WO1998003488A1

WO1998003488A1 - Novel pyrimidine compounds and drug compositions

Info

Publication number: WO1998003488A1
Application number: PCT/JP1997/002408
Authority: WO
Inventors: Yasuyuki Kawanishi; Yasuhiko Kanda; Toshiro Konoike
Original assignee: Shionogi & Co., Ltd.
Priority date: 1996-07-23
Filing date: 1997-07-11
Publication date: 1998-01-29
Also published as: JP4125787B2; AU3459697A

Abstract

Compounds of general formula (I), pharmaceutically acceptable salts thereof, and hydrates of those, wherein A is R1-W- or the like; R1 is optionally substituted aryl; W is SO¿2?NH, SO2NR, CONH or the like; R?2¿ is optionally substituted aryl or the like; R3 is hydrogen, optionally substituted alkyl or optionally substituted aryl; and X is O, S or a single bond.

Description

Description New pyrimidine compounds and pharmaceutical compositions

The present invention relates to compounds useful as medicaments and uses thereof. More specifically, a novel pyrimidine compound which has an endotherin B receptor selective antagonism and is useful for the prevention or treatment of a disease associated with endothelin B receptor, a pharmaceutical composition containing the novel pyrimidine compound, or endoselin B It relates to a receptor selective antagonist. Background art

Endothelin is a vasoactive peptide derived from endothelial cells consisting of 21 amino acids and is involved in vasosystemogenesis. Endothelin is also involved in some cardiovascular diseases, such as exacerbation of cardiovascular diseases such as hypertension, cerebral vasoconstriction, acute renal failure, acute proliferative nephropathy, acute myocardial infarction, and intimal hyperplasia. It exerts its action via end serine receptor as a factor.

To date, two subtypes of endothelin receptors, endothelin A receptor and endothelin B receptor, are known.Receptor antagonists are A receptor selective, B receptor selective and AB Three types of receptor nonselectivity are considered. It is becoming increasingly clear what types of receptors are involved in the disease, and selective endothelin A receptor antagonists may not be effective in the acute phase of cardiovascular disease However, satisfactory results have not been obtained. This suggests that not only endothelin A receptor but also endothelin B receptor may be involved in the development and progression of cardiovascular lesions.In addition, endothelin b is associated with metabolism of blood endothelin, It is also thought to be involved in intimal thickening of blood vessels and development and differentiation of certain cells.

A compound having an endothelin receptor antagonistic action and having a pyrimidine structure is disclosed in JP-A-5-222003, but there is no mention of endothelin B selectivity at all. Further, as a non-peptide endothelin B receptor selective antagonist, a compound having a pyrimidine skeletal structure is disclosed in FEB Letters (Vol. 383, pp. 37-41). .

While many endocrine receptor antagonists are being developed, there are relatively few endocrine B receptor selective antagonists, and most of them are non-peptide and have high selectivity. Not. Under the circumstances where the function of endothelin B receptor is still being elucidated, it has high activity and selectivity as a prophylactic and therapeutic agent for diseases involving endothelin B and a useful reagent for elucidating the function of the receptor. There has been a need for the development of a selective serine antagonist of noserine B receptor. Disclosure of the invention

The present inventors have found that the compound represented by the following formula (I) has high activity and selectivity as an antagonist, and have completed the present invention. That is, the present invention provides a method of formula (I):

(Where A is RL—W—, OHC—Y—py or halogen, R ¹ is an optionally substituted aryl, W is SO ₂ NH, SO ₂ NR ⁴ , CONH, ( CH ₂ ) nNH, O or S, R ² is an optionally substituted aryl, R ³ is hydrogen, an optionally substituted lower alkyl or an optionally substituted aryl, ⁴ is lower alkyl, X is 0, S or a single bond, Y is lower alkylene or lower alkenylene, and n is an integer of 0 to ^2. When X is a single bond, R ² is hydrogen or halogen. May be

Preferably the formula (I '):

(Wherein, R ¹ and R ² are each independently an optionally substituted aryl, and R 3 is hydrogen, an optionally substituted lower alkyl or an optionally substituted aryl. , X is 〇, S or a single bond, and Y is lower alkylene or lower alkylene.

Or a pharmaceutically acceptable salt thereof or a hydrate thereof. The present invention also provides a pharmaceutical composition containing the compound (I) and a selective antagonist of endothelin B receptor. Further, as another embodiment, there is provided a method for treating and / or preventing a disease caused by endothelin B, which comprises administering compound (I). The present invention also relates to the use of compound (I) for producing a medicament for treating and / or preventing a disease caused by endothelin B.

Further, the formula (IV):

Wherein H a 1 is halogen, R ² , R ³ , X and Y are as defined above, and Ζ is protected formyl.

And a compound represented by the formula (ΠΓ):

R ¹ 1 S 0 ₂ ΝΗΜ (ΙΙΓ)

(Wherein, R ¹ is as defined above, and 、 is a metal atom.)

Wherein the compound represented by the formula is reacted with a compound represented by the formula (II ′):

(Wherein, R], R ² , R ³ , X, Y and Z are as defined above)

And a method for producing the compound (I ′), which is characterized by further deprotection.

Also, an intermediate (IV), which is an intermediate used in the production method:

Wherein H a 1 is halogen, R ² , R ³ , X and Y are as defined above, and Z is protected formyl.

Or a salt thereof. BEST MODE FOR CARRYING OUT THE INVENTION

In the present specification, the term “aryl” specifically includes phenyl, naphthyl and the like, and is preferably phenyl. The term “optionally substituted aryl” means that it may have one or more substituents such as lower alkyl, lower alkoxy, halogen, hydroxy, methylenedioxy or ethylenedioxy, and may be cyclobutyl, cyclopentyl, cyclohexyl. And aryl which may be condensed with a saturated or unsaturated carbocycle such as cyclopentenyl.

“Lower alkyl” means a straight or branched alkyl having 1 to 6 carbons. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl and the like, and preferably t-butyl. “Optionally substituted lower alkyl” is an alkyl optionally having one or more substituents at any position, and examples of the substituent include halogen, hydroxy, lower alkoxy, carboxy, and lower alkoxycarbonyl. And acyl.

The “lower alkylene” is a group represented by one (CH ₂ ) _m — (m = 1-6), and specifically includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene. Preferably, it is trimethylene.

"Lower alkenylene" is a straight or branched group having at least one double bond and having 2 to 7 carbon atoms, and specifically, vinylene, probenylene, butenylene, Butagenylene, pentenylene, pentagenenylene, hexenylene, hexenenylene, hexatorienylene, heptenylene, heptanegenylene, heptanetrienylene and the like. The positions of these double bonds may be arbitrary.

“Lower alkoxy” refers to straight or branched alkoxy having 1 to 6 carbon atoms. Taste, specifically, includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, pentyloxy, hexyloxy, etc., and is preferably methoxy. These may have halogen, hydroxy or the like as a substituent.

“Halogen” refers to fluorine, chlorine, bromine or iodine.

The term "protected formyl" refers to a cyclic acetate or a diol such as ethylene glycol, propylene glycol or 2,2-dimethylpropanol or a monool such as methanol or ethanol as a protecting group. These include groups converted to dialkyl acetals, groups converted to 1,3-oxathiolane using mercaptoethanol, and the like, groups converted to dithioacetals using thiol, dithiol, or trimethylsilyl ether thereof.

The "compound of the present invention" also includes pharmaceutically acceptable salts of compounds (I) and Z or (1 '). For example, salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid; formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid Salts of organic acids such as ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthylenesulfonic acid, camphorsulfonic acid; salts of organic bases such as ammonium, trimethylammonium, and triethylammonium; sodium, And salts of alkaline metal such as potassium or alkaline earth metal such as calcium and magnesium. These salts can be formed by a commonly used method.

The compound of the present invention also includes a hydrate thereof, and may be bound to any number of water molecules per one molecule of the compound of the present invention. The compound of the present invention can be synthesized, for example, by the following method.

[A method; A-R ¹ — W— and X = 0 or S]

f d-a)

First, in the presence of a base such as an alkali metal alcoholate, a compound a and a phenolic compound such as guaiacol, m-methoxyphenol, or o-methoxybenzene represented by the general formula R ² -XH in a solvent such as alcohol. A compound b is obtained by reacting a thiol compound such as thiol or m-methoxybenzene thiol.

Subsequently, the compound b is condensed with amidine or a salt thereof (for example, formamidine acetate, pyrimidine-12-carboxamidine benzenesulfonate, etc.) in the presence of a base such as alkali gold alcoholate in a suitable solvent. To give compound c. Next, compound c is reacted with a halogenating agent or the like in the presence or absence of an organic base to obtain compound d. The solvent in this case may be any organic solvent that does not react with the halogenating agent, but when the organic base or the halogenating agent is in a liquid state, it can be used as a solvent.

Compound e is compound R ¹ —W ′ (W ′ is S0 ₂ NH ₂ , CONH ₂ , (CH ₂ ) nNH ₂ , OH, SH or a metal salt thereof, or a metal salt thereof; hereinafter, abbreviated as compound (III). ) Is reacted. The compound (III) to be reacted is preferably 1.5 to 2 mol with respect to the compound d, and may be reacted in a solution such as dimethyl sulfoxide or dimethylformamide.

Then, compound e and a diol such as ethylene glycol, propylene glycol, 1,4-butanediol, 1,5-pentanediol, and 1,6-hexanediol in the presence of a base such as sodium hydride and butyllithium. To react The product f is obtained and further oxidized to obtain the target compound. In the reaction between compound e and diols, it is preferable to use diols in excess, and diols may be used as a solvent. In the oxidation reaction of the compound f, an oxidizing agent which can be generally used in the oxidation reaction of alcohols to aldehydes may be used, and the oxidation is performed in a solvent inert to the oxidizing agent such as methylene chloride.

In the case where W of the target compound is S 0 ₂ NR ⁴ , after obtaining a compound in which W is S 0 ₂ NH ⁴ by the above method, the compound such as methyl iodide or the like is dissolved in a solvent such as dimethylformamide. Alkylation may be carried out using a luciferating agent.

The reaction temperature in each step is from 178 to 150 ° C., and a desired temperature can be selected. In addition, for a compound having a substituent that hinders the reaction, the compound may be protected in advance and eliminated at an appropriate stage.

Known compounds may be used as the compound (III). For example, when W ′ is SO ₂ NH ₂ or a metal salt thereof (hereinafter, referred to as compound (ΠΙ ′)), a known compound is obtained by the following method. It is also possible to synthesize more.

R ¹ -S0 ₂ CI ~ R -S0 ₂ NH ₂ ^ΜΟπ »R ¹ -S0 ₂ NHM

^9h (III ¹ ) First, known compound g is reacted with aqueous ammonia in an appropriate solvent such as toluene to obtain compound h, and then compound h is dissolved in a solvent such as methanol, ethanol, or the like. Compound (III ') can be obtained by reacting with an alkali such as sodium hydroxide (MOH; M is a metal atom, for example, potassium or sodium).

[Method B; A = R ¹ — W— or halogen and X = single bond]

d-b ')

When A of the target compound is R ¹ —W—, the 4- and 6-positions of 4,6-halogenobilimidine are first substituted in the same manner as above to obtain compound i, and N-prosuccinimide or the like is obtained. Halogenating the 5-position with to give compound j. Next, a palladium-catalyzed cross-coupling reaction with aryltin compounds (Journal of Organic Chemistry, Vol. 58, 1963-1966) P. 1993), the desired compound can be obtained by introducing the substituent R ² . When W of the target compound is S 0 ₂ NR ⁴ after obtaining W is S_〇 ₂ NH compound (I one a) in the manner described above, Bayoi them alkylation.

When A of the target compound is a halogen, for example, the halogen of the compound d ′ is once converted into a different substituent by a usual method, and the substituent R ² is introduced in the same manner as described above. The target compound may be synthesized by introducing O—Y—CHO and halogen.

[Method C; X = O or S]

_R 3 乂 N N OY-CHO k (I

When A of the target compound is R ¹ _W—, compound d obtained by the same method as above and compound H〇—Y—Z (where Y is as defined above, and Z is protected In the presence of a base such as sodium hydride or butyllithium, under ice-cooling to heating, preferably under ice-cooling, using tetrahydrofuran, dimethylformamide, dimethylsulfoxide or the like as a solvent. The reaction is performed for minutes to several hours to obtain compound (IV). The HO-YZ to be reacted is preferably about 1 to 1.3 mol per 1 mol of the compound d.

The obtained compound (IV) and compound (ΙΠ) are reacted in a solution of dimethyl sulfoxide or dimethylformamide at 0 :： 150 at a time of several hours to several tens of hours to obtain a compound (II). Deprotection reaction gives the desired compound. The compound (III) to be reacted is preferably 1.5 to 2 mol with respect to the compound (IV). For the deprotection reaction, a suitable method can be used from the usual methods depending on the formyl protecting group used. For example, hydrolysis may be performed using an acid such as formic acid. When A in the target compound is a halogen, compound (IV) may be subjected to a deprotection reaction. When A of the target compound is OHC—Y—O—, compound HO—YZ is reacted with compound d in the same manner as above to obtain compound k, which is then subjected to deprotection. I just need. The desired compound can be suitably obtained by using about 2 to 4 moles of the HO-YZ to be reacted with respect to 1 mole of the compound d. [D method; A = 〇HC— Y _ 0— and X = single bond]

d 'm

O-Y-CHO O-Y-CHO

Hal

To N Person ²

, Λ N O-Y-CHO 'person N person O-Y-CHO

n (i-c)

Compound d 'to in the Method B of the same搽by reacting H_〇 one Y- CH ₂ OH, to give the compound 1, after the title compound is obtained is reacted in a manner similar to Method B. The compounds of the present invention each have high activity and selectivity as a selective antagonist of endoselin B receptor, and can be used as a medicament. Endothelin B causes circulatory diseases such as hypertension, acute renal failure, heart failure, renal ischemia, cerebral ischemia, cerebral infarction, cerebral edema, migraine, etc., metabolism of blood endothelin and intimal thickening of blood vessels, etc. As it is thought to be involved, it is very useful as a therapeutic and prophylactic agent for these diseases. It is also useful as a reagent for elucidating the function of endothelin B.

When the compound of the present invention is administered as a medicament, it can be safely administered orally or non-periodically. Oral administration may be carried out in a usual dosage form such as tablets, granules, powders, capsules, pills, liquids, suspensions, syrups, buccals or sublinguals according to a conventional method. For parenteral administration, any commonly used dosage form, such as injections such as intramuscular administration, suppositories, transdermal absorbents, and inhalants, can be suitably administered, but oral administration is particularly preferred.

The pharmaceutical composition of the present invention requires various pharmaceutical additives such as excipients, binders, wetting agents, disintegrants, lubricants and diluents suitable for the final dosage form in an effective amount of the active ingredient. Can be prepared by mixing. In the case of injections, the preparation may be prepared by sterilizing with an appropriate carrier.

Specifically, the excipients include lactose, sucrose, glucose, starch, calcium carbonate Binder such as methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin or polyvinylpyrrolidone; disintegrants such as carboxymethylcellulose, carboxymethylcellulose sodium, starch, sodium alginate, agar powder or Lubricants such as sodium lauryl sulfate include talc, magnesium stearate and macrogol. As a suppository base, cocoa butter, macrogol, methylcellulose, or the like can be used. In addition, when prepared as a liquid formulation or an emulsion or suspension injection, commonly used solubilizing agents, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are appropriately added. In the case of oral administration, a flavoring agent, a fragrance and the like may be added.

The dose of the endothelin B receptor selective antagonist should be determined in consideration of the patient's age, weight, administration route, disease type and degree, etc., but when administered orally to humans For adults, l / g to 200 mgZk gZ days may be administered once to several times a day. In the case of parenteral administration, it may vary greatly depending on the administration route, but it is usually sufficient to administer 0.1 μg to 2 OmgZkg gZ once or several times a day.

The compound represented by the above general formula (I) or (1 ') has not only a potent endothelin B receptor selective antagonistic activity, but also can be administered orally, and has no effect when administered to normotensive rats. It has some features and is very useful. Among them, the following compounds are preferred because of their high endothelin B antagonistic activity and high selectivity for endothelin B.

In equation (I),

(1) A is R ¹ - S_〇 _{^{2 NH-, R 1 - C ONH}} -, RiNH-, OHC-YO- or halogen, (2) preferably ^{_{R 1 - S0 2 NH-, R}} 'NH- or OHC — Y— O—, (3) more preferably R ¹ — S0 ₂ NH— or OHC— Y—O—, (4) most preferably A is R ¹ — S 0 ₂ NH—, and R ^A compound wherein 1 is phenyl substituted with lower alkyl,

(5) R ² is phenyl optionally substituted with lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy, benzyloxy, (6) preferably lower phenyl A phenyl substituted with alkoxy, (7) a compound which is more preferably a methoxy-substituted phenyl,

(8) compounds wherein R ³ is hydrogen,

(9) X is O or a single bond, (10) a compound, preferably O

(11) Y is a lower alkylene, (12) preferably an alkylene having 1 to 4 carbon atoms, (13) a compound more preferably trimethylene,

(14) A is ^{_{R 1 - S0 2 NH -,}} R 1 -CONH-, R 1 NH -, OHC- Y - O is one or a halogen, R ² is lower alkyl, lower alkoxy, lower alkylene Njiokishi arsenide Dorokishi A phenyl optionally substituted with benzyloxy, a compound wherein R ³ is hydrogen, X is O or a single bond, and Y is lower alkylene; (15) preferably A is R ¹ — SO ₂ NH—, R— or OHC— Y

A compound wherein R ² is phenyl substituted with lower alkoxy, R ³ is hydrogen, X is O, and Y is alkylene having 1 to 4 carbon atoms, (16) Preferably, A is R ¹ —S 0 ₂ NH— or OHC—Y—O—, R ² is phenyl substituted by lower alkoxy, R ³ is hydrogen, X is 、, and Y is carbon (17) Most preferably, A is R ¹ —S 0 ₂ NH—, R ¹ is phenyl substituted by lower alkyl, and R ² is methoxy-substituted phenyl A compound wherein R ³ is hydrogen, X is 0 and Y is trimethylene;

(18) A is R ¹ — SO ₂ NH—, R ¹ is phenyl substituted with lower alkyl, and R ² is substituted with lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy, and benzyloxy A compound wherein R ³ is hydrogen, X is 〇 or a single bond, and Y is lower alkylene;

(19) A is R ¹ — S〇 ₂ NH—, R ¹ — CONH—, R ^ H-, OHC— Υ— Ο one or halogen, R ^{2 is} methoxy-substituted phenyl, and R ³ is hydrogen Wherein X is O or a single bond, and Y is lower alkylene;

(20) A is R ¹ -S 0 ₂ NH-, R ¹ -CONH-, R ¹ NH-OH-Y-O- or halogen, and R ² is lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy Is phenyl optionally substituted by benzyloxy Wherein R ³ is hydrogen, X is O or a single bond, and Y is trimethylene;

In equation (I '),

(1) a phenyl wherein R ¹ is substituted with a lower alkyl or fused to a carbocycle; (2) a phenyl preferably substituted with a lower alkyl; (3) more preferably a phenyl having 3 to 6 carbon atoms A phenyl substituted with alkyl, (4) a compound which is more preferably phenyl substituted with tert-butyl,

(5) R ² is phenyl optionally substituted with lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy, or benzyloxy; (6) phenyl preferably substituted with lower alkoxy; (7) more preferably Is a phenyl substituted with an alkoxy having 1 to 3 carbon atoms, (8) a compound which is most preferably a phenyl substituted with a methoxy,

(9) a compound wherein R ³ is hydrogen,

(10) a compound wherein X is O or a single bond, (11) preferably O

(12) a compound wherein Y is alkylene having 1 to 4 carbon atoms, (13) a compound which is more preferably trimethylene

(14) R ¹ is phenyl substituted with lower alkyl or fused to a carbocyclic ring, and R ² is substituted with lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy, or benzyloxy. A compound wherein R ³ is hydrogen, X is 0 or a single bond, and Y is alkylene having 1 to 4 carbon atoms;

(15) R ¹ is phenyl substituted with lower alkyl, R ² is phenyl substituted with lower alkoxy, R ³ is hydrogen, X is ◦ or a single bond, and Y is 1 carbon atom. A compound that is an alkylene of from 4 to 4,

(16) R ¹ is phenyl substituted with alkyl having 3 to 6 carbons, R ² is phenyl substituted with alkoxy having 1 to 3 carbons, R ³ is hydrogen, X is O or Or a single bond, wherein Y is alkylene having 1 to 4 carbon atoms,

(17) R ¹ is phenyl substituted with tert-butyl, R ² is phenyl substituted with methoxy, R ³ is hydrogen, X is 〇 or a single bond, and Y is A compound which is an alkylene having 1 to 4 carbon atoms,

(18) The compound wherein R ¹ is phenyl substituted with tert-butyl, R ² is phenyl substituted with methoxy, R ³ is hydrogen, X is 、, and Y is trimethylene. .

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

Indicates the meaning of the abbreviations in this embodiment,

M e methyl

i-Pri s o — propyl

t-B u t e r t-butyl

O Me methoxy

P h phenyl

M D Methylenedioxy

E D Ethylenedioxy

DMF Dimethylformamide

D M S O Dimethyl sulfoxide

N B S N—Promo Succinimide

P C C Pyridinium chlorochromate

T H F Tetrahydrofuran Example 1 4-tert-butyl-N- [5- (2-methoxyphenoxy) -61- (4-oxoptoxy) -pyrimidine-1- 4-benzenebenzenesulfonamide

Synthesis of (I) [Method A]

28% NH ₃ KOH

t-Bu- -so ₂ ci t-Bu-8 ■ S0 ₂ NH _? -t-Bu- VS0 ₂ NHK Tonolen MeOH

twenty three

(First step) Compound 1 (4-tert-butylbenzenesulfonyl chloride, 9.9 g, 42.5 mm o 1, Aldrich's Chemical Co., Ltd., manufactured by Rinpa Corporation) in toluene (100 ml) was added to a 28% aqueous ammonia solution. (100 ml) was added with stirring and reacted at room temperature for 4 hours. The reaction solution was concentrated, adjusted to pH = 13 with concentrated hydrochloric acid under ice cooling, and separated. The aqueous layer was further adjusted to pH = 7 with concentrated hydrochloric acid, and extracted with ethyl acetate. On the other hand, the organic layer was concentrated, combined with ethyl acetate from the aqueous layer, dried over anhydrous magnesium sulfate, and evaporated to give 8.88 g of compound 2 (4-tert-butylbenzenesulfonamide). Was.

98% yield

! HNMRCDMSO-dG) δ ppm: 1.30 (s, 9Η) '7.26 (s, 2Η), 7.56-7.77 (m, 4H).

(2nd step)

Potassium hydroxide (928 mg) and water (4 ml) were added to a solution of compound 2 (3.0 g, 14.4 Ommo 1) in methanol (20 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, methanol was added, and the procedure of reconcentration was repeated three times to obtain 3.18 g of compound 3 (potassium 4-tert-butylbenzenesulfonamide).

90% yield

ONMRiDMSO-de) δ ppm: 1.27 (s, 9H), 7.29, 7.57 (ABq, 4H, J = 8.4Hz, Mule = 85.4Hz).

(3rd step)

1.33 mo 1/1 sodium methylated tomole solution 1 50. Oml, under ice-cooling, 25.0 g (0.2mo1) of guaiacol was added dropwise over 10 minutes. The mixture was stirred at the same temperature for 10 minutes. Compound 4 (dimethyl chloroformate, 37.0 g, 0.2 m 01, manufactured by Aldrich Chemical Company) was added dropwise thereto over 20 minutes under ice-cooling, and the mixture was reacted at room temperature for 2.5 hours. Was. The reaction solution was concentrated, water was added, and extracted with toluene. The organic layer was sequentially washed with a 1% aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by distillation under reduced pressure (3 mmHg, 142-145) to obtain compound 5 (dimethyl-12-methoxyphenoxymalonate, 29.3 g).

Yield 58%

_{iHNMR (CDC1 3) <5 ppm} : 3.85 (s, 6H), 3.86 (s, 3H), 5.27 (s, 1H), 6.82-7.10 (m, 4H)

(4th step)

1 mo 1 Z1 solution of sodium methylate in methanol 30.4 ml, under ice cooling, add 1.lg of formamidine acetate and compound 5 (1.4 g, 5.5 mmo 1) The reaction was carried out at the same temperature for 1 hour. Concentrate the reaction mixture, add water, and extract with toluene. Issued. The aqueous layer was adjusted to pH = 4 with 1N hydrochloric acid under ice-cooling, and the precipitated crystals were collected by filtration and washed repeatedly with water to give compound 6 (5- (2-methoxyphenoxy) -1H-pyrimidine-14, 6-dione, 1.12 g) was obtained.

Yield 8 7%

! HNMR (CDsOD) δ ppm: 3.87 (s, 3H), 6.68-7.04 (m, 4H), 7.97 (s, 1H).

Anal.Calcd for C11H10N2O40.37H ₂ O

C, 54.85; H, 4.49; N, 11.63;

Found C, 54.82; H, 4.53; N, 11.78.

(Fifth step)

Add collidine (1.41 ml) to compound 6 (1.0 g, 4.27 mmo 1), add phosphorus oxychloride (5.8 ml) in portions under ice-cooling, and add an oil bath. The reaction was carried out at a temperature of 135 for 4 hours. After cooling, the mixture was concentrated, the residue was poured on ice, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate and brine in that order, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography to obtain compound 7 (4,6-dichloro-5- (2-methoxyphenoxy) -pyrimidine, 1.0 g).

86% yield

ΝΜΪΙ (CDCls) δ ppm: 3.88 (s, 3H), 6.64-6.68 (m, 1H), 6.84-7.17 (m, 3H), 8.63 (s, 1H).

(Step 6)

A solution of compound 7 (2.0 g, 5.97 mmo 1) and compound 3 (3.43 g, 13.6 mmo 1) in dimethyl sulfoxide (10 ml) was reacted at 12 Ot: for 2 hours. Was. After cooling, 1N aqueous hydrochloric acid (10 ml) was added, and the mixture was extracted with ethyl acetate. After washing with water three times and drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography to give compound 8 (4-tert-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -pyrimidine-l-4-yl] benzenesulfonamide, 2.7 8 g) were obtained.

Yield 84%

! HNMR (CDCh) <5 ppm: 1.33 (s, 9H), 3.97 (s, 3H), 6.88-7.20 (m, 4H), 7.49, 7.97 (ABq, 4H, J = 8.6Hz, Δv = 95.6Hz), 8.41 (s, 1H).

(Step 7)

60% sodium hydride (145 mg, 3.63 mmo 1) was added to 1,4-butanediol (4.3 ml) and reacted at room temperature for 30 minutes. Compound 8 (412 mg, 0.92 mmo 1) was added thereto, and the mixture was reacted at an oil bath temperature of 100 for 3 hours. After cooling, the pH was adjusted to 1 with 1N aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. After washing with water three times and drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography to give compound 9 (4-tert-butyl-N- [6- (4-hydroxybutoxy)-5- (2-methoxyphenoxy) -pyrimidine-14-yl] -benzenesulfone Amide, 369 mg).

80% yield

! HNMR (CDCla) δ ppm: 1.30 (s, 9H), 1.39-1.53 (m, 2H), 1.62-1.77 (m, 2H), 3.48-3.57 (m, 2H), 3.88 (s, 3H), 4.27 -4.33 (m, 2H), 6.76-7.10 (m, 4H), 7.33-7.48 (m, 2H), 7.78-7.98 (m, 2H), 8.17 (s, 1H).

(8th process)

To a solution of compound 9 (500 mg, 1.0 mmol) in methylene chloride (5 ml) was added pyridinum chromatochromate (430 mg, 2.0 mmol) at room temperature, and the mixture was added at room temperature. Allowed to react for hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain the desired compound (1-1; 378 mg).

Yield 82%

ONMR (CDCls) (5 ppm: 1.33 (s, 9H), 1.88-2.01 (m, 2H), 2.32 (t, 2H, J = 7.0Hz), 3.94 (s, 3H), 4.34 (t, 2H, J = 6.2Hz), 6.80-7.16 (m, 4H), 7.48, 8.00 (ABq, 4H, J = 8.6Hz, Δv = 104.2Hz), 8.23 (s, 1H), 9.64 (s, 1H). 2 4 -tert-Butyl-1-N— [5— (3-Methoxyphenoxy) -1 6- (4—oxothoxy) pyrimidine—4-yl] benzenesulfonamide

Synthesis of (I-2) [Method A]

(First step)

Use m-methoxyphenol (manufactured by Wako Pure Chemical Industries, Ltd.) instead of Guayakol 6ΐ

. : Kai (suio s Ή? ^ R ^ ¾--[(y--^^? {-(+ / E oo + 4 ^ — ε)-g-(ku- ro ^ — t — 9] -Η- Λ (-ί-} J 3} —,) I i ^>

(S ェ s¾)

(HI ^<s ) 6 8 '( ^Ζ Η S'86 = ▽

'HI'?) OZ'L '(HI ^{> m} ) "99.9' (HI '" 0 2 ^ 9-0 ^ -9' (HI 6ε'962 9 '(HS' s ) S '(H6' s): i «dd ρ (εΐθαθ) ΗΙΜΝΗι

% 885 * Kir ° -7fi¾ (39

^ _ 9] I N -ΙΓΐ, ^ Ι-J a 1-t ') ε I 8 ¾ ^

(D

^{• (HI 's) 698'} (zH3'8 = f 'HI L' (HI 'ω) U'9'99'9

'(ws = f' HI 'Ϊ) s 9' (HI '«8ε · 9-εε · 9' (Ηε 's) ΐ8 · ε:" ^ d _ρ (ειοαο)

% 2 L South Kit (§ ε-z 5-(/ e ^ ^-ε) one s — mouth b ^, one 9 ')

(HT ' ^s ) Ι0 ・ 8' (Ηΐ ' ^ω ) LVL- L' (ΗΙ ') S'9' (Η3 '^) I'9.8S'9'(HS' s) U'S ^{: UJ} dd ρ (ap -OSWQ) H Maraud Hi

% I 9

. ^ (380-Z 'く — 9' ー t Π 3— H τ-(乙 ^ ^ — ε) — s) τ τ '¾ ø

(g z)

'HI' ΐ) 6ΓΔ '(Ηε 89) 9-9 ^' 9 '(Η9 ^{, s} ) 58Έ' (HS 's) eLS- ^ ^dd 9 ( ^ε 1θαθ) H

% 0 l umbrella ¾f (3 L · ε '^^ d 2 rom 1 (e /: 1 4-ε)-Ζ) 011: ^

8 strokes df / IDd 88W0 / 86OAV

NHR (CDCla) δ ppm: 1.34 (s, 9H), 1.78-1.91 (m, 2H), 2.19 (t, 2H, J = 7.0 Hz), 2.47 (s, 3H), 3.77 (s, 3H), 4.27 (t, 2H, J = 6.2 Hz), 6.32-6.41 (m, 2H), 6.60-6.65 (m, 1H), 7.15 (d, IH, J = 8.0 Hz), 7.51 (d, 2H, J = 8.8 Hz), 8.05 (t, 2H, J = 8.6 Hz), 9.54 (s, IH).

(I-7)

> H NHR (CDCI3) <5 ppm: 1.33 (s, 9H), 1.88-1.97 (m, 2H), 2.31 (t, 2H, J = 6.9 Hz), 2.43 (s, 3H), 3.95 (s, 3H ), 4.31 (t, 2H, J = 6.0 Hz), 6.79-7.10 (m, 4H), 7.48, 8.03 (ABq, 4H, J-8.4 Hz, △ = 164.2 Hz), 8.51 (brs, IH), 9.63 (s, IH).

(I-8)

> H NHR (CDC) δ ppm: 1.31 (s, 9H), 1.84- 1.98 (m, 2H), 2.23 (t, 2H, J = 7.0 Hz), 3.78 (s, 3H), 4.42 (t, 2H, J = 6.0 Hz), 6.39-6.47 (m, 2H), 6.62-6.68 (m, IH), 7.18 (t, IH, J = 8.0 Hz), 4.43-7.47 (m, 3H), 7.51, 8.08 (ABq, 4H, J = 8.8 Hz, Δ = 113.3 Hz), 8.22-8.27 (m, 2H), 9.56 (s, IH).

(I-9)

NHR (CDCh) 6 ppm: 1, 30 (s, 9H), 1.95-2.08 (m, 2H), 2.36 (t, 2H, J = 7.4 Hz), 3.98 (s, 3H), 4.48 (t, 2H, J = 6.4 Hz), 6.82-7.16 (m, 4H), 7.40-7.50 (m, 5H), 8.05 (d, 2H, J = 8.6 Hz), 8.20-8.25 (m, 2H), 8.56 (s, IH ), 9.66 (s, IH).

(I-10)

lU NHR (CDCI3) (5 ppm: 1.25 (d, 6H, J = 7.0 Hz), 1.88-2.04 (m, 2H), 2.32 (t, 2H, J = 7.0 Hz), 2.89-3.30 (m, IH) , 3.94 (s, 3H), 4.34 (t, 2H, J = 6.2 Hz), 6.81-7.15 (m, 4H), 7.33, 8.00 (ABq, 4H, J = 8.2 Hz, Δv = 135.2 Hz), 9.64 (s, IH). Example 11 Synthesis of Compound (I-11) [Method B]

(First to third steps)

Example 1 Compounds 16, 7, and 18 were obtained in the same manner as in the sixth to eighth steps.

Compound 1 6

Yield 71%

^] H NHR (CDCls) β ppm: 1.34 (s, 9H), 5.05 (s, 1H), 7.53, 7.86 (ABq, 4H, J = 11.0 Hz, Δv = 66.3 Hz), 8.74 (s, IH).

Compound 1 7

Yield 51%

Ή NHR (CDCI3) <5 ppm: 1.33 (s, 9H), 1.69-1.90 (m, 4H), 4.11 (t, 2H, J = 6.3 Hz), 4.37 (t, 2H, J = 6.3 Hz), 6.64 (s, IH), 7.51, 7.83 (ABq, 4H, J = 8.7 Hz, Δv = 97.4 Hz), 8.64 (s, IH).

Compound 1 8

78% yield

Ή NHR (CDCls) δ ppm: 1.34 (s, 9H), 2.05-2.15 (m, 2H), 2.63 (t, 2H, J = 7.5 Hz), 4.38 (t, 2H, J = 6.3 Hz), 6.66 ( s, IH), 7.53, 7.85 (ABq, 4H, J = 8.4 Hz, Δv = 95.0 Hz), 8.63 (s, 1H), 9.84 (s, IH).

(4th step)

Compound 18 (2.0 g.5.3 mmol) in a DMF (10 ml) solution was cooled on ice. N-promosuccinimide (1.23 g, 6.9 mmo 1) was charged and reacted at the same temperature for 30 minutes. Aqueous sodium sulfite was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain the desired compound 19 (1.33 g).

55% yield

Ή NHR (CDCb) (5 ppm: 1.33 (s, 9H), 2.07-2.15 (m, 2H), 2.62 (t, 2H, J = 6.9 Hz), 4.42 (t, 2H, J = 6.3 Hz), 7.53 , 8.03 (ABq, 4H, J = 9.0 Hz, Δv = 166.6 Hz), 7.86 (s, 1H), 8.29 (s, 1H), 9.82 (s, 1H).

(Fifth step)

Compound 19 (147 mg, 0.32 mmol) in a solution of dioxane (2 ml) was added to

4-methylphenyltributyltin (compound 20: 351 mg), bis (triphenylphosphine) palladium (II) chloride (47 mg), copper chloride (I)

(20 mg) and 2,6-di-t-butyl cresol (2 to 3 grains) were added, and the mixture was distilled for 1.5 hours. After cooling, ethyl acetate and aqueous potassium fluoride solution were added, and the mixture was stirred at room temperature for 30 minutes. The insoluble material was filtered, and the filtrate was acidified with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue is purified by silica gel column chromatography, and the target compound (1-11) 9

5 mg were obtained.

63% yield

NHR (CDCla) (5 ppm: 1.33 (s, 9H), 1.91-1.99 (m, 2H), 2.37-2.42 (m, 3H), 2.42 (s, 3H), 4.30 (t, 2H, J = 6.3 Hz ), 7.10-7.58 (m, 6H), 8.00 (d, 2H, J = 7.6 Hz), 8.38 (s, 1H), 9.62 (s, 1H). Reference Example 1 Synthesis of Compound 20

21 20

Compound 21 (2 O ml, 1 mo 1/1 solution in ether) was diluted with tetrahydrofuran (15 ml), tributyltin chloride (0.543 ml) was added, and the mixture was refluxed for 19 hours. did. After cooling, an aqueous solution of ammonium chloride was added, and the mixture was extracted with ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain Compound 20. Examples 12 to 14 Synthesis of Other Compound (I) [Method B]

The following compounds were synthesized in the same manner as in Example 11.

(1-1 2)

lU NHR (CDCls) δ ppm: 1.32 (s, 9H), 1.87-2.03 (m, 2H), 2.38 (t, 2H, J = 8.0 Hz), 4.28 (t, 2H, J = 6.2 Hz), 7.16- 7.27 (m, 2H), 7.36-7.52 (ra, 5H), 7.96 (d, 2H, J = 7.8 Hz), 8.34 (s, 1H), 9.58 (s, IH).

(1-1 3)

lR NHR (CDCls) δ ppm: 1.32 (s, 9H), 2.04-2.13 (m, 2H), 2.63 (t, 2H, J = 6.9 Hz), 4.38 (t, 2H, J = 6.6 Hz), 6.66 ( m, 1H), 7.48-7.54 (m, 2H), 7.82-7.88 (m, 2H), 8.70 (s, IH), 9.81 (s, IH).

(1-1 4)

^! H NHR (CDCla) δ ppm: 1.33 (s, 9H), 2.07-2.15 (m, 2H), 2.62 (t, 2H, J = 6.9 Hz), 4.41 (t, 2H, J = 6.3 Hz), 7.53 , 8.09 (ABq, 4H, J = 9.0 Hz, Δ v = 166.6 Hz), 7.86 (s, IH), 8.29 (s, 1H), 9.82 (s, IH). Example 15 Compound (I — 2) Synthesis of [Method C]

(First to third steps) Four

23 24

Example 1 Compounds 22 to 24 were obtained in the same manner as in the third to fifth steps.

Compound 22 yield 67%

Compound 23 yield 93%

Compound 24 yield 93%

(4th step)

A solution of compound 26 (202.5 g, 1.16 mol) obtained by the method of Reference Example 2 in tetrahydrofuran (300 ml) was hydrogenated at 60% under ice cooling. Sodium (46.5 g, 1.16 mo 1) was charged and the mixture was distilled for 30 minutes. After cooling, compound 24 (300 g, 1.11 mo 1) was added thereto, and the mixture was distilled for 3 hours. After cooling, water was added and extracted with toluene. After washing with water three times and drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain the desired compound 25 (402 g).

Yield 89%

_{lH NHR (CDC1 3) δ ppm} : 0.70 (s, 3H), 1.16 (s, 3H), 1.50-1.60 (m, 2H), 1.72- 1.86 (m, 2H), 3.35 (d, 2H, J = 10.6 Hz), 3.55 (d, 2H, J = 10.6 Hz), 3.78 (s, 3H), 4.33-4.43 (m, 3H), 6.36-6.41 (m, IH), 6.47 (t, IH, J = 2.2 Hz ), 6.60-6.65 (m, IH), 7.17 (t, IH, J = 8.2 Hz), 8.41 (s, IH). (Fifth step)

Example 1 Compound 28 was obtained in the same manner as in the sixth step.

Yield 71%

»H NHR (CDCh) δ ppm: 0.69 (s, 3H), 1.13 (s, 3H), 1.34 (s, 9H), 1.39-1.50 (m, 2H), 1.60-1.75 (m, 2H), 3.32 ( d, 2H, J = 10.8 Hz), 3.53 (d, 2H, J = 10.8 Hz), 3.77 (s, 3H), 4.25-4.31 (m, 3H), 6.30-6.36 (m, 1H), 6.40 (t , IH, J = 2.2 Hz), 6.60-6.65 (m, IH), 7.14 (t, IH, J = 8.3 Hz), 7.51, 8.02 (ABq, 4H, J = 8.9 Hz, Δv = 103.3 Hz), 8.28 (s, IH).

(Step 6)

Compound 28 (351.3 g, 0.6 mo 1) was added to a 6% aqueous solution of formic acid in which sodium formate (204 g, 3. Omo 1) was dissolved. The reaction was performed for 5 hours. After cooling, water was added and extracted with toluene. The organic layer was adjusted to PH = 8 with saturated aqueous sodium hydrogen carbonate, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography and recrystallized from isopropyl acetate to obtain 242 g of the desired compound (1-2).

Yield 8 1%

^J H NHR (CDCla) δ ppm: 1.34 (s, 9H), 1.82-1.90 (m, 2H), 2.17 (t, 2H, J = 6.9 Hz), 3.77 (s, 3H), 4.29 (t, 2H, J = 6.0 Hz), 6.33-6.40 (m, 2H), 6.62-6.66 (m, 1H), 7.16 (t, IH, J = 9.6 Hz ), 7.52, 8.03 (ABq, 4H, J = 8.4 Hz, Δv = 156.4 Hz), 8.28 (s, IH), 9.53 (s, IH). Reference Example 2-Synthesis of Compound 26

29 26

Compound 29 (13.37.3 g, 12.84 mo 1) was dissolved in 4% aqueous hydrochloric acid, and 2,3-dihydrofuran (900 g, 12.84 mo) was added under ice-cooling. 1) was added dropwise. After reacting at room temperature for 17 hours, the mixture was neutralized with 4 N sodium hydroxide under ice cooling and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by distillation to obtain the desired compound 26 (1419.5 g).

Yield 63%

^! H NHR (CDCla) <5 ppm: 0.72 (s, 3H), 1.19 (s, 3H), 1.66-1.80 (m, 4H), 2.36 (brs, IH), 3.43 (d, 2H, J = 10.8 Hz ), 3.62 (d, 2H, J = 10.8 Hz), 3.64 (t, 2H, J = 5.7 Hz), 4.48 (t, 1H, J: 4.2 Hz). Examples 16 to 23 Other Compounds (I [Method C]

The following compounds were obtained in the same manner as in Example 15.

(I-1) Same as above

(1 — 1 5)

Ή NHR (CDCla) (5 ppm: 1.31 (s, 9H), 1.81-1.97 (m, 2H), 2.21 (t, 2H, J = 7.1 Hz), 4.30 (t, 2H, J = 6.1 Hz), 5.18 (s, 2H), 6.80-6.94 (m, 2H), 6.96-7.10 (m, 2H), 7.28-7.41 (m, 5H), 7.45, 7.93 (ABq, 4H, J = 8.5 Hz, Δv = 97.5 Hz), 8.22 (s, IH), 8.42 (s, IH), 9.57 (s, IH).

(1-16)

NHR (CDCb) (5 ppm: 0.69 (s, IH), 1.13 (s, 3H), 1.34 (s, 9H), 1.39-1.50 (m, 2H), 1.60-1.71 (m, 2H), 3.33 (d, 2H, J = 11.4 Hz), 3.53 (d, 2H, J = 11.1 Hz), 3.77 (s, 3H), 4.25-4.31 (m, 3H ), 6.31-6.36 (m, IH), 6.40 (t, IH, J = 2.4 Hz), 6.62 (dd, IH, J = 2.4, 8.3 Hz), 7.14 (t, IH, J = 8.3 Hz), 7.51 , 8.02 (ABq, 4H, J = 8.9 Hz, Δv = 103.3 Hz), 8.28 (s, IH).

(1-1 9)

^J H NHR (CDC) δ ppm: 1.78-1.93 (m, 2H), 2.06-2.24 (m, 2H), 2.18 (t, 2H, J = 7.0 Hz), 2.96 (t, 4H, J = 7.5 Hz) , 3.78 (s, 3H), 4.28 (t, 2H, J = 6.1 Hz), 6.34 (dd, IH, J = 2.4, 8.4 Hz), 6.39 (dd, 1H, J = 2.4, 2.4 Hz), 6.64 ( dd, IH, J = 2.4, 8.4 Hz), 7.17 (dd, IH, J = 8.4, 8.4 Hz), 7.32 (d, 1H, J = 8.1 Hz), 7.91 (s, IH), 8.27 (s, IH ), 9.53 (s, IH).

(1-20)

Ή NHR (CDCb) δ ppm: 1.76-1.91 (m, 6H), 2.18 (t, 2H, J = 7.2 Hz), 2.75-2.88 (m, 4H), 3.78 (s, 3H), 4.29 (t, 2H , J = 6.0 Hz), 6.34 (dd, IH, J = 2.4, 8.2 Hz), 6.39 (dd, IH, J = 2.4, 2.4 Hz), 6.64 (dd, IH, J = 2.4, 8.2 Hz), 7.17 (d, IH, J = 8.7 Hz), 7.64 (s, IH), 7.76-7.83 (m, 2H), 8.27 (s, IH), 9.54 (s, IH).

(1-2 1)

Ή NHR (CDCb) <5 ppm: 1.31 (s, 9H), 1.88-1.97 (m, 2H), 2.26 (t, 2H, J = 7.5 Hz), 3.79 (s, 3H), 4.35 (t, 2H, J = 6.3 Hz), 6.50-6.55 (m, 2H), 6.62-6.65 (m, IH), 7.20 (t, IH, J = 7.8 Hz), 7.34-7.38 (m, 2H), 7.46-7.49 (m , IH), 8.26 (s, IH), 9.59 (s, IH).

(1-2 2)

lH NHR (CDCla) (5 ppm: 1.93-2.07 (m, 4H), 2.39 (t, 4H, J = 7.0 Hz), 3.78 (s, 3H), 4.40 (t, 4H, J = 6.4 Hz), 6.37 -6.47 (m, 2H), 6.57-6.62 (m, IH), 7.16 (t, IH, J = 8.2 Hz), 8.23 (s, IH), 9.66 (s, 2H).

( one two Three )

Ή NHR (CDCb) δ ppm: 1.91-2.00 (m, 2H), 2.29 (t, 2H, J = 6.9 Hz), 3.79 (s, 3H), 4.40 (t, 2H, J = 5.7 Hz), 6.37- 6.41 (m, IH), 6.46 (t, IH, J = 2.4 Hz), 6.63- 6.66 (m, IH), 7.19 (t, IH, J = 8.1 Hz), 8.41 (s, IH), 9.61 (s , IH). Example 24 Synthesis of Compound (I-I7) [Method C]

To a dichloromethane (4 ml) solution of compound (1-2) (602 mg) was added a 1 M boron tribromide dichloromethane solution (1.205 ml) with stirring under ice-cooling, and the mixture was reacted at room temperature for 4 hours. I let it. The reaction solution was concentrated, and the residue was poured into ice-cold water and extracted with ethyl acetate. After washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the desired compound (I-117). Ή NHR (CDCls) 6 ppm: 1.33 (s, 9H), 1.81-1.91 (m, 2H), 2.20 (t, 2H, J = 7.5 Hz), 4.28 (t, 2H, J = 5.7 Hz), 6.30- 6.37 (m, 2H), 6.56-6.59 (m, 1H), 7.10 (t, 1H> J = 8.1 Hz), 7.51, 8.03 (ABq, 4H, J = 8.7 Hz, Δv = 153.1 Hz), 8.26 ( s, 1H), 9.52 (s, 1H). Example 25 Synthesis of 5 Compounds (I-18) [Method C]

Similarly, compound (1-18) was synthesized from compound (I-11).

! H NHR (CDCls) δ ppm: 1.34 (s, 9H), 1.81-1.93 (m, 2H), 2.20 (t, 2H, J = 6.0 Hz), 4.28 (t, 2H, J = 5.7 Hz), 5.85 -6.05 (m, IH), 6.49-6.60 (m, IH), 6.68-6.78 (m, 1H), 6.97-7.05 (m, 2H), 7.53, 8.05 (ABq, 4H, J = 8.4 Hz, Δy = 157.8 Hz), 7.90-8.10 (m, 1H), 8.27 (s, IH), 9.55 (s, IH). Example 26 Synthesis of Compound (I-I24) [Method C]

To a solution of the compound (1-2) (20 mg) in DMF (0.3 ml) was added, at room temperature, lithium carbonate (6.6 mg) and methyl iodide (0.025 ml). Stirred for 12 hours. The reaction solution was poured into ice water and adjusted to pH = 1 with 1N hydrochloric acid. After extraction with ethyl acetate, washing with water, drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the desired compound (1-24).

NHR (CDCla) δ ppm: 1.34 (s, 9H), 1.85-1.98 (m, 2H), 2.23 (t, 2H, J = 7.0 Hz), 3.15 (s, 3H), 3.78 (s, 3H), 4.37 (t, 2H, J = 6.2 Hz), 6.41-6.50 (m, 2H), 6.60-6.65 (m, IH), 7.17 (t, IH, J = 8.2 Hz), 7.50, 7.89 (ABq, 4H, J = 8,6 Hz, Δv = 77.3 Hz), 8.43 (s, IH), 9.59 (s, IH). οε

(HT 's) 896' (HI ' ^s ) LIS' (^ H 98 = P 'HT' ί) 9ΓΖ, '(S 2S = ▽' ^Z H 9'8 = P 'H' ^b 8V) Ϊ0 Α ' S 9 '(HI' ^w ) 39 9 'S'9' (RZ ^<m ) 9 '(HI' ∞) '(ΖΗ Z 9 = f' RZ 'Z £ f' (HS 's) Lf' (HS ' ^s ) 9L'2' (9.9 = P 'HZ

' ^b ) L98' (zH 0 · um = f 'UZ% Z'Z' (UZ '^) 66 T "68'T: ™ dd ρ (qoaD) HHN Ht

. Tsu ^^ (L z- i)

[¾o] ^ ω (i z-i) 6 z m

(HI ' ^s ) 89'6' (HI 's) 6Γ8' (UZ '"SS' -OS 'm' (HS '« ZZ'L- VL' (HS ^<UI ) Ι9'9Δ8 "9 ' (ZH L'Q = P 'HZ' Ρ) 9 f '(^ H 0 "9 = f' KZ 'ί) ZS f' (HS ' ^s ) 9f £' (ZH Z'L = P Ή2 'ί) 9Z'Z '(RZ ^{> m} ) 96 -Δ8 "!' (H6 's) θε · ΐ:« idd g (^ οαθ) HHN Hi

(9 2-1) '' Q

9 ¾g ΐ. ¾ o ε, is is τ ι— 乙 ^ 4 mouth Ma / ι π ^ ^ ^ マ Ma 6 ^ 邈 Character 氺 ^. : I iflt} li Mf4 ^ Υ¾ 氺氺 ¾Ι1ϊ ^ ° ^ $ ^ ¾ ^ ¾Π 0 S I (S S 9 S) ミ Λ (^ Λ (-ί:-ί J 3 ί-7 (3 ui 2 ι ι ζ

[¾D] (9 z-I) 8 z ^.

(HI ^<s ) S9 "6 '(HI' s) 69'8 '(^ H 3'62T = ▽' ^Z H 9'8 = P ' ^b 9V) 6'L' 6fL '(HI' ^m ) 80 ..10 · '(HI' ∞) 86 · 9262 9 '(UZ' ω) 9 '(ζΗ = f' HS 'ϊ)' (HE 's) 98 S' (HS 's) l '£' (ZH 2'9 = f

'RZ'?) LI 2 '(ZH S'9 '39 = P' HS '^) LS I' (H6 's) εΐ ™ dd ρ (εΐθαθ) HHN Hi

(s z— I) 呦导 (τ-I) 呦 ^ ¾¾:

[¾] (s ε-I) ~~ L z m

WPZ0IL6d £ ll3d m £ o OAV Example 30 Synthesis of Compound (1-28) [Method C]

Under ice-cooling, 60% sodium hydride (64 mg) was added to a DMF solution of 4-tert-butyl monobutylphenol (360 mg), and reacted at room temperature for 30 minutes. Compound 27 (32 27 mg) was added thereto and reacted at a pass temperature of 100 for 1 hour. After cooling, the mixture was poured into ice water and extracted with toluene. After washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain compound 31. Subsequently, compound (I-28) was obtained in the same manner as in Example 15, sixth step. Ή NHR (CDCla) (5 ppm: 1.31 (s, 9H), 1.94-2.08 (m, 2H), 2.39 (t, 2H, J = 7.4 Hz), 3.79 (s, 3H), 4.43 (t, 2H, J = 6.2 Hz), 6.48-6.64 (m, 3H), 7.19 (t, IH, J = 8.2 Hz), 6.92, 7.48 (ABq, 4H, J = 8.6 Hz, Δv = 111.9 Hz), 8.25 (s , IH), 9.65 (s, IH). Examples 31 to 32 Synthesis of Compounds (I-29) and (I-130) [Method C] In the same manner as in Example 30, The following compounds were synthesized.

(1-2 9)

Ή NHR (CDCls) 6 ppm: 1.32 (s, 9H), 1.89-1.98 (m, 2H), 2.25 (t, 2H, J = 6.9 Hz), 3.77 (s, 3H), 4.39 (t, 2H, J = 6.0 Hz), 6.46-6.53 (m, 2H), 6.61-6.66 (m, IH), 7.20 (t, IH, J = 8.1 Hz), 7.46, 7.72 (ABq, 4H, J = 8.1 Hz, Δv = 77.9 Hz), 8.43 (brs, 1H), 8.55 (brs, 1H), 9.53 (s, IH).

(1-3 0)

> H NHR (CDCls) <5 ppm: 1.33 (s, 9H), 1.85-1.98 (m, 2H), 2.24 (t, 2H, J = 7.4 Hz), 3.79 (s, 3H), 4.35 (t, 2H , J = 6.2 Hz), 6.43-6.52 (m, 2H), 6.60-6.66 (m, IH), 7.19 (t, IH, J = 8.2 Hz), 7.40-7.50 (m, 4H), 8.32 (s, 1H), 9.57 (s, IH).

Table 2

Test example Measurement of (ETA-R) affinity for endothelin A receptor

Rats were obtained from the preparative aortic smooth muscle A 7 r 5 ^{1 25} I-labeled endothelin-one 1 strength to inhibit binding to the cells. Specifically, after washing the cells with buffer and incubated in 4 8-well plate, containing ^{1 25} I-labeled endothelin-one 1 with various proteolytic enzyme inhibitors of 8. 3 X ¹ 0- 1 ² M The HE PES buffered Hanks' solution (0.3 ml) was 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 completion of the reaction, the reaction solution was removed by suction, and the cells were washed with a Hank's solution buffered with HE PES. Then, the radioactivity bound to the cells was measured with a gamma counter. Specific binding is 1 0 - non-specific binding was determined under conditions comprising ⁷ M nonradioactive Endoserin 1 Was obtained by subtracting And it was one of the specific binding 50% inhibitory prejudice present compound漉度^{_{(IC 50) - 1 2 5}} I -labeled endothelin. Table 3 shows the results. Test Example 2 Measurement of affinity for endothelin B receptor (ETB-R)

Descriptor endothelin B receptions evening ^{1 2 5} I-labeled E Ndoserin to CO S- 7 cells expressing an - 3 was determined from the intensity of inhibiting binding. Specifically, a plasmid vector incorporating the putaendothelin ETB receptor Yuichi 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 25 I -labeled Endoserin HEPES-buffered Hank's solution containing one 3 and various protease inhibitors M (0. 1 ml) to 1 0 ³ was suspended to 1 0 ⁴ cells, the present invention compounds presence, or absence, 3 7: incubation for 1 hour. After completion of the reaction, the radioactivity bound to the cells was separated by glass fiber filter paper, and measured by gamma counting. Specific binding was obtained by subtracting nonspecific binding determined under conditions comprising 1 0- ⁷ M nonradioactive Endoserin 1. ^{1 2 5} to a concentration of I-labeled Endoserin one third singular binding to 5 0% inhibition to the present invention compounds (IC ₅ 0). Table 3 shows the results.

W

Table 3

Table 3 shows that the compounds of the present invention have strong endothelin B receptor selective antagonism. Formulation example

Compound (I-) 50 mg

Lactose 4 6 mg

Corn starch 20 mg

Low substituted hydroxypropylcellulose 8 mg

Hydroxypropyl methylcellulose 5 mg

Magnesium stearate 1 mg

Total 130 mg

Excluding hydroxypropyl methylcellulose and magnesium stearate After uniformly mixing the above ingredients, tablet granules were prepared by wet granulation using an 8% (w / w) aqueous solution of hydroxypropylmethylcellulose as a binder. After mixing with magnesium stearate, it was formed into a tablet with a diameter of 7 mm and a tablet weight of 13 Omg using a tableting machine. Industrial applicability

As described above, the compound of the present invention has strong endothelin B receptor antagonism, and its selectivity is very high. Therefore, it is useful as an endothelin B receptor selective antagonist.

Claims

The scope of the claims

1. Formula (I):

(Where A is R ¹ —W—, OH C— Y—O— or halogen, R ¹ is an aryl which may be substituted, W is S 0 ₂ N to I, S 0 ₂ NR ^4, C 0 NH, a (CH ₂₎ n NH, O or S, R ² is Ariru optionally substituted, R ³ is hydrogen, lower alkyl which may be substituted or substituted R ⁴ is lower alkyl, X is 0, S or a single bond, Y is lower alkylene or lower alkenylene, and n is an integer of 0 to 2. X is a single bond Where R ² may be hydrogen or halogen)

Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

2. Formula (I '):

(Wherein, R ¹ and R ² are each independently an optionally substituted aryl, and R ³ is hydrogen, an optionally substituted lower alkyl or an optionally substituted aryl. , X is 〇, S or a single bond, and Y is lower alkylene or lower alkylene.

Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or hydrate thereof, wherein R ³ is hydrogen.

4. The compound according to claim 1 or 2, wherein R ¹ is phenyl substituted with lower alkyl, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

5. The compound according to claim 1 or ^{2, wherein} R ² is phenyl substituted with lower alkoxy, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5.

7. A selective endothelin B receptor antagonist comprising the compound according to any one of claims 1 to 5.

8. A method for treating and Z or preventing a disease caused by endothelin B, which comprises administering the compound according to any one of claims 1 to 5.

9. Use of the compound according to any one of claims 1 to 5 for producing a medicament for treating and / or preventing a disease caused by endothelin B.

10. Equation (IV):

Wherein H a 1 is halogen, R ² , R ³ , X and Y are as defined in claim 2, and Z is protected formyl.

And a compound represented by the formula (ΙΠ '):

R ¹ -S 0 ₂ NHM (III ')

(Wherein, R ¹ has the same meaning as in claim 2 and M is a metal atom). A compound represented by the formula (II ′):

(Wherein, R ¹ , R ² , R ³ , X and Y are as defined in claim 2 and 2 is as defined above)

A method for producing a compound represented by the formula:

1 1. A method for producing a compound according to claim 2, wherein the method further comprises deprotection following the method according to claim 10.

1 2. Equation (IV)

Wherein H a 1 is halogen, R ² , R ³ , X and Y are as defined in claim 2, and Ζ is protected formyl.

Or a salt thereof.