WO2005097764A1

WO2005097764A1 - Thiazole derivative

Info

Publication number: WO2005097764A1
Application number: PCT/JP2005/007106
Authority: WO
Inventors: Hiroshi Fukushima; Masato Takahashi; Tsuyoshi Busujima; Takanori Kawaguchi
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 2004-04-07
Filing date: 2005-04-06
Publication date: 2005-10-20
Also published as: JP2007261945A

Abstract

Disclosed is a compound having a sufficient curative effect because of its 11β-HSD1 inhibitory actions and thus is satisfactory as a pharmaceutical drug. Specifically disclosed are a thiazole derivative represented by the formula (I) below and pharmaceutically acceptable salts thereof. [In the formula (I), R1 represents an adamantane-1-yl group or the like; R2 represents a hydrogen atom or the like; R3 represents a hydrogen atom, a methyl group, an ethyl group, an isobutyl group, a 4-methoxybenzyl group, a 2-hydroxy-ethyl group, a carbamoylmethyl group or the like; ring A represents a phenyl group or the like; and R4-R8 respectively represent a hydrogen atom or a substituent.]

Description

Specification

Thiazole derivatives

Technical field

The present invention relates to a novel thiazole derivative useful as an II-HSD1 (11) 8-hydroxysteroid dehydrogenase type 1) inhibitor, a pharmaceutically acceptable salt thereof, a solvate thereof and the like. Background art

11) 8-HSD1 An enzyme that converts cortisone to cortisone. 113-HSD1 is expressed in the liver, visceral fat, etc., and is thought to function as a factor that amplifies intracellular cortisol levels at the level of each organ. 11) 8-HSD1 has been suggested to be involved in gluconeogenesis in the liver. Therefore, inhibition of 11j8-HSD1 activity is expected to be able to suppress hepatic gluconeogenesis. Furthermore, 11-HSD1 has been suggested to be involved in visceral fat accumulation. Therefore, inhibition of 11i8-HSD1 activity is expected to suppress visceral fat accumulation. 11) As inhibitors of 8-HSD1, reports by Barf T et al. (J Med Chem. 2002: 3813-5), WO 01/090090, WO 01/090091, WO 01/090092 WO 01/090093, W0

Thiazole derivatives described in WO 01/090094, WO 03/043999 are known.

W001 / 090090 (Patent Document 1) discloses an 11 / S-HSD1 inhibitor containing a thiazole derivative represented by the following formula. In the following formulas, X is is methylene group, or carbonyl group; over Y is methylene group, a carbonyl group, or a single bond; - R ² is like-alkyl (same publication page 6, 9 Lines-page 8 line 11).

WO 01/090091 (Patent Document 2) discloses an 11; 8-HSD 阻害 inhibitor containing a thiazol derivative represented by the following formula. In the following formula, A is an alkyl group, a vinyl group, or 3- (ethyl-3-methylbutane).

W001 / 090092 (Patent Document 3) discloses an 11 ^ -HSD1 inhibitor containing a thiazole derivative represented by the following formula: In the following formula, A is an aryl group which may have a substituent, or a heteroaryl ring (page 6, line 26 to page 8, line 7).

WO 01/090093 (Patent Document 4) discloses a 113-HSD1 inhibitor containing a thiazol derivative represented by the following formula. As can be seen from the following formula, the 4-position of the thiazole ring disclosed in this document is unsubstituted.

W001 / 090094 (Patent Document 5) discloses an 11; 8-HSD1 inhibitor containing a thiazole derivative represented by the following formula.

W003 / 043999 (Patent Document 6) discloses an 11) 8-HSD1 inhibitor containing a thiazole derivative represented by the following formula. In the following formula, B is a hydrogen atom, a C ₁ -C ₆ alkyl, or a dimethylaminomethyl group (page 6, line 25 to page 8, line 22 of the same publication).

2 no Y—X

That is, an 11-HSD1 inhibitor containing a thiazole derivative having an adamantyl group is not known.

Although not an IliS-HSDI inhibitor, the following compounds are known as thiazole derivatives having an adamantyl group (Patent Document 7 (U.S. Patent Specification Mo. 5, 378, 706, Nos. 13 and 14). Column) As can be seen from the following formula, this compound does not have a sulfonyl group (one SO _? —).

[Patent Document 1] W001 / 090090

[Patent Document 2] W001 / 090091

[Patent Document 3] W001 / 090092

[Patent Document 4] W001 / 090093

[Patent Document 5] W001 / 090094

[Patent Document 6] W003 / 043999

[Patent Document 7] U.S. Patent Specification No. 5, 378, 706

[Non-patent Document 1] J Med Chem. 2002: 3813-5 Disclosure of the invention

The known 11; 8-HSD1 inhibitors described above have insufficient inhibitory activity and are not satisfactory as pharmaceuticals. For this reason, there is a demand for the development of a compound that has a sufficient therapeutic effect by 11i8-HSD1 inhibitory action and is satisfactory as a pharmaceutical. The present inventors have conducted intensive studies to achieve the above object, and as a result, have found that a specific thiazole derivative having an adamantyl group has excellent 11) 8-HSD1 inhibitory activity, thereby completing the present invention. Reached.

That is, the present invention relates to the following novel thiazole derivatives, pharmaceutically acceptable salts thereof, and solvates thereof.

[Where,,

R ¹ represents an adamantyl group or an adamantyl group having 1 to 3 substituents selected from “hydroxyl group, halogen atom, (; broad alkyl group, and ~ alkoxy group”;

R ² has 1 to 3 substituents selected from a hydrogen atom, an alkoxycarbonyl group, a ( ₅ alkyl group, or a “hydroxyl group, a halogen atom, and an alkoxy group” (^ to (: ₅ alkyl groups Represents;

R ³ is a hydrogen atom, an alkyl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group; or a “hydroxyl group, a carbamoyl group, a halogen atom, an alkoxy-phenyl group, an amino group, an alkyl group; an amino group, ~ ~ alkyl group having 1 to 3 substituents selected from Jiarukiruamino group and a C广C ₅ alkoxy group "; Ring A represents an aryl or heteroaryl group;

R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ each represent a halogen atom, a cyano group, a nitro group, a formula X ¹ — X ² — X ³ (wherein X ¹ is a single bond, an oxygen atom, Sulfur atom, sulfinyl group, sulfonyl group, carbonyl group, formula —NX ⁴ —, formula — CO— NX ⁴ —, formula — NX ⁴ — CO—, formula — NX ⁴ — CO— NX ⁴ —, formula — NX ⁴ — CO- O-, formula _{^{- S 0 2 - NX 4 -}} , wherein one NX ⁴ _S0 ₂ -, and Table formula one CO- O-or formula -O- CO-; X ² is a single bond, - an alkylene group X ³ and X ⁴ are each a hydrogen atom, an alkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, an aryl group, a heteroaryl group or to alicyclic represents a heterocyclic group. However, X ^2, X ³ and X ⁴ may have 1 to 3 substituents selected from the following substituent group Y.), or the formula ^{^{^{X 1 - X 5 - X 6}}} ( wherein, X ¹ is as defined above; X ⁵ represents a C广C ₅ alkylene group; X ⁶ has the formula -ox ^7, wherein one NX ⁷ X ⁸ , Formula — CO— NX ⁷ X ⁸ , Formula NX ⁷ — CO— X ⁷ , Formula 1 S0 ₂ — NX ⁷ X ⁸ , Formula — NX ⁷ — S 0 ₂ — X ⁸ , Formula — CO— O— X ⁷ or . formula - 0- CO- represents X ^7; X ⁷ and X ⁸ each represent a hydrogen atom, Ariru group or ~ alkyl group provided ^{^{that, X 5, X 6, X}} 7 and X ^8, following substituent group Y. 1 to may have three substituents selected from the group.) or represents, or!? ^4, two neighboring groups of RR ^6, R ⁷ and R ⁸ summer together X-X ⁵ —X ¹ — (wherein X ¹ and X ⁵ are the same as defined above); and the substituent Y group is a halogen atom, Cyano group, nitro group, hydroxyl group, methyl group, trimethyl group, acetyl Group, a group consisting of methylthio group or main Bok alkoxy group. ] The thiazole derivative represented by these, its pharmaceutically acceptable salt, or its solvate. According to the present invention, a novel thiazole derivative having an excellent 113-HSD1 inhibitory activity, a pharmaceutically acceptable salt thereof, a solvate thereof, and the like can be provided. BEST MODE FOR CARRYING OUT THE INVENTION

The thiazole derivative of the present invention is a compound represented by the following formula (1).

In the formula (1), R ¹ represents an adamantyl group or an adamantyl group having 1 to 3 substituents selected from “hydroxyl group, halogen atom, 〜alkyl group, and じ₅ alkoxy group”. . Preferably, R ¹ is an adamantyl group or an adamantyl group substituted with a hydroxyl group or a CiCg alkoxy group. More preferably, R ¹ is an adamantyl group or a 3-hydroxyadamantyl group.

In the formula (1), R ² is a hydrogen atom, - an alkoxycarbonyl group, - ₍₅ alkyl group, or "hydroxyl, ~ having a halogen atom, and (a barrel selected from-alkoxy group J ~ 3 substituents Represents an alkyl group, preferably is a hydrogen atom, an alkyl group, or an alkyl group substituted with a hydroxyl group, and more preferably, R ² is a hydrogen atom or a methyl group.

In the formula (1), R ³ is a hydrogen atom, ～〇 ₅ alkyl group, Ji广alkenyl Le group, C Cs alkynyl group; or "hydroxyl, force Rubamoiru group, halogen atom, C广C ₅ alkoxy - phenyl It represents group, an amino group, - an alkylamino group, a C Cs alkyl groups having from 1 to 3 substituents selected from C ₂ -C ₇ dialkylamino group and ~ alkoxy group ". Preferably, R ³ is a hydrogen atom, a di- or di-alkyl group. More preferably, R ² is a hydrogen atom or a methyl group.

In the formula (1), the ring A represents an aryl group or a heteroaryl group. Preferred A ring is phenyl, 1-naphthyl, or 2-naphthyl; pyrrolyl, furyl, phenyl, thienyl, oxazolyl, isoxazolyl, imidazolyl Group, thiazolyl group, isothiazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, 1,3,4-year-old oxadiazolyl group, 1,2,4-year-old oxadiazolyl group, 1,2,4-thiadiazolyl group, pyridyl Group, birazinyl group, pyrimidinyl group, pyridazinyl group, 1,2,4-triazinyl group, 1,2,3-triazinyl group, 1,3,5-triazinyl group, benzixyloxazolyl group, benzisoxa Zolyl group, benzothiazolyl group, benzoisothiazolyl group, benzimidazolyl group, benzotriazolyl group, benzothiadiazolyl group, benzofurazanyl group, benzopyranyl group, thianaphthenyl group, isothianaphthenyl group, benzofuranyl group, isobenzofuranyl group, benzofuranzyl group Group, isoindolyl group, indolyl group, indazolyl group, isoquinolyl group, Ryl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, 2,1,3-benzoxadiazolyl, benzoxazinyl, cumaryl, naphthyridinyl, purinyl, pteridinyl, chenofuranyl, imidazothiazolyl , An imidazopyridinyl group, a pyrrolidone pyridinyl group, a pyrrolopyrimidinyl group, and a pyridopyrimidinyl group. More preferred ring A is phenyl, 1-naphthyl or 2-naphthyl; pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, furyl, chenyl, isoxazole, thiazolyl, pyrrolyl. A quinolinyl group, a benzothylphenyl group, a benzofuranyl group, or a benzoxyloxazolyl group. Still more preferred ring A is a phenyl group, a benzothienylphenyl group, a phenyl group, or a benzofuranyl group.

In the formula (1), R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each a halogen atom, a cyano group, a nitro group, a formula —X ¹ —X ² —X ³ (wherein X ¹ is single bond, an oxygen atom, sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, the formula - NX ⁴ -, wherein one C 0- NX ⁴ -, wherein one NX ⁴ - CO-, wherein -NX ⁴ -CO- NX ⁴ —, Formula 1 NX ⁴ — CO— 0—, Formula — S0 ₂ — NX ⁴ —, Formula — NX ⁴ — S0 ₂ —, Formula 1 CO— 0— or Formula 1 0—CO—; X ² a single bond, - (: represents a ₅ alkylene group; X ³ and X ⁴ are each a hydrogen atom, - (: ₅ alkyl group, C ₃ ~ C ₆ cycloalkyl group, C ₂ ~ (; ₆ alkenyl group, Represents a C ₂ to C ₆ alkynyl group, an aryl group, a heteroaryl group or an alicyclic heterocyclic group, provided that X ² , X ³ and X ⁴ are the same as those of the following substituent group Y It may have 1 to 3 substituents selected. X ¹ —X ⁵ -X ⁶ (wherein X ¹ has the same meaning as described above; X ⁵ represents ^ 〜 (: ₅ alkylene group; X ⁶ is a group represented by the formula OX ⁷⁾ , wherein one NX ⁷ X ^8, wherein one CO- NX ⁷ X ^8, wherein one NX ⁷ - CO- X ^7, wherein _{^{^{- S0 2 - NX 7 X 8}}} , Shiki NX ⁷ -S0 ₂ -X ^8, wherein - X— represents X— ⁷ or a formula—CO—X— ⁷ ; X ⁷ and X ⁸ each represent a hydrogen atom, an aryl group or an alkyl group, provided that X ⁵ , X ⁶ , X ⁷ and X ⁸ may have〗 to 3 substituents selected from the following substituent group Y.) or a group adjacent to R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ The two groups together form a ring structure of the formula X ¹ — X ⁵ — X ¹ — (wherein X ¹ and X ⁵ are as defined above); Groups include halogen atoms, cyano groups, nitro groups, hydroxyl groups, methyl groups, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ each represent a halogen atom, a cyano group or a nitro group, each of which represents a methyl group, an acetyl group, a methylthio group or a methoxy group; , Formula 1 X ¹ — X ² — X ³ (where X ¹ is a single bond, an oxygen atom, a sulfonyl group, a carbonyl group, Formula 1 NX ⁴ —, Formula 1 NX ⁴ — CO—, Formula 1 NX ⁴ — CO— NX ⁴ —, formula — NX ⁴ — CO— 0—, formula — S 0 ₂ — NX ⁴ — or formula — CO— 0—; X ² represents a single bond, an alkylene group; X ³ and X ⁴ each represent a hydrogen atom, an alkyl group, a C ₃ -C ₆ cycloalkyl group, an aryl group, a heteroaryl group or an alicyclic heterocyclic group, provided that X ² , X ³ and X ⁴ may have〗 to 3 substituents selected from the following substituent group Y.) or a compound represented by the formula: X ¹ — X ⁵ — X ⁶ , wherein X ′ is Single bond, an oxygen atom, der Li; X ⁵ represents a ~ alkylene group; X ⁶ has the formula one OX ^7, wherein one NX ⁷ X ^8, wherein - CO- ΝΧ ⁷ Χ ^8, wherein one NX ⁷ - CO- represents X. ⁷ or formula one CO- 0- X ^{^7;} X ⁷ and X ^8, which respectively represent a hydrogen atom, Ariru group or ~ alkyl group. However, X ⁵ , X ⁶ , X ⁷ and X ⁸ may have 1 to 3 substituents selected from the following substituent group Y. ) Or two adjacent groups of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are joined together to form a formula — X ¹ — XS-X ¹ — (wherein X ¹ is , A single bond, an oxygen atom, and X ⁵ is an alkylene group); and the substituent group Y is a halogen atom, a cyano group, a dihydroxy group, a hydroxyl group, A group consisting of a methyl group, a trifluoromethyl group, an acetyl group, a methylthio group and a methoxy group. More preferably, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each a halogen atom, a cyano group or a compound of the formula X ¹ —X ² —X ³ (wherein X ¹ is a single bond, an oxygen atom X ² represents a single bond, to an alkylene group; X ³ and X ⁴ each represent a hydrogen atom, to (: ₅ alkyl group, C ₃ to C ₆ cycloalkyl group, heteroaryl) Represents a group or an alicyclic heterocyclic group, provided that X ² , X ³ and X ⁴ may have 1 to 3 substituents selected from the following substituent group Y.) —X ¹ —X ⁵ —X ⁶ (wherein, X ¹ is a single bond or an oxygen atom; X ⁵ represents an alkylene group; X ⁶ is a formula OX ⁷ or a formula NX ⁷ X represents ^8;. X ⁷ and X ^8, which respectively represent a hydrogen atom or - _(5-alkyl group provided that, X ^5, X ^6, X ⁷ and X ⁸ is selected from the following substituent group Y May have 1 to 3 substituents.) Or two adjacent groups among R ⁴ , RR ⁶ , R ⁷ and R ⁸ are taken together to form a group of formula X ¹ — X ⁵ — X ¹ — (wherein, X ¹ is a single bond, an oxygen atom, and X ⁵ is a C ₅ alkylene group); and a substituent group Y Is a group consisting of a halogen atom, a cyano group, a nitro group, a hydroxyl group, a methyl group, a trimethyl group, an acetyl group, a methylthio group or a methoxy group.

Most preferably, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are a halogen atom, a cyano group, a methyl group, an ethyl group, a trimethyl group, and a methoxy group, respectively. Hereinafter, each substituent and the like used in the present specification will be described.

Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Alkyl group J means an alkyl group having 1 to 5 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group And an isopentyl group, a 1,1-dimethylethyl group, a 1,1-dimethylpropyl group, and a 1-ethylpropyl group.

Examples of the “C ₃ -C ₆ cycloalkyl group” include a cyclopropyl group, a clobutyl group, a cyclopentyl group, and a cyclohexyl group. An “aryl group” is a group formed by liberating one hydrogen atom bonded to a ring of an aromatic hydrocarbon, and includes, for example, a phenyl group, a 1.1-naphthyl group and a 2-naphthyl group.

The "heteroaryl group" is a monocyclic or condensed aromatic ring having 1 to 4 elements arbitrarily selected from an oxygen atom, a sulfur atom, and a nitrogen atom in the ring. Group, oxazolyl group, isoxazole group, imidazolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, 1,3,4-year-old Oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, birazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5- Tri azinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, benzotriazolyl, benzothiazole Diazolyl group, benzofurazanyl group, benzopyranyl group, thianaphthenyl group, isothianaphthenyl group, benzofuranyl group, isobenzofuranyl group, benzocenyl group, isoindolyl group, indolyl group, indazolyl group, isoquinolyl group, quinolyl group, phthalazinyl group, quinoxalinyl group Quinazolinyl group, cinnolinyl group, 2,1,3-benzoxadiazolyl group, benzoxazinyl group, cumaryl group, naphthyridinyl group, purinyl group, pteridinyl group, thienofuranyl group, imidazothiazolyl group, Examples thereof include an imidazopyridinyl group, a pyridinyl group having a pyro opening, a pyrimidinyl group having a pyro opening, and a pyridopyrimidinyl group.

`` C ₂ -C ₆ alkenyl group J means a straight-chain, branched or cyclic alkenyl group having 2 to 6 carbon atoms, for example, a vinyl group, an aryl group, a 1-propenyl group, Examples thereof include a monopropenyl group, an isopropenyl group, a 2-butenyl group, a 3-butenyl group, an isobutenyl group, a 4-pentenyl group, and a 5-hexenyl group.

“C ₂ -C ₆ alkynyl group” means a linear, branched or cyclic alkynyl group having 2 to 6 carbon atoms, such as ethynyl group, 1-propynyl group, 2-propynyl group, Examples thereof include a 3-butynyl group, a 4-pentynyl group, and a 5-hexynyl group. "-Alkylene group" means a divalent group derived from the above-mentioned "alkyl group of ~" by removing one arbitrary hydrogen atom, for example, a methylene group,

Examples thereof include a 1,1-ethylene group, a 1,2-ethylene group, a 1,1-propylene group, a 1,3-propylene group, a tetramethylene group, and a pentamethylene group.

Examples of the “alicyclic heterocyclic group” include, for example, an azetidine ring, a pyrrolidine ring, a piperidine ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, and a morpholine ring, a piperazine ring, a thiazolidine ring, Xan ring, imidazoline ring, or thiazoline ring

The

The "～〇 ₅ alkoxy group", the number 1-5 straight, means branched or cyclic alkoxy group, for example, main Bok alkoxy group, E Bok alkoxy group, a propoxy group, isopropoxy Group, cyclopropoxy group, butoxy group, or tert-butoxy group.

The term "-alkoxy-phenyl group" means a phenyl group substituted with the above-mentioned -alkoxy group, and examples thereof include a 4-methoxyphenyl group and a 4-ethoxyphenyl group.

"-Alkylamino group" means an amino group substituted with a linear, branched or cyclic alkyl group having 1 to 5 carbon atoms, such as a methylamino group, an ethylamino group, a propylamino group, Examples include an isopropylamino group, a cyclopropylamino group, a butylamino group, a tert-butylamino group, a pentylamino group, and a neopentylamino group.

The term "-dialkylamino group" means an amino group substituted by two linear or branched or cyclic alkyl groups having 1 to 5 carbon atoms, which are the same or different, such as a dimethylamino group and a methyl group. Examples thereof include an ethylamino group, a getylamino group, and a dipropylamino group. The following are specific examples of the thiazole derivative of the present invention. That is, compound 1: 41- (1-adamantyl) — 2— (1-naphthylsulfonylamino) thiazol, compound 2: 41- (1-adamantyl) — 2— (2, 4 5-Triclomethylphenylsulfonylamino) thiazole, compound 3: 4- (1-adamantyl) 1 2-[(2-Chenylsulfonyl) amino] thiazole, compound 4: 4-1 (1-adamantyl) 1 2 — (4-Bromophenylsulfonylamino) thiazole, compound 5: 4- (1-adamantyl) —2 -— (3-chloromethyl-2-methylphenylsulfonylamino) thiazole, compound 6: 4- (1 -A-damantyl) -1-2- (enylsulfonylamino) thiazole, compound 7: 4— (1-adamantyl) -2-[[(5-promo 6-chloropyridine-13-yl) sulfonylamino] thiazole, i 9: 4— (1 -adamantyl)-2-[(6-morpholinopyridine-3-yl) sulfonylamino] thiazolyl, compound 9: 4— (1-adamantyl) 1 2— [(6-Phenoxypyridine-1 3 — (Yl) sulfonylamino] thiazole, compound 10: 4— (1-adamantyl) 1-2 — [(Pyridine-12-2-yl) sulfonylamino] thiazole, compound 11 1: 4- (1-adamantyl) I 2 — [(Pyridine-13-yl) sulfonylamino] thiazole, compound 12: 4— (1-adamantyl) —2 -— [N- (4-biphenylsulfonyl) -1-N-methylamino] thiazol, compound 1 3: 4 1 (1-adamantyl) 1 2-[N-[(5-chloro-3 -methylbenzo [b] thiaphen-2-yl) sulfonisole] -N-methylamino] thiazole, Compound 14: 4-1- (1-adamantyl) 1-2- [Ντ-methyl-N— (4-η-propylphenylsulfonyl) amino] thiazol, compound 15: 4— (1-adamantyl) 1-2- [ Ν— (4-Fluorophenylsulfonyl) monomethylamino Sol, Compound 16: 4— (1-adamantyl) 1-2— [Ν-methyl-Ν—

(4-Morpholinophenylsulfonyl) amino] thiazol, compound 17: 4-1 (1-adamantyl) 1-2- [Ν-methyl-Ν— [4- (4-methylbiperazinyl) phenylsulfonyl] amino] thiazo-1 Compound 18: 4— (1-Damantyl) 12— [一 — [4- [bis (2-hydroxyethyl) amino] phenylsulfonyl] -1-methylamino] thiazole, Compound 19 : 4— (1-Adamantyl) 1 2— [Ν— [4-[(2-Hydroxyethyl) amino] phenylsulfonyl] —Ν—Methylamino] thiazole, Compound 20: 4-1- (1-adamantyl) 2— [Ν— [4- (2-hydroxyethoxy) phenylsulfonyl] 1-N-Methylamino] thiazole, diamide 21 1: 4- (1-adamantyl) 1-2- [N- (4-fluorophenylsulfonyl) -1-N— (4-methoxybenzyl) amino] thiazole, compound 22 : 4- (1-adamantyl) — 2 -— [N— (4-methoxybenzyl) — N— (4-morpholinophenylsulfonyl) amino] thiazole, compound 23: 4- (1-adamantyl) —2— (4-morpholinophenylsulfonylamino) thiazole, compound 24 4- (1-adamantyl) -2- (N- (4-methoxybenzyl) -1-N— [4- (2-morpholinoethoxy) phenylsulfonyl] [Amino] thiazole, Compound 25: 4- (1-Adamantyl) 1-2— [4- (2-Morpholinoethoxy) phenylsulfonylamino] thiazol, Compound 26: 4- (1-Adamantyl) 1-2— [N— [4-[2-(dimethylamino) Toxi] phenylsulfonyl] —N— (4-methoxybenzyl) amino, thiazol, compound 27: 4- (1-adamantyl) 1-2_ [4- [2- (dimethylamino) ethoxy] phenylsulfonylamino ] Thiazole, compound 28: 4- (1-adamantyl) -2- [4- [2- (4-piperazinyl) ethoxy] phenylsulfonylamino] thiazole, compound 2

9: 4- (1-adamantyl) -1-2 -— [N— (4-hydroxyphenylsulfonyl) -1-N— (4-methoxybenzyl) amino] thiazole, compound 30: 4-

(1-adamantyl) 1 2— [4- (carboxymethoxy) phenylsulfonylamino] thiazole, compound 31: 4- (1-adamantyl) 12— [N— [4 — [(aminocarbonyl) methoxy] Phenylsulfonyl] -1-N— (4-methoxybenzyl) amino] thiazole, compound 32: 4- (1-adamantyl) 1-2- [4-[(aminocarbonyl) methoxy] phenylsulfonyl [Amino] thiazole, compound 33: 4- (1-adamantyl) -12- [N- (3-chloro-2-methylphenylsulfonyl) -1-N-methylamino] thiazole, compound 34: 4-1 (1-adamantyl) 1-2 — [N- (3-chloro-2-methylphenylsulfonyl)-[\ |-(2-hydroxyethyl) amino] thiazole, compound 35: 4- (1-adamantyl) —2— [N— (amino Carbonylmethyl) 1 | \ | — (3—black mouth _ 2-Methylphenylsulfonyl) amino] thiazole, conjugated compound 36: 4- (1-adamantyl) -1-2- [N- (3-chloro-2-methylphen) Nylsulfonyl) 1-N-ethylamino] thiazole, diazole 37: 4- (1 -adamantyl) —2— [N- (3-chloro-2-methylphenylsulfonyl) -N-isobutylamino] thiazole, diamide Compound 38: 4- (1-adamantyl) -2- [2- (hydroxymethyl) phenylsulfonylamino] thiazole, compound 39 (3): 4- (3-hydroxyadamantane) -2- [N-[(5-Chloro-3-methylbenzo [b] thinphen-2-yl) sulfonyl] -N-methylamino] thiazole, compound 40 (2): 4- (1-adama) ) -5- (Ethoxycarbonyl) 1-2- (5-chloro-3-methyl-1-benzo-2-yn) sulfonyl] amino Ithiazole, compound 41 (A): 4- (1 -Adamantyl) — 5-methyl-2--2- (5-chloro-3-methyl-1-benzophen-2-yl) sulfonyl] amino 1 thia Compound 41 (B): 4- (1-adamantyl) -5- (hydroxymethyl) 1-2-{[(5-chloro-3-methyl-1-benzobenzo-2-yl) sulfonyl] amino I Thiazole, Compound 42 (4): 4 1- (1-adamantyl) 1 2— [2- (2-morpholinoethoxy) phenylsulfonylamino] thiazole, Compound 43 (6): 3—Cross— N— [4— (3-methoxy-11-adamantyl) -1,3-thiazol-2-yl] 1-2-methylbenzenesulfonamide, compound 44: 5-chloro-N— [4- (3-methoxy-1-adamantyl) 1-1 , 3-Thiazol-2-yl] -1-methyl-1-benzothiophene-2-sulfonamide, compound 45: 4- (1-adamantyl) -12- (2-naphthylsulfonylamino) thiazole, compound 46: 4 -(1 -adamantyl) 1 2— (2,3,4) Nylsulfonylamino) thiazole, compound 47: 4- (1-adamantyl) 1-2- (2,4,5-trifluorophenylsulfonylamino) thiazole, compound 48: 4- (1-adamantyl) -2 — (2,6-Dichloromouth phenylsulfonylamino) thiazole, compound 49: 4- (1-adamantyl) -2-[(3-promo 5-chlorothiophen-1-yl) sulfonylamino] Thiazole, Compound 50: 4- (1-adamantyl) 1-2- (2,3-dichlorophenylsulfonylamino) Thiazole, compound 51 1: 4-1 (1-adamantyl) — 2 -— (2,4-difuroflov) Enylsulfonylamino) thiazole, compound 52: 41 (1-adamantyl) —2— [(2,5-dichlorothienephen-1-yl) sulfonylamino] thiazole, iridani compound 53: 4-1 (1-adamantyl) one 2—

(3-Mouth—5-methyl-2-methylphenylsulfonylamino) thiazole, compound 4 _ 1: 4- (1-adamantyl) 1 2— (2,4,6-trimethyl) Phenylsulfonylamino) thiazole, compound 4-2: 4- (1-adamantyl) 1-2- (3-trimethyl romethylphenylsulfonylamino) thiazole, compound 4-1 3: 4-1 ( 1-adamantyl) 1- 2- (4-propylphenylsulfonylamino) thiazole, compound 4-4: 4- (1-adamantyl) -2- (2-methylphenylsulfonylamino) thiazole, diamide 4-5: 4- (1-adamantyl) 1-2- (4-fluorophenylsulfonylamino) thiazole, compound 4-6: 4-1 (1-adamantyl) -12- (2,5-dimethylphenylsulfonyl) Mino) thiazole, compound 4 7: 4— (1- Adamantyl) —2— (Biphenylsulfonylamino) thiazole, compound 418: 4— (1-adamantyl) 12— (4,1-, 2,5-dimethylphenylsulfonylamino) thiazole, compound 41 9: 4-1 (1-adamantyl) -12- (3,5-dimethylisoxoxazolesulfonylamino) thiazole, compound 4-10: 4- (1-adamantyl) 1-2 (5-chloro-3-) Methyl benzo [b] thylphen-2-yl-sulfonylamino) thiazole, compound 4-11: 4- (1-adamantyl) -12- (2,5-dichloromouth phenylsulfonylamino) thiazol, compound 4-12: 4— (1-adamantyl) 1 2— (412 phenylsulfonylamino) thiazole, compound 4-13: 4—1 (1-adamantyl) 1 2— (4-meth Xyphenylsulfonylamino Thiazole, compound 4- 14: 4- (1-adamantyl) 1-2- (2,4-dimethoxyphenylsulfonylamino) thiazol, compound 4-15: 4- (1-adamantyl) 1-2- (3-Nitrophenylsulfonylamino) thiazole, compound 4-16: N— [4- (4-adamantane-1-1-yruthiazo-1-ru-2-ylsulfamoyl) -phenyl] acetamide, compound 4-17: 4 — (1-adamantyl) 1 2-(4-phenylsulfonylamino) thiazole, compound 4-18: 4-(1-adamantyl) 1 2-(4-phenoxyphenylsulfur) Honylamino) thiazole, compound 4-1 9: 4- (1-adamantyl) 1 2 _ (4-butylphenylsulfonylamino) thiazole, i-conjugated compound 4 1 0: 4 1 (1-adamantyl) 1 2 — (1,1-Dimethylpropylphenylsulfonylamino) thiazole, compound 4-1 21: 4- (1-adamantyl) —2— (Benzo [b] thifenphen-2-yl-sulfonylamino) thiazole匕匕合 4 — — 物 4 4 4 4 合合 4 合匕合合物合物合合物合合合合合合合物合合合合合合合. Adamantane-1-yl-thiazole-2-ylsulfamoyl) methyl ester monobenzene, compound 4 2 4: 4-1 (4--(adamantane-1-ylutiazole-2-ylsulfamoyl) monobenzeneic acid The compound 4 1 2 5: 4 1 1 - Adama pentyl) over 2- (benzofuran one 3- I Lou sulfonyl § amino) thiazole and the like.

The thiazole derivative of the present invention may be a pharmaceutically acceptable salt thereof, or a solvate thereof. Hereinafter, the thiazole derivative of the present invention, its pharmaceutically acceptable salt, and its solvate are also referred to as “the compound of the present invention”.

In the present specification, examples of the solvate include pharmaceutically acceptable solvates such as hydrates. The thiazole derivative of the present invention may absorb water by being exposed to the air or recrystallized, and may form adsorbed water or may be a hydrate. Pharmaceutically acceptable solvates of the thiazole derivatives of the present invention also include such hydrates.

In the present specification, pharmaceutically acceptable salts include, for example, mineral salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, and nitrate; methanesulfonate Sulfonates such as ethanesulfonate, benzenesulfonate, p-toluenesulfonate; oxalate, tartrate, citrate, maleate, succinate, acetate, benzoate Acid addition salts such as organic acid salts such as mandelate, ascorbate, lactate, dalconate, malate, glycine, lysine, arginine, orditin, glutamate, aspartate Amino acid salts such as salts, or inorganic salts such as lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts or ammonium salts; It may be a salt with an organic base such as a luminamine salt, a diisopropylamine salt, a cyclohexylamine salt, and is preferably a hydrochloride, a hydrobromide, a phosphate, a sulfate, a methanesulfonate, or a Toluene sulfonate, oxalate, tartrate, citrate, acetate, lactate, glutamate, aspartate, sodium, potassium, ammonium, or triethylamine salts, preferably It is a sodium salt, a hydrochloride or a sulfate, and more preferably a hydrochloride. In the present specification, the compound of the present invention also includes a compound which is metabolized in a living body and converted into the compound of the present invention, so-called prodrug.

The thiazole derivative of the present invention may have an asymmetric center, in which case, there are various optical isomers or configurations. Thus, the compounds of the present invention

It can exist as separate (+) and (1) optically active forms and as a racemic or (soil) mixture. In the case of a compound having two or more asymmetric centers, diastereomers due to each optical isomer also exist. The thiazole derivative of the present invention contains all of these types in an arbitrary ratio. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by well-known organic chemistry techniques for this purpose. it can. In addition, the thiazole derivative of the present invention may have isomers such as cis- and trans-isomers. The thiazole derivatives of the present invention include their isomers and those containing these isomers in any proportion. Hereinafter, examples of the reaction scheme used in the method for producing the compound of the present invention will be described. The compound of the present invention can be produced according to known literature including the above-mentioned patent literature and non-patent literature and employing a known organic synthesis technique. In each of the production steps represented by the following reaction formulas, known methods can be employed. The compound serving as a raw material in each step is a known compound or a compound that can be easily synthesized from a known compound. [Reaction formula 1]

(Wherein, RR ² and R ³ have the same meanings as described above. X ^a represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyl group or a trisyl group.)

In this step, the compound (II) is condensed with the compound (III) to obtain an aminothiazole derivative (IV). Examples of the solvent used for this reaction include ethanol, methanol, N, N-dimethylformamide, and chloroform. The reaction can be carried out at 0 to 100 ° C. At this time, a base may be added to capture the generated hydrochloric acid or hydrobromic acid. Examples of the base to be added include amines such as triethylamine and disopropylethylamine, and inorganic bases such as carbon dioxide and sodium hydrogencarbonate. When the obtained compound (IV) is obtained as a salt with an acid, the compound is dissolved in an organic solvent such as ethyl acetate and washed with an aqueous solution of an inorganic base to be isolated as free amine. You can do it.

[Reaction formula 2]

(V) (VI)

(Wherein, R ¹ R ² and R ³ are each as defined above.)

In this step, R ³ is introduced into the amino group of compound (V) to obtain compound (VI).

For example, when reacting with compound (V) using R ³ substituted with a leaving group, that is, R ³ —X ^a (X ^a has the same meaning as described above), the solvent used for the reaction is dichloromethane. Methane, chloroform, N, N-dimethylformamide, ethanol, etc. The reaction can be carried out at 0 to 100 ° C. In this case, the reaction can be carried out using an appropriate base, and examples of the base include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as lithium carbonate and sodium hydrogencarbonate. .

Another example is a reductive amination reaction using an aldehyde derivative and a reducing agent. Examples of the reducing agent include triacetoxy sodium borohydride, sodium cyanoborohydride, sodium borohydride and the like, and if necessary, an acid such as glacial acetic acid or tosylic acid. Can be added. Solvents used for this reaction include dichloromethane, chloroform, tetrahydrofuran, dioxane, 1,2-dichloroethane and the like, and the reaction can be carried out at −20 to 100 ° C.

[

(Wherein R \ R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above.) This step sulfonylates the amino group of compound (IV). This is a step of obtaining a sulfonamide derivative (VII).

For example, a sulfonamide derivative can be obtained by using a sulfonyl halide such as sulfonyl chloride-sulfonyl bromide. Examples of the solvent used in this reaction include pyridine, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, and ethyl acetate. Can be done. In this case, the reaction can be carried out using an appropriate base. Examples of the base include amines such as triethylamine, diisopropylamine, and 4-dimethylaminopyridine; and inorganic bases such as carbon dioxide. Are listed. At this time, R ¹ , R ² and R ³ are liable to react with sulfonyl halide. If there are any groups, this can be done with protection. For example, when a hydroxyl group is present, the desired product can be selectively obtained by preceding trimethylsilylation.

Further, for example, another example of the sulfonamidation reaction can be carried out using an active ester such as 1-benzotriazolyl ester / succinimidyl ester. Examples of the reaction solvent include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, and ethyl acetate. This reaction can be carried out at -50 to 50 ° C.

[Reaction formula 4]

(Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above. X ^b represents a protecting group for an amino group.)

In this step, the protecting group ^Xb of the compound (VII) is deprotected to obtain the compound (VIII). For example, when X ^b is a group that can be deprotected with an acid such as a 4-methoxybenzyl group, the deprotection is performed using an acid such as hydrochloric acid, sulfuric acid, trifluroacetic acid, p-toluenesulfonic acid, and methanesulfonic acid. Can be protected. At this time, the reaction can be performed by diluting or dissolving with an organic solvent or water, and the reaction can be performed at a reaction temperature of −50 ° C. to 50 ° C. Examples of the organic solvent include ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, dichloromethane, chloroform, Ί, 2-dichloro C! Ethane, and the like. [Reaction formula 5]

(Wherein, R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and X ^a are as defined above. Ra is ^{a group} represented by the formula X ¹ —X ² _X ³ or the formula —X ¹ — X ⁵ — Of the groups represented by X ⁶ , X ¹ represents an oxygen atom, a sulfur atom, or a compound represented by the formula _ NX ⁴ — X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ are as defined above.

In this step, the compound (X) having a leaving group as a substituent is subjected to a substitution reaction to obtain a compound (XI) into which R ⁴ has been introduced.

For example, when X ^a is fluorine, Amin using nucleophilic substitution reaction, Anirin, can be introduced alcohol and thiol. Further, for example, when a similar substitution reaction is performed using 2-methylsulfonylethanol or the like, a compound (XI) in which a halogen atom is converted to a hydroxyl group can be obtained as a product. Examples of the solvent used in these reactions include dimethyl sulfoxide, N, N-dimethylformamide, tetrahydrofuran, toluene and the like, and the reaction can be carried out at a temperature of 0 to 200 ° C. In addition, this reaction can be carried out by adding an appropriate base. Examples of the base include sodium hydride, potassium tert-butoxide, n-butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, and the like. And inorganic bases such as carbon dioxide realm. In addition, a metal catalyst can be added as needed. Examples of the metal catalyst include tris (dibenzylideneacetone) dipalladium and palladium acetate.

Also, for example, a carbon-carbon bond such as biaryl can be constructed by a cross-coupling method using a metal catalyst and an organometallic compound. Examples of the solvent used in this reaction include tetrahydrofuran, toluene, 1,2-dimethyloxetane and the like, and the reaction can be carried out at a temperature of 0 to 200 ° C. Metal catalysts include tetrakis (triphenylphosphine) palladium and tris (dibenzylidene) Acetone) dipalladium and hiss (acetyl acetate) nickel. Organometallic compounds include Grignard reagents, organoaluminum compounds and arylboronic acids. This reaction can be carried out by adding an appropriate base, and examples of the base include amines such as triethylamine and diisopropylamine and inorganic bases such as sodium hydroxide, potassium carbonate and sodium carbonate.

[Reaction formula 6]

(Wherein, R ¹ R ² R ³ R ⁵ R ⁶ R ⁷ and R ⁸ are as defined above. R ^4b is a group represented by the formula —X ¹ —XX ³ or the formula —X ¹ —X ⁵ —X ⁶ Among the groups represented, X ¹ represents a group represented by an oxygen atom, and X ¹ X ² X ³ X ⁴ X ⁵ and X ⁶ are as defined above.

In this step, the compound (XI I) having a hydroxyl group as a substituent is

(XI I I). ,

For example, a hydroxyl group can be alkylated by a reaction using an alkyl halide. This reaction can be carried out by adding an appropriate base, and sodium hydride, potassium tert-butoxide, n-butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide can be used as the base. Inorganic bases such as carbon dioxide are included. Solvents used for these reactions include dimethyl sulfoxide, NN-dimethylformamide, tetrahydrofuran, toluene and the like, and the reaction can be carried out at 0 200 ° C. [Reaction formula 7]

(Wherein, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X ¹ , X ⁵ and X ⁷ have the same meanings as described above. X ^b is an amino group Represents a protecting group.)

In this step, deprotection is performed using a compound (XIV) having an amino group protected by a ring A substituent to obtain an amine derivative (XV). For this deprotection, a method described in PROTECTIVE IVE GROUPS IN ORGA IC SYNTHES IS, THEODORA W. GREENE and PETER G. M WUTS can be used. For example, when X ^b is a group that can be deprotected with an acid such as a tert-butoxycarbonyl group, a trityl group, or a 0-2-nitrobenzenesulfenyl group, hydrochloric acid, sulfuric acid, trifluroacetic acid, p- Deprotection can be performed using an acid such as toluenesulfonic acid or methanesulfonic acid. At this time, the reaction can be carried out by diluting or dissolving with an organic solvent or water, and the reaction can be carried out at a temperature of 150 ° C to 50 ° C. Examples of the organic solvent include ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane, and the like. Further, for example, when X ⁹ is a group that can be deprotected by a hydrogenolysis reaction such as a benzyloxycarbonyl group, it can be deprotected by a hydrogenolysis reaction using a metal catalyst such as palladium. As the solvent, a solvent that does not participate in the reaction, such as ethanol, methanol, tetrahydrofuran, and ethyl acetate can be used. The reaction can be carried out at a temperature of 0 to 100 ° C. In addition, hydrogen gas can be used for this reaction, or a combination of reagents such as formic acid-ammonium formate can be used. Further, for example, in the case where R b is a protecting group such as a fluorinated benzyl group which is deprotected with a base, deprotection is performed using a base such as getylamine, piperidine, ammonia, sodium hydroxide, potassium carbonate, etc. be able to. These bases can be used alone or diluted or suspended in a solvent. At this time, the solvent and For example, water, ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane, and the like can be used. The reaction can be carried out at a temperature of 0 to 100 ° C. Further, for example, when X ⁹ is a group which can be deprotected by a metal catalyst such as an arylcarbonyl group, it can be deprotected by using tetrakis (triphenylphosphine) palladium as a catalyst or a reagent. . At this time, the reaction can be carried out in a solvent which does not participate in the reaction, such as dichloromethane, chloroform, tetrahydrofuran and the like. The reaction can be carried out at a temperature of 0 to 100 ° C.

[Reaction formula 8]

(Wherein, R \ R ² , R ³ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above. X ^e represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.)

In this step, a reduction reaction is performed using the compound (XVI) to obtain a hydroxymethyl form (XVII). This reaction can be performed under conditions using an appropriate reduction method. Examples of the reduction method used include a method using lithium aluminum hydride. As a solvent to be used, a solvent that does not participate in the reaction, such as tetrahydrofuran or dioxane, can be used. The reaction can be carried out at between 120 and 100 ° C.

(Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ′, R ⁷ and R ⁸ have the same meanings as described above. X ^d represents a, アルコキシ alkoxycarbonyl group. )

This step is a step of performing a reduction reaction using the compound (XVI II) to directly obtain (XIX), and a step of further performing a conversion reaction using the compound obtained by reduction to obtain (XI X). . This reduction reaction can be performed under conditions using an appropriate reduction method. Examples of the reduction method used include a method using lithium aluminum hydride. As a solvent to be used, a solvent which does not participate in the reaction such as tetrahydrofuran and dioxane can be used. The reaction can be carried out at —20-100 ° C. The compounds of the present invention have an activity of inhibiting 11 i8 -HSD1 activity, as shown in the Examples below. Therefore, the compound of the present invention can be effectively used for diseases associated with 11 i8 -HSD1, for example, suppression of gluconeogenesis in the liver or suppression of accumulation of visceral fat. That is, the compound of the present invention can be used as a drug for 11) an inhibitor of 8-HSD1; suppression of gluconeogenesis in the liver, or suppression of accumulation of visceral fat. The compounds of the present invention can be administered alone or with a pharmaceutically or pharmaceutically acceptable carrier or diluent. When the compound of the present invention is used as a 113-HSD1 inhibitor or the like, the compound of the present invention may be directly administered orally or parenterally. Further, the compound of the present invention may be orally or parenterally administered as an agent containing the compound as an active ingredient. Parenteral administration includes intravenous administration by injection.

When the above agents are administered orally, diluents, excipients, disintegrants, binders, lubricants, antioxidants, coating agents, surfactants, plasticizers, coloring agents, flavoring agents, etc. are mixed. Then, they may be administered as preparations such as granules, capsules, tablets, medicinal drops, troches, hard candy, powders, sprays, etc., containing the compound of the present invention as an active ingredient. In addition, sweetening or flavoring may be performed as appropriate. When the above-mentioned preparations are to be administered parenterally, injections, drops, eye drops, creams, salves, suppositories, jellies, jewels, pastes, mouth lotions, ointments, aqueous suspensions containing the compound of the present invention as an active ingredient It may be administered as a formulation such as a liquid. In formulating, a usual formulation method can be used. The compound of the present invention can be administered orally or parenterally, for example, 1 mg to 1000 mg, preferably 10 mg to 200 mg at a time, for example, once to three times a day. The dose of the compound of the present invention can be appropriately adjusted according to the age, weight and condition of the patient. In order to evaluate the 11) 8-HSD1 activity inhibition of the compound of the present invention, for example, a known method such as the method described in Examples can be used. Hereinafter, the present invention will be specifically described with reference to Reference Examples, Examples, and Test Examples. However, the present invention is not limited to the following examples.

Reference Example 1 Synthesis of 4- (1-adamantyl) -12-aminothiazol hydrobromide

1-adamantyl bromomethyl ketone (4.93 g) was dissolved in ethanol (110 ml), to which was added, and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and a 10: 1 mixed solvent (60 tnl) of isopropyl ether and ethanol was added to the obtained residue, suspended, and stirred for 2 hours. The title compound (6.06 g) was obtained as a colorless powder. ^ MR results were as follows.

1H-Oki (300MHz, drawing-d6) δ: 8.74 (2Η, brs), 6.43 (1 H, s), 2.08-1.98 (3H, rn), 1.88-1.60 (12H, m)

(Reference Example 2) Synthesis of 4- (1-adamantyl) — 2-aminothiazole 41- (1-adamantyl) -12-aminothiazole hydrobromide (700 mg) synthesized in the same manner as in Reference Example 1. Was suspended in 1M aqueous sodium hydroxide solution (80 ml) and extracted with ethyl acetate (200 ml × 3). The collected organic phase was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The title compound (484 mg) was obtained as a colorless amorphous. -The results of R were as follows. , H-concealed (300 MHz, optional-d6) δ: 6.78 (2H, brs), 6.00 (1H, s), 2.10-1.98 (3H, m), 1.83-1.58 (12H, m)

(Reference Example 3) Synthesis of 4- (1-adamantyl) 1-2- (methylamino) thiazole

1-adamantyl bromomethyl ketone (4.93 g) is suspended in ethanol (58 ml), N-methylthiourea (Ί.73 g) is added, and the mixture is stirred at room temperature for 0.5 hour, and then isopropyl ether (6 Oml) is added. In addition, the mixture was further stirred at room temperature for 1.5 hours. The precipitated solid was collected by suction filtration to give the title compound hydrobromide (3.95 g) as a colorless powder. Similarly, 0.51 g was obtained from the mother liquor. Subsequently, these solids were combined, suspended in water (170 ml), added with sodium hydrogen carbonate (1.61 g), and stirred at room temperature for 2 hours. The solid was collected by suction filtration and washed with water (200 ml) to give the title compound (3.04 g) as a colorless powder. The results of -NMR were as follows.

) Η-Oki (300 MHz, DMS0-d6) δ: 7, 34-7.24 (1 H, m), 6.08 (1H,

s), 2.75 (3H, d, J = 4.8Hz), 2.02-1.95 (3H, m), 1.85-1.79 (6H, m), 1.76-1.62 (6H, m)

Synthesis of 4- (1 -adamantyl) —2— (1-naphthylsulfonylamino) thiazole

4- (1-Adamantyl) -2-aminothiazol hydrobromide (200 mg) was dissolved in pyridine (1.2 ml), and under ice-cooling, 1-naphthalenesulfonyl chloride (144 mg) was added. The mixture was returned to room temperature and stirred overnight. The reaction mixture was added dropwise to an ice-cooled 6 M aqueous hydrochloric acid solution (1 OmI), and after stirring for 2 hours, the precipitated solid was collected by filtration and washed with a 6 M aqueous hydrochloric acid solution (1 OmI) and water (1 OmI). After washing and drying, the title compound (225 mg) was obtained as a light brown solid. The results of the MMR were as follows. H-tumor (300 MHz, DSO-d6) δ: 12.66 (1H, brs), 8.75 (1H, dd, J = 8.3, 0.8Hz), 8.22-8.14 (2H, m), 8.08-8.03 (1H , m), 7.73-7.59 (3H, m), 6.30 (1H, s), 2.04-1.88 (3H, m), 1.82-1.54 (12H, m)

Example 2

Synthesis of 4- (1-adamantyl) -2- (2,4,5-trichloromethylphenylsulfonylamino) thiazole

In the same manner as in Example 1, 4- (1-adamantyl) -2-aminothiazole hydrobromide (20 Omg) and 2,4,5-trichlorobenzenesulfonyl chloride (178 mg) were thinly diluted. The title compound (Ί1 mg) was obtained as a pink solid.

The results of R were as follows.

¹ H-Oki (300 MHz, sleep-d6) δ 12.99 (1Η, brs), 8.14 (1H, s), 8.07 (1H, s), 6.41 (1H, s), 2.04-1.95 (3H, m), 1.84-1.76 (6H, tn), 1.74-1.58 (6H, m)

Example 3

Synthesis of 4- (1-adamantyl) -1-2-[(2-Chenylsulfonyl) amino] thiazole

In the same manner as in Example 1, 4- (1-adamantyl) -12-aminothiazole hydrobromide (20 Omg) and 2-thiensuensulfonyl chloride (116 mg) were obtained as a light brown powder. The title compound (9 Omg) was obtained. The result of NMR was as follows.

¹ H-Odd (300 MHz, DMS0-d6) δ 12.84 (1Η, brs), 7.82 (1H, dd, J = 5.0, 1.4 Hz), 7.55 (1H, dd, J = 3.7, 1.4 Hz), 7.11 ( 1H, dd, J = 5.0, 3.7 Hz), 6.40 (1H, s), 2.10-1.94 (3H, ml, 1.85-1.54 (12H, m)

Example 4

Synthesis of 4- (1-adamantyl) -1-2- (4-bromophenylsulfonylamino) thiazole

4- (1-adamantyl) -2-aminothiazol hydrobromide (200 mg) was dissolved in pyridine (1.2 ml), and 4-dimethylaminopyridine (7.7 mg) was added. Under ice-cooling 4-promobenzenesulfonyl chloride (17 8 mg), and then returned to room temperature and stirred for a while. The reaction mixture was added dropwise to an ice-cooled 6 M aqueous hydrochloric acid solution (1 Oml). After stirring for 2 hours, the precipitated solid was collected by filtration, and a 6 M aqueous hydrochloric acid solution (10 mI) and water (10 mI) were added. ) And dried to give the title compound (239 mg) as a colorless powder. The results of R were as follows.

1H-Oki (300 MHz, DMS0-d6) δ 12.78ΠΗ, brs), 7.79-7.70 (4H, m), 6.36 (ΙΗ's), 2.02-1.94 (3Η, m), 1.84-1.58 (12Η, m )

(Example 4_1 to Example 4-1 23)

Thereafter, Compound 41-11 to Compound 4-23 were obtained in the same manner as in Example 4. Table 1 shows the structural formulas of these compounds and the obtained ¹ H-NMR results. Compounds 4-1 to 4-1-23 are as follows. Compound 4-1 is 4_ (1-adamantyl) 1-2- (2,4,6-trimethylphenylsulfonylamino) thiazole, and compound 4-2 is 4- (1-adamantyl) -2--(3-trifluoromethylphenylsulfonylamino) thiazole; compound 4-1-3 is 4- (1-adamantyl) -12- (4-propylphenylsulfonylamino) thiazole; Compound 4-4 is 4- (1-adamantyl) 1-2- (2-methylphenylsulfonylamino) thiazole, and compound 4-1-5 is 4- (1-adamantyl) 1-2- (4-full Compound 41 is 6- (1 adamantyl) 12- (2,5-dimethylphenylsulfonylamino) thiazole, and Compound 41 is Compound 41. 7 is 4-(1-adamantyl) 1 2-(bihue Compound 4-8 is 4- (1-adamantyl) -12- (4 mono-, 2,5-dimethylphenylsulfonylamino) thiazole and compound 4-9 Is 4- (1-adamantyl) 1-2- (3,5-dimethylisoxazolesulfonylamino) thiazole, and compound 4-10 is 4_ (1-adamantyl) 1-2- (5-chloro-3-methyl —Benzo [b] thylphen-2-ylsulfonylamino) thiazole, compound 411 is 4- (1-adamantyl) —2— (2,5-dichlorophenylsulfonylamino) thiazole , 匕合物 4 ί 、、、 4 4 、 4 4 4 物 4 物 4 物物物 4 4 4 4 4 物物 4 4 物物物 4 4 4 物物物-— 物物物物 4 4 4 4 4-物 — 物物 4 4 4 4 4. —2— (4-Methoxyoxysulfonylamino) thiazole, Compound 414 is 4- (1-adamantyl) -2- (2,4 dimethyloxyphenylsulfonylamino) thiazole, compound 4-15 is 4- (1-adamantyl) -2- (3-nitrophenylphenylsulfonylamino) thiazole, and compound 4-16 is N- [4- (4-adamantane). — 1 —yl-thiazo-l-2-l-l-sulfamoyl) -phenyl] -l-acetamide; compound 4-17 is 4-l- (1-adamantyl) -l 2- Sulfonylamino) thiazole, Compound 418 is 4-1 (1-adamantyl) —2— (4-phenoxyphenylsulfonylamino) thiazole, and Compound 419 is 4-1 (1 -Adamantly) —2— (4-butylphenylsulfonylamino) Compound 4-20 is 4- (1-adamantyl) -2- (1,1-dimethylpropylphenylsulfonylamino) thiazole; compound 4-1 21 is 4- (1-adamantyl) -2-(Benzo [b] thylphen-2yl-sulfonylamino) is a thiazole. Phen-1-ylsulfonylamino) thiazole, compound 4-23 is 2- (adamantane-1-ylutiazol-2-ylsulfamoyl) monobenzene methyl ester, and compound 4-24 is 4- (Adamantane-11, yl-thiazole-2-ylsulfamoyl) is a benzene acid, and compound 4-25 is 4- (1-adamantyl) -2- (benzo [b] furan-2-yl Sulfonylamino) thiazo Is Le.

Table 1. Structural formulas of compounds 411 to 425 and the obtained R results

l.00 / S00idf / X3d f9Z.Z.60 / S00Z OAV

12.98 (1H, brs), 8.05-

7.97 (2H, m), 7.96 (1H, s), 7.53-

4-21 7.43 (2H, m), 6.43 (1H, s), 2.00-

1.92 (3H, m), 1.80-1.73 (6H, m), 1.72-

1.57 (6H, m).

12.74 (1H, brs), 8.45 (1H, s), 8.18-8.13 (1H, m), 8.11-8.06 (1H, m), 7.55-

4-22 oo2: z 7.43 (2H, m), 6.36 (1H, s), 2.00--1.92 (3H, m), 1.80-1 J3 (6H, m), 1.72-1.57 (6H, m) .

12.69 (1H, br s), 7.95-7.91 (1H, m), 7.69-7.62 (2H, m), 7.54-7.51 (1H, m), 6.36 (1H,

4-23

s), 3.73 (3H, s), 2.10-1.90 (3H, m), 1.85-1.75 (6H, m), 1.72-1-1.60 (6H, m).

8.03 (2H, d, J = 8.5Hz), 7.70 (2H, d,

4-24 J = 8.5Hz), 6.78 (1H, s), 2.09-1.89 (9H, m),

1.81-1.62 (6H, m).

13.06 (1H, br s), 7.81-7.74 (1H, m), 7.71- 7.64 (2H, m), 7.52-7.44 (2H, m), 7.40-7.32

4-25 r ^s H ° (1H, m), 6.48-6.45 (1H, m), 2.05-1.56 (15H, m).

Example 5,

Synthesis of 4- (1-adamantyl) -2- (3-chloro-2-methylphenylsulfonylanamino) thiazole

4- (1-Adamantyl) -l- 2-Aminothiazole (20 Omg) is dissolved in pyridin (1.2 ml), and under ice-cooling, 3-chloro-2-methylbenzenesulfonyl chloride (213 mg) is added. Thereafter, the mixture was returned to room temperature and stirred overnight. The reaction solution was added dropwise to an ice-cooled 6 M aqueous hydrochloric acid solution (1 Oml). After stirring for 2 hours, the precipitated solid was collected by filtration, and a 6 M aqueous hydrochloric acid solution (10 mI) and water (10 mI) were added. And washed. The crude crystals were purified by silica gel column chromatography (developing solvent, solvent: chloroform: 100: 1) to give the title compound (309 mg) as a pale brown amorphous. The result of ¹ H-NMR was as follows. ¹ H-Oki (300 MHz, DMSO-d6) 6: 12.73 (1H, brs), 7.91 (1H, dd, J = 8.0, 1.2 Hz), 7.68 (1H, dd, J = 8.0, 1.2 Hz), 7.39 (1H, t, J = 8.0 Hz), 6.33 (1H, s), 2.65 (3H, s), 2.0

2-1.95 (3H, m), 1.83-1.74 (6H, m), 1.73-1.58 (6H, m)

Example 6

Synthesis of 4- (1-adamantyl) 1-2- (phenylsulfonylamino) thiazole

In the same manner as in Example 5, the title compound (64 mg) was obtained as a pale yellow amorphus from 41- (1-adamantyl) -12-aminothiazole (7 Omg) and benzenesulfonyl chloride (53 mg). The results of NMR were as follows.

H-new (300 MHz, DMS0-d6) δ: 12.69 (1Η, brs), 7.84-7.78 (2H, m), 7.64-7.50 (3H, m), 6, 32 (1H, s), 2.02- 1.95 (3H, m), 1.83-1.74 (6H, m), 1.73-1.58 (6H, m)

Example 7

Synthesis of 4- (1-adamantyl) — 2 — [(5-promo-6-chloropyridine-13-yl) sulfonylamino] thiazole

4 Dissolve 2- (1-adamantyl) -1-2-aminothiazole hydrobromide (200 mg) in chloroform (1.2 ml) and add 4-dimethylaminopyridine (7.7 mg) at room temperature. ), And triethylamine (77 μI) and 3_bromo-12-chloropyridine-15-sulfonyl chloride (24 Omg) were added under ice-cooling, and the mixture was returned to room temperature and stirred for a while. Further, 3-promo 2-cyclomouth pyridine-5-sulfonyl chloride (74 mg) was added, and the mixture was stirred at room temperature for 2 days. While cooling with water, the reaction mixture was added with chloroform (1 Oml) and a 0.5% aqueous sodium hydrogen carbonate solution (10 ml), and the precipitated crystals were collected by filtration to give the title compound (colorless powder). 5 Omg). -The result of NMR was as follows.

) H-free (300 MHz, Oki-d6) <5: 13.01 (1H, brs), 8.78 (1H, d, J = 2.2 Hz), 8.46 (1H, d, J = 2.2 Hz), 6.45 (1H, s), 2.04-1.95 (3H, m), 1.83-1.76 (6H, m), 1.74-1.58 (6H, m) Example 8

Synthesis of 4- (1-adamantyl) -1-2-[(6-morpholinopyridine-13-yl) sulfonylamino] thiazole

In the same manner as in Example 7, the title compound was obtained as a colorless powder from 4- (1-adamantyl) -12-aminothiazole hydrobromide (20 mg) and 6-morpholinol 3-pyridinesulfonyl chloride (366 mg). The compound (134 mg) was obtained. Results of ¹ H- Tsuyoshi R were as follows.

H-new (300 MHz, D S0-d6), <5: 12.64 (1H, brs), 8.47 (1H, d, J = 2.5 Hz), 7.81 (1 H, dd, J = 9.0, 2.5 Hz) , 6.89 (1 H, d, J = 9.0 Hz), 6.29 (1 H, s), 3.70- 3.63 (4H, m), 3.60-3.53 (4H, m), 2.02-1.93 (3H, m), 1.82 -1.74 (6H, m), 1.73- 1.58 (6H, m)

Example 9

4-Synthesis of 1- (1-adamantyl) 1-2-[(6-Phenoxypyridine-13-yl) sulfonylamino] thiazole ''

A light yellow powder was obtained from 4- (1-adamantyl) -2-aminothiazol hydrobromide (20 mg) and 6-phenoxy-13-pyridinesulfonyl chloride (376 mg) in the same manner as in Example 7. As a result, the title compound (199 mg) was obtained.

^ -Go R results were as follows: ,

1H-N R (300 MHz, DMS0-d6) (5: 12.83 (1H, brs),

8.52 (1H, dd, J = 2.5, 0.6Hz), 8.17 (1H, dd, J = 8.6, 2.5Hz), 7.49-7.41 (2H, m),

7.30-7.23 (1H, m), 7.22-7.17 (2H, m), 7.15 (1H, dd, J = 8.6, 0.6Hz),

6.37 (1H, s), 2.02-1.93 (3H, m), 1.82-1.74 (6H, m), 1.73-1.58 (6H, m)

Example 1 0

Synthesis of 4- (1-adamantyl) 1-2-[(pyridine-12-yl) sulfonylamino] thiazole

In the same manner as in Example 7, 4- (1-adamantyl) -2-aminothiazole hydrobromide (200 mg) and 2-pyridinesulfonyl chloride (314 mg) were used to give the title compound (142 mg) as a colorless amorphous. ). NMR results were as follows. H-Oki (300 MHz, DMSO-d6) δ: 12.79ΠΗ, brs), 8.67-8.63 (1H, m), 8.03 (1H, td, J = 7.7, 1.8Hz), 7.94 (1H, dt, J = 7.7, 1.1Hz),

7.60 (1H, ddd, J = 7.5, 4.7, 1.3Hz), 6.36 (1 ls), 2.02-1.94 (3H, m), 1.83- 1.76 (6H, m), 1.73—1.58 (6H, m)

Example 11

Synthesis of 4- (1-adamantyl) 1-2-[(pyridine-13-yl) sulfonylamino] thiazole

In the same manner as in Example 7, 4- (1-adamantyl) -1-2-aminothiazole hydrobromide (200 mg) and 3-pyridinesulfonyl chloride (299 mg) were used to give the title compound (159 mg) as a colorless amorphous. Got. The result of ¹ H-NMR was as follows.

1H-NMR (300 MHz, solid -d6):

δ: 12.87 (1Η, brs), 8.96 (1H, d, J = 2.2Hz), 8.78 (1H, dd, J = 4.8, 1.6Hz), 8.17 (1H, dd d, J = 8.0, 2.2, 1.6Hz) ), 7.60 (1H, dd, J = 8.0, 4, 8Hz), 6, 39 (1H, s), 2.02- 1.94 (3H, m), 1.83-1.76 (6H, m), 1.73-1.58 (6H, m)

Example 1 2

Synthesis of 4- (1-adamantyl) _2— [N— (4-biphenylsulfonyl) -1-N-methylamino] thiazolyl,

4- (1-Adamantyl) -12- (methylamino) thiazole (200 mg) was dissolved in pyridine (3.2 ml), and 4-dimethylaminopyridine (98 mg) was added. -Biphenylsulfonyl chloride (407 mg) was added, and then the mixture was returned to room temperature and stirred overnight. The reaction solution was added dropwise to an ice-cooled 6 M aqueous hydrochloric acid solution (15 ml), and after stirring for 2 hours, the precipitated solid was collected by filtration and washed with a 6 M aqueous hydrochloric acid solution (1 Om I) and water (1 Om I). Then, the solid obtained by drying was purified by preparative TLC (developing solvent, chloroform) to obtain the title compound (116 mg) as a colorless amorphous. The result of ¹ H-NMR was as follows. -Hidden (300MHz, D S0-d6) δ: 7.96-7.86 (4H, m), 7.76-7.70 (2H, m), 7.55-7.42 (3Η, m), 6.86 (1H, s), 3.39 (3H, s), 2, 02-1.94 (3Η, m), 1.83—

1.76 (6Η, m), 1.73- 1.58 (6H, m)

Example 1 3

4- (1-Adamantyl) -1-2- [N-[(5-chloro-3-3-methylbenzo [b] thinphen-2-yl) sulfonyl] -1-N-methylamino] thiazol Example 12 Colorless amorphous from 4- (1-adamantyl) -2- (methylamino) thiazole (20 Omg) and 5-chloro-3,3-methylbenzo [b] thinphen-2-phenyl-2-sulfonyl chloride (453mg) in the same manner as As a result, the title compound (42 mg) was obtained. The result of NMR was as follows.

^] HNR (300MHz, DMS0-d6)

δ: 8.15 (1Η, dd, J = 8.7, 0.5Hz), 8.11 (1H, dd, J = 2.2, 0.5Hz), 7.64 (1H, dd, J = 8.7, 2.2Hz), 6.97 (1H , s), 3.41 (3H, s), 2.46 (3H, s), 2.02-1.94 (3H, m), 1.77- 1.58 (12H, m),

Example 14

Synthesis of 4- (1-adamantyl) -1-2 — [— methyl—N— (4-n-propylphenylsulfonyl) amino] thiazole

4- (1-adamantyl) -2- (methylamino) thiazol (200 mg) was dissolved in chloroform (1.2 ml), and 4-dimethylaminopyridine (98 mg) was added. Then, 4-n-propylbenzenesulfonyl chloride (352 mg) was added, and then the mixture was returned to room temperature and stirred for a while. While cooling with water, a 3M aqueous solution of hydrochloric acid (5rrH) was added to the reaction solution, and the mixture was extracted with chloroform (18 ml). The organic phase was extracted with a 3M aqueous solution of hydrochloric acid (5ml) and 5% sodium bicarbonate. Washed sequentially with an aqueous solution (5 ml), water (5 ml), and a saturated saline solution (5 ml). After the organic phase was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (developing solvent, black-mouthed form) to give the title compound (95 mg) as a colorless solid. The results of R were as follows. ^-MR (300MHz, D S0-d6)

δ: 7.70 (2H, d, J = 8.6Hz), 7.44 (2H, d, J = 8.6Hz), 6.84 (1H, s), 3.23 (3H, s), 2.63 (2H, t, J = 7.4 Hz) ), 2.01-1.93 (3H, m), 1.78-1.52 (14H, m),

0.86 (3H, t, J = 7.4 Hz)

Example 1 5

Synthesis of 4- (1-adamantyl) -2-CN- (4-fluorophenylsulfonyl) -1-N-methylamino] thiazole

In the same manner as in Example 14, the title compound (403 mg) was obtained as a colorless solid from 4- (1-adamantyl) -12- (methylamino) thiazole (50 Omg) and 4-furoserobenzenesulfonyl chloride (588 mg). Got. ^ -NMR results were as follows.

^ -R (300MHz, DMSO-d6)

δ: 7.89 (2H, dd, J = 8.9, 5.0Hz), 7.49 (2H, t, J = 8.9Hz), 6.87 (1H, s), 3.35 (3H, s), 2.02.1.93 (3H, m), 1.82-1.58 (12H, m)

Example 16

Synthesis of 4- (1-adamantyl) -1-2- [N-methyl-N- (4-morpholinophenylsulfonyl) amino] thiazole

To a DMSO suspension (1 ml) of 4- (1-adamantyl) -2- [N- (4-fluorophenylsulfonyl) -N-methylamino] thiazole (11 mg) obtained in Example 15 was added. Morpholine (236 mg) and carbonated lithium (41 mg) were added, and the mixture was stirred at 160 ° C for 2 hours. While cooling with water, a 1: 1 mixture (5 ml) of water and saturated saline was added to the reaction mixture, and the mixture was stirred. After extraction with chloroform (15 ml), the organic phase was combined with water and saturated saline. The mixture was washed sequentially with a 1: 1 mixture (5 ml IX 3) and saturated saline (5 ml). After the organic phase was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, black-mouthed form) to give the title compound (9 Omg) as a colorless solid. The result of NMR was as follows.

】 H- 瞧 (300MHz, D S0-d6)

δ: 7.60 (2Η, d, J = 9.2Hz), 7, 05 (2H, d, J = 9.2Hz), 6.78 (1 H, s), 3, 74- 3.67 (4H, m), 3.32-3.25 (7H, m), 2.02-1.93 (3H, m), 1.82-1.74 (6H, m), 1.73—1.58 (6H, m)

Example 17

Synthesis of 4- (1-adamantyl) -2- (N-methyl-N— [4- (4-methylpyrazinyl) phenylsulfonyl] amino] thiazole

In the same manner as in Example 16, 4-1- (1-adamantyl) -12- [N- (4-fluorophenylsulfonyl) -1-N-methylamino] thiazole (11 Omg) and 1-methylbiperazine (27 1 mg ) To give the title compound (126 mg) as a pale-yellow amorphous. The results of NW1R were as follows.

^ -NR (300MHz, DMS0-d6)

δ: 7.56 (2Η, d, J = 9.2Hz), 7.03 (2H, d, J = 9.2Hz), 6.78 (1H, s), 3.37-3.26 (7H, m), 2.41-2.38 (4H, m) , 2.20 (3H, s), 2.02-1.94 (3H, m), 1.80- 1.75 (6H, m), 1.74-1.59 (6H, m)

Example 18

Synthesis of 4- (1-adamantyl) 1-2- [N- [4- [bis (2-hydroxyethyl) amino] phenylsulfonyl] -N-methylamino] thiazole

In the same manner as in Example 16, 4- (1-adamantyl) -2-[[N- (4-fluorophenylsulfonyl) -N-methylamino] thiazolyl (12 mg) and diethanolamine ( From 31 Omg), the title compound (28 mg) was obtained as a colorless powder. The results of the MMR were as follows.

Ή-NMR (300MHz, DMS0-d6)

(5: 7.50 (2H, d, J = 9.OHz), 6.79 (2H, d, J = 9.0Hz), 6.76 (1H, s), 4.79 (2H, t, J = 5.0Hz), 3.59-3.44 (8H, m), 3.28 (3H, s), 2.04-1.93 (3H, m), 1.86-1.60 (12H, m)

Example 19

Synthesis of 4- (1-adamantyl) —2— [N— [4-[(2-hydroxyethyl) amino] phenylsulfonyl] —N-methylamino] thiazole

In the same manner as in Example 16, 4-1- (1-adamantyl) -2-[[N- (4-fluorophenylsulfonyl) -methylamino] thiazole (12 Omg) And 2-aminoenol (90 mg) to give the title compound (1 O Omg) as a pale yellow amorphous. The results of ¹ H-R were as follows.

^ -NM (300MHz, D S0-d6)

δ: 1.46 (2Η, d, J = 9.OHz), 6.81 (1H, t, J = 5.5Hz), 6.76 (1H, s), 6.65 (2H, d, J = 9.0Hz), 4.75 (1H, t, J = 5.4Hz), 3.53 (2H, td, J = 5.8, 5.4Hz), 3.27 (3H, s), 3.14 (2H, td, J = 5.8, 5.5Hz), 2.02-1.94 (3H , m), 1.82-1.76 (6H, m), 1.75-1.60 (6H, m)

Example 2 O

Synthesis of 4- (1-adamantyl) -1-2- [N— [4- (2-hydroxyethoxy) phenylsulfonyl] -1-N-methylamino] thiazole

4- (Padamantyl) 1-2- [N- (4-fluorophenylsulfonyl) -1-N-methylamino] thiazole obtained in Example 15 (120 mg) and ethylene glycol (0.3 ml) While cooling the N, N-dimethylformamide (DMF) solution (0.9 ml) with water, sodium hydride (26 mg of 60% oil) was added, and the reaction temperature was raised to 90 ° C. Warmed and stirred for 1.5 hours. While cooling with water, add an aqueous ammonium chloride solution (5 ml) to the reaction solution, stir the mixture, extract with chloroform (15 ml), and saturate the organic phase with aqueous ammonium chloride solution (5 ml) and water. The mixture was washed successively with a 1: 1 mixture of saline (5 ml × 2) and saturated saline (5 ml). After the organic phase was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, solvent: form: methanol = 160: 1). The product was further purified by preparative TLC (developing solvent, black-mouthed form) to give the title compound (1 O Omg) as a colorless amorphous. The result of NMR was as follows.

^-NMR (300MHz, DMS0-d6)

δ: 7.73 (2Η, d, J = 9.OHz), 7.14 (2H, d, J = 9.OHz), 6.82 (1H, s), 4.92 (1H, t, J = 5.4Hz), 4.07 (2H, t, J = 4.8), 3.72 (2H, td, J = 5.4, 4.8Hz), 3.32 (3H, s), 2.02-1, 94 (3H, m), 1.82-1.76 mouse m), 1.75 -1.60 (6H, m)

Example 2 1

Synthesis of 4- (1-adamantyl) -1-2- [N- (4-fluorophenylsulfonyl) -N- (4-methoxybenzyl) amino] thiazole DMF solution of 4- (1-adamantyl) 1-2-[(4-furofilophenylsulfonyl) amino] thiazole (200 mg) obtained in Example No. 4-5

(4.0 ml) was added with sodium hydride (22 mg of 60% oil) under water cooling, followed by p-methoxybenzyl chloride (0.1 ml) and potassium iodide (1 ml). 27 mg) and stirred at room temperature for 2 hours. After adding water (1 Om I) under ice cooling and stirring, extracting with ethyl acetate (20 ml), the organic phase was washed successively with water (10 ml X4) and saturated saline (1 Oml). . After the organic phase was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: black-mouthed form to black-mouthed form: methanol = 200: 1) to obtain the title compound (21 1 mg) as a pale yellow oily substance. The results were as follows.

^-NMR (300MHz, DMS0-d6)

δ: 7.89 (2Η, dd, J = 8.9, 5.1 Hz), 7.47 (2H, t, J = 8.9Hz), 7.26 (2H, d, J = 8.7Hz), 6.89-6.83 (3H, m), 4.98 (2H, s), 3.71 (3H, s), 2.02-1.94 (3H, m), 1.78-1.61 (12H, m) Example 22

Synthesis of 4- (1-adamantyl) -2- (N- (4-methoxybenzyl) -1-N- (4-morpholinophenylsulfonyl) amino] thiazole

In the same manner as in Example 16, 4-1- (1-α-damantyl) -12- [N— (4-fluorophenylsulfonyl) -1-N— (4-methoxybenzyl) amino] thiazole (20 Omg) The title compound (17 Omg) was obtained as a colorless amorphous from morpholine (0.3 ml). The result of -NMR was as follows.

^ -Country R (300MHz, DMS0-d6)

δ: 7.61 (2Η, d, J = 9.2Hz), 7.30 (2H, d, J = 8.8Hz), 7.02 (2H, d, J = 9.2Hz), 6.85 (2H, d, J = 8.8Hz), 6.76 (1H, s), 4.94 (2H, s), 3.74-3.67 (7H, m), 3.32-3.26 (4H, m), 2.02--1.94 (3H, m), 1.78-1.61 (12H, m)

Example 23

Synthesis of 4- (1-adamantyl) -1- (4-morpholinophenylsulfonylamino) thiazole 4- (4-adamantyl) -2-1- (4-methoxybenzyl) -1-N- (4-morpholinophenylsulfonyl) amino] thiazole obtained in Example 22

To the solution (102 mg) was added trifluoroacetic acid (0.5 ml) and anisol (50 I) while cooling with water, and the mixture was stirred for 5 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel gel column chromatography (developing solvent, chromate form: solvent = 80: 1) to give the title compound (44 mg) as a colorless amorphous. Was. The results of Oki R are as follows.

^ -N R (300MHz, D S0-d6)

a: 12.52 (1 H, brs), 7.62 (2H, d J = 9.0 Hz), 7.00 (2H, d, J = 9.0 Hz), 6.26 (1 H, s), 3.75 -3.68 (4H, m), 3.25-3.18 (4H, m), 2.02-1.94 (3H, m), 1.80-1.75 (6H, tn), 1 · 74-1.59 (6H, m)

Example 24

Synthesis of 4- (1-adamantyl) -1-2- [N— (4-methoxybenzyl) —N— [4- (2-morpholinoethoxy) phenylsulfonyl] amino] thiazole 4 obtained in Example 21 1- (1-adamantyl) — 2 -— [M— (4-fluorophenylsulfonyl) -1-N— (4-methoxybenzyl) amino] thiazole (2 10) and 1 \ 1- (2-hydroxyethyl) To a solution of morpholine (0.1 ml) in DMF (2. Om I), sodium hydride (36 mg of 60% oil) was added, and the mixture was stirred at room temperature for about 5 minutes. Under ice-cooling, a 1: 1 mixture of water and saturated saline (5 ml) was added, and the mixture was stirred and extracted with chloroform (15 ml). The organic phase was mixed with water and saturated saline 1:〗. The mixture was washed successively with a mixed solution (5 ml IX 3) and a saturated saline solution (5 ml). After the organic phase was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 1: 1 to ethyl acetate) to obtain the title compound (149 mg) as a pale yellow oily substance. The result of -NMR was as follows.

] H-Oki (300MHz, D S0-d6)

δ: 7.73 (2Η, d, J = 9.0Hz), 7.28 (2H, d, J = 8.9Hz), 7.13 (2H, d, J = 9.0Hz), 6.85 (2H, d, J = 8.9Hz), 6.80 (1H, s), 4.95 (2H, s), 4.17 (2H, t, J = 5.6Hz), 3.70 (3H, s), 3.59- 3.53 (4H, m), 2.69 (2H, t, J = 5.6Hz), 2.48-2.42 (4H, m), 2.02-1.94 (3H, m), 1.78- 1.61 (12H, m)

Example 25

4- (1-adamantyl) -1-2- [4- (2-morpholinoethoxy) phenyl Synthesis of sulphonylaminoaminothiazol tritrifluoroacetate

In the same manner as in Example 23, 4- (1-adamantyl) —2- [N— (4-methoxybenzyl) —N— [4- (2-morpholinoethoxy) phenylsulfonyl] amino] thiazol ( 143 mg) to give the title compound (144 mg) as a colorless amorphous. The result of NMR was as follows.

^-MR (300MHz, DMS0-d6)

δ: 12.63 (1Η, brs), 7.77 (2Η, d, J = 9.OHz), 7.12 (2H, d, J = 9.OHz), 6.31 (1H, s), 4.40 (2H, brs) , 4.10-3.00 (m), 2.02-1.94 (3H, m), 1.80-1.75 (6H, m), 1.74- 1.59 m

Example 26

Synthesis of 4- (1-adamantyl) 1-2- [N— [4- [2- (dimethylamino) ethoxy] phenylsulfonyl] —N— (4-methoxybenzyl) amino] thiazole

In the same manner as in Example 24, 4- (1-adamantyl) -12- [N- (4-fluorophenylsulfonyl) -1-N- (4-methoxybenzyl) amino] thiazole (204 mg) and N, N- The title compound (147 mg) was obtained as a colorless powder from dimethylethanolamine (80 μI). -The results of R were as follows.

H-rigid R (300MHz, DMS0-d6) δ: 7.73 (2Η, d, J = 9.OHz), 7.28 (2H, d, J = 8.7Hz), 7.13 (2H, d, J = 9.OHz) ), 6.85 (2H, d, J = 8.7Hz), 6.79 (1H, s), 4.96 (2H, s),

4.17 (2H, t, J = 5.7Hz), .3.71 (3H, s), 2.63 (2H, t, J = 5.7Hz), 2.20 (6H, s), 2.02- 1.94 (3H, tn), 1.78- 1.60 (12H, m)

Example 27

4--1- (1-adamantyl) -1-_2— [4- [2- (Dimethylamino) ethoxy] phenylsulfonylamino] thiazol / trifluroacetate 05007106

45 4- (1-adamantyl) -12- [N_ [4- [2- (dimethylamino) ethoxy] phenylsulfonyl] —N— (4-methoxybenzyl) amino in the same manner as in Example 23 The title compound (111 mg) was obtained as a pale pink amorphous from thiazole (133 mg). The result of ¹ H-NMR was as follows. H-Oki (300MHz, D S0-d6) δ: 7.77 (2H, d, J = 9.OHz), 7.12 (2H, d, J = 9.OHz), 6.31 (1H, s), 4.37 (2H , t, J = 5. OHz), 3.51 (2H, t, J = 5. OHz), 2.84 (6H, s), 2.02- 1.94 (3H, m), 1.78- 1.60 (12H, m)

Example 28

Synthesis of 4- (1-adamantyl) 1 2— 〖4- [2- (4-piperazinyl) ethoxy] phenylsulfonylamino] thiazol

(1) 4- (1-adamantyl) -1-2- (M— [4- [2- [4- (t-butoxycarbonyl) piperazinyl] ethoxy] phenylsulfonyl-N_ (4-methoxybenzyl) amino ] Synthesis of thiazole

In the same manner as in Example 24, 4- (1-adamantyl) -2- [N- (4-fluorophenylsulfonyl) -1-N— (4-methoxybenzyl) amino] thiazol (25 Omg) and t- Butyl 4- (2-hydroxyethyl) pidazine-1-carboxylate (225 mg) gave the title compound (128 mg) as a yellow oil. The result of ¹ H-NMR was as follows.

1H-NMR (300MHz, DMS0-d6)

δ: 7.73 (2Η, d, J = 9, OHz), 7.28 (2H, d, J = 8.7Hz), 7.13 (2H, d, J = 9.OHz), 6.85 (2H, d, J = 8.7Hz) ), 6.79 (1H, s), 4.95 (2H, s), 4.18 (2H, t, J = 5.4Hz), 3.71 (3H, s), 3.34- 3, 27 (4H, m), 2.72 (2H, t, J = 5.4Hz), 2.45-2.38 (4H, m), 2.02-1.94 (3H, m), 1, 78-1.60 (12H, m), 1.39 (9H, s)

(2) Synthesis of 4- (1-adamantyl) -1-2- [4- [2- (4-piperazinyl) ethoxy] phenylsulfonylamino] thiazole

In the same manner as in Example 23, 4- (1-adamantyl) —2-—N— [4- [2- [4- (t-butoxycarbonyl) piperazinyl] ethoxy] phenylsulfo 2-N— (4-methyl After obtaining the crude product from [methoxybenzyl) amino] thiazole (114 mg), silica gel column chromatography (developing solvent: chloropho Purification was performed using a solution of room temperature: room temperature: 28% aqueous ammonia solution = 15: 1: 0.1 to 10: 1: 0.1) to obtain the title compound (50 mg) as a colorless powder. -The result of NMR was as follows.

^-MR (300MHz, D S0-d6)

δ: 7.68 (2Η, d, J = 8.7Hz), 6.97 (2H, d, J = 8.7Hz), 6.06 (1H, s), 4.10 (2H, t, J = 5.5Hz), 2.93-2.86 (4H , m), 2.73 (2H, t, J = 5.5Hz), 1.58-2.47 (4H, m), 2.01- 1.92 (3H, m), 1.79-1.58 (12H, m)

Example 29

Synthesis of 4- (1-adamantyl) — 2 -— [N— (4-hydroxyphenylsulfonyl) -N— (4-methoxybenzyl) amino] thiazole

DMF solution of 4- (1-adamantyl) -1-2- [N— (4-fluorophenylsulfonyl) -1-N— (4-methoxybenzyl) amino] thiazole (496 mg) and 2- (methylsulfonyl) ethanol (1 To 5 ml), sodium hydride (116 mg of 60% oil) was added under ice-cooling, and the mixture was stirred for 5 minutes under ice-cooling, then returned to room temperature and stirred for 30 minutes. Under ice-cooling, a 1 M aqueous hydrochloric acid solution (1 Oml) was added, the mixture was stirred until foaming ceased, and the mixture was extracted with ethyl acetate (20 ml). Organic phase with water

(1 Om I X3) and saturated saline (10 ml). After the organic phase was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, solvent: methanol: 100: 1) to give the title compound (2.1 mg) as a pale yellow amorphous. The NWIR results were as follows.

Ή-NMR (300MHz, DMS0-d6)

(5: 10.70 (1H, brs), 7.64 (2Η, d, J = 8.9Hz), 7.28 (2H, d, J = 8.9Hz), 6.90 (2H, d, J = 8.9 Hz), 6.85 (2H, d, J = 8.9Hz), 6.78 (1H, s), 4.94 (2H, s), 3.71 (3H, s), 2.02-1.94 (3H, m), 1.78-1.61 (12H, m)

Example 30

4-1- (1-adamantyl) -1-2- Synthesis of [4- (carboxymethoxy) phenylsulfonylamino] thiazole (1) 4- (1-adamantyl) -1-2- [N— [4-[(t_butoxycarbonyl) methoxy] phenylsulfoninole] —N— (4-methoxybenzyl) amino] thiazole Synthesis

A solution of 4- (1-adamantyl) —2- [N— (4-hydroxyphenylsulfonyl) -1-N— (4-methoxybenzyl) amino] thiazole (243 mg) obtained in Example 29 in DMF ( To 2.5 ml) was added sodium hydride (60 mg oil, 116 mg) under ice-cooling, and after stirring for 5 minutes, t-butyl acetate (13 mg) was added to the mixture, and the mixture was brought to room temperature. It was returned and stirred for 2 hours. Under ice-cooling, water (10 ml) was added, the mixture was stirred until foaming stopped, and the mixture was extracted with ethyl acetate (20 ml). The organic phase was washed successively with water (1 Om I X4) and saturated saline (1 Oml). After the organic phase was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 9: 1) to give the title compound (254 mg) as a colorless amorphous. The result of NMR was as follows.

^ -NWIR (300MHz, DS0-d6)

δ: 7.75 (2Η, d, J = 9.OHz), 7.28 (2H, d, J = 8.8Hz), 7.09 (2H, d, J = 9.OHz), 6.85 (2H, d, J = 8.8Hz) ), 6.80 (1H, s), 4.96 (2H, s), 4.80 (2H, s), 3.71 (3H, s), 2.02- 1.94 (3H, m), 1.78-1.60 (12H, m), 1.41 ( 9H, s),

(2) Synthesis of 4- (1-adamantyl) -1-2- [4- (carboxymethoxy) phenylsulfonylamino] thiazole

In the same manner as in Example 23, 41 (1-adamantyl) 1 2— [N— [4

-[(t-Butoxycarbonyl) methoxy] phenylsulfonyl] -N- (4-methoxybenzyl) amino] thiazole (209 mg) gave the title compound (145 mg) as a white powder. -The IIR results are as follows.

'W-R (300MHz, DMS0-d6)

δ: 12.61 (IH, brs), 7.72 (2H, d, J = 9.OHz), 7.03 (2H, d, J = 9.OHz), 6.30 (IH, s), 4.76 (2H, s), 2.02 -1.94 (3H, tn), 1.78—1.60 (12H, m)

Example 3 1 Synthesis of 4- (1-adamantyl) _2- [| [1- [4-[(aminocarbonyl) methoxy] phenylsulfonyl] -1-N— (4-methoxybenzyl) amino] thiazole

Example 29 The 4- (1-adamantyl) —2- [N— (4-hydroxyphenylsulfonyl) —N— (4-methoxybenzyl) amino] thiazol (21 mg) obtained in Example 9 Sodium hydride (60% oil, 18mg) was added to the DMF solution (2. Oml) under ice-cooling, and the mixture was stirred for 5 minutes. Then, 2-chloroacetamide (77mg) was added, and the mixture was returned to room temperature. Stirred for 2 hours. Further, potassium iodide (136 mg) was added, and the mixture was stirred at room temperature for 3 hours, and then heated to 80 ° C and stirred for 3 hours. Under ice-cooling, a mixture of water and saturated saline 1: 5 (5 ml) was added, and the mixture was stirred until bubbling ceased, and the mixture was extracted with chloroform (20 m. The organic phase was mixed with water and saturated saline 1: 5). The mixture was washed successively with 1 mixture (10 m IX 2) and saturated saline (1 Oml) .The organic phase was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, liquid: form: methanol = 80: 1) to give the title compound (16 Omg) as a pale brown oily substance. there were.

1H-NMR (300MHz, DMS0-d6)

d: 7.77 (2H, d, J = 9.0Hz), 7.62 (1H, brs), 7.43 OH, brs), 7.29 (2H, d, J = 8.8Hz), 7.12 (2H, d, J = 9.0Hz) ), 6.85 (2H, d, J = 8.8Hz), 6.79 (1H, s), 4.96 (2H, s), 4.55 (2H, s), 3.71 (3H, s), 2.02-1.94 (3H, m), 1.79-1.61 (12H, ra)

Example 3 2

Synthesis of 4- (1-adamantyl) -1-2- [4-[(Aminocarbonyl) methoxy] phenylsulfonylamino] thiazole

In the same manner as in Example 23, 4- (1-adamantyl) -12- [N- [4-[(aminocarbonyl) methoxy] phenylsulfonyl] -1-M- (4-methoxybenzyl) amino] thiazo The title compound (Ί08 mg) was obtained as a colorless powder from one liter (16 Omg). The I1R results were as follows. ¹ HNR (300MHz, DMSO-d6)

δ: 12.6.1 (1H, brs), 7.77 (2H, d, J = 9.0Hz), 7.58 (1H, brs), 7.41 (1H, brs), 7.05 (2H, d, J = 9.OHz), 6.30 (1H, s), 4.51 (2H, s), 2.02-1.92 (3H, m), 1.84-1.56 (12H, m) Example 33

Synthesis of 4- (1-adamantyl) -2- [N- (3-chloro-2-methylphenylsulfonyl) -1-N-methylamino] thiazol

A solution of 4- (1-adamantyl) -2- (3-chloro-2--2-methylphenylsulfonylamino) thiazole (1 O Omg) obtained in Example 5 in DMF (1.

Oml), add sodium hydride (11 mg of 60% oil) under ice-cooling, stir for 3-0 minutes, add methyl iodide (15 ^ 1), return to room temperature, and stir overnight did. Under ice-cooling, add water (5 ml), stir until foaming stops, and add ethyl acetate (1

Oml). The organic phase was washed successively with a 1: 1 mixture of water and saturated saline (5 ml IX 2) and saturated saline (5 ml). After the organic phase was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 20: 1) to give the title compound (57 mg) as a colorless oil. The results of ¹ H-MMR were as follows.

^ -NM (300MHz, DMS0-d6),

6: 7.92 (1Η, d, J = 8.OHz) '7.83 (1H, d, J = 8.OHz), 7.50 (1H, t, J = 8.OHz), 6.87 (1H, s), 3.39 ( 3H, s), 2.43 (3H, s), 2.02-1.94 (3H, m), 1.78-1.61 (12H, m)

Example 34

Synthesis of 4- (1-adamantyl) -1-2- [N- (3-chloro-2-methylphenylsulfonyl) -1-N- (2-hydroxyethyl) amino] thiazole

(1) 4 1 (1-adamantyl) 1 2— [N- (3-chloro- 2 -methylphenylsulfonyl) 1 W— [2-(tetrahydro-2H-pyran-2-ylyl) Synthesis of ethyl] amino] thiazole

In the same manner as in Example 33, 4- (1-adamantyl) -12- (3-chloro-2-methylphenylsulfonylamino) thiazole (90 mg) and 2- (2-promethoxy) tetrahydro -Colorless oil from 2H-pyran (32 μI) / v: / O 9s / -00s00ifcl £ 60sosAV

.

(s0¾9ρια ¾--,

9

s

(«Cn ^^) 丄 (v 6ϋ% ίιl09 ^ -υEM .. £ After stirring for 0 minutes, 2-chloroacetamide (11 mg) and potassium iodide (19 mg) were added, and the mixture was returned to room temperature and stirred for 1.5 hours. The reaction temperature was raised to about 00 ° C, and the mixture was stirred for 4 hours. After adding 2-chloroacetoamide (1 mg) and lithium iodide (19 mg) and stirring at 100 ° C for 3 hours, the reaction temperature was raised to 130 ° C and 6 Stirred for hours. Further, 2-chloroacetoamide (1 I mg) and potassium iodide (19 mg) were added, and the mixture was stirred at 130 ° C for 3 hours. Under ice-cooling, a 1: 1 mixture of water and saturated saline (5 ml) was added, and the mixture was extracted with ethyl acetate (15 ml). The organic phase was washed successively with a 1: 1 mixture of water and saturated saline (5 ml × 2) and saturated brine (5 ml). After the organic phase was dried over anhydrous magnesium sulfate, the drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, chromate form: methanol = 80: 1) to obtain the title compound (27 mg) as a yellow oily substance. The result of ¹ H-NMR was as follows.

1H-NMR (300MHz, D S0-d6)

(5: 8.02 (1H, d, J = 8.0Hz), 7.82 (1H, d, J = 8.0Hz), 7.54 (1H, brs), 7.48 (1H, t, J = 8.OHz), 7.18 ( 1H, brs), 6.81 (1 H, s) 4.49 (2H, s), 2.02-194 (3H, m), 1.78-1.61 (12H, m) Example 36

Synthesis of 4- (1-adamantyl) -2-1- (3-chloro-2-methylphenylsulfonyl) -N-ethylamino] thiazole

In the same manner as in Example 33, 4- (1-adamantyl) -1- (3-chloro-

The title compound (49 mg) was obtained as a yellow oil from 2-methylphenylsulfonylamino) thiazol (88 mg) and iodide tyl (23 I). ^-

The result of NMR was as follows.

Ή-N R (300MHz, DMS0-d6)

δ: 7.91 (1Η, d, J = 8.OHz), 7.82 (1H, d, J = 8.0Hz), 7.49 (1H, t, J = 8.0Hz), 6.91 (1H, s)

, 3.90 (2H, q, J = 7.OHz), 2.42 (3H, s), 2.02-1.96 (3H, m), 1.78-

1.61 (12H, m), 1.19 (3H, t, J = 7. OHz)

Example 37 Synthesis of 4- (1-adamantyl) -1-2-CN- (3-chloro-2-methylphenylsulfonyl) -1-N-isobutylamino] thiazole

In the same manner as in Example 33, 4- (1-adamantyl) -12- (3-chloro-2-methylphenylsulfonylamino) thiazole (90 mg) and isobutyl iodide (122 μI) were used as a yellow oily substance. The title compound (28 mg) was obtained.

The results of 1H-R are as follows.

^{- 1 HN R (300MHz, DMS0} -d6)

δ: 7.88 (1Η, d, J = 8.OHz), 7.80 (1H, d, J = 8.0Hz), 7.46 (1H, t, J = 8.0Hz), 6.94 (1H, s), 3, 71 ( ZH, d, J = 7.OHz), 2.38 (3H, s), 2.02-1.92 (3H, m), 1, 91-1.80 (1H, m), 1.78-1.58 (12H, m), 0.87 (6H , d J = 7. OHz).

Example 38

Synthesis of 4- (1-adamantyl) -1- [2- (hydroxymethyl) phenylsulfonylamino] thiazole

Example 4 4- (1-adamantyl) 1-2- [2- (methoxycarbonyl) phenylsulfonylamino] thiazole (250 mg) obtained in 23 was dissolved in tetrahydrofuran (1 OmL). Ice cooled. To this solution, lithium aluminum hydride (44 mg) was added over 5 minutes. After stirring for 1 hour under ice cooling and 3 hours at room temperature, the reaction solution was poured into diluted hydrochloric acid. The resulting solution was extracted with chloroform (5 OmL), washed with saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate: n-hexane = 1: 1) to obtain the title compound (180 mg) as a pale yellow amorphous.

The results were as follows.

^ -NR (300 MHz, DMS0-d6). (5: 12.62 (1H, br s), 7.86 (1H, d, J = 7.8 Hz), 7.76 (1H, d, J = 7.8 Hz), 7.59 (1H , t, J = 7.5 Hz),

7.39 (1H, t J = 7.5 Hz), 6.31 (1H, s), 5.31 (1H, t, J = 5.5 Hz), 4.95 (2H, d, J = 5.5 Hz), 2.04-1.94 (3H, m) , 1.86-1.76 (6H, m), 1.74-1.60 (6H, m)

Example 39 (1) Synthesis of 1- (3-hydroxyadamantyl) ethanone

A solution of 3-hydroxyadamantane-11-carboxylic acid (98 1 mg) in tetrahydrofuran (20 ml) was cooled on ice, and a 1.2 M methyllithium solution (Ί2.5 ml, getyl ether) was added. Solution) was added dropwise over 10 minutes. After the addition was completed, the temperature was raised to room temperature, and the mixture was stirred for 6 hours. The reaction solution was poured into water, extracted with ethyl acetate (50 ml), and washed with saturated saline (50 ml). After the organic phase was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the title compound (40 Omg) as a colorless solid. The result of NMR was as follows.

, [■! -Hidden (300MHz, DMS0-d6) δ: 4.51 (1Η, s), 2.20- 2.10 (2H, m), 2.06 (3Η, s), 1.62-1.7 (12Η, m)

(2) Synthesis of 4- (3-hydroxyadamantane-1Jyl) 1-1,3-thiazole-12-amine

To a solution of 1- (3-hydroxyadamantane-11-yl) ethanone (39 Omg) in chloroform (1 Oml) was added bromine (0.11 ml) at room temperature. The mixture was gradually heated to 60 ° C and stirred at the same temperature for 10 minutes. The solvent was distilled off under reduced pressure, the residue was dissolved in ethanol (1 Oml), and thioprea (152 mg) was added, followed by stirring at room temperature for 2 days. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform: methanol: 28% aqueous ammonia = 100: 5: 0.5) to give the title compound as a colorless solid. (25 Omg). -The result of NMR was as follows.

] Η-Hidden (300MHz, DMS0-d6) δ: 6.77 (2Η, br

s), 6.00 (1 H, s), 4.40 (1 H, s), 2.14 (2H, br s), 1.70-1.47 (12H, m)

(3) 4- (3-hydroxyadamantane-1) -1 2-[[N _ [(5-chloro-3-methylbenzo [b] thiophen-2-yl) sulfonyl] -1-N-methylamino ] Synthesis of thiazole

4- (3-Hydroxyadamantan-1-yl) -1,3-thiazol-2-amine (22 Omg) is dissolved in chloroform (5 ml), and triethylamine (0.2) is dissolved under ice-cooling. 70 ml) and trimethylsilyl chloride (0.123 ml) were added, and the mixture was stirred at room temperature for 6 hours. Cool again on ice and add 4-dimethylaminopyridine (1 08 mg) and 5-methyl-3 -methylbenzo [b] thiaphen-2-enesulfonyl chloride (495 mg) were added, and the mixture was returned to room temperature and stirred overnight. After adding 28% ammonia water (0.2 ml) and stirring at room temperature for 2 hours, 35% hydrochloric acid (1 ml) and methanol (5 ml) were added and stirred for 15 minutes. To the solution was added black-mouthed form (50 ml), and the mixture was washed with saturated saline (30 ml IX 3). After the organic phase was dried over anhydrous magnesium sulfate A, the desiccant was removed by filtration and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, chromate form: methanol = 100: 3), ethyl acetate was added thereto, and the precipitated solid was collected by filtration to give the title compound as a pale yellow solid. (153 mg). -The results of the MMR are as follows.

¹ H-NMR (300MHz, D S0-d6) δ 12.98 (1Η, br

s), 8.06 (1 H, d, J = 8.6 Hz), 7.98 (1 H, d, J = 2.1 Hz), 7.54 (1 H, dd, J = 8.6,

2.1Hz), 6.40 (1H, d, J = 1.9Hz), 2.61 (3H, s), 2.14 (2H, br s), 1.76-1.45 (12H, m)

(1) Synthesis of 4- (1-adamantyl) -5- (ethoxycarbonyl) -2-aminothiazole hydrobromide

Bromine (0.4 ml) was added to an ethanol solution (20 ml) of ethyl 3- (1-adamantyl) -3-oxopropionate (2.0 Og), and the mixture was stirred at 80 ° C for 30 minutes. Thereafter, the mixture was returned to room temperature, and stirred at 45 ° C. for 3 hours, and then returned to room temperature and stirred overnight. The precipitated solid was collected by suction filtration to give the title compound (1.31 g) as a colorless powder. The result of NMR was as follows.

¹ H-NMR (300 MHz, DS0-d6) δ: 4.17 (2Η, q, J = 7.1 Hz), 2.15-2.08. (6H, m), 2.04-1.95 (3H, m), 1.78-1.64 (6H , m), 1.24 (3H, t, J = 7.1 Hz)

(2) 4- (1-adamantyl) -5- (ethoxycarbonyl) -12-([(5-chloro-3-methyl-1-benzophen-2-yl) sulfonyl] amino 1-thiazole In the same manner as in Example 4, 4- (1-adamantyl) -5- (ethoxycarbonyl) -2-aminothiazole hydrobromide (500 mg) and 5-chloro-3-methylbenzo [b] thiophene were used. From 2-sulfonyl chloride (762 mg), pale orange The title compound (723 mg) was obtained as amorphous. ] The results of H-I \ IMR are as follows.

! H-MR (300MHz, DMS0-d6) δ: 8.09 (1Η, d, J = 8.6Hz), 8.03 (1H, d, J = 2.0Hz), 7.57 (1H, dd, J = 8.6, 2.0 Hz) , 4.25 (2H, q, J = 7.1 Hz), 2.63 (3H, s), 2.12-1.95 (9H, m), 1.75-1.60 (6H, m), 1.27 (3H, t, J = 7.1 Hz) Example 4 1

Synthesis of 4- (1-adamantyl) -1-5-methyl-2- (5-chloro-3-methyl-1-benzo-2-en) sulfonyl] amino ithiazolyl (A) and 4- ( Synthesis of 1-adamantyl) -5- (hydroxymethyl) 1-2-{[(5-chloro-3-methyl-1-benzocen-2-yl) sulfonyl] amino) thiazole (B)

Example 40 4- (1-Adamantyl) -5- (ethoxycarbonyl) 1-2- (5-co- mouth-3-methyl-1-benzocen-2-yl) sulfonyl] a obtained in (2) Lithium aluminum hydride (83 mg) was added to a tetrahydrofuran solution (24 ml) of (amino) thiazole (600 mg) under ice-cooling, and the mixture was returned to room temperature, stirred for 3 hours, and further mixed with lithium aluminum hydride (41 mg). ) And stirred at room temperature. The reaction solution was added dropwise to a 0.5 M aqueous hydrochloric acid solution (30 ml) under ice-cooling, then extracted with chloroform (50 m and washed with saturated saline (30 tnl). The organic phase was dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel chromatography (developing solvent: chloroform: methanol = 100: 1), and further purified by preparative TLC (developing solvent: chloroform: methanol). = 80: 1) to give the title compound (A) (236 mg) as a colorless amorphous and the title compound (B) (118 mg) as a pale yellow powder. Met.

Title compound (A)

1H-NMR (300MHz, DMS0 ~ d6) δ 12.40 (1Η, br s), 8.05 (1H, d, J = 8.6Hz), 7.97 (1H, d, J = 2.1Hz), 7.54 (1H, dd, J = 8.6, 2.1 Hz), 2.60 (3H, s), 2.27 (3H, s), 1.92-2.02 (9H, ml, 1.75-1.60 (6H, m)

Title compound (B) ^-MR (300MHz, DIWS0-d6) δ: 13.06 (1H, s), 8.06 (1H, d, J = 8.6Hz), 7.95 (1H, d, J = 2.1Hz), 7.54 (1H, dd, J) = 8.6, 2.1 Hz), 5.79 (1H, t, J = 5.5Hz), 4.60 (2H, d, J = 5.5Hz), 2.60 (3H, s), 2.00-1.89 (9H, m), 1.75—1.59 (6H, m)

Example 42

(1) Synthesis of 4- (1-adamantyl) -1-2-([2-furofilophenylsulfonyl) amino] thiazole

In the same manner as in Example 4, 4- (1-adamantyl) -2-aminothiazole hydrobromide (600 mg) and 2-furoserobenzenesulfonyl chloride (74 1 mg) were used as a light brown powder. The title compound (882 mg) was obtained. The results of ¹ H-go R 'were as follows.

^{1 H-NMR (300MHz, DMS0} -d6) <5: 12.84 (1H, br s), 7, 99 (1Η, m), 7.84 (1Η, m), 7.20-7.45 (2Η, m), 6.36 (1H , s), 1.60-2.06 (15H, m)

(2) 4- (1-adamantyl) _2— [N— (2-fluorophenylsulfonyl) — N— (4

-Medoxybenzyl) amino] thiazole

Example 21 In the same manner as in Example 1, 4- (1-adamantyl) 1-2-[(2-full-age phenylsulfonyl) amino] thiazo "(800 mg) and P-methoxybenzyl chloride (444 MI ) To give the title compound (20 Omg) as a brown oily substance.The results of ^ -NMR were as follows.

^-MR (300MHz, DMS0-d6) 6: 7.92 (1H, td, J = 7.5, 1.7Hz), 7.80 (1H, m), 7.55-7.40 (2H, m), 7.28 (2H, d, J = 8.8Hz), 6.87 (2H, d, J = 8.8 Hz), 6.80 (1H, s,), 5.06 (2H, s), 3.71 (3H, s), 2.02-1.94 (3H, m), 1.75-1.60 (12H, m)

(3) Synthesis of 4 -— (1-adamantyl) — 2 -— [N— (4-Methoxybenzyl) 1N—C2- (2-morpholinoethoxy) phenylsulfonyl] aminoaminothiazole

In the same manner as in Example 24, 41- (adamantyl) -12- [N- (2-fluorophenylsulfonyl) -N- (4-methoxybenzyl) amino] thiazole (188 mg) and N- (2-hydroxyethyl) morpholine (96 mg) to give the title compound (79 mg) as a pale brown oil. The results of ¹ H-R were as follows.

^-MR (300MHz, DMS0-d6) δ 7.93 (1Η, dd, J = 7.9, 1.7Hz), 7.65 (1H, ml, 7.36 (2H, d, J = 8.7Hz), 7.29 (1H, d, J = 8.4Hz), 7.12 (1H, t, J = 7.9 Hz), 6.87 (2H, d, J = 8.7 Hz), 6.65 (1H, s), 5.24 (2H, s), 4.20 (2H, t,

J = 6.0Hz), 3.71 (3H, s), 3.52 (4H, m), 2.58 (2H, t, J = 6.0Hz), 2.40 (4H, m), 2.02-1.94 (3H, m), 1.80- 1.60 (12H, m)

(4) Synthesis of 4- (1-adamantyl) -1-2- [2- (2-morpholinoethoxy) phenylsulfonylamino] thiazole

In the same manner as in Example 23, 4- (1-adamantyl) 1-2- [N— (4-methoxybenzyl) —N— [2- (2-morpholinoethoxy) phenylsulfonyl] amino] thiazole (67 mg) The title compound (48 mg) was obtained as a colorless amorphous. The result of ¹ H-NMR was as follows.

1H-NMR (300MHz, DS0-d6) 6: 7.82 (1H, dd, J = 7.7, 1.7Hz), 7.52 (1H, m), 7.19 (1H, d, J = 8.6Hz), 7.04 (1H, m), 6.32 (1H, s), 4.10 (2H, t, J = 6.6 Hz), 3.55 (2H, m), 2.55-2.37 (6H, m), 2.04-1.58 (15H, m)

Example 43 '

(1) Synthesis of 3-Methoxy-adamantane-l-rubinic acid methyl ester Sodium hydride (60% oil, 40 Omg) was washed with n-hexane (2 Om IX 3) and DMF (30 ml) Was added, and 3-hydroxyadaman-1-yl rubonic acid (98 Omg) was further added, followed by stirring at room temperature for 1 hour. Methyl iodide (0.93 ml) was added to this solution, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl ether (150 ml) and washed with water (10 Om IX 3) and then with saturated saline O 0 Om I). After the organic phase was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate: _n- hexane: = 1: 4) to give the title compound (80 Omg) as a colorless oily substance. The result of ¹ H-NMR was as follows. ¹ H-note (300MHz, DMS0-d6) δ: 3.67 (3H, s), 3.25 (3H, s), 2.36- 2.14 (2H, m), 1.92-1.53 (12H, m)

(2) Synthesis of 3-methoxydamantane

3-Methoxyadamantane-1-carboxylic acid methyl ester (71 Omg) was dissolved in methanol (5 ml), a 5 M NaOH aqueous solution (0.95 ml) was added, and the mixture was stirred for a while. The mixture was further stirred at 70 ° C for 2 hours. The solvent was distilled off under reduced pressure, a 0.5 M aqueous hydrochloric acid solution (20 ml) was added to the residue, and the mixture was extracted with chloroform (50 ml). The porthole form phase was washed with saturated saline and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the title compound (650 mg) as a colorless solid. The result of ¹ H- was as follows.

] H-hidden (300MHz, DMS0-d6) δ 12.11 (1Η, s), .3. Π (3Η, s), 2.23—

2.13 (2Η, m), 1.74-1.48 (12Η, m)

(3) Synthesis of Ν, 3-dimethyloxyΝ-methyladamantane-1-carboxamide

3-Methoxy adamantane 1-carboxylic acid (6 Ί Omg), 0-dimethylhydroxylamine hydrochloride (284 mg), 1-hydroxybenzotriazole monohydrate (426 mg), triethylamine (0.44 ml) To a DMF (6 ml) solution of the above was added 1-ethyl-3- (3-dimethylaminopropyl) carboimide hydrochloride (604 mg) under ice-cooling, and the mixture was stirred for 1 hour and then at room temperature overnight. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. After the organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate == 1: 1) to give the title compound (540 mg) as a colorless oil. The result of -NMR was as follows.

^ -NMR (300MHz, DMS0-d6) «5: 3.68 (3H, s), 3.26 (3H, s), 3.17 (3H, s), 2.16 — 2.36 (2H, m), 2.01-1.96 (2H, m ), 1.94-1.87 (3H, m), 1.78-1.68 (4H, m), 1.64-1.54 (3H, m)

(4) Synthesis of 1- (3-methoxy-1-1-adamantyl) ethanone Under a nitrogen atmosphere, a 3M methylmagnesium bromide getyl ether solution (3M methylmagnesium bromide) was added to a tetrahydrofuran (8ml) solution of N, 3-dimethyloxyn-methyladamantane-11-carboxylic acid amide (540mg) under ice cooling. 2.82 ml) was added dropwise, and the mixture was stirred at the same temperature for 3 hours. After the completion of the reaction, the reaction solution was poured into saturated aqueous ammonium chloride (40 ml), extracted with chloroform, and washed with saturated saline. After the organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (40 Omg) as a colorless oily substance. The results of R were as follows.

'W- (300MHz, DMS0-d6) δ: 3.25 (3Η, s), 2.41-2.24 (2Η, m), 2.12 (3Η, s), 1.83-1.70 (9H, m), 1.66-1.51 (3H, m)

(5) Synthesis of 4- (3-Methoxy-1-adamantyl) —1,3-thiazol-2-amine hydrobromide

Example 39 In the same manner as in (2), 1- (3-methoxy-1-adamantyl) ethanone (400 mg), bromine (0.1 ml) and thiaurea (146 mg) were obtained as a colorless powder. The compound (49 Omg) was obtained. -The result of NMR was as follows.

^ -NMR (300MHz, DWIS0-d6) δ: 6.50 (1Η, s), 3.14 (3H, s), 2.39-2.12 (2H, m), 1.87-1.43 (12H, m)

(6) Synthesis of 3-chloro-N- [4- (3-methoxy-1-adamantyl) -1-1,3-thiazo-1-yl-2-yl]-2-methylbenzenesulfonamide

In the same manner as in Example 4, 4- (3-methoxy-1-adamantyl) -1,3-thiazole-2-amine hydrobromide (103 mg) and 3-chloro-2-methylbenzenesulfonyl chloride (135 mg) to give the title compound (8 Omg) as a colorless powder. The result of NMR was as follows.

^-MR (300MHz, D S0-d6) δ: 12.75 (1Η, br s) 7.91 (1H, dd, J = 7.9, 1.4 Hz), 7.68 (1H, d, J = 7.9 Hz), 7.39 (1H, t like, J = 7.9), 6.39 (1H, s), 3.11 (3H, s), 2.65 (3H, s), 2.26-2.10 (2H, m), 1.80-1.73 (2H, m), 1.73-1.68 (4H, m), 1.67--1.59 (4H, m), 1.58-1.47 (2H, m)

Example 44 Synthesis of N- [4- (3-Methoxy-1-adamantyl) —1,3-thiazo-1-yl-2-yl] -3-methyl-1-benzothienephen-1--2-sulfonamide

In the same manner as in Example 4, 4- (3-methoxy-1-adamantyl) -1,3, thiazol-2-aminehydrobromide (103 mg) and 5-chloro-1-benzothiophene were used. The title compound (61 mg) was obtained as colorless powder from 2-sulfonyl chloride (168 mg). ^ -NMR results were as follows.

^-MR (300MHz, D S0-d6) <5: 12.96 (1H, brs), 8.06 (1H, d, J = 8.7 Hz), 7.98 d 'd, J = 2.0 Hz),, 7.54 OH, dd, J = 8.7, 2.0 Hz), 6.45 (1H, s), 3.11 (3H, s), 2.61 (3H, s), 2.29-2.09 (2H, m), 1.77-1.73 (2H, m), 1.73-1.67 (4H, m), 1.66-1.59 (4H, m), 1.57-1.46 (2H, m)

Example 45

4-Synthesis of 1- (1-adamantyl) 1-2- (2-naphthylsulfonylamino) thiazole

To a solution of 4- (1-adamantyl) -12-aminothiazole (50 mg) in chloroform (3 ml) obtained in Reference Example 2 was added pyridine (68.3 μ. \), And then 2-naphthalene. Sulfonyl chloride (191.19 mg) was added, and the mixture was stirred at 100 ° C. for about 5 minutes using a microbeak reactor. To the reaction mixture was added chloroform, washed with a saturated aqueous ammonium chloride solution, and the organic phase was concentrated under reduced pressure. The resulting residue was purified using a TLC plate (TLC plate NH, manufactured by Fuji Silicon Chemicals Ltd.) to give the title compound (40.1 mg) as a colorless solid. -The result of NMR was as follows.

^-MR (300MHz, DMS0-d6) δ: 9.45ΠΗ, s), 8.52 (1Η, s), 8.06-7.79 (4Η, m), 7.76-7.45 (2H, tn), 5.93 (1H, s), 2.20-1.96 (3H, m), 1.95-1.46 (12H, m)

Example 46

Synthesis of 4- (1-adamantyl) -1-2- (2,3,4-trichloromethylphenylsulfonylamino) thiazole The title compound was obtained in the same manner as in Example 45. -The results of R were as follows.

^ -NMR (300MHz, DMS0 ~ d6) 6: 8.10 (1H, d, J = 8.6 Hz), 7.51 (1H, d, J = 8.6 Hz), 6.00 (1H, s), 2.21-2.01 (3H, m ), 1.93-1.62 (12H, m)

Example 47

Synthesis of 4- (1-adamantyl) -1-2- (2,4,5-trifluorophenylsulfonylanamino) thiazole

The title compound was obtained in the same manner as in Example 45. The results of ¹ H-R were as follows.

(300MHz, DMS0-06) δ: 9.93 (1H, br s), 7.93-7.77 (1H, m), 7.09-

6.93 (1H, m), 6.02 (1H, s), 2.22-2.02 (3H, m), 1.92-1.66 (12H, m)

Synthesis of 4- (1-adamantyl) -1-2- (2,6-dichroic phenylsulfonylamino) thiazole

The title compound was obtained in the same manner as in Example 45.刚 The results of R were as follows.

¹ H-NMR (300 MHz, DMS0-d6) δ: 9.85 (1Η, br s), 7.49-7.37 (2H, m), 7.33-

7.20 (1H, m), 5.98 (1H, s), 2.18-2.04, (3H, m), 1.92-1.66 (9H, m), 1.65-1.51 (3H, m)

Example 49

Synthesis of 4- (1-adamantyl) -1-2-([3-promo 5-chlorothiophene-2-yl) sulfonylamino] thiazole

The title compound was obtained in the same manner as in Example 45. The results of R were as follows.

^-MR (300MHz, D S0-d6) δ: 9.83 (1Η, br s), 6.90 (1H, s), 6.03 (1H, s), 2.20-2.05 (3H, m), 1.95-1.54 (12H, m)

Example 50

Synthesis of 4- (1-adamantyl) -1-2- (2,3-dichroic phenylsulfonylamino) thiazole The title compound was obtained in the same manner as in Example 45. The results of the MMR are as follows.

'W-MR (300MHz, DMS0-d6) δ: 9.85 (IH, br s), 8.16 (1H, dd, J = 7.9, 1.55 Hz), 7.61 (1H, dd, J = 8.1, 1.55 Hz), 7.37 -7.29 (1H, m), 5.99 (1H, s), 2.18-2.0.4 (3H, m), 1.92-1.51 (12H, m)

Example 5 1

Synthesis of 4- (1-adamantyl) -1-2- (2,4-difluorophenylsulfonylamino) thiazole

The title compound was obtained in the same manner as in Example 45. The results of the MMR are as follows.

^ -NMR (300MHz, DMS0-d6) δ: 9.87 (ΙΗ 'br s), 8.17-7.89. (1H, m), 7.04-6.81 (2H, m), 5.99 (1H, s), 2.22-2.00' (3H, m), 1.97-1.57 (12H, m) Example 52

Synthesis of 4- (1 -adamantyl) —2— [(2,5-dichlorothienephen-3--3-yl) sulfonylamino] thiazole

^-MR (300MHz, DMS0-d6) δ: 9.81 (ΙΗ ,, br s), 7.19 (1H, s), 6.00 (1H, s), 2.23-1.97 (3H, m), 1.95-1.57 (12H, m)

Example 53

Synthesis of 4- (1 -adamantyl) -1-2- (3-chloro- mouth-5-full-rough 2-methylphenylsulfonylamino) thiazole

The title compound was obtained in the same manner as in Example 45. The NMR results were as follows.

^ -R (300MHz, DMS0-d6) δ: 9.84 (IH, br s), 7.86 (IH, d, J = 7.5 Hz), 7.16 (IH, d, J = 9.3 Hz), 5.98 (IH, s) , 2.38 (3H, s), 2.19-2.03 (3H, m), 1.93-1.61 (12H, m)

Table 2 summarizes the structures of the compounds obtained in the above Examples.

Table 2. Represents the structures of the compounds obtained in Examples I to 53.

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MS (APCI) Compound number Structural formula Molecular formula

[M + H] ⁺

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54-2 C23H30N2O2S2 431

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The 11βHSD1 inhibitory activity of the test compound was evaluated as follows.

To the reaction solution containing 200 nM NADPH in 30 mM TrisHCI (pH 7.4) / 1 mM EDTA buffer, human liver microsomal enzyme (Tissue Transformation Technologies) as an enzyme source was added as lO zg / ml, and the test compound was added. Was added. Thereafter, a cortisone solution as a substrate was added to a final concentration of 100 nM, and the reaction was started. After incubation at 37 ° C for 80 minutes, the reaction was stopped by adding a non-specific inhibitor, 18) 3 glycyrrhetinic acid, as a final concentration of ΙΜ ΙΜ. The amount of generated cortisol was quantified using a detection kit (Nippon Schering Co., Ltd.) by the HTRF8 (Homogeneous Time-Resolved Fluorescence) method. This system detects the fluorescence resonance energy transfer that occurs between the anticortisol antibody labeled with europium and the cortisol labeled with XL665.When unlabeled cortisol is added, the binding signal is generated by a competitive reaction. Attenuate. At this time, a standard curve was prepared using cortisol of a known concentration included in the kit, and the amount of cortisol generated by the reaction was evaluated. Background cortisol production of Ueru without enzyme, cortisol production of Ueru without compound as 100% of enzyme activity was assessed per dilution series of common ratio 3 from 50μ for each compound, IC ₅₀ values Calculated. '

Compound IC _{5 ()} value of Example 4-10 16 nM

Compound IC ₅ Example 4 21. Value 42nM Industrial availability

The thiazole derivative of the present invention can be used as a novel compound in various fields including medical treatment.

The thiazole derivative of the present invention, a pharmaceutically acceptable salt thereof, and a solvate thereof can be used as an 11 / 8-HSD1 inhibitor and an active ingredient of a pharmaceutical composition.

The HSD1 inhibitor and the pharmaceutical composition of the present invention can be used as a medicine.

Claims

Scope

1

[Where,

R ¹ represents an adamantyl group or an adamantyl group having 1 to 3 substituents selected from “hydroxyl group, halogen atom, d to C ₅ alkyl group, and —alkoxy group”;

Represents a hydrogen atom, an alkoxycarbonyl group, an alkyl group, or an alkyl group having 3 substituents selected from a hydroxyl group, a halogen atom, and an alkoxy group J;

R3 is hydrogen atom, C, - C ₅ alkyl group, C ₂ ~ C ₆ alkenyl group, C ₂ -C ₆ alkynyl group; or "hydroxyl, force Rubamoiru group, a halogen atom, ~ alkoxy one Hue group, an amino group , An alkylamino group, a dialkylamino group, and an alkoxy group, each having 1 to 3 substituents;

Ring A represents an aryl or heteroaryl group;

^{^{R 4, R 5 6, R}} 7 and R ⁸ each represents a halogen atom, Shiano group, Two Bok port group, the formula ^{^{^{- X 1 - X 2 -X 3}}} ( wherein, X ¹ is a single bond, an oxygen atom, sulfur atom, a sulfinyl group, a sulfonyl group, carboxy group, the formula - NX ⁴ _ the formula - CO- NX ⁴ -, wherein - NX ⁴ - CO-, wherein -NX ^⁴ - CO_ NX ⁴ -, wherein one NX ⁴ — CO— 0—, equation — S 0 ₂ — NX ⁴ —, equation— NX ⁴ — SO ₂ —, equation—CO—0—or equation—0—CO— Teeth; X ² is a single bond, - (; ₅ represents an alkylene group; X ³ and X ⁴ are each a hydrogen atom, - alkyl, (; _3-cycloalkyl group, c _2-c ₆ alkenyl group, c _{2 to} c _{6 represents an} alkynyl group, an aryl group, a heteroaryl group or an alicyclic heterocyclic group, provided that X ² , X ³ and X ⁴ are Ί to 3 substituents selected from the following substituent group Y ) Or

Wherein ^{^{- X 1 - X 5 - X}} 6 ( wherein, X ¹ is as defined above; X ⁵ is (^ ~ a represents alkylene group; X ⁶ has the formula -OX ^7, wherein one Nyukai ⁷ chi ^8, wherein - CO- ΝΧ ⁷ Χ ^8, wherein -v X ⁷ - CO- X ^7, wherein one S0 ₂ - NX ⁷ X ^8, Shiki ⁷ -30 ₂ - ^8, wherein one CO- O-X ⁷ or the formula - 0- CO- represents X ^{^7;.} X ⁷ and X ⁸ each represent a hydrogen atom, Ariru group or ~ alkyl group provided ^{^{that, x 5, x 6, X}} 7 and X ^8, following substituent And may have 1 to 3 substituents selected from the group Y.) or two adjacent groups of R ⁴ , RR ⁶ , R ⁷ and R ⁸ are taken together. Te formula - X ^¹ - χΐχ ¹ - (wherein, X ¹ and X ⁵ are the same as defined above) to form a ring structure you express in; the substituent Υ group, a halogen atom, Shiano group, a nitro Group, hydroxyl group, methyl group, trifluoromethyl group, Butyl group, a thiazole derivative represented by the representative.] The group consisting of methylthio group or main Bok alkoxy group, a pharmaceutically salt allowable, or solvate thereof.