cycloalkyl optionally having substituent (s), aryl (s) optionally having substituent (s), R ² and R ³ are each hydrogen, and R ⁴ is hydrogen, lower alkyl optionally having substituent (s), which is lower alkoxy optionally having or lower alkylthio optionally having substituent (s). Or a aryl which may have a substituent, wherein X is —0—,

More preferably, R ¹ is a lower alkyl which may have a substituent, a cycloalkyl which may have a substituent, an aryl or a substituent which may have a substituent. A compound wherein R ² and R ³ are each hydrogen, R ⁴ is hydrogen or a lower alkyl optionally having substituent (s), and X is —O—,

(10) R ¹ is hydrogen, lower alkyl optionally having substituent (s), cycloalkyl optionally having substituent (s), aryl which may have substituent (s), having substituent (s) Lower alkoxy which may be substituted, lower alkylthio which may have a substituent, lower acyl which may have a substituent, amino which may have a substituent, and a substituent Optionally Rubamoyl or one NHS 0 ₂ R ⁸ , R ² and R ³ are each independently hydrogen or a lower alkyl optionally having substituent (s), R ⁴ is hydrogen, Lower alkyl which may be substituted, lower alkoxycarbonyl which may have a substituent, acyl which may have a substituent, nitryl, hydrazono lower alkyl, hydroxymino lower alkyl X is a lower alkoxyimino lower alkyl, optionally substituted carbamoyl, optionally substituted labamoyloxy lower alkyl or optionally substituted aryl. X Wherein Z is phenyl which may have a substituent, naphthyl which may have a substituent, and naphthyl which may have a substituent. A compound which is an indanyl which may have a substituent or a phenyl which may have a substituent,

More preferably, R ¹ is a lower alkyl which may have a substituent, a cycloalkyl which may have a substituent, an aryl or a substituent which may have a substituent. R ² and R ³ are each independently hydrogen or a lower alkyl optionally having substituent (s), and R ⁴ is hydrogen or a substituent having lower substituent (s). A good lower alkyl or an aryl which may have a substituent; X is —0—; and Z is substituted with lower alkyl, halogen, lower alkoxy, lower alkylamino, lower alkoxycarbonyl or cycloalkyl. Compounds that are

Most preferably, R ¹ is lower alkyl which may have a substituent, R ² and R ³ are each hydrogen, and R ⁴ is hydrogen or lower alkyl which may have a substituent, A compound wherein X is -0- and Z is aryl which may be substituted with lower alkyl, halogen, lower alkoxy, lower alkylamino, lower alkoxycarbonyl or cycloalkyl,

(11) R ¹ is hydrogen, lower alkyl optionally having substituent (s), cycloalkyl optionally having substituent (s), aryl which may have substituent (s), having substituent (s) Lower alkoxy which may be substituted, lower alkylthio which may have a substituent, lower acyl which may have a substituent, amino which may have a substituent, and a substituent which may be force Rubamoiru or single NHS_〇 a ₂ R ^8, R ² and R ³ are each independently lower alkyl der may have hydrogen or a substituent Ri, R ⁴ is hydrogen, a substituent Lower alkyl which may have a substituent, lower alkoxycarbonyl which may have a substituent, acyl which may have a substituent, nitrile, hydrazono lower alkyl, and hydroxymino lower Alkyl, lower alkoxyamino lower alkyl, optionally substituted rubamoyl, optionally substituted lower alkamoyloxy lower alkyl or optionally substituted aryl. R ⁵ , R ⁶ and R ⁷ are each independently hydrogen, halogen, lower alkyl optionally having substituent (s), lower alkenyl optionally having substituent (s), lower optionally having substituent (s) R ⁵ and R ^{6 which} are an alkoxy, a carbonyl, an optionally substituted lower alkoxycarbonyl, a hydroxy, a nitrogen, or an optionally substituted amino, or wherein adjacent R ⁵ and R ⁶ are Together form one W— (CR ¹² R ¹² ) m -W one, X is O, and Z is a phenyl which may have a substituent, even if it has a substituent A compound which is a good naphthyl, an optionally substituted 1,2,3,4-tetrahydronaphthyl, an optionally substituted indanyl, or an optionally substituted thienyl,

More preferably, R ¹ is a lower alkyl which may have a substituent, a cycloalkyl which may have a substituent, an aryl or a substituent which may have a substituent. R ² and R ³ are each independently hydrogen or a lower alkyl optionally having substituent (s), and R ⁴ is hydrogen or a substituent having lower substituent (s). R ⁵ , R ^6, and R ⁷ are each independently hydrogen, halogen, or a lower alkyl which may have a substituent. A lower alkoxy or nitrogen atom which may have or an adjacent R ⁵ and R ⁶ together form one W— (CR ¹² R ¹² ) m -W-and X is -O And Z is lower alkyl, halogen, lower alkoxy, lower alkylamino, Substituted with lower alkoxycarbonyl or cycloalkyl A compound which is an aryl which may be

Most preferably, R ¹ is lower alkyl which may have a substituent, R ² and R ³ are each hydrogen, and R ⁴ is hydrogen or lower alkyl which may have a substituent, R ⁵ , R ⁶ and R ⁷ are each independently hydrogen, halogen, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s) or nitro, or are adjacent to each other R ⁵ and R ⁶ together form one W— (CR ¹² R ¹² ) m-W one, X is —O—, and Z is lower alkyl, halogen, lower alkoxy, lower alkyl amide. And compounds that are aryls which may be substituted with lower alkoxycarbonyl or cycloalkyl.

Is preferred.

More preferably, formulas (II ') and formulas (II'):

(Wherein, R ′ to R ⁴ , X, Z and wavy line are as defined above)

Or a pharmaceutically acceptable salt or hydrate thereof, particularly preferably the following:

In the above equation (II '),

(1) R ¹ is hydrogen, lower alkyl which may have a substituent, cycloalkyl which may have a substituent, aryl which may have a substituent, Lower alkoxy which may be substituted, lower alkylthio which may have a substituent, lower acyl which may have a substituent, amino which may have a substituent, and a substituent which may force Rubamoiru or single NHS_〇 compound is ₂ R ^8,

More preferably, hydrogen, lower alkyl which may have a substituent, cycloalkyl which may have a substituent, aryl which may have a substituent, and a substituent Optionally substituted lower alkoxy or optionally substituted lower alkylthio Compounds that are

More preferably, a lower alkyl which may have a substituent, a cycloalkyl which may have a substituent, an aryl which may have a substituent or a group which has a substituent. A compound which may be a lower alkylthio,

Most preferably, a compound which is lower alkyl optionally having substituent (s),

(2) a compound wherein R ² and R ³ are each independently hydrogen or a lower alkyl optionally having substituent (s)>

More preferably compounds, each of which is hydrogen,

(3) R ⁴ is hydrogen, lower alkyl optionally having substituent (s), lower alkoxyl optionally having substituent (s), alkenyl optionally having substituent (s), nitrile, Hydrazono lower alkyl, hydroxymino lower alkyl, lower alkoxyimino lower alkyl, optionally substituted rubamoyl, optionally substituted rubamoyloxy lower alkyl or substituted A compound which is an aryl which may be

Most preferably a compound wherein hydrogen or lower alkyl optionally having substituent (s), a compound wherein () X is —O—,

(5) Z is phenyl which may have a substituent, naphthyl which may have a substituent, 1, 2, 3, 4 which may have a substituent. A compound which is indanyl which may have a substituent or chenyl which may have a substituent,

More preferably, a compound which is an aryl optionally substituted with lower alkyl, halogen, lower alkoxy, lower alkylamino, lower alkoxycarbonyl or cycloalkyl,

(6) R ² and R ³ are each independently hydrogen or lower alkyl optionally having substituent (s), and R ⁴ is hydrogen, lower alkyl optionally having substituent (s), Optionally substituted lower alkoxycarbonyl, optionally substituted acyl, nitryl, hydrazono lower alkyl, hydroxymino lower alkyl, lower alkoxymino lower alkyl, having a substituent A compound which is an optionally substituted rubamoyl, an optionally substituted rubamoyloxy lower alkyl or an optionally substituted aryl.

(7) R ¹ is hydrogen, lower alkyl which may have a substituent, cycloalkyl which may have a substituent, aryl which may have a substituent, Lower alkoxy which may be substituted, lower alkylthio which may have a substituent, lower acyl which may have a substituent, amino which may have a substituent, and a substituent Rbmoyl or one NHS 〇 ₂ R ⁸ , R ² and R ³ are each independently hydrogen or a lower alkyl optionally having substituent (s), and R ⁴ is hydrogen or a substituent Lower alkyl which may be substituted, lower alkoxycarbonyl which may have a substituent, acyl which may have a substituent, nitryl, hydrazono lower alkyl, hydroxymino lower alkyl, lower alkoxy Imino Which may have a substituent force Rubamoiru a good § reel may have an optionally substituted force Rubamoiruokishi lower alkyl or substituted group compound,

More preferably, R ¹ is hydrogen, lower alkyl optionally having substituent (s), cycloalkyl optionally having substituent (s), aryl optionally having substituent (s), A lower alkoxy optionally having a substituent or a lower alkylthio optionally having a substituent, wherein R ² and R ³ are each hydrogen, R ⁴ is hydrogen, and Compounds which are lower alkyl or aryl which may have a substituent

(8) R ¹ is hydrogen, lower alkyl which may have a substituent, cycloalkyl which may have a substituent, aryl which may have a substituent, R ² and R ³ are each hydrogen, R ⁴ is hydrogen, lower alkyl optionally having substituent (s), optionally lower alkoxy or lower alkylthio optionally having substituent (s), Optionally substituted lower alkoxycarbonyl, optionally substituted acyl, nitril, hydrazono lower alkyl, hydroxyimidyl Lower alkyl, lower alkoxymino lower alkyl, optionally substituted rubamoyl, optionally substituted rubamoyloxy lower alkyl or optionally substituted A compound wherein X is -o-, more preferably R ¹ is lower alkyl optionally having substituent (s), cycloalkyl optionally having substituent (s), or Is an optionally substituted aryl or an optionally substituted lower alkylthio, wherein R ² and R ³ are each hydrogen, R ⁴ is hydrogen, an optionally substituted lower alkyl Or a compound having a substituent, wherein X is _O—,

(9) R ¹ is lower alkyl which may have a substituent group, it may also have a substituent group I cycloalkyl, substituents which may § Li Lumpur have, have a substituent R ² and R ³ are each independently hydrogen or a lower alkyl which may have a substituent, and R ⁴ is a lower alkylthio optionally having a substituent or a lower alkylthio optionally having a substituent. Is hydrogen, lower alkyl optionally having substituent (s), lower alkoxycarbonyl optionally having substituent (s), acyl optionally having substituent (s), nitril, hydrazono lower alkyl, hydroxy Mino lower alkyl, lower alkoxy Mino lower alkyl, optionally substituted rubamoyl, optionally substituted rubamoyloxy lower alkyl or optionally substituted Re X is -◦ and Z is phenyl which may have a substituent, naphthyl which may have a substituent, 1, 2, or 3 which may have a substituent , 4-tetrahydrodronaphthyl, a compound which is an indanyl which may have a substituent or a phenyl which may have a substituent,

More preferably, R ¹ is lower alkyl optionally having substituent (s), cycloalkyl optionally having substituent (s), aryl optionally having substituent (s), or substituent (s) having substituent (s). R ² and R ³ are each independently hydrogen or a lower alkyl optionally having a substituent, R ⁴ is hydrogen, lower alkyl which may have a substituent or aryl which may have a substituent, X is --◦--, Z is lower alkyl, halogen, lower alkoxy, lower Alkylamino, lower alkoxyl Or a compound which is aryl which may be substituted with cycloalkyl or cycloalkyl, more preferably lower alkyl wherein R ¹ may have a substituent, cycloalkyl which may have a substituent, An aryl which may have a group or a lower alkylthio which may have a substituent, wherein R ² and R ³ are each hydrogen, R ⁴ is hydrogen, X is --unique, and Z is substituted with lower alkyl, halogen, lower alkoxy, lower alkylamino, lower alkoxycarbonyl or cycloalkyl. A compound which is an aryl which may be

Most preferably, R ¹ is lower alkyl optionally having substituent (s), R ² and R ³ are hydrogen, R ⁴ is hydrogen or lower alkyl optionally having substituent (s), A compound wherein X is —O— and Z is an aryl optionally substituted with lower alkyl,

(1 0) N— (4—Isopropylphenylsulfonyl) 1- (2—ethyl-3-3-pyridyloxy) — 1,3—benzenedioxole—5—acetamide, N—

(4 -isopropylphenylsulfonyl) 1 α-(2-η -propyl-3-pyridyloxy)-1, 3-benzenedioxole-5-acetoamide, Ν-(4-isopropyl A compound selected from the group consisting of phenylsulfonyl) 1 α-(6-tyl-2-η-propyl-3-pyridyloxy)-1, 3-benzoxol-5-acetoamide;

In the above formula (III '),

(1) R ¹ is hydrogen, lower alkyl which may have a substituent, cycloalkyl which may have a substituent, aryl which may have a substituent, Lower alkoxy optionally having, lower alkylthio optionally having a substituent, lower acyl optionally having a substituent, amino optionally having a substituent, having a substituent A compound which is optionally Lubamoyl or —NHSO ₂ R ⁸ ;

Further preferably, a compound which is a lower alkyl optionally having a substituent,

(2) a compound wherein R ² and R ³ are each independently hydrogen or a lower alkyl optionally having a substituent, More preferably compounds each being hydrogen,

(3) compounds wherein R ⁴ is hydrogen, lower alkyl optionally having substituent (s), or aryl which may have substituent (s),

More preferably a compound that is hydrogen or lower alkyl optionally having substituent (s),

(4) a compound wherein X is — O —,

(5) R ¹ is hydrogen, lower alkyl optionally having substituent (s), cycloalkyl optionally having substituent (s), aryl (s) optionally having substituent (s), Lower alkoxy optionally having, lower alkylthio optionally having a substituent, lower acyl optionally having a substituent, amino optionally having a substituent, having a substituent Ri good force Rubamoiru or single NHS 〇 ₂ R ⁸ der also be, and R ² and R ³ have each independently hydrogen or a substituent is also optionally substituted lower alkyl, R ⁴ is hydrogen, substituted A lower alkyl which may have a group or an aryl which may have a substituent, wherein X is —O—,

More preferably, R ¹ is lower alkyl which may have a substituent, R ² and R ³ are each hydrogen, and R ⁴ may be hydrogen or may have a substituent Compounds that are lower alkyl and X is -O-

Is preferred.

Reference to the "compound of the present invention" includes, where possible, pharmaceutically acceptable salts thereof. For example, alkali metals (sodium, calcium, lithium, etc.), alkaline earth metals (calcium, magnesium, etc.), ammonium or organic bases, salts with amino acids, etc., and inorganic acids (hydrochloric acid, etc.) , Hydrobromic acid, phosphoric acid, sulfuric acid, etc.) or salts with organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.). These salts can be formed by a commonly used method.

The compounds of the present invention also include the aminoxides.

In addition, the compound of the present invention also includes hydrates thereof, and one molecule of the compound of the present invention. A hydrate may be formed with one or more molecules of water.

Although the compound of the present invention has optical isomers, any of the R configuration, the S configuration, and a mixed configuration thereof are within the scope of the present invention. In particular, the R configuration is preferred.

The compound (I) of the present invention, that is, the compounds (II) and UI1) can be produced, for example, by the following method.

(ΙΠ)

(Wherein, R ¹ ~: R ⁷ are as defined above, X 'is - OH, - SH or - NHR ¹ ^6, H a ¹ is halogen, R is lower alkyl)

In this production method, the compound (X) is condensed under an appropriate condition with the compound (V I) and the compound (X).

The compound (III) is obtained by hydrolyzing the compound (I) in a usual manner. The condensation reaction is carried out, for example, in a solvent such as dimethylformamide, acetonitril, and aceton, in a solvent such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, or the like. The reaction may be carried out in the presence of a base at room temperature to under heating, preferably around room temperature, for several hours to 24 hours, preferably for about 2 to 5 hours. In the hydrolysis, the compound (XI) is dissolved in a lower alcohol such as methanol or ethanol, and a suitable concentration, for example, a base such as 1 N sodium hydroxide or an aqueous solution of potassium hydroxide is dissolved. The compound (III) can be obtained by reacting the mixture under cooling to heating, preferably at about room temperature for about 1 to 24 hours.

(HI) (ΧΠ) (II)

Next, the compound (II) is activated by activating the carboxyl group of the compound (III) dissolved in the solvent and condensing with the sulfonamide compound (XII) in the presence of a base under cooling to warming, preferably around room temperature. obtain.

As the solvent, for example, tetrahydrofuran, getyl ether, dimethoxyethane, methylene chloride, 1,2-dichloroethane, or the like may be used. For activation of the carboxyl group, for example, 1,1′-carbonyldiimidazole is used. . As the base, for example, 1,8-diazabicyclo [5.4.0] indene-17-ene can be suitably used.

Since the compound (III) of the present invention obtained by the above method is in a racemic form, if necessary, it can be converted to a quaternary salt with a chiral amine and then dissociated with an acid to obtain an optically active compound. it can. For example, the racemic compound of the present invention (III) and (R)-(+) I-methylbenzylamine, (1S, 2R) -1-(+)-norephedrine, (1S, 2S) -(+) — 2 — Amino 1 — Phenyl 1, 3, 3-propanediol, D — Threo (one) 1-2 — Amino 1-1 (412 trophenyl) 1-1,3 — Pronondiol Is dissolved in an organic solvent such as ethyl acetate, acetonitril, methanol, ethanol, or isopropanol, and then the solvent is distilled off, and recrystallization is repeated with the above solvent. A quaternary salt of the compound (III) of the present invention in the R configuration is obtained. Further, by dissociating this quaternary salt with an inorganic acid such as hydrochloric acid or sulfuric acid or an organic acid such as drunk acid or oxalic acid, a compound having the R configuration of the compound (III) of the present invention can be obtained. In addition, chiral amines such as (S)-(-1) -α-methylbenzylamine and (1R, 2S)-(-1) -nor-ephedrine are used to perform optical resolution by the same method. This gives a compound having the S configuration of the compound (III) of the present invention.

By using the optically active compound (III) of the present invention thus obtained, the compound of the present invention can be obtained. An optically active form of the compound (II) can also be suitably obtained.

As the compounds (VI) and (X) used in the above synthesis method, known compounds or compounds which can be derived from a known substance by an ordinary method may be used. Further, compounds synthesized by the following method may be used. Can also be used.

(Here, ¹ ′ to R ⁴ ′ are groups that can be converted into shaku ¹ to？ ⁴ by ordinary methods.) Compound (VI) can be obtained, for example, by the following method.

First, a known compound or a compound (IV) obtained by a known method is prepared for several hours to several days at 0 t: to 100 t :, preferably 40: to 60, preferably for 1 hour to 24 hours. The reaction is followed by acylation to obtain compound (V). Next, the compound (V) is mixed with a suitable alcohol containing ammonia or ammonium hydroxide or the like at room temperature to under heating, preferably at 150: or more, for several hours to several days, preferably for 10 hours to 48 hours. The compound (VI) in which X ′ = OH is obtained by reacting to a certain degree.

Specifically, for example, compound (IV) is converted to an acid anhydride (eg, n-butyric anhydride, propionic anhydride) or an acid chloride (eg, 4-tert-butylbutylsulfonyl chloride, acetyl chloride) corresponding to the target compound The compound (V) is obtained by reacting with an acylating agent such as amide, propionyl chloride or the like at 0 to under heating, preferably at 40: to 6O: to obtain the compound (V). If necessary, a buffer such as phosphoric acid may be used. Next, a compound (VI) in which X ′ = OH can be obtained by mixing and heating with an ammonia-containing ethanol or ammonium hydroxide solution or the like.

The compound (VI) in which X ′ = NHR ¹⁶ may be a commercially available product, or may be obtained as a by-product of the above method for producing the compound (VI) in which X ′ = OH.

To obtain a compound (VI) where X '= SH, a compound (V I) can be thiocarbamoylated by a commonly used method, subjected to a rearrangement reaction, carbamoylthiolated, and finally converted to X ′ = SH.

Specifically, in a solvent such as acetone, methylethyl ketone, and acetonitrile, in the presence of a base such as triethylamine, N-methylmorpholine, an auxiliary such as dimethylaminopyridine, and a dimethylthiocarbamoyl alcohol The thiocarbamoyl is reacted with a thiocarbamoylating agent such as a ride at 0 to under heating, preferably at about room temperature for several hours to several days to obtain thiocarbamoyl. Next, a rearrangement reaction is carried out at a high temperature of 20 O: or higher with a high boiling point solvent such as diphenyl ether, dougham, etc., to form carbamoylthio, and further, a solvent such as tetrahydrofuran, getyl ether, dimethoxane, etc. After reacting an alkali metalating agent such as sodium hydride and potassium hydride with an H arsenic agent such as 1-propanethiol under ice-cooling to room temperature for several minutes, 3-dimethylcarbamoyl Add the desired pyridine compound such as thio-2-n-propylpyridin and react for several hours to several days under ice-cooling to room temperature to obtain the desired compound.

The substituents R ¹ ′ to R ⁴ ′ of the compound (IV) and the compound (V) are finally converted to the substituents ¹ to! Of the target compound (VI) by a usual method. ? Any group can be used as long as it can be converted to ⁴ . The substituents R i ′ to R ⁴ ′ can be converted into the substituents R ¹ to R ⁴ at an appropriate stage using a commonly used chemical reaction, for example, the following reaction.

To obtain a compound (VI) in which X ′ is ある H and any of the substituents R ¹ to R ⁴ is a sulfonamide, first, X ′ is OH, and any of the substituents is An amino compound (VI) and a sulfonylating agent such as 4-tert-butylbenzenesulfonyl chloride and methanesulfonyl chloride in a solvent such as pyridine and DMF are preferably cooled on ice to under heat. Reacts at room temperature for several minutes to several hours to obtain a compound in which X ′ is sulfonylated, and then reacts it with n-butyllithium hexane in a solvent such as tetrahydrofuran, getyl ether, or dimethoxane. By reacting with an anionizing agent such as -80 t: to 0 :, preferably around 17 for several minutes to several hours, the desired compound can be obtained.

When the compound (VI) in which any of the substituents is alkoxy is obtained, Compound (VI) in which the substituent is a halogen is dissolved in a solvent such as DMF or tetrahydrofuran in the presence of a base such as sodium hydride or potassium hydride, and an alcohol such as methanol or ethanol. The reaction may be carried out at a temperature between 0 and under heating, preferably at around 110 ° C. for several hours to several days.

In order to obtain the compound (VI) in which any substituent is lower alkylthio, the compound (VI) in which any substituent is one SH is prepared in a solvent such as acetonitrile and tetrahydrofuran. The reaction may be carried out with an alkylating agent such as acetyl iodide or propyl bromide at room temperature to under heating, preferably at around 80, for a few minutes to several hours.

When the compound (VI) in which either group is lower alkyl is obtained, the compound (VI) in which either group is lower alkyl may be added to the compound (VI) having metaclo-peroxybenzoic acid, hydrogen peroxide, acetic acid, peracetic acid, or acetic acid. An oxidizing agent such as trifluoroperacetic acid, perbenzoic acid, or dimethyldioxysilane is reacted to obtain an aminoxide compound, which is usually used at room temperature to under heating for several tens of minutes to several hours, for example, acetic anhydride, trifluoric anhydride, etc. May be reacted with the acylating agent. Compound (VI) in which either group is hydroxy lower alkyl and an acylating agent similar to the above may be added, if necessary, in a solvent such as methylene chloride or dichloromethane under ice-cooling to room temperature for several hours. The reaction may be performed for up to several tens of hours.

When the compound (VI) in which either group is hydroxy lower alkyl is obtained, the compound in which either group is alkoxy lower alkyl is treated with sodium hydride or hydrogen in a solvent such as methanol or ethanol. A base such as potassium oxide may be reacted. When the compound (VI) in which any substituent is lower alkoxy lower alkyl is obtained, the compound (VI) in which any substituent is hydroxy lower alkyl is combined with a halogen such as thionyl chloride, phosphoryl chloride, oxalyl chloride and the like. The reaction is carried out under ice-cooling to 0X: preferably under ice-cooling for several hours, and the reaction is carried out in a solvent such as toluene, benzene, chloroform, methylene chloride or the like, in the presence of a base such as sodium metal. The reaction may be carried out with an alcohol such as ethanol, ethanol, or the like according to the purpose.

When the compound (VI) in which any group is a lower alkyl group is obtained, the compound (VI) in which any group is a hydroxy lower alkyl is converted into a solvent such as acetonitrile or tetrahydrofuran. , One 5 Ot: ~ several hours at room temperature, The carbamoylation may be carried out by a usual method using a carbamoylating agent such as rosulfonyl isocyanate or trichloroacetyl isocyanate.

In order to obtain the compound (VI) in which either group is an aldehyde, the compound (VI) in which either group is a hydroxy lower alkyl is prepared by dissolving the compound (VI) in a solvent such as dichloromethane or tetrahydrofuran. 0 to room temperature for acetic anhydride, anhydrous Application Benefits Furuoro acetate, S_〇 ₃ - using Bok Riechiruami down, DCC-Application Benefits Furuoro齚酸, as an activator of P ₂ 0 _5, etc. - pyridinium Jin, (COC 1) 2 DM SO oxidation may be performed. Moreover, PCC, PDC, may be oxidized using an oxidizing agent such as M N_〇 _2, KM n 0 _4.

When a compound (VI) in which either group is lower alkyl substituted with imino or hydrazone is obtained, the compound (VI) in which either group has an aldehyde is converted to an alcohol such as methanol or ethanol. The reaction may be performed by mixing with an amino compound such as hydroxyaluminum, dimethylhydroxylamine, hydrazine or the like in an ice-cooled room temperature at room temperature for several minutes to several hours.

In order to obtain the compound (VI) in which either group is carboxy, the compound having any group in the form of an aldehyde can be obtained by cooling a compound such as acetonitrile or tetrahydrofuran under ice-cooling or heating. Oxidation with sodium chlorite may be performed for several hours in the presence of hydrogen peroxide, sulfamic acid, and 2-methyl-2-butene.

In order to obtain a compound (VI) in which any of the groups is cyano, first, a compound (VI) in which any of the substituents is hydrogen is converted into an aminoxide compound in the same manner as described above. The compound is reacted with a methylating agent such as dimethyl sulfate or methyl iodide to form a methoxypyridinium compound, which is heated at room temperature to under heating for several hours to several tens of hours, and is treated with sodium cyanide or potassium cyanide. The reaction may be carried out with a cyanating agent such as chromium to form a cyanogen. In this reaction, it is also possible to use dimethyl sulfate as a methylating agent in a solvent amount.

In order to obtain the compound (VI) in which any group is a lower alkyloxycarbonyl, the compound (VI) in which any group is a carboxy can be obtained by cooling the compound (VI) in a solvent such as methylene chloride or dichloromethane under ice-cooling. It is reacted with a halogenating agent such as thionyl chloride or oxalyl chloride at room temperature for several tens of minutes to several hours to form acyl chloride. You can react with the call.

In order to obtain a compound (V 1) in which one of the groups is carbamoyl which may have a substituent, the compound in which any of the groups is carboxy is dissolved in a solvent such as methylene chloride, dichloromethane, or the like. The reaction may be carried out with a halogenating agent such as thionyl chloride or oxalyl chloride to form acyl chloride under cooling to room temperature for several tens of minutes to several hours, followed by reaction with an amine compound such as ammonia or dimethylamine.

Compound (X) can be synthesized, for example, by the following method.

(VII) (VIII) (IX) (X)

First, a known compound or a compound (VII) obtained by a known method, for example, piperonal and chloroform are dissolved in a suitable solvent, and benzyltriethylammonium chloride, benzyltriethyl bromide is dissolved. In the presence of a phase transfer agent such as ammonium, a base such as sodium hydroxide or potassium hydroxide is added dropwise while heating, preferably around 50T: ~ 70 ^. Dropping may be performed over several hours to several days depending on the amount of the reaction compound. As the solvent, a mixed solution of water with an organic solvent such as ether or black form is used, and a preferred organic solvent is black form as well as the reagent and the solvent. Then, this is neutralized with an acid such as sulfuric acid or hydrochloric acid to obtain a compound (VIII).

Next, the compound (VIII) is esterified by heating and refluxing an alcohol solution of methanol, ethanol, propanol and the like in the presence of an acid such as sulfuric acid and hydrochloric acid according to a usual method to obtain a compound (IX). If the reaction is carried out under heating, preferably in the vicinity of 70 to 90, the desired compound can be suitably obtained.

Then, the substitution reaction between hydroxy and halogen (H a1: for example, bromine, chlorine, iodine, etc.) is performed.For example, the substitution reaction for halogen is, for example, ethylene chloride, 1,2-dichloroethane, chloroform, ethyl acetate. Solution of a compound (IX) dissolved in a suitable solvent such as thiocyanyl chloride, phosphorous trichloride, phosphorous oxychloride, phosphorous pentachloride, phosphorous trichloride, etc. At room temperature under cooling to room temperature, preferably The reaction may be carried out at ~ 5 "C for several hours to several tens of hours, preferably 10 to 20 hours. The compound (X) can be obtained by extracting the reaction product obtained here.

The compound (I) of the present invention, in particular, the compound (II) has a strong endothelin receptor antagonism and is also excellent in blood translocation, so that it has high bioavailability and is extremely excellent. Medicine. Further, the compound U 11) is also useful as an intermediate of the compound (II). Therefore, all of these compounds are useful as endocerin receptor antagonists.

Since the endoselin receptor is considered to be involved in the development of various diseases including the circulatory system, the compound (I) of the present invention, its aminoxide or a pharmaceutically acceptable salt thereof can be used. Acceptable salts or their hydrates are diseases caused by endoselin, such as hypertension, coronary artery disease, heart failure, renal ischemia, myocardial ischemia, renal failure, dialysis, cerebral ischemia, cerebral infarction, cerebral edema, Migraine, subarachnoid hemorrhage, Reino's syndrome, pulmonary hypertension, atherosclerosis, restenosis after balloon-induced vasodilation, inflammation, gastric ulcer, duodenal ulcer, leg ulcer (u 1 cuscruris) ), Gram-negative sepsis, shock, glomerulonephritis, renal colic, endometriosis, asthma, diabetic nephropathy, diabetic complications, complications in cyclosporine administration, etc. it can. The compound (I) of the present invention and salts or hydrates thereof can be safely administered orally or parenterally. Oral administration may be carried out in a commonly used dosage form such as powder, granules, tablets, pills, capsules, liquids, buccals or sublinguals. For parenteral administration, any commonly used dosage form such as suppositories, transdermal absorbents, injections (intramuscular injection, intravenous injection, etc.), inhalants and the like can be suitably administered. Oral administration is particularly preferred as the administration route.

Pharmaceutical preparations can be prepared by mixing, as necessary, excipients, binders, wetting agents, disintegrating agents, lubricants and other pharmaceutical additives suitable for the dosage form with the effective amount of the present compound. In the case of injections, they should be sterilized with a suitable carrier to give a preparation.

Specifically, lactose, sucrose, glucose, starch, calcium carbonate or crystalline cellulose is used as a vehicle, and methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin or poly is used as a binder. vinyl Disintegrators such as carboxymethylcellulose, sodium carboxymethylcellulose, starch, sodium alginate, agar powder or sodium lauryl sulfate, and disintegrants such as talc and stearyl. Magnesium phosphate or macrogol. As the base of the suppository, cocoa butter, Macrogol or methylcellulose can be used. When prepared as a liquid or emulsifying or suspending injection, commonly used solubilizing agents, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. May be added as appropriate, and in the case of oral administration, a flavoring agent, a fragrance and the like may be added.

The dose of the compound of the present invention as a medicament is desirably determined in consideration of the patient's age, body weight, administration route, type and degree of disease, and the like. It is in the range of 0.01 to 1000 mg / kg / day, preferably in the range of 0.01 to 10 mg / kg / day. In the case of parenteral administration, it varies greatly depending on the route of administration, but it is usually 0.001 to 10011 1 ^ / day, preferably 0.01 to 10 mg / kg / day. Within range. It may be administered once or several times a day.

Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited thereto. Example

Abbreviations used in this example are as follows:

A c O E t

B u butyl

c-B u cyclobutyl

c — P e nt

c-P r cyclopropyl

E t etil

H e p t heptyl

M e methyl P ent Pentyl

P h phenyl

P r propyl

D B U 1, 8 — diazabicyclo [5.4.0] — 7 — ndecene

D F dimethylformamide

D M S O Dimethyl sulfoxide

T H F Tetrahi Drofuran

Reference Example 1 Synthesis of compounds (VI-3) and (VI-3)

The method of W. Gruber et al. (Canadian Journal of Chemistry, Vol. 31, pp. 564 (1953)) Compound (VI-3) was prepared according to the following procedure. That is, a mixture of 3.4 g (50 mm o 1) of furan (manufactured by Tokyo Kasei Co., Ltd.) and 15.8 g (0.1 mo 1) of n-butyric anhydride was heated to 40, and 85% 1.5 g of phosphoric acid was added, and the mixture was stirred at 60 for 3 hours. After cooling, the reaction mixture was washed with a sodium hydrogen carbonate solution and water, dried over magnesium sulfate, concentrated, and distilled under reduced pressure to give 7.2 g of 21-butyrylfuran (yield 96.3%). ) Was obtained (b.p.75-77t: / 5mm). Next, 40.5 2 g of the obtained 2-n-butyrylfuran was dissolved in 150 ml of a 28% aqueous ammonium hydroxide solution, placed in a glass tube, sealed, and then heated at 160 for 16 hours. did. After cooling, the solvent was distilled off. Separation by column chromatography (Quick chromatographic tube, manufactured by Nippon Riken Kikai, solvent: chloroform-methanol, 9: 1) using silica gel (120 g). Then, the product was recrystallized from ethyl acetate to obtain 19.13 g (47.5%) of 3-hydroxy-2-n-propylpyridine (VI-3).

When a 4 N hydrochloric acid-ethyl ester solution was added to the mother liquor, crystals precipitated. This was collected by filtration and washed with ethyl acetate, to obtain 2.02 g (4.0%) of 3-amino-2_n-propylpyridine hydrochloride (V1-37).

Reference Example 2 Synthesis of Compound (VI-24)

2—Amino 3—Hydroxypyridine (VI-18); Neil Crowson 1 (10 mmo 1) and 2.79 g (12 mmo 1) of 4 l-tert-butylbenzenesulfonyl chloride The mixture was dissolved in 15 ml of gin and stirred at room temperature for 1 hour. The precipitated yellow solid was filtered and recrystallized from ethyl acetate to obtain 2.9 g (95%) of 2-amino-3- (4-tert-butylbenzenesulfonyl) oxypyridine. (M.p.1

66-1 69)

A nalytical (O bs) F or C 1 5 H 1 8 N 2 O 3 SFW 3 0 6 3 8 C:.. 5 8 8 0 H:. 5 9 2 N:. 9 1 4 S:. 1 0 4 7 (C: 5 8.8

7 H: 5.94 N: 9.36 S: 10. 6 3)

^{_{! HNMR (in CDC 1 3)}} δ 7. 9 4 (1 H, dd, J = 1. 6, 5. 0 H z), 7. 8 2 (2 H. D, J = 8. 8 H z) , 7.56 (2H, d, J = 8.8Hz), 7.20 (1H, d, d, J = 1.6, 8.0Hz), 6.58 ( 1H, d, d, J = 5.0, 7.8 Hz), 4.57 (1H, br), 1.35 (9H, s).

2—Amino 3— (4-tert-butylbenzenesulfonyl) oxypyridin 490 mg (1.6 mmol) of THFSO ml solution was cooled to 168 X :, and 1.6 M n— 3.5 ml of butyllithium-hexane solution was added, and the mixture was stirred at 168 "C for 1 hour and then returned to room temperature. The reaction mixture was neutralized with 1N hydrochloric acid, extracted with ethyl acetate, dried, and distilled. When the residue was separated by column chromatography using 20 g of silica gel, 2-(4-tert-butylbenzenesulfonamide) 13-hydroxypyridine (VI-24) 308 mg (63%) (m.p. 175-175).

¹ HNMR (in CDC 13) δ 9.4-8.2 (2 Η br), 7.87 (2H.d, J = 8.6 Hz), 7.47 (2H, d, J = 8.6 Hz), 7.16 (1H, d, d, J = 1.4, 6.6 Hz). 7.07 (1H, d, d, J = 1.0, 7.4 Hz), 6.58 (1H, d, d, J = 6.6, 7.8Hz), 1.32 (9H, s). Reference Example 3 Synthesis of Compound (VI-32)

According to the report of Takeo Naito et al. (Pharmaceutical Magazine, Vol. 79, pp. 1277 (1995)), while mixing 40 ml of thionyl chloride with ice and stirring, 3-hydroxy-1- 2 — (Hydroxymethyl) pyridine hydrochloride (VI_38; manufactured by Aldrich (A1drich)) 8. Og was added, and the mixture was refluxed for 2 hours. After cooling, 100 ml of toluene was added, and the precipitate was collected by filtration and dried. 8.7 lg of this substance was added dropwise to a solution of 2.72 g of sodium metal in 55 ml of methanol, and the mixture was refluxed for 1 hour. The reaction mixture was neutralized with 10% hydrochloric acid, extracted with a mixed solution of chloroform-methanol (9: 1), dried and evaporated. The residue was purified by column chromatography on 40 g of silica gel and recrystallized from ethyl succinate-hexane to give 3-hydroxy-12-methoxymethylviridine (VI-32) 1.5. 6 g (17.5%) were obtained. Reference Example 4 Synthesis of Compound (VI-33)

2—Black mouth—3—Hydroxypyridine (VI—39; manufactured by Aldrich) Agitate 4 mg solution of 260 mg (2 mmo1) in 4 ml of acetone under ice-cooling While adding, 41.6 mg (2.4 mmo1) of calcium carbonate and 2861 of benzyl bromide were added. After stirring at room temperature for 18 hours, the reaction solution was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography to obtain 348 mg (79%) of 2-chloro-3-benzyloxypyridine.

1HNMR (in CDC13) <58.00 (1H, d, d, J = 1.6, 4.6Hz), 7.50-7.12 (7H, m) , 5.19 (2 H, s). Ethanol 591 (lmmol) 4 Omg (lmmol) in 5 ml of DM FO. Was added and stirred at room temperature for 15 minutes. To this was added a solution of 2-cyclohexyl 3-benzyloxypyridine 11 O mg (0.5 mmo 1) in DMF at room temperature. After stirring at 110 for 67 hours, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. It was concentrated after drying with a shim. The residue was purified by silica gel chromatography to obtain 80 mg (70) of 3-benzyloxy-2-ethoxypyridine.

1 HNMR (in CDC 13) δΊ.72 (1Η, d, d, J = l.6, 5.OHζ), 7.46-7.2.28 (5Η, m), 7 0 4 (1 Η, d, d, J = 1.6, 7.8 Η), 6.74 (1 Η, d, d, J = 5.0, 7.8 Ζ), 5 16 (2, s), 4.47 (2, q, J = 7. 7), 1.46 (3, t, J = 7.0 Η).

To a 2.5 ml solution of 79 mg (0.34 mmo 1) of 3-benzyloxy-2-2-ethoxypyridine in 10 ml of ethanol was added 10 mg of 10% palladium on carbon, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-mg-ethoxy-3-hydroxypyridine (VI-33) 21 mg (44). Reference Example 5 Synthesis of Compound (VI-34)

2 — Mercapto-1 3 — Pyridinol (VI — 40; Janssen Chemica) 1.27 g (10 mmo 1) and iodide chilled 1.87 g (1 2 mmo1) was stirred with 30 ml of acetonitrile at 80 for 4 hours. The reaction solution was concentrated under reduced pressure, dissolved in clog mouth form, washed with a saturated sodium hydrogen carbonate solution, dried and evaporated. The residue was purified by silica gel chromatography to obtain 1.29 g (83%) of 2-ethylthio-3-hydroxypyridine (VI-34). Reference Example 6 Synthesis of Compound (VI-35)

To the compound (VI-3) (13.7 g), add 1.76 g of dimethylthiocarbamoylcide mouth, 20.24 g of triethylamine and 1.2 g of dimethylaminopyridine, and add acetate The mixture was stirred at room temperature for 3 days in 300 ml of ethanol. The residue was subjected to column chromatography using 200 g of silica gel (Michael Miller column tube, manufactured by Yamazen Corporation, solvent: Separation with n-hexane monoethyl acetate, 2: 1) gave oily 3_dimethylthiolrubamoyloxy_2-n-propylpyridine 10.47 g (46.8%). 1 HNR (in CDC 13) <5 8.45 (1H, d, J = 4.6 Hz), 7.37 (1H, d, J = 8.2 Hz), 7. 20 (1H, d, d, J = 4.6, 8.2Hz), 3.48 (3H, s), 3.39 (3H, s), 2.72 ( 2 H, t, J = 7.9 H z), 1.77 (2 H, sext, J = 7.4 H z), 0.98 (3 H, t, J = 7.4 H z ).

3_Dimethylthiocaproluvamoyloxy 2-n-propylpyridine 10.47 g was refluxed together with diphenyl ether 20 ml for 15 minutes to effect rearrangement. The reaction mixture was separated by column chromatography using 60 g of silica gel (quick chromatograph, manufactured by Nippon Rikakiki Co., Ltd., solvent: n-hexane-ethyl acetate, 2: 1). 8.13 g (77.6%) of oily 3-dimethylcarbamoylthio-1-n-propylpyridine was obtained.

¹ HNMR (in CDC 13) <58.55 (1H, d, d, J = 20, 4.8Η), 7.78 (1Η, d, d, J = 2. 0, 7.8 Η ζ), 7 16 (1 Η, d, d, J = 4.6, 7.8 Η Ζ), 3.12-3.04 4 (2.9 5 (2Η, t, J = 7.8Η), 1.74 (2Η, sext J = 7.7Hζ), 0.98 (3Η, t, J = 7.5 5) Sodium hydride (60%, oi 1 suspension, manufactured by Nakarai Co., Ltd.) 1. Add 3.6 ml of 1-propanethiol to 85 ml of 73 g of THF and add 10 ml under ice-cooling. After stirring for 3 minutes, a solution of 8.13 g of 3-dimethylcarbamoylthio-2-n-propylpyridine in 5 ml of anhydrous THF was added dropwise, and the mixture was stirred for 3 hours under ice-cooling and then for 16 hours at room temperature. To the mixture was added a 1N aqueous sodium hydroxide solution. After liquid separation, the alkali solution was neutralized with a 1N hydrochloric acid solution, extracted with chloroform, dried and evaporated to give an oil.

3—Mercapto-2-n-propylpyridine (VI-35) 3.74 g (67.

4%). Reference Example 7 Synthesis of other compound (VI)

Hereinafter, in the formula (IV), as the raw material compounds, those in which R ⁴ is methyl or ethyl are those commercially available (manufactured by Tokyo Chemical Industry), and those in which R ⁴ is n-propyl or n-butyl are J yh— H orng - S heu method (journal 'O Bed auger two Kkukemisu Application Benefits one ^ J ournalof O rgnic C hemistry) 5 Volume 4, No. 5 1 2 6 page according (1 9 8 9)), R 4 is The phenyl compound was prepared according to the method of A. Peter et al. (Synthesis, 1987, Volume 51), and the compound (VI) was synthesized in the same manner as described above.

Table 1 shows the above results.

No R ¹ R ² R ³ R ⁴ X 'mp Analytical (Obs%) FW 1HNMR (inCDCl ₃ + CD ₃ OD) δ

VI- n-He HHH OH 107-8 C "H l7 NO 179.26 oo-7.o (IH.br), o.Ul (1 H, a, d, J = 1.o, 5.UHz), 7.17 (1H, 11 xyl C: 73.70 H: 9.56 N: 7.81 d, d, J = 1.2,8.2Hz), 7.04 (lH, d, d, J = 5.0,7.8Hz), 2.89 (

(C: 73.79 H: 9.51 N: 7.81) 2H, t, J = 7.8Hz), 1.70 (2H, m), 1.29 (6H, m), 0.84 (3H, t,

(J = 7.0Hz)

VI- n-He HHH OH 104-6 C ₁₂ H ₁₉ NO 193.29 8.6-7.8 (lH.br), 8.03 (lH, d, d, J = 1.4,4.6Hz), 7.16 (1H, 12pt C: 74.57 H: 9.91 N: 7.25 d, d, J = 1.4,7.8Hz), 2.89 (2H, t, J = 7.9Hz), 1.70 (2H, m),

(C: 78.54 H: 7.05 N: 6.64) 1.24 (8H, m), 0.85 (3H, t, J = 7.0Hz)

VI- i-Bu HHH OH 158-9 C ₉ H ₁₃ NO 151.21 7.99 (lH, d, d, J = 1.6,4.8Hz), 7.12 (lH, d, d, J = 1.4,8.2Hz), 13C : 71.49 H: 8.67N: 9.26 6.99 (lH, d, d, J = 5.0,8.2Hz), 2.72 (2H, d, J = 7.4Hz), 2.16

(Q71.29 H: 8.63 N: 9.19) (lH, mJ6.9Hz), 0.929 6H, d, J = 6.8Hz)

VI- t-Bu HHH OH 184-7 (¾Η ₁₃ ΝΟ 151.21 8.04 (lH, d, d, J = 2.8,4.0Hz), 7.02 (lH, s), 7.00 (1 H, 14 C: 71.49 H: 8.67 : 9.26 d, J = 1.6Hz), 2.1-1.6 (lH, br), 1,45 (9H, s)

(C: 71.43 H: 8.66 N: 9.21)

VI- c-Bu HHH OH 159- C _g H _n NO 149.19 8.06 (lH, d, d, J = 1.8,4.6Hz), 7.05 (lH, d, d, J = 1.6,15 160 C: 72.46 H: 7.43 N: 9.39 7.8Hz), 6.98 (lH, d, d, J = 4.6,8.2Hz), 3.95 (IH.quint,

(C: 72.18 H: 7.36 N: 9.41) J = 8.8Hz), 2.38 (4H, m), 2.04 (2H, m)

VI- c-Pe HHH OH 197-8 C _I0 N ₁₃ NO 0.3H ₂ O 172.03 8.01 (lH, d, d, J = 1.6, 4.4Hz), 7.06 (lH, d, d, J = 1.6, 16 nt C: 69.82 H: 8.32 N: 9.77 8.2Hz), 6.96 (lH, d, d, J = 4.8,8.2Hz), 3.52 (2H, t, J =

(C: 69.55 H: 8.62 N: 10.07) 7.7Hz), 2.89 (lH, br), 1.86 (8H, m)

VI- Ph HHH OH 210-1 C,, H ₉ NO 171.20 8.16 (lH, d, d, J = 1.6,4.8Hz), 7.84 (2H, d, d, J = 1.6,17C: 77.17 H: 6.30 N: 8.18 8.2Hz), 7.50-7.37 (3H, m), 7.24 (lH, d, d, J = 1.6,

(C: 77.11 H: 5.29 N: 8.28) 7.8Hz), 7.12 (lH, d, d, J = 4.6,8.2Hz), 3.02 (lH, br)

O 97/10214

7/10214

Reference Example 8 Synthesis of benzo [1,3] dioxo-5-ylbromoacetic acid ethyl ester (X ')

(νπ ') (IX *) (χ')

Dissolve 22.5 g (1.5 mo1) of peronal (VII ') in 240 ml of black mouth form and add 18.8 3 g (82.5 mm o 1) was added. While heating at 55, a 37% aqueous sodium hydroxide solution (375 ml) was added dropwise over 23 hours, and the mixture was further stirred at that temperature for 1 hour. The reaction mixture was poured into ice water and acidified with sulfuric acid to precipitate a solid. The solid was dissolved in ethanol, a small amount of sulfuric acid was added, and the mixture was heated under reflux to be converted into ethyl ester (IX ′). After concentration of the solvent, the residue was dissolved in toluene, washed with a saturated sodium hydrogen carbonate solution, dried and evaporated. The residue was purified by column chromatography using 300 g of silica gel (quick chromatographic tube, manufactured by Nippon Rikakiki Co., Ltd., solvent-closed form-acetone, 9; 1) and purified by ethyl ester. 157.3 g (yield 53.5%) of a compound (IX ′) was obtained (mp 65-66 t :).

63 g (0.28 mo1) of this ethyl ester form (IX ') was dissolved in 100 ml of dichlorotan, cooled to -15 with a cryogen, and cooled to 83.7 g (0.3 g) of phosphorus tribromide. A solution of 309 mo 1) in 50 ml of dichloromethane was added dropwise over 30 minutes. Thereafter, the mixture was stirred at 0 for 16 hours, the reaction solution was poured into ice water, and extracted with a cross-hole form. After washing the cross-hole form solution with saline solution and drying over magnesium sulfate, column chromatography (quick chromatographic tube, manufactured by Nippon Rikakiki Co., Ltd., solvent: ethyl acetate-toluene, using 100 g of silica gel) 1: 4) to give 78.87 g (yield 97.6%) of benzo [1,3] dioxol-5-ylbromoacetic acid ethyl ester (X ′). Example 1 Synthesis of H- (2-n-propyl-1-3-pyridyloxy) 1-1,3-benzodioxo-lu-5-acetic acid (III-13) Dissolve Compound (VI-3) 274 mg (2 mmo1) and Compound (Χ ') 574 mg (2 mmo1) in 10 ml of anhydrous DMF, and add 288 mg of potassium carbonate (8 6 mmo1) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water, extracted with ethyl acetate, and the ethyl acetate solution was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (Michael Mirror Column, manufactured by Yamazen Corporation, solvent: ethyl hexane monoacetate, 2: 1). The eluted ethyl ester (588 mg) was dissolved in ethanol (2 ml), 1N sodium hydroxide (2 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with 1N sulfuric acid, extracted with black form, and the black form solution was dried over magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate to obtain 418 mg of the compound (III-13) (yield: 66.3%). Example 2 Synthesis of a— (6—t—butyldimethylsilyloxymethyl-2_n_propyl 3—pyridyloxy) —1,3—benzodioxole-5—drunkic acid (III-138)

(First step)

25 g (70.0 mmol) of the compound (XI) obtained by reacting the compound (VI-8) with the compound (X ') was dissolved in 250 ml of methylene chloride, and 13.5 g (78. 4 mmol) of benzoic acid was added with stirring under ice cooling. After stirring for 4 hours under ice-cooling, the reaction solution was washed successively with an aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate and concentrated. The residue was solidified in a mixed solution of diisopropyl ether (20 ml) and hexane (10 ml), and a- (6-methyl-2-n-propyl-13-pyridyloxy) -11,3- Benzo dioxo-l-u-ethyl ester-N-l-oxide was obtained in an amount of 22.1 g (85%).

^{_{1 HNMR (in CDC 1 3)}} <5 1 -.. 0 3 (. 3 H, t, 7 4 H z) 1 2 1 (3 H, t, 7 2 Η ζ.), 1 6 4 -. 1 8 6 (2 words, m), 2.44 (3 words, s), 2.99-3.24 (2 words, m), 4.18 (2 words, dq, 1.4) , 7.2 Hz), 5.48 (1H, s), 6.00 (2H, s), 6.62 (1H, d. 8.6Hz), 6.83 (1H , D, 7.8 Hz). 6.9 1-7.02 (3H.m)

(2nd step)

7.5 g (20.0 mmol) of the compound obtained in the first step was dissolved in 30 ml of acetic anhydride and stirred at 130 with stirring for 30 minutes. After cooling, anhydrous anhydride was distilled off under reduced pressure. Ice water and a saturated aqueous solution of sodium hydrogen carbonate were added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel force chromatography, and a- (6-acetoxymethyl-2-n-propyl-13-pyridyloxy) -11,3-benzodioxol_5_ethyl acetate 6. 26 g (75%) were obtained.

^{_{1 HNMR (in CDC 1 3)}} <5 1 0 0 (3 H, t, 7 2 H z.), 1 2 1 (3 H, t, 7 2 H z.), 1 6 8 -... 1 8 9 (2 H, m), 2.12 (3 H, s), 2.86-2.97 7 (2 H, m), 4.18 (2 H, dq, 1.8 , 7.2 Hz), 5.12 (2H, s), 5.48 (lH, s), 6.00 (2H, s), 6.

80-7 .1 2 (5 H, m)

(3rd step)

To 60 ml of ethanol, 63 mg (l6.6 mmo 1) of 60% sodium hydride was added with stirring under ice-cooling, and the mixture was stirred for 30 minutes. To this, 15 ml of an ethanol solution of 6.26 g (15. lmmol) of the compound obtained in the second step was added while stirring under ice-cooling, and the mixture was stirred for 20 minutes. 0.95 ml of acetic acid was added and the solvent was distilled off under reduced pressure. Ice water and a saturated aqueous solution of ammonium chloride were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was solidified in a mixed solution of diisopropyl propylene (2 ml) and hexane (15 ml), and α- (6-hydroxymethyl-2—η-propyl-13-pyridyloxy) 1-1,3 —Benzodioxol— 5—ethyl acetate 4.89 g (87%) was obtained. W 1 1

^{.. 1 HNMR (in CDC 1} 3) δ 1 0 0 (. 3 H, t, 7 4 H z), 1 2 0 (3 H, t, 7 2 H z.), 1 6 6 -. 1. 9 1 (2H, m), 2.87-2.97 (2H, m), 3.70 (1H, br), 4.18 (2H, dq, 1.7, 7.2 Hz), 4.65 (2H, d, 2.2 Hz), 5.48 (1H, s), 6.00 (2H, s), 6.80 -7.0.08 (5H, m)

(4th step)

2.5 g (6.70 mmo 1) of the compound obtained in the third step was dissolved in 25 ml of methylene chloride, and 0.684 g (10.Ommol) of imidazole and t 1. Illg (7.36 mmol) of 1-butyldimethylsilyl chloride was added with stirring under ice-cooling. After stirring for 2.5 hours under ice cooling, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography, and a— (6_t—butyldimethylsilyloxymethyl-2—n—propyl-13—pyridyloxy) 1-1,3—benzodioxoyl-5—ethyl acetate 3 23 g (99) were obtained.

^{_{1 HNMR (in CDC 1 3)}} δ 0 -.. 1 0 (6 Η, s), 0 9 4 (9 Η, s), 0 9 9 (. 3 Η, t, 7 6 Η ζ), 1. 2 1 (3 Η, t. 7. Ο Η), 1.65-1.87 (2 H, m), 2.88 (2, t, 7.4 7), 4. 18 (2, dq, 1.0, 7.4), 4.76 (2H, s), 5.48 (lH, s), 5.99 (2H, s) ), 6.83 (1 Η, d, 7.8 Η), 6.98-7.09 (3 m, m), 7.2 1 (1 Η, d, 8.6 ζ) )

(Fifth step)

2.0 g (4.1 Ommol) of the compound obtained in the fourth step was dissolved in 30 ml of ethanol, and 2.05 ml of 2N sodium hydroxide was added with stirring under ice-cooling. . After stirring for 4 hours under ice cooling and 1.5 hours at room temperature, ethanol was distilled off under reduced pressure. Ice water on the residue To the mixture was added 2.5 ml of 2N hydrochloric acid while stirring under ice-cooling. The aqueous layer was extracted with ethyl acetate, combined with the black form layer, and washed with water. After drying over anhydrous magnesium sulfate and concentrating, α-(6-t-butyldimethylsilyloxymethyl-2 n-propyl-3-pyridyloxy) 1-1, 3-benzodioxole-5-acetic acid 1 84 g (98) were obtained. Example 3 Synthesis of a- (6-cyan-2-n-propyl-l-3-pyryloxy) -l, 3-benzodioxol_5-denoic acid (III-39)

(Step 1)

Using the compound (VI-3) and the compound (IX) obtained from the compound (X ') as a raw material, α- (2-η-propyl-13-pyridyloxy) 1-1 was obtained in the same manner as in Example 2. ,

3-Benzodoxo-l-uyl 5-ethyl sulphate ester was synthesized. 2.5 g (7.0 mmol) of the compound was suspended in 0.66 ml (7.0 mmol) of dimethyl sulfate, and the mixture was stirred at 90 for 5 hours. After cooling, the mixture was dissolved in 80 ml of water, and 0.85 ml of sodium cyanide was added thereto with stirring under ice cooling. After stirring for 1 hour under ice-cooling and for 4 hours at room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography, and a — (6 — cyano 1 — n — propyl 13 — pyridyloxy) 11, 3 — benzodioxole-5 — ethyl acetate 4 48 mg (18%).

^{.. 1 HNMR (in CDC 1} 3) δ 1 0 0 (. 3 Η, t, 7 4 Η ζ), 1 2 2 (3 Η, t, 7 2 Η ζ.), 1 7 0 -. 1. 9 1 (2 Η, m), 2.44 (3 Η, s), 2.87-2.99 9 (2 Η, m), 4.27 (2 d, dq, 2.0, 7.2 Hz), 5.34 (1st, s), 6.01 (2st, s), 6.84 (1st, d, 8.

6.95-7.0.02 (3Η, m) .7.4.7 (1Η, d, 8.4 4)

(2nd step) 37 mg (0.10 mmo1) of the compound obtained in the first step was dissolved in 0.75 ml of ethanol, and 2N sodium hydroxide 501 was added with stirring under ice-cooling. Was. After stirring for 5 hours under ice cooling, ethanol was distilled off under reduced pressure. Ice water and 2N hydrochloric acid 501 were added to the residue. The aqueous layer was extracted with ethyl acetate and washed with water. After drying over anhydrous magnesium sulfate and concentrating, α- (6 -cyano 2-η-propyl- 13 -pyridyloxy) 11, 3 -benzodioxo-l-5-5-acetic acid 34 mg (100%) was obtained. Was. Example 4 Synthesis of 1- [2- (1-t-butyldimethylsilyloxy) -propyl-6-methyl-3-pyridyloxy] 1-1,3-benzodioxol-5-acetic acid (III-40)

(First step)

Example 2 100 mg (0.268 mmo1) of the compound obtained in the first step was dissolved in 1 ml of dimethylformamide, 0.3 ml of trifluoracetic anhydride was added, and the mixture was stirred at room temperature for 3 days. . Ice water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in methylene chloride, a 2N aqueous solution of potassium carbonate was added, and the mixture was stirred at room temperature for 10 hours. Ice water and 1 N hydrochloric acid were added to the reaction solution to neutralize the aqueous layer, and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography, and purified with [1- (1-hydroxy) -1-propyl-16-methyl-3-pyridyloxy] 1-1,3-benzodioxoyl-5-ethyl acetate 2 5 mg (25%) were obtained.

^{_{. 1 HNR (in CDC 1 3}} ) <5 0. 8 6- 1. 0 5 (6 H, m), 1 1 3- 1. 3 0 (6 H, m), 1. 5 5 - 2. 2 5 (4 H, m), 2.47 (6 H, s), 4.08-4.25 (4 Η, m), 4.71 (2,, br), 4.86 -5.23 (2 Η, m). 5.48 (2 Η, s), 5.99 (4 Η, s), 6.78-7.05 (10 Η, m) (2nd step)

25 mg (0.669111111) of the compound obtained in the first step was dissolved in 0.5 ml of methylene chloride, and 13.6 mg (0.201 mmol) of imidazole and t-Butyldimethylsilyl chloride (22.0 mg, 0.147 mmol) was added with stirring under ice-cooling. After stirring at room temperature for 24 hours, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography, and α- [2— (1-t-butyldimethylsilyloxy) -propyl-6-methyl-3-pyridyloxy] 1-1,3-benzodioxoyl— 5-Ethyl acetate 25 mg (77) was obtained.

^{_{1 HNMR (in CDC 1 3)}} δ - 0. 0 8 (3 H, s), - 0. 0 7 (3 H, s), - 0. 0 6 (3 Η, s), 0. 0 2 ( 3 H, s), 0.96 — 1.06 (6Η, m), 1.15-1.27 (6 6, m), 1.66 — 1.98 (4Η) , m), 2.48 (6 H, s), 4.11-4.25 (4 ,, m), 5.10 — 5.22 (2 Η, m), 5.4 3 (lH, s), 5-45 (lH, s), 5.99 (binary, s). 6.00 (binary, s), 6.79-7.09 (1 0 Η, m)

(3rd step)

25 mg (0.513 mmo1) of the compound obtained in the second step was dissolved in 0.25 ml of ethanol, and 2N sodium hydroxide 271 was stirred under ice-cooling. While adding. After stirring at room temperature for 40 minutes, ethanol was distilled off under reduced pressure. Ice water and black-mouthed form were added to the residue, and 2N hydrochloric acid 281 was added with stirring under ice cooling. The aqueous layer was extracted with ethyl acetate, combined with the black form layer, and washed with water. After drying over anhydrous magnesium sulfate, the mixture is concentrated and then dried. — [2 — (1 t-butyldimethylsilyloxy) — propyl— 6 — methyl-3- 3-pyridyloxy] _ 1, 3 — benzodioxole _ 5 — acetic acid 2 2.5 mg (95%) were obtained. Example 5 Synthesis of other compound (III) Hereinafter, the other compound (III) was synthesized in the same manner. However, the compound (VI) corresponding to the compounds (III-11), (111-9), (111-10) and (II-25) is manufactured by Aldrich (A1drich), ( Compound (VI) corresponding to 111-119) was synthesized using a commercial product manufactured by Tokyo Chemical Industry Co., Ltd. Table 2 shows the results.

2S

M∑0l / L6O.

L09ZOI96df / lDd Example 6 N- (4-Isopropylphenylsulfonyl) -Hi- (2-n-propyl-Pyr-1-3-Pyridyloxy 1,3-benzenedioxole-5-acetamide_ (II-I 3a)

1.26 g (4 mmo 1) of the compound (III-5) and 1.3 g (8 mmo 1) of 1,1′-carboeldiimidazole were refluxed in 5 ml of anhydrous THF for 3 hours. The reaction product was ice-cooled, 1.59 g (8 mmo1) of isopropylbenzenesulfonamide and 1.22 g (8 mmo1) of DBU were added thereto, and the mixture was stirred at room temperature for 17 hours. . The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, the chloroform solution was washed with 1N NH 4 C 1 and water, dried over magnesium sulfate and evaporated. The residue was separated and purified by column chromatography (Michael Miller column, manufactured by Yamazen Co., Ltd., solvent: black form-methanol, 9: 1) using 100 g of silica gel. The eluted material was recrystallized from isopropanol-ethyl ether to obtain 600 mg (yield: 30. 2%) of a compound (II-3a).

m. p. 16 4 to 16 6 "C, decomposition

Mass spectrum (mZz) 469 [m + H]. Example 7 N- (4-Isopropylphenylsulfonyl) -1-α- (6-dihydroxymethyl-2-n-propyl-13-pyridyloxy) 1-1-3— ^ nzodoxy_sole-5-a Synthesis of Cetamide (II-38a)

1.74 g (3.8 mm o 1) of the compound (III-38) and 0.92 g (5.7 mm o 1) of 1,1'-carbonyldiimidazole were added to 30 ml of THF. And stirred under reflux for 4 hours. The reaction solution was cooled on ice, and thereto was added 1.3 g (5.7 mmo1) of isopropylbenzenesulfonamide and 85 ml (5.7 mmo1) of DBUO. Stir for 5 hours. The reaction solution was concentrated under reduced pressure, ice water and ethyl acetate were added to the residue, and the aqueous layer was adjusted to pH = 5 with 1N hydrochloric acid. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in 30 ml of THF, 3.8 ml of a 1.0 M tetrabutylammonium fluoride THF solution was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, ice water and ethyl acetate were added to the residue, and the mixture was diluted with 1 N hydrochloric acid. The aqueous layer was set at pH = 5. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then filtered. The residue was purified by silica gel column chromatography to obtain 1.20 g (60) of a compound (II_38a). Example 8 N- (4-Isopropylphenylsulfonyl) -α- (6-acetoxysimeter-1 2-η-propyl-1 3-pyridyloxy) 1-1,3-benzodiol-5- Synthesis of acetate amide (II-38b)

Dissolve 50 mg (0.095 mmo 1) of compound (II — 38a) in 0.4 m 1 of pyridine, and cool anhydrous 1 1 1 (0.14 mmol) with ice The mixture was added under stirring and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, ice water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 30 mg (56%) of a compound (II_38b). Example 9 N- (4-Isopropylphenylsulfonyl) -α_ (6-Rubamoyloxymethyl-2-1 η-Propyl-1-3-pyridyl-^-) 1-1,3—Benzodioxol-5— Synthesis of acetate amide (II-38c)

50 mg (0.09 δ mmo 1) of the compound (II_38a) was dissolved in 2 ml of acetonitrile, and chlorosulfonylisocyanate 13 1 (0.14.3 mmo 1) was dissolved. Was added at 130, and the mixture was further stirred for 1.5 hours. 75 ml of 2N hydrochloric acid was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Ice water and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction solution to adjust the pH to 4, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 13 mg (24%) of a compound (II-38c). Example 10 0 N— (4—Isopro _ ^ _ ruphenylsulfonyl) —α— (6—formyl-1-2— _η— propyl-13—pyridyloxy) 1-1,3—benzodioxole Synthesis of 5-acetamide (II-38d) Dissolve 0.66 ml (7.6 mmol) of oxalyl chloride in 50 ml of THF, add 10.8 ml of DS (1.4011110 1) with -78, and stir for 25 minutes. did. 2.0 g (3.8 mmol) of the compound (II-38a) was added, and the mixture was stirred at 178 for 1 hour and at -50 for 1.5 hours. 3.70 ml (22.6 mmol) of triethylamine was added, and the mixture was stirred at 150 at 30 minutes and at 0 at 15 minutes. Ice water and ethyl acetate were added to the reaction solution, and 11.4 ml of 1N hydrochloric acid was added to adjust the pH of the aqueous layer to pH = 5. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 1.63 g (82%) of the compound (II-38d). Example 1 1 N— (4—Isopropylpyrphenylsulfonyl) -a- (6 hydride mouth xymininomethyl-1 2—n—Propyl-1-3-pyridyloxy) 1-1,3—Benzodioxol — 5 — Synthesis of acetamido (II — 38 e)

49 mg (0.093 mmo 1) of the compound (II-38d) was dissolved in 0.5 ml of pyridine and 0.5 ml of ethanol, and 32 mg (0.4 mg) of hydroxylaminate hydrochloride was dissolved. 65 mm o 1) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, ice water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 33 mg (65) of a compound (II-38e). Example 1 2 N-(4-isopguchi I ^ phenylsulfoni)-a-(6-methoxyminomethyl _2-n-propyl-3-pyridyloxy)-1, 3_-benzodioxytool — 5 — Synthesis of acetamide (II — 38 f)

Compound (II_38d) 31 mg (0.059 mmo 1) was dissolved in 0.3 ml of pyridine and 0.3 ml of ethanol, and 25 mg of 0-methylhydroxylamine hydrochloride was dissolved. 0.295 mmo 1) was added under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, ice water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. Residue is purified by silica gel column chromatography. The product was purified by chromatography to obtain 24 mg (73%) of a compound (I 1-38 f). Example 13 3N— (4-Isopropylpyrphenylsulfonyl) — (6—Hydofuzonomethyl—2—n-Propyl-13_pyridyloxy) 1-1,3-Benzoxoxo-Lu-5—Ace Synthesis of Toamide (II-38g)

30 mg (0.057 mmo1) of the compound (II-38d) was dissolved in 0.5 ml of ethanol and 0.1 ml of water, and hydrazine monohydrate was dissolved in 8.3 1 (0.3%). 17 1 mm 0 1) was added under ice-cooling, and the mixture was stirred at room temperature for 25 minutes. The reaction solution was concentrated under reduced pressure, ice water and a saturated aqueous solution of ammonium chloride were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain 21 mg (68%) of a compound (II-138 g). Example 1J_N- (4-isopropyloxyphenylsulfonyl) -α- (6-carboxy-2—η-propyryl-3—pyridyl-xy) 1-1, _3—benzodioxol—5_ Synthesis of acetate amide (II_38h)

Dissolve 0.8 g (1.53 mmo1) of the compound (II-138d) in 8.5 ml of acetonitrile, add 8.5 ml of water and sodium dihydrogen phosphate. 0.24 g (l.53 mmol) of dihydrate was added. 3 1% aqueous hydrogen peroxide (0.174 ml, 1.59 mmo 1) was added under ice cooling, and the mixture was stirred under ice cooling for 4.5 hours and at room temperature for 0.5 hours. 13 mg of sodium thiosulfate was added to the reaction solution, and the mixture was stirred for 10 minutes. Ice water and 1N hydrochloric acid were added to the residue, the aqueous layer was adjusted to pH = 4, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was triturated with diisopropyl ether-hexane to obtain 0.729 g (89%) of a compound (II-138 h). Example 1 5N— (4-Isopropylphenylsulfonyl) _α— (6—Toxicarbonyl-1-2—η-Propyl-13—Pyridyloxy) 1-1-3—Benzodi Synthesis of xyl-5-acetamide (I 1 -38i)

50 mg (0.093 mmo 1) of the compound (II-38 h) was dissolved in 1.0 ml of methylene chloride, and pyridine 301 (0.370 mmol) and thionyl chloride 16 U 1 (0.185 mmol) was added under ice cooling, and the mixture was stirred for 1 hour. 100 ml of methanol was added to the reaction solution, and the mixture was stirred for 15 minutes. Ice water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 31 mg (61%) of the compound (I 1 −38 i). Example 1 6 N- (4-Isopropylphenylsulfonyl) -α- (6-Irvamoyl 2-—η-propyl_ 3 _pyridyloxy) 1 1.3-Benzoxoxolu 5 _acetamide ( II — 3 8 j)

33 mg (0.061 mmo 1) of the compound (II-38 h) was dissolved in 0.7 ml of methylene chloride, and pyridine 15 // 1 (0.183 mmol), chloride Thionyl 11 ml (0.122 mmol) was added under ice-cooling, and the mixture was stirred for 30 minutes. The residue was concentrated under reduced pressure and dissolved in THF 0.7 ml. 28% aqueous ammonia 100 m under ice-cooling

1 was added and the mixture was stirred for 45 minutes. Ice water and 1 N hydrochloric acid were added to the reaction solution to adjust the pH to 4, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography,

(II-38j) 12 mg (36%) was obtained. Example 1 7 N— (4-sopropylpyrphenylsulfonyl) histidine— (6—dimethylmethylcarbamoyl —2—η—propyl-13—pyridyloxy) —1,3—benzodioxo-l-5-acetamine Synthesis of de (II-38k)

Dissolve 29 mg (0.054 mmo 1) of compound (II-38 h) in 0.6 ml of methylene chloride, and add pyridine llwl (0.134 mmol) and thionyl chloride 5.6 1 (0.064 mmol) was added under ice-cooling, and the mixture was stirred for 30 minutes. Add 2 M dimethylamine THF solution (200 w1) (0.402 mmo1) to the reaction mixture, and add 1 ml under ice-cooling. For a while. Ice water and IN hydrochloric acid were added to the reaction mixture to adjust the pH to 4, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 20 mg (66%) of a compound (II-38k). Example 1 8 N- (4-Isopropylphenylsulfonyl) -I Q-(6-Cyano-l-n-n-p-pyr ^ -pyri-ziloxy) 1-1,3-Ben-zodioxo-l-l Synthesis of acetate amide (I 1-39)

Dissolve 34 mg (0.100 mmo 1) of compound (III-39) and 25 mg (0.150 mmol) of 1,1'-carbonyldiimidazole in 8 ml of TH FO. The mixture was stirred under reflux for 3 hours. The reaction mixture was cooled on ice, and 30 mg (0.150 mmo 1) of isopropylbenzenesulfonamide and DBU23 / l (0.150 mmo 1) were added thereto. Stirred for hours. The reaction solution was concentrated under reduced pressure, ice water and ethyl acetate were added to the residue, and the aqueous layer was adjusted to pH = 5 with 1N hydrochloric acid. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and dried. The residue was purified by silica gel column chromatography to obtain 28 mg (53) of the compound (I 1 -39). Example 1 9 N- (4-Isopropylphenylsulfonyl) -1-a- [2- (1-hydroxypropyl) —6—Cyl-31-Pyridyloxy] -1.3-benzodioxol-5-ace Compound (III-40) 22.5 mg (0.049 mmo)) of toamides (II-140a) and (I1-40b) and 1,1'-carbonyldiyl 12 mg (0.073 mmo 1) of midazole was dissolved in 45 mL of THFO, and the mixture was stirred under reflux for 2 hours. The reaction mixture was cooled on ice, and thereto was added 15 mg (0.073 mmo1) of isopropylbenzenesulfonamide and DBUll (0.073 mmo1), and the mixture was stirred at room temperature for 17 hours. Stirred. The reaction solution was concentrated under reduced pressure, ice water and ethyl acetate were added to the residue, and the aqueous layer was adjusted to pH = 5 with 1N hydrochloric acid. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. 0.5 ml of the residue in ethanol , 25 ml of 2N hydrochloric acid was added, and the mixture was stirred at 70 for 1 hour. The reaction solution was concentrated under reduced pressure, ice water and ethyl ethyl acetate were added to the residue, and the aqueous layer was adjusted to pH 5 with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography-3.1 mg (12%) of two diastereomers (II-140a) and 4.7 mg of compound (II-140b). (18%). Example 20 0 N- (4—Isopropylphenylssolefonyl) — HI— [2— (1—oxopropyl) -1 6—Methyl-3—Pyridyloxy 1_-1, 3—Benzodioxosol 5 _ Synthesis of acetate amide (II-140c) _

2.3 mg (4.37 mo1) of the compound (II-140a) was dissolved in 0.1 ml of clog form, and 3.8 mg (43.7 o1) of manganese dioxide was added. For 65 hours. Further, 3.8 mg (43.7 umol) of manganese dioxide was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with a filter form, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.8 mg (78%) of a compound (II_40c). Example 21 Synthesis of Other Compound (II)

Thereafter, the other compound (II) was synthesized in the same manner. The results are shown in Tables 3-5.

S9S6 / 9〇 6 o

υ

halla

0 / 96dT-1 .3d: Mi / T 6 OAV

s-l〇

3d 2Z o-i

89

L09Z0 / 96df / 13d

Ol / M6 OAV

£ 09r0 / 96df / 13d U09s / 96dr / l: wsl / -6 OAV •

97/10214

09s, 96DdivJ. Is / Sol

9

L09Z0 / 96df / lDd flZ0I / 6 OM

3d

08

L09Z0 / 96df / lDd fll0l / L6 O

Example 2 Optical Resolution of 2- (1-n-propyl-1-3-pyridyloxy) 1-1,3-ben, J-dioxol-5-acetic acid (III-13)

Dissolve 500 g of the compound (III-3) and 240 g of (IS, 2R)-(+)-norefedrine in 175 ml of methanol and add 6 L of warm MeCN. A crystal was deposited. The precipitated crystals were washed with MeCN 800 m1x2 and dried to obtain crude crystals (324 g, 87.6%, 93% e.e.). The crude crystals were dissolved in 1.44 L of methanol, added with 4.32 L of warm MeCN, and recrystallized. This was filtered, washed with 800 mL of MeCN 800, and dried to obtain 281 g of a quaternary salt (76.0%, 100% e.e.). (M.p. 1992-194t :)

A nalytical (%) F or C 2 8 H 3. N ₂ 0 ₆ FW 4 6 ₆ .5 4

C a 1 cd C: 66.94 H: 6.48 N: 6.00 0

F ou n d C: 66.82 H: 6.39 N: 6.22.

[a] _D (23.5)-51.9 ° (c = l, methanol) 150 g of the above quaternary salt was suspended in a mixture of 7.50 ml of water and 1.5 L of ethyl acetate The reaction mixture was adjusted to pH 3.8 with 1N hydrochloric acid (3543 ml, 1.1 eq), and after separation, the aqueous layer was extracted with ethyl acetate (750 ml × 1). The ethyl acetate layers were combined, washed with water (750 ml × 2), and dried over sodium sulfate. When seeds were added, crystals began to precipitate. The crystals are filtered, washed with cold ethyl acetate 250 m 1, and dried to give (.R) — (1)-a-(2-n-propyl-13-pyridyloxy) 1-1,3-benzenebenzene. 86 g (84.8%, 100% e.e.) of toluene-5-acid (III-3R) was obtained. (M.p.107-110)

A nalytical (%) For C ₁₇ H ₁₇ N 0 ₅ FW 3 1 5. 3 3

C a 1 cd C: 64.75 H: 5.4 3 N: 4.44

F ou n d C: 64.70 H: 5.44 N: 4.72.

[a] _D (23:)-109.0 ° (c = l, methanol)

(2 n propyl 1 3 — pyriyloxy) 3 — benzoxo —Ru—5—Acetic acid (I II—3) can be (S)-(+)-a- ( 2 — n — propyl — 3 — pyridyloxy) 1, 1, 3 — benzenedioxoluru 5 — acetic acid (III— 3 S) was obtained. (M.p.1 1 3-1 15)

[a] _D (23:) + 109.2 ° (c = l, methanol) Example 23-(6-methyl-2-η-propyl-1-pyridyloxy) _ 1,

3 — Benzenedoxol-5 — Optical resolution of diacid (I I I-18)

Compound (I I I-8) 100 g and (I S, 2 R) 1 (+)-norephedrine 4

59 g was dissolved in 0 L of MeCN and 1 L of isopropanol, and crystals were deposited when left to stand. The precipitated crystals are filtered, washed with 2.5 L of MeCN and dried to obtain crude crystals.

130 g (71.0%) were obtained. The crude crystals were dissolved in a mixture of isopropanoyl MeCN (1: 1) by heating, 8 L of MeCN was added to recrystallize, and after filtration, washed with MeCN2LX2 and dried As a result, 923 g (63.3%, 100% e.e.) of the quaternary salt was obtained. (M. P. 18 0-18 2)

A nalytical () For or C _{2 7} H _{3 2} N ₂ O ₆ FW 4 80 .5 6

C a 1 cd C: 67.48 H: 6.7 1 N: δ .83

F ou n d C: 67.51 H: 6.70 N: 6.02.

[] _D (at 25)-50.2 ° (c = l, methanol) Suspension of 92.2 g of the above quaternary salt in 3.7 L of water, 959 ml of 2N hydrochloric acid (1 (0.0 eq) was added and crystals precipitated. After cooling with ice, the crystals are filtered, washed with 2 L of cold water, dissolved hot in 2.46 L of methanol, added with 2.46 L of ethyl ethyl acetate and concentrated under reduced pressure, and the crystallized crystals are filtered. Take and dry (R)-(1)-Hi-1 (6-Methyl-2-n-Propyl-3 _ pyridyloxy) 1 1, 3-Benzenedoxo-1-5-Acetic acid (III-8 R) 72 g (90.6%, 100% e.e.) were obtained. (M.p. 15 6-15 8)

A nalytical (%) For C ₁₈ H ₁₉ N 0 ₅ FW 3 2 9. 3 5 C a 1 cd C: 6 5.64 H: 5.8 2 N: 4.25

F o u n d C: 65.5 H: 5.82 N: 4.46

[] _D (23)-1 12.0 ° (c = l, methanol) Compound (III-18) was converted to (1R, 2 S)-(-)-norephedrine as above. Optical resolution yielded (S)-(+)-a- (6-methyl-2-n-propyl-3-pyridyloxy) 1-1,3-benzenedioxo-l-5-acetic acid (ΙΠ—8S). . (With m.p.1 5 5—1 5 7)

[] _D (at 23) + 1 1 1.2. (C = l, methanol) Compound UII-8) was optically resolved using (D)-(+)-1-phenylethylamine in the same manner as above, and the structure was analyzed by X-rays. The absolute structure was confirmed. Example 2 4N— (4-Isopropylphenylsulfonyl) -1-a- (2-π-pyropenyl-3--3-pyridyloxy) _1,3-benzenedioxo-1-lu 5-acetamido (II 3a) optical resolution

The compound (II-3a) was fractionated on a column of Chiralpak AD (CHIRALP AKAD, manufactured by Daicel Chemical Co., Ltd.) (solvent: n-hexane-ethanol-ethanol-trifluoroacetic acid); 90: 10: 0. 1) and (R)-(I) -N- (4—Isopropylphenylsulfonyl) —H— (2-N—Propyl-3-Pyridyloxy) —1,3_Benzenedioxytool—5— Acetamide (I 1-33 length; retention time 27 minutes) and (S) 1 (+)-N- (4-isopropylphenylsulfonyl) 1 (2—n 1 propyl _ 3-Pyridyloxy) 1-1,3-benzenedioxole-5-acetamide (II-3aS; retention time: 30 minutes) was separated.

Compound (II-1aR)

m. p. 1 6 8— 1 7 0

A nalytical (%) F or C 2 6 H 2 8 N 2 0 6 S FW 4 9 6. 5 8 C a 1 cd C: 6 2. 8 9 H:. Δ 6 8 N: 5. 6 4 S: 6. 4 6 Found C: 62.86 H: δ.69 N: 5.64 S: 6.59.

[H] _D (22 :)-79.9 ° (c = 1.0, methanol) Compound (II-13aR) hydrochloride (II_3aRHCl)

m.p. 1 7 6-1 8 1

A nalytical (%) F or C 2 6 H 2 9 C 1 N 2 0 6 SFW 5 3 3 0 4 C a 1 cd C:.. 5 8 5 9 H:. 5 4 8 C 1:. 6 6 5 N: 5.26S: 6.02

F oun d C: 58.68 H: 5.49 C 1: 6.44 N: 5.16 S: 6.0 3.

[a] _D (23)-81.6 ° (c = 1.0, methanol) Compound (II-13aS)

m.p. 1 6 8-1 7 0 "C

A na 1 ytica 1 (%) For C _{2 6} H _{2 8} N ₂ 0 ₆ SFW 4 96 .5 8

C a 1 cd C: 62.89 H: 5.68 N: 5.64 S: 6.46

Foun d C: 62.66 H: 5.77 N: 5.55 S: 6.48.

[] _D (22) + 80.5 ° (c = 1.0, methanol) Compound (II-3 a S) hydrochloride (II-3 a SHC l)

m-p. 18 1-18 9 X:

A nalytical (%) F or C 2 6 H 2 9 C 1 N 2 O e SFW 5 3 3 0 4 C a 1 cd C:.. 5 8 5 9 H:. 5 4 8 C 1:. 6 6 5 N: 5.26S: 6.02

Foun d C: 58.59 H: 5.δ3C 1: 6.64 N: δ.30S: 6.08.

[a] _D (23 ° C) + 82.3 ° (c = 1.0, methanol) Example 2 5N— (4-Isopropylphenylsulfonyl) a (6—tyl n_propyl-13_pyridyloxy) .3—Benzodoxyl

—Optical resolution of the acetate amide (II-1a)

The compound (II-8a) is fractionated on a column of CHIRALPAKAD (manufactured by Daicel Chemical Co., Ltd.) (solvent; n-hexane-ethanol-trifluoroacetic acid; 90: 10: 0.1). And (R)-(-)-N- (4—isopropylphenylsulfonyl) -α- (6-monomethyl-2—η—propyl—3—pyridyloxy) 1,3,3-benzenebenzene Cetamide (11-83 length; retention time 44 minutes) and (S)-(+) — —— (4—isopropylpyrenylsulfonyl) —Hi (6—methyl_2—η— Propyl-3- (pyridyloxy) -11,3_benzenedioxol_5_acetoamide (II-18aS; retention time 56 minutes) was separated. Compound (II-1aR)

m.p. 1 5 8-1 5 9

A nalytical (%) F or C 2 7 H 3 0 N 2 O 6 SFW 5 1 0 6 1 C a 1 cd C:.. 6 3 5 1 H:. 5 9 2 N:. Δ 4 9 S: 6 . 2 8

Foun d C: 63.34 H: 5.97 N: 5.60 S: 6.55.

[a] _D (23 t:)-76.2 ° (c = 1.0, methanol) Compound (II-8 a R) Hydrochloride (II _ 8 a RHC l)

m.p.1 7 1-1 7 5 t:

A nalytical (%) F or C 2 7 H 3 1 C 1 N 2 0 6 SFW 5 4 7 0 7 C a 1 cd C:.. Δ 9 2 8 H:. 5 7 1 C 1:. 6 4 8 N: 5.12 S: δ-8 6

F ou n d C: 59.09 H: δ.79 C 1: 6.26 N: 5.71 S:

1.

[a] _D (22 V,)-75.8 ° (c = 1.0, methanol) Compound (II-18aR) sodium salt (I—8aRNa)

m.p.2 5 3-2 5 5:

A nalytical (%) For or C _{2 7} H _{2 9} N ₂ 0 ₆ SN a FW 5 3 2 5 9 C a 1 cd C: 60.89 H: 5.49 N: δ. 26 S: 6.02 Na4.32

Foun d C: 60.75 H: 5.54 N: 5.51 S: 6.02 Na45.5.

[a] _D (25 * 0-81.1 ° (c = 1.0, methanol) compound (II-18aS) hydrochloride (II-18a SHCl)

m. p. 1 7 1-1 7 5 X:

A na 1 ytica 1 (%) For C _{2 7} H _{3 1} C 1 N ₂ 0 ₆ SFW 5 4 7. 0 7

C a 1 cd C: 59.28 H: 5.71 C 1: 6.48 N: 5.12 S: 5.86

F ou n d C: 59.08 H: 5.8 1 C 1: 6.3 3 N: 5.34 S: 5.8 2.

[a] _D (22) + 75.6 ° (c = l.0, methanol) Example 26 (R) -N- (4-Isopropylphenylsulfonyl) per (6 methyl—2 — N — Propyl 3- _ pyridylloquine 3 — Benzodoxo-l-ul 5 _ Synthesis of acetamido-nox (II-18hR)

The compound (II-8aR) was dissolved in anhydrous methylene chloride (40 ml), m-chloroperoxybenzoic acid (828 mg, 1.25 equivalent) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with a saturated sodium hydrogen carbonate solution and water, dried over magnesium sulfate and evaporated. The residue was purified by silica gel chromatography, recrystallized from 95% ethanol, and amide oxide (II_ShR) of compound (II-18aR) 109 mg (54%). m.p.2 6 1-2 6 3

A nalytical (%) F or C _{2 7} H _{3 0} N ₂ O ₇ S l. 5 H ₂ OFW .5 5 1.6 .2

C a 1 cd C: 5 8.79 H: 5.66 N: 5.08 S: 5.81

F ou n d C: 58.52H: δ.20N: 5.00S: 5.79.

[a _D (23.5 :)-76.1 ° (c = l. 0, methanol)

^ NMR (CDC 13 + CD 3 OD) <5: 7.4 (2H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.4 Hz) ), 7.01-6.78 (4H, m), 6.70 (1H, d, J = 8.0Hz), 5.93 (2H, d, J = 2 2 H z), 5-35 (1 H, s), 3.06-2.89 (3 H, m), 2.39 (3H, s), 1.6 3 (2 H, m), 1.23 (6H, d, J = 7.0Hz), 0.92 (3H, t, J = 7.2Hz) Test Example 1 Endoserine A Receptor Measurement of affinity for Yuichi (ETA-R)

Rat aortic smooth muscle A 7 r ^{5 1 2} 5 I-labeled ene Doseri in to the cells - 1 was determined couple from strength to harm inhibitory. Specifically, 4 8 after the cells cultured in the hole plates were washed with ^{buffer, 8. 3 X 1 0 - 1} 2 M of ^{1 2 5} I-labeled ene Doseri down _ 1 and various protease inhibitors HEPES-buffered Hanks' solution (0.3 ml) containing the above was added, and the mixture was incubated at 37 for 1 hour in the presence or absence of the compound of the present invention. After completion of the reaction, the reaction solution was removed by suction, and the cells were washed with HEPES-buffered Hanks' solution, and the radioactivity bound to the cells was measured with a gamma counter. Specific binding is 1 0 - was obtained by subtracting the non-specific binding was determined under conditions comprising 1 - ⁷ M nonradioactive ene Doseri down. ^{1 2 5} 1 labeled ene Doseri emissions - (. IC ₅₎ concentration of 1 specific binding of 50% inhibition for the compound of the present invention and the. Test Example 2 Measurement of Affinity for Endothelin B Receptor (ETB_R)

Butaen Doseri emissions B receptor was expression COS - 7 was determined from ^{1 2 5} I-labeled ene Doseri down one 3 strength to inhibit binding to the cells. More specifically, A plasmid vector incorporating the B-receptor gene was introduced into COS-7 cells by the lipofectin method. After washing the cultured cells with ^{buffer, 2 5 X 1 0- 1 2} 1 2 5 1 labeled ene Doseri emissions of M - 3 HEPES-buffered Hank's containing a variety of proteolytic enzyme inhibitors (H ank 's) solution (0.1 ml), 10 ³ to 10 ⁴ cells were suspended and added, and the mixture was incubated at 37 t: for 1 hour in the presence or absence of the compound of the present invention. . After the reaction was completed, the radioactivity bound to the cells was separated by glass fiber filter paper and measured with a gamma counter. Specific binding was obtained Ri especially good subtracting non-specific binding was determined under conditions comprising 1 0- ⁷ M nonradioactive ended cell Li Hmm 1. To a concentration of ^{1 2 5} I-labeled ene Doseri down one third specific binding 50% inhibition to the present invention compounds (IC 5 0).

Table 6 shows the results of the test examples.

Table 6 Compounds ETA-R ETB-R 11-3 g3.080 Number (n M) (n)

11-3 h 1.. 1 1 4 0

11-1 1 8 1 3 0 0

11-3 I 0. 7 5 1 1 0

11-2 a 0.7 8 1 2 0

【I— 3 j 4.0 0 1 5 0

11-2b 2.9 4 5 0

11-3 k 2 0. 0 1 1 0 0

11-2c 2.8.2 0

11-4 7. 7 8 6

II-2 d 3.. 3 2 4 0

I 1-5 2 0 2 0 0

II-2 e 2. 6 1 7 0

11-6 a 2 0 2 7 0

11-2 f 0.6 0.6 4 3

11-6 b 1 8 6 9

Π- 2 g 2.2. 2 1 2 0

11- 7 9 3 3 9 0

11-3 a 0. 8 8 8 8

11-8a 0.2 3 5 9

11-3 b 2. 1 3 3 0

I I-8 b 0.4 8 1 1 0

11 1 3 c 3 .0 1 7 0

II-3 d 5.7 2 6 0 11-8 c 0 .3 9 1 8

11-3 e 3.8 1 1 0 11-8 d 0.5 0.5 1 3 0

11-3 f 0 .6 8 3 0 11-8 e 0 .4 0 9 4

111-6 3 0 0 28000 II I 16 2 0 0 14000

111 1 7 2 2 0 22000 111-17 9 5 0> 100000

111-11 2 2 0 9 1 0 0 III 1 22 5 5 0 11000

111-12 2 0 0 7 6 0 0 111-30 9 0 0 9 5 0 0

HI-13 4 7 0 27000 111-35 3 5 0 48000

111-1 δ 2 5 0 16000 Example 8 Formulation example

Compound of the present invention 200 mg

Microcrystalline cell opening 0.4 5 mg

Magnesium stearate 0.0 5 mg

These mixtures were tableted with a single-shot tableting machine to obtain tablets of an appropriate size. Example 9 Formulation example

Compound of the present invention 100 mg

Heavy magnesium oxide 200 mg

Lactose 7 0 0 mg

These were uniformly mixed to obtain a powdery or fine-grained powder, and filled into a capsule container to obtain a capsule. The invention's effect

As described above, the compound (I) of the present invention antagonizes the binding of endoselin in the endoselin receptor and strongly suppresses the action of endoselin. Therefore, these compounds are useful as therapeutic and / or prophylactic agents for diseases caused by endoselin.

Claims

The scope of the claims

1. Formula (I)

(In the formula, R ¹ is hydrogen, halogen, lower alkyl optionally having substituent (s), lower alkenyl optionally having substituent (s), cycloalkyl optionally having substituent (s), Aryl which may be substituted, heteroaryl which may have a substituent, lower alkoxy which may have a substituent, lower alkylthio which may have a substituent, Lower alkoxycarbonyl which may be possessed, hydroxyl, lower acyl which may have a substituent, amino which may have a substituent, hydrazono lower alkyl, hydroxymino lower alkyl, Lower alkoxyimino lower alkyl, optionally substituted rubamoyl, optionally substituted rubamoyl lower alkyl, optionally substituted rubamoyl Shea lower alkyl, One NH COR ⁸ or a _{^{NH S 0 2 R 8 (R}} 8 in here which may have a lower alkyl or substituted group which may have a substituent Ariru) der O.

R ⁴ is hydrogen, halogen, lower alkyl optionally having substituent ( ^s) , one NH COR ⁸ ′ (where R ^s ′ is lower alkyl optionally having substituent ( ^s) or Optionally substituted), lower alkoxycarbonyl which may have a substituent, acyl which may have a substituent, carboxy, nitryl, hydrazono lower alkyl, hydroxymino lower alkyl, lower Alkoxymino lower alkyl, optionally substituted rubamoyl, optionally substituted rubamoyl lower alkyl, optionally substituted rubamoyloxy lower alkyl or Is an aryl which may have a substituent,

R ⁵ , R ⁶ and R ⁷ are each independently hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted Lower alkoxy, aryl which may have a substituent, carboxy, lower alkoxycarbonyl which may have a substituent, hydroxy, nitro, amino which may have a substituent, and a substituent Optionally, valmomoyl, — NH COR ⁸ ",-NHS 02 R ⁸ " (where R ⁸ '' is optionally substituted lower alkyl or substituted A good aryl) or one of S 0 n R ⁹ (where n is an integer from 0 to 2 and R ⁹ is lower alkyl) or R ⁵ and R ⁶ are adjacent to each other and together W— CR-CR ^{1 1} —, one W— CR ^{1 0} = N—,-W-N = CR ^{1 0} -.-W- (CR ^{1 2} R ^{1 2} ) m-W one, — W-CR ^{1 2} R ^{1 2} — CR ^{1 2} R ^{1 2-} , — CR ^{1 0} = CRH— W—, one N = CR ^{1 0} — W—, one CR ^{1 2} R] 2— CR ^{1 2} R i 2 one _w one, - CR ^^ CR ^ CR ^ ^ CR 1 1 - ( wherein W and W 'one O- each independently one SO p-, or - NR ^{1 3} - a and, R ¹⁰ and R ¹¹ are each independently hydrogen, lower alkyl optionally having substituent (s), lower alkenyl optionally having substituent (s), cycloalkyl optionally having substituent (s) , Halogen, carboxy, lower alkoxycarbonyl optionally having substituent (s), rubamoyl optionally having substituent (s), amino which may have substituent (s), NH COR ⁸ ′ ″ or One NH S 0 ₂ R ⁸ ″ (where R ⁸ ″ has the same meaning as described above), lower alkoxy optionally having a substituent, one SO n R ⁹ (where n and R ⁹ are the same as above) synonymous) or a _{^{^{S 0 2 NR 1 3 R 1}}} 4 der Ri, R ^{1 2} is water A lower alkyl optionally having a substituent, a lower alkenyl optionally having a substituent, hydroxy, an amino which may have a substituent, a hydroxyl group having a substituent, and a substituent Optionally substituted lower alkoxycarbonyl or one NHC〇R ⁸ ′ ′ (where R ⁸ ″ is as defined above), R ¹³ is hydrogen, lower alkyl optionally having substituent (s), A substituted or unsubstituted aryl or a substituted or unsubstituted cycloalkyl, wherein R ¹⁴ is a optionally substituted lower alkyl or a substituted or unsubstituted alkyl; Good aryl, optionally substituted cycloalkyl or optionally substituted tetrazo And m is 1 or 2 and p is an integer from 0 to 2).

X is —O—, 1 S— or 1 NR ¹⁵ — (where R ¹⁵ is hydrogen or a lower alkyl optionally having substituent (s));

Y is hydroxy or 1 NH ₂ O ₂ —Z (where Z is an aryl which may have a substituent or a heteroaryl which may have a substituent);

Or a pharmaceutically acceptable salt thereof or a hydrate thereof.

2. Equation (II):

(Wherein, shaku ¹ ~! ⁷ , X, Z and wavy line are as defined in claim 1), an aminoxide or a pharmaceutically acceptable salt thereof or Their hydrates.

3. Expression UI '):

(ΙΓ)

(Wherein, R i to R ⁴ , X, Z and wavy line are as defined above)

Or a pharmaceutically acceptable salt thereof or a hydrate thereof.

4. R ¹ is hydrogen, lower alkyl optionally having substituent (s), cycloalkyl optionally having substituent (s), aryl which may have substituent (s), having substituent (s) Lower alkoxy, lower alkylthio optionally having substituent (s), lower acyl optionally having substituent (s), amino which may have substituent (s), even having substituent (s) good force Rubamoiru or single NHS 0 ₂ R ⁸ in which claims the first term of the second term or a compound of paragraph 3, wherein salts or their hydrated its amino Nokisai de also can properly be their pharmaceutically acceptable object.

5. R ² and R ³ are each independently hydrogen or a lower alkyl optionally having substituent (s), and R ⁴ is hydrogen, lower alkyl optionally having substituent (s), or a substituent. Optionally substituted lower alkoxycarbonyl, optionally substituted acyl, nitryl, hydrazono lower alkyl, hydroxymino lower alkyl, lower alkoxymino lower alkyl, having a substituent 4. The compound according to claim 1, wherein the compound is an optionally substituted rubamoyl, an optionally substituted rubamoyloxy lower alkyl or an optionally substituted aryl. An amide oxide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

6. R ¹ is hydrogen, lower alkyl optionally having substituent (s), cycloalkyl optionally having substituent (s), aryl which may have substituent (s), or substituent (s) R ² and R ³ are each hydrogen, and R ⁴ is hydrogen, lower alkyl optionally substituted or substituted. 4. The compound according to claim 1, 2 or 3, wherein X is -O-, which is an aryl group optionally having a group, or an amine oxide or a compound thereof. Pharmaceutically acceptable salts or hydrates thereof.

7. Z is phenyl which may have a substituent, naphthyl which may have a substituent, 1, 2, 3, 4 -tetrahedral naphthyl which may have a substituent, 4. The compound according to claim 2 or 3, which is an indanyl which may have a substituent or a phenyl which may have a substituent, or an amide or a pharmaceutically acceptable salt thereof. Acceptable salts or hydrates thereof.

8. N- (4-Isopropylphenylsulfonyl) -1-α_ (2-Ethyl-3-P Lysiloxy) — 1,3 —benzenedioxo-l-5-acetamide, N— (4-isopropylphenylsulfonyl) — HI-I (2-n-propyl-1-3-pyridyloxy) 1.3 —Benzodioxo-l-5—acetamide, N— (4-Isopylpyrphenylsulfonyl) -1-α_ (6—methyl—2—η-propyl-13—pyridyloxy) 1-1,3—Benzoxo 2. The compound according to claim 1, wherein the compound is selected from the group consisting of 1-5-acetamide.

9. Formula (ΠΙ '):

(Wherein, R ¹ , R ² , R ³ , R ⁴ , X and wavy line are as defined above)

Or a pharmaceutically acceptable salt thereof or a hydrate thereof.

10. The compound according to any one of claims 1 to 9, its aminoxide, or a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient. Pharmaceutical composition.

11. The compound according to any one of claims 1 to 9, its aminoxide, or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. End serine receptor antagonist.

1 2. A compound according to any one of claims 1 to 9, its aminoxide, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. A method for preventing and / or treating a disease associated with endoselin.

1 3. The compound according to any one of claims 1 to 9 for the manufacture of a medicament for the prophylaxis and prevention or treatment of a disease involving endoselin, and the aminoxide thereof. Or use of their pharmaceutically acceptable salts or their hydrates.