WO2006068199A1

WO2006068199A1 - Metabolically stable 3-oxy-1,2,4-triazole derivatives

Info

Publication number: WO2006068199A1
Application number: PCT/JP2005/023526
Authority: WO
Inventors: Manabu Itoh; Masahiko Ohta
Original assignee: Mochida Pharmaceutical Co., Ltd.
Priority date: 2004-12-22
Filing date: 2005-12-21
Publication date: 2006-06-29

Abstract

It is intended to provide a compound which has a remarkably high stability in human serum and is expected as highly useful as a medicine. A medicinal composition to be administered to a patient with a need for the inhibition of 11β-HSD1 or the regulation of the activity of 11β-HSD1 which contains, as the active ingredient, a 3-oxy-1,2,4-triazole derivative represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate of the same.

Description

Specification

Metabolically stable 3_oxy _ 1, 2, 4_triazole derivatives

Technical field

[0001] The present invention relates to the use of substituted 3-oxy-1,2,4-triazole derivatives in the medical field and 11-β-hydroxysteroid dehydrogenase 'type 1 enzyme (hereinafter referred to as 11 β-HSD1). BACKGROUND ART Related to a pharmaceutical composition characterized in that the derivative used for the treatment of diseases by controlling the activity is an active ingredient, and a method for producing the derivative

[0002] An important role of 11 β -HSD1, the role of regulating hepatic glucose production by regulating the effects of local darcocorticoids, has already been demonstrated today (Jamieson et al. (2000) J. Endocrinol. 165: p.685-692). In addition, glucose in blood and hepatic glucose production were decreased in the mice knocked out of the 11β-HSD1 gene. From the data obtained with this model, it is expected that basal levels of phosphoenopyruvic acid (PEPCK) and glucose 6-phosphatase (G6Pase) are regulated independently of darcocorticoids even when 11 β -HSD1 is suppressed. It has been confirmed that it does not cause hypoglycemia (Kotelevtsev, Y. et al. (1997) Proc. Natl. Acad. Sci. US 94: 14924-14929).

[0003] Obesity is an important factor in Syndrome X and most type 2 diabetes, and it appears that the network plays a central role. Abdominal obesity is closely related to glucose hypersensitivity, hyperinsulinism, hyperglyceridemia, and other so-called syndrome X factors such as increased blood pressure, decreased HDL levels, and increased VLDL levels (Montague & O'Rahill y, Diabetes 49: 883-888, 2000). It was found that inhibition of enzymes in preadipocytes (stromal cells) reduces the rate of separation into adipocytes. As a result, it is expected that the degree of swelling of the omental adipose tissue will decrease (probably decrease), that is, the central obesity will decrease (Bujalska, IJ, S. Kumar, and PM Stewart (1997) Lancet 349: 1210 -1213).

[0004] By inhibiting 11 β -HSD1 in mature adipocytes, plasminogen Terin inhibitor 1 (PAI-1) —expected to dilute the secretion of a separate cardiovascular risk factor (Halleux, CM et al. (1999) J. Clin. Endocrinol. Metab. 84: 4097-4105). Furthermore, there is a clear correlation between darcocorticoid “activity” and cardiovascular risk factors, and this fact suggests that reducing the effects of darcocorticoids is beneficial for cardiovascular events. (Walker, BR et al. (1998) Hypertension 31: 891-895; Fraser, R. et al. (1999) Hypertension 33: 1364-1368).

[0005] When the adrenal gland is removed, the effect of increasing both food intake and hypothalamic neuropeptide sputum expression due to fasting can be suppressed. This fact supports the role of darcocorticoids in increasing food intake, suggesting that suppression of 11β-HSD1 in the brain increases satiety and thus decreases food intake. (Woods, SC et al. (199 8) Science, 280: 1378-1383).

Inhibition of 11 β -HSD1 in isolated murine spleen j8 cells improves insulin secretion by glucose stimulation (Davani, B. et al. (2000) J. Biol. Chem. November 10, 2000) 275 (45): 34841-4) o It has been previously known that darcocorticoids reduce splenic insulin release in vivo (Billaudel, B. and BCJ Sutter (19 79) Horm. Metab. Res. 11: 555-560). Therefore, due to the inhibitory effect of 11β-HSD1, it is expected that positive effects will appear in the treatment of diabetes in addition to the effects on liver and fat.

[0006] In addition, inhibition of 11 β -HSD1 activity may have a positive effect on recognition and dementia, possibility of using immunoregulatory function, possibility of intraocular pressure adjustment, application to osteoporosis (Patent Document 1). It is also suggested that 11 β -HSD1 inhibitory drugs can be applied to dyslipidemia, hypertension, cardiovascular disease, arteriosclerosis, atherosclerosis, myopathy, muscle atrophy, and neurodegenerative diseases (patents) Reference 2).

Patent Document 2 describes the chemical formula or structural formula of many 3-thio-1,2,4 triazole derivatives, and on the basis of this, 11 β-for a very wide range of 1,2,4-triazole derivatives. Attempts have been made to disclose utility as HSD1 inhibitors. However, specific chemical formulas and structural formulas have not been disclosed at all for specific compounds, especially 3 oxy 1,2,4-triazole derivatives! Non-Patent Literature l: Jamieson et al. (2000) J. Endocrinol. 165: p. 685-692

Non-Patent Document 2: Kotelevtsev, Y. et al. (1997) Proc. Natl. Acad. Sci. USA 94: 14924-1492

9

Non-Patent Document 3: Montague & O'Rahilly, Diabetes 49: 883-888, 2000

Non-Patent Document 4: Bujalska, I.J., S. Kumar, and P.M.Stewart (1997) Lancet 349: 1210-

1213

Non-patent literature 5: Halleux, C.M. et al. (1999) J. Clin. Endocrinol. Metab. 84: 4097-4105 Non-patent literature 6: Walker, B.R. et al. (1998) Hypertension 31: 891-895

Non-Patent Document 7: Fraser, et al. (1999) Hypertension 33: 1364-1368

Non-Patent Document 8: Woods, S.C. et al. (1998) Science, 280: 1378-1383

Non-Patent Document 9: Davani, B. et al. (2000) J. Biol. Chem. November 10, 2000; 275 (45): 348

41-4

Non-Patent Document 10: Billaudel, B. and B.C.J.Sutter (1979) Horm. Metab. Res. 11: 555-5 60

Disclosure of the invention

Problems to be solved by the invention

[0007] Diabetes, obesity, glaucoma, osteoporosis, cognitive impairment, immune disorder, depression, dyslipidemia, hypertension, cardiovascular disease, arteriosclerosis, atherosclerosis, myopathy, muscular atrophy, neurodegenerative disease, As for Syndrome X, a wide variety of compounds have been searched for in the past, but sufficient onset mechanisms have not yet been elucidated, and new compounds useful for the prevention or treatment of these diseases are eagerly desired. . Under these circumstances, recently, therapies for the above-mentioned diseases using compounds that suppress the activity of human 11β-HSD1 have attracted attention, but compounds that have cleared various pharmaceutical problems such as activity, physical properties, and pharmacokinetics. Is still under development.

Means for solving the problem

[0008] A 3-oxy 1,2,4-triazole derivative represented by the formula (I) or a salt thereof, or Are their solvates. Alternatively, a pharmaceutical composition comprising the derivative or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.

The invention's effect

[0009] The present inventors have intensively studied paying attention to the 3-oxy 1,2,4-triazole derivative represented by the formula (I), and the 3-oxy compound group has an excellent 11 β -HSD1 inhibitory action. In addition, the present inventors have found that the metabolic stability is significantly superior to that of 3thio-1,2,4-triazole derivatives. Specifically, the compound group in which the oxygen atom in formula (I) is converted to a sulfur atom is metabolized very quickly and extensively in human serum or in human liver microsomes, making it a practical drug for humans. While there is great concern about whether it is possible, the compound of the present invention has a remarkable stability in human serum, and is expected to have high potential as a medicine.

BEST MODE FOR CARRYING OUT THE INVENTION

[0010] [Aspect of the Present Invention]

The present invention is a pharmaceutical composition shown in the following embodiment, or a novel compound or a pharmaceutical use thereof.

The present invention will be described in detail by the following embodiments.

[0011] Aspect 1

Formula (I)

[0012] [Chemical 1]

[Wherein R ¹ is

I ^ a) hydrogen atom,

R ^ C

1-6 straight or branched aliphatic hydrocarbon groups Linear or branched aliphatic hydrocarbon group represented by I ^ cD Q ¹ (CO) c, or m 丄 to o

Is

R ¹ e) a linear or branched aliphatic hydrocarbon group represented by R ⁴ R ⁵ N- (CO) C n 1-6

R ⁴ and R ⁵ are independently a hydrogen atom, a straight or branched aliphatic carbon represented by C

1-6

A hydride group or a force R ⁴ R ⁵ N-that is Q ¹ may further contain 1 to 4 heteroatoms optionally selected from nitrogen atom, oxygen atom, sulfur atom, saturated or partially unsaturated Represents a 3- to 10-membered heterocyclic group,

CO is a carbonyl group, m and n are each independently an integer 0 or 1, and Q ¹ is

Q ¹ 1) C aryl group,

6-10

Q '^ C alicyclic hydrocarbon group,

3-10

(^ 3) Nitrogen atom · Oxygen atom · Sulfur nuclear power 5 to 10-membered heteroaryl group containing 1 to 4 hetero atoms arbitrarily selected,

Q ¹ ^ Nitrogen atom · Oxygen atom · Sulfur nuclear energy A cyclic group that also has 1 to 4 heteroatoms selected arbitrarily and also has a 3 to 10 membered alicyclic hydrocarbon group,

Q ¹ may be further substituted with 1 to 4 groups arbitrarily selected from the substituent group A.

R ² is

R may be substituted with a hydroxyl group or a C alkoxy group.

1 "" ^ '6 1

A branched aliphatic hydrocarbon group or C alicyclic hydrocarbon group, or

3-10

R ² b) C linear or branched aliphatic hydrocarbon group substituted by Q ²

1-6

Q ²

Q ² 1) C aryl group,

6-10

Q ² 2) C alicyclic hydrocarbon group,

3-10

Q ² 3) Nitrogen atom · Oxygen atom · Sulfur nuclear power 5- to 10-membered heteroaryl group containing 1 to 4 hetero atoms optionally selected,

Q ² 4) Nitrogen atom · Oxygen atom · Sulfur nuclear power It is a cyclic group that also has 1 to 4 hetero atoms arbitrarily selected and also has 3 to 10 membered alicyclic hydrocarbon group power,

Q ² may be further substituted with 1 to 4 groups arbitrarily selected from Substituent Group B R ³ is

R ³ a) C Linear or branched aliphatic hydrocarbon group

1-6

R ³ b) Q ³

R ³ c) C 3 linear or branched aliphatic hydrocarbon group substituted by Q ³ — Y—

1-6

c alicyclic hydrocarbon group

3-10

Q ³

Q ³ 1) C aryl group,

6-10

Q ³ 2) C alicyclic hydrocarbon group,

3-10

Q ³ 3) Nitrogen atom · Oxygen atom · Sulfur nuclear power 5- to 10-membered heteroaryl group containing 1 to 4 hetero atoms arbitrarily selected,

Q ³ 4) Nitrogen atom · Oxygen atom · Sulfur nuclear power It is a cyclic group that also has 1 to 4 hetero atoms selected arbitrarily and also has 3 to 10 membered alicyclic hydrocarbon group power,

Q ³ may be further substituted with 1 to 4 substituent groups C with any group selected.

Y is a force that is a single bond, an oxygen atom, NR ⁶ , CONR ⁶ , NR ⁶ CO, NR ⁶ SO or SO N zz

R ⁶ and

z is an integer 1 or 2,

R ⁶ is hydrogen atom, C alkyl group, C aryl group, nitrogen atom, oxygen atom, sulfur source

1-6 6-10

5 to 10-membered heteroaryl group containing 1 to 4 heteroatoms arbitrarily selected from children, C aryl C alkyl group, nitrogen atom, oxygen atom, sulfur atom

6 ~: L0 1 ~ 6

A 5- to 10-membered heteroaryl C alkyl group containing 1 to 4 heteroatoms,

1-6

Substituent groups A, B, C are independently

Halogen atom, hydroxyl group, C alkoxy group, C aryloxy group, amino group, C

1 '6 6 "" ^ 10 1 "^ ·' 6 Mono- or di-substituted with a group selected from an alkyl group or a c-aryl group

6-10

Amino group, trifluoromethyl group, trifluoromethoxy group, carboxyl group, cyano group, nitro group, C aryl group or C alkyl group

6 ~: L0 1 ~ 6

May be substituted with amino carbo group, oxo group, C alicyclic hydrocarbon group, nitrogen

3-10

C containing 1 to 4 heteroatoms arbitrarily selected from elemental atoms, oxygen atoms, sulfur atoms C alicyclic hydrocarbon groups, C aryl groups, nitrogen atoms, oxygen atoms, sulfur atoms 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from: a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms arbitrarily selected from nitrogen atoms, 'oxygen atoms' and sulfur atoms The alkyl group, C alkylsulfol group, C alkyl group

1 "" ^ '6 1 "^ ·' 3 1" ^ · '6 No- or di-substituted aminosulfol groups, mono- and C-aryl groups

6-10

Or a di-substituted aminosulfol group, C aryl group

6-10

Or a di-substituted 5 or 10-membered heteroarylamino group containing 1 to 4 heteroatoms arbitrarily selected from an aminosulfifer group, nitrogen atom, oxygen atom and sulfur atom Sulfonyl group, nitrogen atom, oxygen atom, sulfur atom containing 1 to 4 hetero atoms arbitrarily selected from 5 to 10-membered heteroarylaminosulfier group, nitrogen atom 'oxygen atom' arbitrarily selected from sulfur atoms 1 to 4 heteroatoms containing 5 to 5: L0 membered heteroloxy group, 1 to 4 heteroatoms optionally containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom Arylaminocarbol group, C aryl C

6-: L0 1-6 Coxy group, C alkyl carbo group, C aryl carbo group, C aryl

1 ~ 6 6 ~: L0 6 ~: L0

C alkylcarbonyl group, C arylaminocarbonyl group, N-methyl-N-C

1 ~ 6 6 ~: L0

Arylamine carbo group, C alkoxy carbo group, C alkyl carbo group

6 ~: L0 1 ~ 6 1 ~ 3

Boramino group, C aryloxycarboxylic group, C alkylsulfo-lumino group

6—10 1-3

Group, C arylsulfo-lumino group, nitrogen atom · oxygen atom · sulfur nuclear power arbitrarily selected

6-10

5- to 10-membered heteroarylsulfo-lumino group containing 1 to 4 heteroatoms, hydroxyl group 'norogen atom' C alkoxy group 'C alkylcarbonyl group' C alkyl

1 to 3 1 to 3 1 to 3 Luamino groupCarboxyl group Alkoxycarbon groupCarboxy C aryl

1 ~ 3 6 ~: L0

• C alkylsulfonyl group · trihalogenomethylsulfonyl group · C alkylsulfonyl

1-3 1-3

-L group 'C arylsulfol group -C C alkyl optionally substituted by a alkylthio group

6 to: L0 1 to 3 1 to 6 (which also has an alkyl group), or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient,

1) 11 j8 -HSD1 inhibition or

2) Regulation of 11 18 -HSD1 activity

A pharmaceutical composition for administration to a patient in need.

Known diseases [patent document 1] to [non-patent document 10] Specifically, diabetes, glaucoma, cognitive impairment, immune disorder, depression, dyslipidemia, cardiovascular disease, arteriosclerosis, atherosclerosis, myopathy, muscular atrophy, neurodegeneration Disease, Cushing's syndrome, Addison's disease, tuberculosis, psoriasis, diabetic complications [eg retinopathy, nephropathy, neuropathy, osteopenia, cataract, macrovascular disorder, diabetic hyperosmotic coma, infection (eg Osteoporosis, urinary tract infection, respiratory infection, digestive tract infection, lower limb infection, skin soft tissue infection), hearing loss, xerostomia, diabetic gangrene, cerebrovascular disorder, peripheral blood circulation disorder], obesity , Cachexia (e.g., cancer cachexia, diabetic cachexia, tuberculosis cachexia, endocrine cachexia, hematological cachexia, infectious cachexia or acquired immunodeficiency syndrome) ), Fatty liver, hypertension, polycystic ovary syndrome, kidney Disease (eg, diabetic nephropathy, glomerulonephritis, nephrotic syndrome, end-stage renal disease, glomerulosclerosis, hypertensive nephrosclerosis), muscular dystrophy, myocardial infarction, angina, cerebrovascular disorder (eg, brain Infarction, stroke), insulin resistance syndrome, syndrome and metabolic syndrome (type 2 diabetes, impaired glucose tolerance or insulin resistance, and has at least one of obesity, hypertension, dyslipidemia or microalbuminuria) ), Hyperinsulinemia, sensory disturbance in hyperinsulinemia, tumor (eg, leukemia, breast cancer, prostate cancer, skin cancer), irritable bowel syndrome, acute or chronic diarrhea, low back pain Cystitis, inflammatory diseases (eg, rheumatoid arthritis, osteoarthritis, osteoarthritis, gout, sore throat, inflammation after surgery or trauma, swelling, nerves , Inflammatory bowel disease, cystitis (including non-alcoholic steatohepatitis), pneumonia, knee inflammation, ulcerative colitis, gastric mucosal damage (including gastric mucosal damage caused by aspirin)), visceral obesity syndrome Aspect 2

In a pharmaceutical composition of embodiment 1, R ¹ of the compound of formula (I) is

RQ ^ R ^ Q ¹ — (CO) — C Linear or branched aliphatic hydrocarbon group, or m 1〜

Is

R ¹ e) R ⁴ R ⁵ N- (CO) —C linear or branched aliphatic hydrocarbon group, R ⁴ and R ⁵ are independently hydrogen atom, C linear or branched chain An aliphatic hydrocarbon group or

1-6

Or R ⁴ R ⁵ N is optionally selected from nitrogen, oxygen, and sulfur atoms Including 14 tero atoms, which may be a saturated or partially unsaturated 3- to LO-membered heterocyclic group, CO is a carbo group, and mn each independently represents an integer 0 or A composition representing 1.

[0016] Aspect 3

In the pharmaceutical composition of embodiment 1, wherein the compound of formula (I) is

R may be substituted with a hydroxyl group or a C alkoxy group.

1 1 "^ · '6

A composition which is a branched aliphatic hydrocarbon group or a C alicyclic hydrocarbon group.

3 10

[0017] Aspect 4

R ³ b) Q ³

R ³ c) C linear or branched aliphatic hydrocarbon group substituted with Q ³ Y— or C

1 6

3 Compositions that are 10 alicyclic hydrocarbon groups

[0018] Aspect 5

I ^ cD Q ¹ (CO) — C linear or branched aliphatic hydrocarbon group or

m ι 4

R ¹ e) R ⁴ R ⁵ N- (CO) — C is a linear or branched aliphatic hydrocarbon group, R ⁴ R ⁵ is independently a hydrogen atom, C

1 6 linear or branched aliphatic hydrocarbon group or R ⁴ R ⁵ N further includes 14 terror atoms optionally selected from nitrogen atom, oxygen atom, sulfur atom, So, saturated or partially unsaturated 3 to: L represents a 0-membered heterocyclic group, CO is a carbo group, and mn independently represents an integer 0 or 1.

But

R may be substituted with a hydroxyl group or a C alkoxy group.

1 1 "^ · '6

A branched aliphatic hydrocarbon group or C alicyclic hydrocarbon group, or

3 10

R ² b) C linear or branched aliphatic hydrocarbon group substituted by Q ²

1 6

But

R ³ b) Q ³ or R ³ c) C linear or branched aliphatic hydrocarbon group substituted with Q ³ Y— or C

1-6

Compositions that are 3-10 alicyclic hydrocarbon groups

[0019] Embodiment 6

In the pharmaceutical composition of aspect 1, the combination of R ¹ , R ² and R ³ of the compound of formula (I) (hereinafter referred to as (R ¹ , R ² , R ³ )) consists of any one of the following forces: A composition that is

(R'a, R ² a, R ³ a), (R'a, R ² a, R ³ b), (R'a, R ² a, R ³ c), (R'a, R¾, R ³ a), (R'a, R ² b, R ³ b), (R'a, R ² b, R ³ c),

(R'b, R ² a, R ³ a), (R'b, R ² a, R ³ b), (R'b, R ² a, R ³ c), (R'b, R¾, R ³ a), (R'b, R ² b, R ³ b), (R'b, R ² b, R ³ c),

(R'c, R ² a, R ³ a), (R'C, R ² a, R ³ b), (R'C, R ² a, R ³ c), (R'C, R¾, R ³ a), (R'C, R ² b, R ³ b), (R'c, R ² b, R ³ c),

(R'd, R ² a, R ³ a), (R'd, R ² a, R ³ b), (R'd, R ² a, R ³ c), (R'd, R¾, R ³ a), (R'd, R ² b, R ³ b), (R'd, R ² b, R ³ c),

(R'e, R ² a, R ³ a), (R'e, R ² a, R ³ b), (R'e, R ² a, R ³ c), (R'e, R¾, R ³ a), (R'e, R ² b, R ³ b) or (I ^ e, R ² b, R ³ c).

[0020] Aspect 7

In the pharmaceutical composition of embodiment 5, R ¹ of the compound of formula (I) is

I ^ cD Q ¹ (CO) — C linear or branched aliphatic hydrocarbon group or

m ι〜4

R ¹ e) R ⁴ R ⁵ N- (CO) C is a linear or branched aliphatic hydrocarbon group,

R ⁴ and R ⁵ are independently a hydrogen atom, a C linear or branched aliphatic hydrocarbon group or

1-6

Is a force R ⁴ R ⁵ N— which is Q ¹ and may further contain 1 to 4 heteroatoms optionally selected from nitrogen atoms, oxygen atoms and sulfur nuclear power 3 to saturated or partially unsaturated 3 to: LO member represents a heterocyclic group, CO is a carbo group, and m and n each independently represent an integer 0 or 1.

Q ¹ is

Q ¹ 1) C aryl group,

6-10

Q '^ C alicyclic hydrocarbon group, (^ 3) Nitrogen atom · Oxygen atom · Sulfur nuclear power 5 to 10-membered heteroaryl group containing 1 to 4 hetero atoms arbitrarily selected,

A nitrogen atom, an oxygen atom, a sulfur nuclear power, a 3- to 10-membered alicyclic hydrocarbon group containing 1 to 4 hetero atoms arbitrarily selected,

[0021] R ² is also selected as R ² a) or R) force,

R ² a) is substituted with a hydroxyl group or the same alkoxy group, and may be a C straight chain or

1 to 3 1 to 4

A branched aliphatic hydrocarbon group or c alicyclic hydrocarbon group, or

3-10

R ² b) is a C linear or branched aliphatic hydrocarbon group substituted by Q ²

1-6

Q ² is Q ² 2 and R ³ is selected from R ³ b) or R ³ c)

R ³ b) is Q ³ or

R ³ c) is a C linear or branched aliphatic hydrocarbon group substituted by Q ³ — Y— or

1-6

Is an alicyclic hydrocarbon group,

3-10

Q ³

Q ³ 1) C aryl group,

6-10

Q ³ 2) C alicyclic hydrocarbon group,

3-10

Q ³ 3) A cyclic group consisting of a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms arbitrarily selected from nitrogen atom, oxygen atom and sulfur nuclear power,

The pharmaceutical group, wherein the substituent groups A, B, C, and Y have the same definitions as in embodiment 1.

[0022] Aspect 8

In the pharmaceutical composition of embodiment 7,

. ), The Q ¹ in R ^4, R ⁵ in R) and I ^ e),

Phenyl group, cyclohexyl group, 2 pyridyl group, 3 pyridyl group, 4 pyridyl group, 2-furyl group, 3 furyl group, 2 chael group, 3 chael group, 2 pyrimidyl group, 4 -Pyrimidinyl group, 5-pyrimidinyl group, pyrajuryl group, 3-pyridazyl group, 4-pyridazil group, 2 imidazolyl group, 4 imidazolyl group, 2 thiazolyl group, 4 thiazolyl group, 5 thiazolyl group, 1, 3 , 4-thiadiazole 2-yl group, 1-piperidyl group, 4 morpholinyl group or 1-piperazinyl group

R ² a) is a methyl group, an ethyl group, a propyl group, an isopropyl group, a 2-hydroxyethyl group, 3 hydroxypropyl group, 2-methoxyethyl group, 3-methoxypropyl group or cyclopropyl group,

Q ^{3 in} R ³ b) or R ³ c) is a phenol group, adamantyl group, noradamantyl group, cyclohexyl group or bicyclooctyl group,

R ⁶ and

z is an integer 1 or 2,

1-3 3-10

6 ~: L0 1-3

A 5- to 10-membered heteroaryl C alkyl group containing 1 to 4 heteroatoms,

1-3

Substituent groups A, B and C are independently

Group, rogen atom, hydroxyl group, C alkoxy group, C aryloxy group, amino group, C

1 6 "" ^ 10 1 "^ · Mono- or di-substituted with a group selected from an alkyl group or a c-aryl group

6-10

Amino group, trifluoromethyl group, trifluoromethoxy group, carboxyl group, cyano group, nitrogen group, C alkyl group, C aryl group or C alkyl group

1 '6 6 "" ^ 10 1 "^ ·

A mono- or di-substituted aminocarbol group, C aryl group

6-10

Alkyl group strength Mono- or di-substituted with a selected group may be used.

1-6

Either a minocarbonyl group or an oxo group,

Substituent group C includes C ³ alicyclic hydrocarbon when Q ³ is a bicyclooctyl group.

3-10

Groups, 1 to 4 hetero atoms arbitrarily selected from nitrogen atom, oxygen atom and sulfur atom 3 to 10-membered alicyclic hydrocarbon group, C aryl group, nitrogen atom, oxygen atom and sulfur atom

6-10

A 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms optionally selected from

6 aryl C alkyl group, nitrogen atom, oxygen atom, sulfur atom

~ 10 ι ~ 6

5- to 10-membered heteroaryl C alkyl group containing 1 to 4 terror atoms, nitrogen atom '

1-6

5- to 10-membered heteroarylaminocarbonyl group, Caryl C alkoxy group, C alkyl containing 1 to 4 heteroatoms arbitrarily selected from oxygen atoms and sulfur atoms

6 "" ^ 10 1 "^ · 1" ^ · '6 carbo group, c caryl carbo group, C carrele C alkyl carbo group Group, carboxy C alkyl group, carboxy C aryl C alkyl group, C

6 10

Lucoxycarbo group, c alkylcarbolumino group, C aryloxy group

6 10

Ball group, C alkylsulfo-lumino group, C arylsulfo-lumino group, nitrogen

1 3 6-10

Hetero atoms selected from elemental atoms, oxygen atoms, sulfur atoms 1 to 4 containing 5 10-membered heteroarylsulfo-lamino groups, hydroxyl groups 'halogen atoms' C alkoxy groups

13

• C alkyl carboyl group 'C alkyl sulfonyl group' trihalogenomethyl sulfo

1 3 1 3

-L group 'C alkylsulfier group' C arylsulfol group 'C alkyla

1 3 6 L0 1 3 Mino group 'C Alkyl group optionally substituted with alkylthio group Force that can be selected.

1 3 1 3

[0024] Embodiment 9

In the pharmaceutical composition of Embodiment 7 or 8, the combination of R ¹ , R ² and R ³ of the compound of formula (I) (hereinafter referred to as (R ¹ , R ² , R ³ )) A pharmaceutical composition comprising:

(R'c, R ² a, R ³ b), (R'c, R ² a, R ³ c), (R'C, R¾, R ³ b), (R'C, R¾, R ³ C ), (R'd, R ² a, R ³ b), (R'd, R ² a, R ³ c), (R'd, R¾, R ³ b), (R'd, R¾, R ³ C), (R'e, R ² a, R 3b), (R'e, R ² a, R ³ c), (R'e, R¾, R) or (I ^ e, R¾, R ³ c).

[0025] Each group in the above embodiment will be described.

[0026] The "C linear or branched aliphatic hydrocarbon group" is a saturated hydrocarbon having 16 carbon atoms.

1 6

Sum or unsaturated hydrocarbon groups such as C alkyl groups, C alkenyl groups,

1 6 2 6

C Alkynyl group etc. are mentioned. Examples of the “c alkyl group” include a methyl group,

2 6 1 6

Tyl, propyl, isopropyl, butyl, isobutyl, sec butyl, tert butyl, pentyl, isopentyl, neopentyl, tert pentyl, 1 methylbutyl, 2-methylbutyl, 1, 2— Dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl group, 1,3 dimethylbutyl group, 2,3 dimethylbutyl group, 3,3 dimethylbutyl group, 1 butylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethyl Examples include a propyl group, a 1-ethyl-1-methylpropyl group, and a 1-ethyl-2-methylpropyl group.

[0027] Examples of the "C alkenyl group" include a vinyl group, an aryl group, a propenyl group, and an isopropyl group. -L group, 2-methylaryl group, butenyl group, pentenyl group, hexyl group and the like.

Examples of the “C alkyl group” include an ethur group, a 1 propyl group, and a 2-propyl group.

2-6

Group, butyur group, pentyl group, hexyl group and the like.

[0028] The "C aryl group" represents a monocyclic or condensed aromatic ring group, such as a phenyl group,

6-10

Examples include α and β naphthyl groups.

“C alicyclic hydrocarbon group” includes saturated or partially unsaturated carbon atoms of 3 to 10 carbon atoms.

3-10

A saturated monocyclic, condensed cyclic or bridged cyclic alicyclic hydrocarbon group, such as a cycloalkyl group. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, a bicyclooctyl group, a noradamantyl group, and an adamantyl group.

Examples of the “5- to 10-membered heteroaryl group containing 1 to 4 hetero atoms arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom” include a pyrrolyl group, a furyl group, a enyl group, and oxazolyl Group, imidazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, tetrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, birazinyl group, thiadiazyl group, quinolyl group and the like.

[0029] As "a 3 to 10-membered alicyclic hydrocarbon group containing 1 to 4 heteroatoms arbitrarily selected from nitrogen atom, oxygen atom and sulfur atom (saturated or partially unsaturated)" Is a monocyclic or condensed, saturated or partially unsaturated 3- to 10-membered heterocyclic group, preferably having 1 or 2 heteroatoms, such as an azetidinyl group, oxalyl Group, oxetanyl group, pyrrolidyl group, tetrahydrofuryl group, thiolanyl group, virazolyl group, virazolidyl group, piperidyl group, tetrahydrobiranyl group, morpholinyl group, piperazine group, tetrahydroquinolyl group, A decahydroquinolyl group etc. are mentioned.

“Halogen atom” includes fluorine atom, chlorine atom, bromine atom and iodine atom.

Examples of the “C alkoxy group” include methoxy group, ethoxy group, propoxy group, isopropyl group.

1-6

Poxy group, butoxy group, sec butoxy group, tert butoxy group, pentyloxy group, 1,2 dimethylpropyloxy group, 1,1 dimethylpropyloxy group, 2,2-dimethylpro Pyroxy group, 2-Ethylpropyloxy group, Hexyloxy group, 1,2-Dimethylbutoxy group, 2,3 Dimethylbutoxy group, 1,3 Dimethylbutoxy group, 1-Ethyl-2-methylpropyl An oxy group, a 1-methyl-2-ethylpropyloxy group, and the like.

The “C aryloxy group” includes a monocyclic or condensed aromatic oxy group,

6-10

Examples thereof include a phenoxy group, an α or β naphthyloxy group, and the like.

Examples of the “C alkylsulfol group” include a methanesulfol group, an ethanesulfol group, and the like.

1-3

Group, propanesulfol group and the like.

[0030] Examples of the "5- or 6-membered heteroaryloxy group containing 1 or 2 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom, and a sulfur atom" include a pyrrolyloxy group, a furyloxy group, a cheniloxy group, Oxazolyloxy group, imidazolyloxy group, isoxazolyloxy group, thiazolyloxy group, isothiazolyloxy group, virazolyloxy group, tetrazolyloxy group, pyridyloxy group, pyridazinyloxy group, pyrimidyl-loxy group, pyrazoloxy group And thiadiazinyloxy group.

Examples of the “C alkyl carbonyl group” include a acetyl group, a propiol group, a butyryl group, and the like.

1-6

Group derived from an aliphatic saturated carboxylic acid having 2 to 6 carbon atoms, such as thiol group, valeryl group, isovaleryl group, bivaloyl group, force propyl group, etc. And groups derived from aliphatic unsaturated carboxylic acids having 3 to 6 carbon atoms.

Examples of the “C alkoxy carbonyl group” include a methoxy carbo yl group, an ethoxy carbo ol group, and the like.

1-6

Examples thereof include a ball group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbon group, a sec butoxycarbon group, a tert-butoxycarbonyl group, and a pentoxycarbonyl group.

[0031] "R ⁴ R ⁵ N may further contain 1 to 4 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Saturated or partially unsaturated 3 to: LO Examples of the “membered heterocyclic group” include 1-piperidinyl group, 1-piperazyl group, 1 morpholinyl group and the like.

Examples of the “C aryl C alkyl group” include benzyl group, phenethyl group, α Or j8-naphthylmethyl group.

"Mono- or di-substituted with groups selected from C alkyl groups or C aryl groups

1 ~ 6 6 ~: LO

Examples of the “amino group” include a dimethylamino group, an N-ferro-N-methylamino group, and the like.

“C aryl group or C alkyl group

6 ~: LO 1 ~ 6

Examples of “converted! /, May! /, Aminocarbonyl group” include, for example, a dimethylaminocarbo ol group, an N-phenyl N-methylaminocarbo ol group and the like.

Examples of the “5- to 10-membered heteroaryl C alkyl group containing 1 to 4 heteroatoms arbitrarily selected from nitrogen atom, oxygen atom and sulfur atom” include 2 pyridylmethyl group, 2

1-6

A furylmethyl group etc. are mentioned.

Examples of the “5- to 10-membered heteroaryl C alkyl group containing 1 to 4 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom” include 2 pyridylmethyl groups, 2

1-6

A furylmethyl group etc. are mentioned.

"C aminosulfo group optionally mono- or di-substituted with alkyl group"

1-6

Examples thereof include a methylaminosulfol group and Ν, Ν dimethylaminosulfol group.

“An aminosulfol group optionally mono- or di-substituted with a C aryl group” and

6-10

Examples thereof include a phenol aminosulfol group and a naphthylaminosulfol group.

“C-aryl group which may be mono- or di-substituted by a aryl group” and

6-10

Examples thereof include a phenol aminosulfier group and an α-naphthylaminosulfur group.

Examples of the “5- to 10-membered heteroarylaminosulfonyl group containing 1 to 4 heteroatoms arbitrarily selected from nitrogen atom, oxygen atom and sulfur atom” include 2 pyridylaminosulfonyl group, 2— And furylaminosulfo group.

`` 5- to 10-membered heteroarylaminosulfenyl group containing 1 to 4 heteroatoms arbitrarily selected from nitrogen atom, oxygen atom and sulfur atom '', for example, 2 pyridylaminosulfyl group, 2-furylamino And sulfiel groups. Examples of the “5- to 10-membered heteroarylaminocarbonyl group containing 1 to 4 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom, and a sulfur atom” include, for example, a 2-pyridylamino force group , 2-furylaminocarbo group and the like.

Examples of the “C aryl C alkoxy group” include a phenylmethyloxy group, a phenyl group, and the like.

6 ~: L0 1 ~ 6

Examples include a rubutyloxy group.

Examples of the “c alkylcarbonyl group” include acetyl group and valeryl group.

1-6

The

Examples of the “c arylcarbonyl group” include a benzoyl group.

6-10

Examples of the “C aryl C alkylcarbonyl group” include 2-oxo-2-phenol.

6 ~: L0 1 ~ 6

Examples thereof include a ruetyl group such as a 3-oxo-3-phenylpropyl group.

Examples of the “C arylaminocarbol group” include N-phenylaminocarbol.

6-10

A methyl group etc. are mentioned.

Examples of the “N-methyl N—C arylaminocarboxyl group” include N—

6-10 (4-halogenophenyl) N methylaminocarboromethyl group and the like can be mentioned.

Examples of the “C alkyl carbolumino group” include a methyl carbolumino group and a buty

1-3

And a rucarbonylamino group.

Examples of the “C alkoxy carbonyl group” include a methoxy carbo yl group and a butoxy carbo yl group.

1-6

Bonyl group etc. are mentioned.

Examples of the “c aryloxy group” include, for example, a phenyl group,

6-10

a Naphthoxycarbonyl group and the like.

Examples of the “C alkylsulfo-lamino group” include methanesulfo-lamino group and butane.

1-3

Examples include a sulfonylamino group.

Examples of the “C arylsulfo-lumino group” include a phenol sulfo-lumino group, α

6-10

And a naphthylsulfonylamino group.

Examples of the “5- to 10-membered heteroarylsulfo-lumino group containing 1 to 4 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom, and a sulfur atom” include, for example, a 2-pyridylsulfo-lamino group, 2- And furylsulfo-ramino group.

'Hydroxyl group''Norogenatom''C alkoxy group' C alkylcarbonyl group 'C alkyl Lamino group · Carboxyl group Alkoxycarbole group · Carboxy C aryl

1 3 6 L0

• C alkylsulfonyl group · trihalogenomethylsulfonyl group · C alkylsulfonyl

1 3 1 3

-L group 'C arylsulfol group' C C optionally substituted with alkylthio group

As the `` 6 L0 1 3 1 6 alkyl group '', for example, a methyl group, a hydroxyethyl group, a 1 halogenoethyl group, a methoxychetyl group, a acetylmethyl group, an N-methylaminomethyl group, a carboxymethyl group, a methoxycarboromethyl group, Examples thereof include a benzoylmethyl group, a methanesulfonylmethyl group, a trifluoromethanesulfonylmethyl group, a methanesulfurmethyl group, a phenylsulfomethyl group, and a methylthioethyl group.

Where R ¹ is preferably

I ^ cD Q ¹ (CO) — C linear or branched aliphatic hydrocarbon group or

m 1 2

R ¹ e) R ⁴ R ⁵ N- (CO) — C linear or branched aliphatic hydrocarbon group, R ⁴ R ⁵ n 1 2

Is independently a hydrogen atom, c

1 6 linear or branched aliphatic hydrocarbon group or R ⁴ R ⁵ N may further contain 14 hetero atoms optionally selected from nitrogen atom, oxygen atom, sulfur nuclear energy Good 3 ~: L0-membered alicyclic hydrocarbon group, CO is a force sulfonyl group, mn each independently represents an integer 0 or 1

Q ¹ is

Q ¹ 1) C aryl group,

6 10

(^ 3) Nitrogen atom · Oxygen atom · Sulfur nuclear power 5 Heteroaryl group containing 10 hetero atoms chosen arbitrarily 5

Nitrogen atom · Oxygen atom · Sulfur nuclear energy 3 or 6 6-membered alicyclic hydrocarbon group containing 1 or 2 heteroatoms arbitrarily selected, and more preferably the following substituent group force .

4-logenophenyl group, 4-logenobenzyl group, 4-logenophenethyl group, 2- (1 —piperidyl) ethyl group, 2 cyclohexylethyl group, 2 -— (4 morpholyl) ethyl group, 2 -— (4-methyl-1- Piperazuryl) ethyl group, 2 oxo-2- (4-logenophenol) ethyl group, 2-oxo-2- (2-pyridyl) ethyl group, 2-oxo-2- (2-furyl) ethyl group, N — (4 Logenophyl) N-Methylaminocarboromethyl group , N— (2-Pyridyl) —N—Methylaminocarboromethyl group, N— (2—Chel) —N-Methylaminocarboromethyl group, 2-Oxo-2- (1-piperidyl) ethyl group , 2-oxo-2- (4 morpholinyl) ethyl group, 2-oxo-1- (4-methyl-1-piperadyl) ethyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, two-one (2-pyridyl) Ethyl group, 2- (3 pyridyl) ethyl group, 2- (4 pyridyl) ethyl group, 4 pyrimidyl-methyl group, 2 pyradyrethyl group, 2 furyl group, 3 furyl group, 2 furylmethyl group, 3 furylmethyl group, 2 — (2 furyl) ethyl group, 2— (3 furyl) ethyl group, 2 chael group, 3 chael group, 2 chalcyl group, 3 cherylmethyl group, 2— (2 chael ) Ethyl group, 2— (3 Chel) ethyl group, 4 Imidazolylmethyl group 1, 3, 4-thiadiazol-2-ylmethyl group, 2- (4-methyl-5thiazolyl) ethyl group.

R ² is preferably R ² a) and is substituted with a hydroxyl group or a C alkoxy group

1-6

C linear or branched aliphatic hydrocarbon group or C alicyclic hydrocarbon

1 ~ 6 3 ~: L0

A group selected from a methyl group, an ethyl group, a cyclopropyl group, a 3-hydroxypropyl group, and a 3-methoxypropyl group.

R ³ is preferably R ³ b), R ³ c), and is a C straight chain substituted by Q ³ , Q ³ — Y— or

1-6

Is a branched chain aliphatic hydrocarbon group or a group of c selected from alicyclic hydrocarbon groups

3-10

Yes,

More preferably, 1-adamantyl group, 3-noradamantyl group, bicyclo [2,2,2] otatan-1-yl group, cyclohexyl group, 4-halogenobenzyl group, N- (4-halogenophenyl) aminomethyl 1-yl group, 3-hydroxyadamantane 1-yl group, 3 aminoadamantane 1-yl group, 4-halogenobicyclo [2, 2, 2] octane 1-yl group 4-methoxycarbo-bicyclo [2,2,2] octane-1-yl group, 4-pentylbicyclo [2,2,2] octane-1-yl group, 4 (propoxy) methylbicyclo [2,2,2] octane-1-yl group, 4 [2 (Ethanesulfo) ethyl] bicyclo [2, 2, 2] octane 1-yl group, 4-methylcyclohexyl group, 4-methoxycyclohexyl group, 4, 4-dihalogenocyclohexyl group, 4-amino Cyclohexyl group, 4 Methyl benzyl group, 4-hydroxybenzyl group, 4-methoxybenzyl group, 4-aminobenzyl Groups, 1-methyl-1 (4-logenophenyl) ethyl, 1- (4-methoxyphenyl) cyclopropyl, 1- (4-logenophenyl) cyclobutyl and 1- (4-logenophenol) cyclopentyl Is a group selected from

[0036] Embodiment 10

Formula (I)

[0037] [Chemical 2]

(Wherein R ¹ is 4-halogenophenyl group, 4-halogenobenzyl group, 4-halologenethyl group, 2- (1-piperidyl) ethyl group, 2 cyclohexylethyl group, 2- (4 morpholinyl) ethyl) 2- (4-methyl-1-piperadyl) ethyl, 2-oxo-2— (4-logenophenyl) ethyl, 2-oxo-2- (2-pyridyl) ethyl, 2-oxo 2- (2 Furyl) ethyl group, N— (4 logenophenol) —N-methylaminocarboromethyl group, N— (2-pyridyl) N-methylaminocarboromethyl group, N— (2—cell) — N-methylaminocarboromethyl group, 2-oxo-2- (1-piperidyl) ethyl group, 2-oxo 2- (4 morpholyl) ethyl group, 2-oxo-1 (4-methyl-1 piperazine) ethyl Group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group 2- (2 pyridyl) ethyl group, 2- (3 pyridyl) ethyl group, 2- (4 pyridyl) ethyl group, 4 pyrimidyl-methyl group, 2 pyradruethyl group, 2 furyl group, 3 -furyl group, 2-furylmethyl group, 3-furylmethyl group, 2- (2 furyl) ethyl group, 2- (3 furyl) ethyl group, 2 chael group, 3 chael group, 2 chalcyl group, 3 chanel Rumethyl group, 2- (2 cheyl) ethyl group, 2- (3 cheel) ethyl group, 4 imidazolylmethyl group, 1,3,4-thiadiazole-2-ylmethyl group, 2- (4 methyl 5— Thiazolyl) ethyl group is a group of choice,

[0038] R ² represents a methyl group, an ethyl group, a cyclopropyl group, a 3-hydroxypropyl group, and a 3- Methoxypropyl group is a group of choice,

R ³ is 1-adamantyl group, 3 noradamantyl group, bicyclo [2, 2, 2] octane 1-yl group, cyclohexyl group, 4 logenobenzyl group, N— (4 logenophenol) aminomethyl group, 3-halogenoadamantane 1-yl group, 3 hydroxyadamantane 1-yl group, 3 aminoadamantane 1-yl group, 4-halogenobicyclo [2, 2, 2] otatan 1-yl group, 4-methoxycarbobibicyclo [2 , 2, 2] octane 1-yl group, 4 pentylbicyclo [2, 2, 2] octane 1-yl group, 4 (propoxy) methylbicyclo [2, 2, 2] octane-1-yl group, 4 [2- (ethanesulfo- L) ethyl] bicyclo [2,2,2] octane-1-yl group, 4-methylcyclohexyl group, 4-methoxycyclohexyl group, 4,4 dihalogenocyclohexyl group, 4 aminocyclohexyl group Group, 4-methylbenzyl group, 4-hydroxybenzyl group, 4-methoxybenzyl group, 4-aminobenzyl group, 1-methyl-1- (4-halogenophenyl) ethyl group, 1- (4-methoxyphenyl) cyclopropyl group, 1- (4 -Halogenophyl) cyclobutyl group and 1- (4-halogenophenyl) cyclopentyl group are also selected groups), pharmaceutically acceptable salts or solvates thereof.

[0039] Embodiment 11

A pharmaceutical composition comprising the compound of embodiment 10, a pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

[0040] Embodiment 12

Comprising the compound of embodiment 10, a pharmaceutically acceptable salt or a solvate thereof as an active ingredient,

1) 11 j8 -HSD1 inhibition or

2) Regulation of 11 18 -HSD1 activity

A pharmaceutical composition for administration to a patient in need.

[0041] Embodiment 13

Aspect 1 characterized by containing as an active ingredient a compound defined by any one of formulas (I) of claim 10, a pharmaceutically acceptable salt thereof or a solvate thereof, and has diabetes, obesity, glaucoma, osteoporosis Cognitive impairment, immune disorder, depression, dyslipidemia, hypertension, heart A pharmaceutical composition for treating or preventing at least one of visceral vascular disease, arteriosclerosis, atherosclerosis, myopathy, muscular atrophy, or neurodegenerative disease.

[0042] Embodiment 14

A compound comprising any one of the formulas (I) defined in any one of embodiments 1 to 10, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, the following treatment for diseases Or a pharmaceutical composition intended to prevent or reduce side effects caused by treatment with a darcocorticoid receptor agonist by being used in combination with a darcocorticoid receptor agonist, and the disease is Cushing's disease Symptoms · Allergic immune diseases · Respiratory system diseases; Infectious visceral diseases; Immune, connective tissue and joint diseases; Endocrine diseases; Hematological diseases; Vomiting due to cancer and chemotherapy; Muscle and neuromuscular cell diseases; Surgery and transplantation Preoperative or postoperative treatment; brain tumor, vomiting, infection, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, medullary disease or saccular aneurysm The. Examples of such side effects include osteoporosis, aseptic osteonecrosis, Cushing-like facial appearance, psychiatric symptoms, insulin resistance, hypertension, myopathy, cataract or glaucoma.

[0043] Embodiment 15

A compound comprising any one of the formulas (I) defined in any one of embodiments 1 to 10, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, and the prevention of the following diseases Or a pharmaceutical composition intended to be used in combination with a darcocorticoid agonist for the purpose of treatment, wherein the disease is Cushing's disease, Cushing's syndrome, asthma, athletic dermatitis, cystic fibrosis, emphysema, Bronchitis, hypersensitivity, pneumonia, eosinophilic pneumonia, pulmonary fibrosis, Crohn's disease, ulcerative colitis, reactive arthritis, rheumatoid arthritis, schilaren syndrome, systemic lupus erythematosus, lupus nephritis, Hahn-Hossien line Purpura, gener granulomatosis, temporal arteritis, systemic sclerosis, vasculitis, sarcoidosis, dermatomyositis / polymyositis, pemphigus vulgaris, hyperthyroidism, low Dosteronism, hypopituitarism, hemolytic anemia, thrombocytopenia, paroxysmal nocturnal hemoglobinuria, spinal cord tumor compression, brain tumor, acute lymphoblastic leukemia, Hodgkin's disease, chemotherapy nausea, myasthenia gravis Disease, heriditary muscular disease, Duchenne muscular dystrophy, trauma, postoperative stress, surgical stress, kidney transplantation, liver transplantation, lung transplantation, islet transplantation of spleen, blood stem cell transplantation, Bone marrow transplantation, heart transplantation, adrenal transplantation, tracheal transplantation (intestinal transplantation), corneal transplantation, skin transplantation, corneal transplantation, lens metastasis, nausea, infectious disease, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis What is the disease

[0044] Aspect 16

The pharmaceutical composition for the combination therapy according to embodiment 14 or 15, wherein the darcocorticoid receptor agonist is also selected from the following group of drugs

Betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, beclomethasone, butychicort, clobetasol, flunizolide, full strength thizone (and its analogs), mometasone, triamcinolone acetonide, triamcinolone hexacetate 698 NXC-1015, NXC-1020, NXC-1021, NS-1 26, P-4112, P-4114, RU-24858, and T-25.

[0045] Embodiment 17

Embodiments 1-10 The carriers, excipients, and diluents that are acceptable for use in the pharmaceutical product are collectively administered as the first administration, and the darcocorticoid receptor agonist, the carrier that is acceptable for use in the pharmaceutical product, A kit contained in the same container, in which the form and diluent are combined into a second dose.

[0046] Embodiment 18

A compound comprising any one of the formulas (I) defined in any one of embodiments 1 to 10, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, and the prevention of the following diseases Alternatively, a pharmaceutical composition intended to be used in combination with an antihypertensive drug for the purpose of treatment, wherein the disease is any of metabolic syndrome, insulin resistance, dyslipidemia, obesity or hypertension .

[0047] Embodiment 19

The combination according to embodiment 18, wherein the antihypertensive drug is selected to be

Beta blocker, beta 2 blocker, ACE (angiotensin converting enzyme) inhibitor, calcium 'channel' blocker, alpha blocker, diuretic, loop diuretic, potassium-retaining diuretic, endothelin ΕΤ-Α antagost, endothelin antagost , Renin inhibitor, vasopressin VI antagonist, vasopressin V2 antagonist, アン typena Thorium excretion peptide agonist, angiotensin 11 antagonist, 5-HT2 agonist, adenosine A1 antagonist, thromboxane A2 antagonist, endopeptidase inhibitor, nitric oxide antagonist, dopamine D1 antagonist, dopamine D2 agonist, n-3 fatty acid, prostacyclin agonist, PGE1 agonist, Na + / K + ATPase modulator, potassium channel activator, vaccine.

[0048] Embodiment 20

Alopreno Noreno, Ateno Ronore, Timolo Norole, Pindronore, Pro Planolo Norole, Meto Prolo Norole, Bispro Ronoref Melato, Esmolonole, Asetello Norole, Asetro Norole, Betaxo Norole, Seripro Noreno, Remo Amsoralol, carvedilol, labetalol, sathenolol, OPC-1085, quinapril, isinopril, enalapril, captopril, benzepril, perindopril, trandolapril, fuocinopril, ramipril, cilazapril, delapril, piripril, epripril

[0049] Aspects of the pharmaceutical composition according to aspects 1 to 20 of the present invention are, in other words,

(1) Use of a compound of formula (I) or the like to produce a pharmaceutical composition of interest using the compound of formula (I) defined in each embodiment,

(2) A method for preventing or treating the target disease or symptom or a combination therapy, characterized by using a compound of formula (I) as defined in each embodiment, or the darco It is a method for reducing or preventing side effects in corticoid agonist therapy.

[0050] The compound (I) of the present invention may form an acid addition salt. Depending on the type of substituent, a salt with a base may be formed. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and specifically, a base such as an alkali metal such as sodium, potassium, magnesium, calcium, or aluminum or an alkaline earth metal. And salts; mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, Organic carboxylic acids such as formic acid, malic acid, tartaric acid, citrate, and mandelic acid, organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, 2-hydroxyethanesulfonic acid, Acid addition salts with acidic amino acids such as aspartic acid and glutamic acid; salts with organic bases such as methylamine, ethylamine, triethylamine, ethanolamine, pyridine, lysine, arginine, ornithine, ammonia And salt.

[0051] The salt of the compound of the present invention may include a mono salt, a di salt, or a tri salt. Alternatively, the compound of the present invention can simultaneously form both an acid addition salt and a base salt, depending on the side chain substituent. The compound of the present invention may have an asymmetric carbon, and the compound of the present invention includes a mixture of various isomers such as geometric isomers, tautomers and optical isomers, and isolated isomers. Isolation and purification of powerful isomers can be achieved by those skilled in the art using conventional techniques through resolution or asymmetric synthesis using column chromatography once the preferential crystals are obtained.

Furthermore, the present invention includes various pharmaceutically acceptable solvates and crystal polymorphs of Compound (I). Of course, the present invention is not limited to the compounds described in the examples below, but 3-oxy-1,2,4-triazole compounds represented by the formula (I) or pharmaceutically acceptable salts thereof. Is included. It also includes pharmacologically acceptable solvates. Although it does not specifically limit as a solvate, Specifically, a hydrate, alcohol solvate (For example, methanol solvate, ethanol solvate, propanolate solvate, etc.), ether solvate (ethyl ether solvate, THF solvate, etc.) ), Esterates (such as ethyl acetate), and acetates.

[0052] [Method for producing compound of the present invention]

Hereinafter, the ability to explain the production method of the 3-oxy-1,2,4-triazole derivative (I) of the present invention The present invention is not limited to this method.

[0053] [Production method]

The compound represented by the general formula (I), a salt thereof or a solvate thereof can be produced, for example, by the following method (Reaction Formula 1).

[0054] [Chemical 3] R '

(Scheme 1)

[0055] (where

R ² and R ³ have the same meaning as described above, A represents an oxygen atom or a sulfur atom, and X represents a leaving group represented by a halogen atom or an alkylsulfol group. That is, the compound represented by the formula (I) is a compound represented by the formula (III) that is commercially available or known in the literature, or that can be easily obtained by the production method described later. It can be produced by reacting with the compound represented by the formula (IV) after conversion to the compound represented.

Compound Power Represented by Formula (I) Conversion to the compound represented by Formula (III) can be carried out by the following methods depending on the types of A and X, respectively.

[0056] [When A is an oxygen atom and X is a halogen atom]

The compound represented by the formula (Π) is reacted with a halogenating agent typified by salt 匕 thionyl, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, etc. in a solvent that does not participate in the reaction. The compound represented by the formula (III) can be produced by reacting for a time during which the reaction sufficiently proceeds within the temperature range at which the compound is refluxed. Preferred reaction solvents are aromatic hydrocarbon solvents such as toluene and benzene, halogenated solvents such as chloroform, methylene chloride, and 1,2-dichloroethane. The reaction temperature is from room temperature to the reaction mixture. The return temperature is preferred.

[0057] [When A is a sulfur atom and X is a halogen atom]

Halogenating agent typified by chlorine, bromine, sulfuryl chloride, sulfuryl bromide and the like in a solvent that does not participate in the reaction of the compound represented by the formula (Π) and a temperature range at which the reaction mixture is refluxed at -20 ° C. Thus, the compound represented by the formula (ΠΙ) can be produced by reacting for a time during which the reaction proceeds sufficiently. Solvents that do not participate in the reaction include water, polar solvents such as methanol, aromatic hydrocarbon solvents such as toluene and benzene, chloroform, and chloride. The reaction temperature at which halogen-based solvents such as tylene and 1,2-dichloroethane are preferred is preferably 0 ° C to 50 ° C. When using a sulfuryl halide, the reaction can be carried out in the presence of a nitrate represented by potassium nitrate, and in this case, acetonitryl is preferred as the solvent.

[When A is a sulfur atom and X is an alkylsulfonyl group]

In a solvent that does not participate in the reaction of the compound represented by the formula (Π), preferably in a polar solvent such as N, N dimethylformamide, 1,3 dimethyl-2-imidazolidinone, potassium carbonate, cesium carbonate, sodium hydroxide Alkyl halides, sulfuric acid alkyl esters, etc. in the presence of inorganic bases such as potassium hydroxide, sodium hydride, organic bases such as triethinoleamine, pyridine, N, N dianolenorea-phosphorus, lithium diisopropylamide, etc. After reacting with an alkylating agent represented by the above for a time that the reaction proceeds sufficiently in the temperature range where the reaction mixture refluxes from 20 ° C, the resulting alkylthio form does not participate in the reaction !, solvent, preferably Is peroxygenated in polar solvents such as water and alcohol, halogenated solvents such as chloroform, methylene chloride and 1,2-dichloroethane. A compound represented by the formula (ΠΙ) can be produced by acidification with a peracid compound such as hydrogen, peracetic acid, 3-chloroperbenzoic acid and the like.

[0059] The production of the compound represented by the formula (I) does not involve the compound represented by the formula (III) in the reaction! It can be carried out by reacting with a compound represented by the formula (IV) in a solvent in the presence of a base. Solvents not involved in the reaction include aromatic hydrocarbon solvents such as toluene and benzene, polar solvents such as water, methanol, N, N dimethylformamide, 1,3 dimethyl-2-imidazolidinone, dimethyl sulfoxide, triethylamine, pyridine Use basic solvents such as chloroform, chloroform, methylene chloride, halogen solvents such as 1,2-dichloroethane, ether solvents such as jetyl ether, tetrahydrofuran and 1,4 dioxane, or a mixture of these. The base may be an inorganic base such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or sodium hydride, or triethylamine, pyridine, N, N Dialkylaline, Lithium diisopropyla Come out is possible to use an organic base of the earth or other. Solvent and base combinations include N, N dimethylformamide, 1, 3 dimethyl A polar solvent such as chill-2-imidazolidinone and an inorganic base typified by sodium hydride are preferred. The reaction can be carried out at a temperature of -78 ° C at a temperature at which the solvent is refluxed. However, if the reaction is difficult to proceed, it can also be carried out at a temperature higher than the boiling point in the sealed tube. The reaction time is the time for which the reaction proceeds sufficiently.

This reaction is carried out by converting the compound represented by formula (IV) into the corresponding metal alkoxide and then reacting with the compound represented by formula (III) in the absence of a base according to the above conditions. Can be done.

When R ² and R ³ have a reactive substituent (for example, a hydroxyl group, an amino group, a carboxyl group, etc.), the protecting group can be removed after carrying out the reaction by appropriately protecting these groups. Such protecting group introduction / removal methods are based on the group to be protected or the type of protecting group as appropriate. For example, (Protective Groups in Organic Synthesis, 3rd edition, 1999, John This can be done by the method described in the review of [Willie and Sons].

And the formula (I)

The functional groups present in R ² and R ³ can be converted to other functional groups according to a known method or a similar method.

For example, when the functional group has a lower alkoxy carbo group,

1) Conversion to hydroxymethyl group by reduction reaction

'Conversion to hydroxyoxymethyl group by alkylation of hydroxymethyl group

'Conversion of hydroxymethyl group to formyl group by oxidation

2) Conversion to formyl group by reduction reaction

• Conversion of formyl group to alkenyl group by Wittig reaction and conversion of alkyl group to alkyl group by hydrogenation

• Conversion of formyl group to alkylaminomethyl group by reductive amination

3) Conversion to carboxyl group by hydrolysis

• Conversion to carboxyl group by alkylation of carboxyl group

• Conversion of carboxyl group to alkylamide group with alkylamino group

It is possible to convert into various functional groups.

The compound represented by the formula (Π) used as a starting material for (Reaction Scheme 1) is a known method in the literature or Accordingly, it can be produced, for example, according to the following (Scheme 2).

[0061] [Chemical 4]

R ² -N = C = A

(VI) H H

H ₂ N-NH ₂ H ₂ N ' ^N y ^N -R ² (VII)

(V) A

O

R ³ OH R ³ people OH

(VIII) (VIII)

R ³ '

(Scheme 2)

[Wherein R ¹ R ² R ³ and A represent the same meaning as described above.]

Reaction of hydrazine represented by formula (V) or a hydrate thereof with a compound represented by formula (VI) and HN.

s

The compound represented by the formula (VII) thus obtained is reacted with cal HN bonic acid represented by the formula (VIII) or its active compound to obtain a compound represented by the formula (IX). Can be cyclized under basic conditions to produce a compound represented by the formula (Π).

The compound represented by the formula (IX) is obtained by reacting a hydrazine represented by the formula (V) or a hydrate thereof with a carboxylic acid represented by the formula (V III) or an active compound thereof. ) And then reacting with the compound represented by the formula (VI). Among the compounds represented by the formula (VII), the compound (νΐΓ) in which A is a sulfur atom can also be produced according to a method known in the literature or according thereto, for example, according to the following (Scheme 3).

[0063] [Chemical 5]

(XI)

(Scheme 3) (Wherein R ² represents the same meaning as described above.)

That is, a compound represented by the formula (XI) is reacted with carbon dioxide and then alkylated with methyl iodide to obtain a compound represented by the formula (ΧΠ), and then represented by the formula (V). The compound represented by the formula (νπ ′) can be produced by reacting with hydrazine or its hydrate.

The compounds represented by formula (IV), formula (VI), formula (VIII) and formula (XI) in (Scheme 1), (Scheme 2) and (Scheme 3) above are commercially available products. It can be produced by a known method.

[0065] For example, among the compounds represented by the formula (VIII), R ³ may be substituted bicyclo [2.

2.2] The compound that is an octane 1-yl group is the journal of the American Chemical Society 75, 637-640, 1953, JB Roberts et al. The Journal of Organic Chemistry SS by NB Chapman et al. SS, 917-923, 1970, Journal of the American Chemical Society by HD Holtz et al. (Jo urnal of the American Chemical Society), 5183-5188, 1964, or the like.

[0066] Test Example 1 11 | 8 -HSD1 inhibitory activity test

The excellent 11 β -HSD1 inhibitory activity of the compound of the present invention is confirmed by the following test examples.

11 Inhibitory activity against β-HSD1 was measured using a 384-well plate by the following method: o

That is, the reaction was started by adding a mixed solution of a test drug (specimen, compound of the present invention), cortisone and NADPH to a well in which an 11 β-HSD1 enzyme solution was previously added. As the enzyme, a homogenate of Cos-1 cells in which human 11 β-HSD1 was forcibly overexpressed using a vector for mammalian cells was used. The composition of the reaction solution (final concentration) was 0.01 to 0.03 mg / ml enzyme, 150 nM cortisone, 2 mM NADPH, 2% DMS0, 1 to 10,000 nM sample, 0.15 mM EDTA, 20 mM sodium phosphate buffer, pH = 7.4. . Out of these wells A well containing no specimen was used as a control group, and a well containing neither specimen nor enzyme was used as an enzyme blank.

After incubation at room temperature for 1 hour, the reaction solution in each well was diluted 30-fold with the reaction stop solution, and the concentration of cortisol in the diluted solution was measured using a kit based on the HTRF method of Cisbio. As the reaction stop solution, 10 M carbenoxolone-containing, 20 mM sodium phosphate buffer, pH = 7.4 was used. The inhibitory activity (%) was calculated by linearly regressing the cortisol concentration of each well, assuming that the cortisol concentration of the control group was 0% inhibition and the cortisol concentration of the enzyme blank group was 100% inhibition. IC value shows a value where the inhibitory activity is around 50%, 2 or 3

50

Using the point data, the logarithmic value of the analyte concentration and the inhibitory activity value were calculated by linear regression.

[0067] The IC value for 11 β -HSD1 of the compound of the present invention is usually between l-ΙΟ and ΟΟΟηΜ.

50

To do. In order to explain the present invention, IC values of the following compounds of the present invention against human 11β-HSD1 were measured.

50

[0068] [Table 1]

[0069] Test Example 2 Metabolic stability test in human liver microsomes

Using human moon dried microsomes, the metabolic degradation rates of the compounds in the f column 1, 2, 3, 8, 9, 10, 11, 12 and the reference f column 1, 2 were examined. Specifically, a phosphate buffer solution (ρΗ7.4) containing the compound (final concentration 1 μΜ) and liver microsomes (final protein concentration 0.5 mgZmL) was preincubated at 37 ° C for 5 minutes, and the NADPH production system After the addition, the reaction was allowed to proceed for 20 minutes, the reaction was stopped by adding acetonitrile, and the concentration of unchanged product in the centrifugal supernatant was measured. The metabolic degradation rate was calculated as the rate of decrease of unchanged substance by comparing the unchanged substance concentration of the unreacted specimen and the specimen reacted for 20 minutes. The results are shown in Table 1. [0070] Table 1 Metabolic degradation rate in liver microsomes

A. Metabolic degradation rate of Reference Example 1 2 in human liver microsomes

[0071] [Table 2]

[0072] B. Metabolic degradation rate of human liver microsomes in Examples 1 2 3 8 9 10 11 12 [0073] [Table 3]

[0074] In the formula (I), as a general substituent for R ¹ , (1) a simple aralkyl group (2) an aromatic group ( 3) Select an aliphatic hydrocarbon group substituted with a heterocyclic group, and representative examples are 4-halogenobenzyl group, 4-halogenophenethyl group, 4-halogenophenyl group, 2- (piperidine). — 1—yl) ethyl group was selected. As a general substituent R ³ (1) Simple aliphatic cyclic hydrocarbon group (2) bulkyヽcyclic hydrocarbon group (3) Select an aromatic group, a cycloalkyl Representative substituents each A xyl group, adamantyl group, 4-no, and logenophenyl group were selected.

All of the 3-thio derivatives as shown in Table 1A were rapidly and significantly metabolized, whereas the 3-oxy-derivatives of the compounds of the present invention shown in Table 1B had a significantly improved metabolic rate. It is not difficult for those skilled in the art to understand that the susceptibility to metabolism of 3-thio-derivatives, which is a powerful part of drug development, can have fatal consequences.

From the above experimental results, the compound of the present invention having the basic skeleton of the formula (I) of aspect 1 is more metabolically stable in human liver microsomes than the compound in which a sulfur atom is inserted instead of an oxygen atom. It will be readily appreciated by those skilled in the art that In particular, those skilled in the art will be able to combine R ¹ with R R′d, R ² with R ² a, R and R ³ with R¾ and R ³ c (combinations of compounds 7 to 8). In the compound of the formula (I) described in Embodiment 10, an improvement in stability is easily inferred.

In VIVO testing

(1) The in vivo inhibition test of 11 β-HSD1 of the present invention in mammals is described in a known report, for example, ASSAY: MEASUREMENT OF IN V IVO INHIBITION (p. 29-30) of WO 2004/058741. It can be implemented with reference to the following method.

Generally, the test compound is administered orally to a mammal at a predetermined time from 1 to 24 hours. Tritium-labeled cortisone is administered intravenously, and blood is collected after several minutes. Steroids are extracted from the separated serum and measured by HPLC. ³ H-cortisone and its metabolite ³ H-cortisol are measured in animals receiving the drug or in control animals receiving the vehicle. The inhibition rate of change is obtained from these values.

More specifically, the test compound is vehicle (5% hydroxypropyl mono-β cyclodex Trizin vZv HO) for oral administration, typically 10 mg at the desired concentration

2

A dose of Zkg is administered. After the animals are fasted overnight, ICR mice (Charles River) are orally tested in groups of 3 animals at a dose of 0.5 mL per animal.

After a desired time, between 4 and 16 hours, 3 what was added to the dPBS 0. 2 mL of mu Micromax of ³ .eta. cortisone injection the tail vein. After restraining the animal in the CO room for 2 minutes,

2

Collect blood while alive. Blood is serum separated in a separation tube within 30 minutes at room temperature. At the end of the incubation, the serum is centrifuged for 10 minutes at 3000Xg and 4 ° C.

In the analysis of steroids, an organic solvent is first extracted. 0. Transfer 2 mL of serum to a clean microcentrifuge tube, add 1. OmL of ethyl acetate and infiltrate vigorously for 1 min. Quickly centrifuge to precipitate the aqueous phase and obtain the supernatant of the organic layer. 0. Transfer 85 mL of organic layer to a fresh microcentrifuge tube and dry. Suspend the dried material in 0.250 mL DMSO containing high concentrations of cortisone and cortisol for HPLC use.

0. Elution of target steroids with a linear concentration gradient up to 50% methanol on a Metachem Inertsil C-18 chromato column or equivalent reversed-phase chromatographic column equilibrated with 30% methanol. To do. At the same time, measure the unlabeled internal standard at UV254nm. Tritium signals are collected using a radiochromatography detector and analyzed. ³ H- conversion to ³ H- cortisone cortisone, calculated as the ratio of AUC for cortisol with respect to the composite AUC between Col Chizon and cortisol.

(2) Or alternatively, test drugs are orally administered daily for 3 to 28 days in a pathological model, blood is collected, blood glucose, serum lipids, serum insulin, etc. are measured, or after overnight fasting, oral dalcose After loading, glucose tolerance is measured by collecting blood over time and measuring blood glucose, or measuring body weight every day by measuring body weight gain, or autopsy after completion of continuous injection, Experiments such as measuring the lipid content in the liver can be conducted to examine anti-diabetic, anti-hypertensive, anti-hyperlipidemic, anti-obesity, and body fat reduction effects. Pathological models include, for example, spontaneously diabetic, obese or hypertensive mice and rats, such as spontaneously type 2 obese diabetic model mice, such as db / db mice, ob / ob Means mouse or KK-Ay mouse drug-induced diabetes, obese or hypertensive mice and rats, special diet (high fat diet, high sucrose diet, etc.)-Induced diabetes, obese or hypertensive mice and rats. Such a test can be carried out, for example, with reference to the method described in Endocrinology 144 (11): 4755-4762, 2003, in particular pages 4756-4758.

[0076] Next, the pharmaceutical composition of the present invention will be described below. As solid compositions for oral administration, capsules, pills, tablets, powders, granules and the like are used. Such solid compositions are made by combining one or more active substance forces with at least one inert carrier. More specifically, excipients (eg lactose, sucrose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, metasilicic acid), binders (eg crystal cell mouths, sugars) , Dextrin, hydroxypropyl cell mouthpiece, hydroxypropyl pill methyl cell mouthpiece, polybulurpyrrolidone, macrogol), lubricant (eg magnesium stearate, calcium stearate, talc), disintegrant (eg corn starch) , Carboxymethyl cellulose, calcium calcium glycolate), stabilizers (eg sugar alcohols such as lactose), solubilizers and solubilizers (eg cholesterol, triethanolamine, glutamic acid) , Aspartic acid), coloring agents, flavoring agents, preservatives, tonicity agents, dispersants, anti-oxidation agents (eg Asukorubin acid, heptyl hydroxy § - Seo - le), buffering agents, preservatives (e.g. parabens, benzyl alcohol - may include le). If necessary, tablets, pills, granules, etc. may be subjected to enteric film coating for gastric soluble sputum such as sucrose, gelatin, hydroxypropyl methylcellulose mouth sphthalate.

Injections for parenteral administration include sterile aqueous or non-aqueous solubilizers, suspensions, and emulsions. Examples of carriers for aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of carriers for water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and polysorbate 80 (TM).

[0077] Such a composition may further contain additives such as the above-mentioned isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers or solubilizers. These are for example membra It is sterilized by filtration with a water filter, blending of a bactericide or ultraviolet irradiation. They can also be used as injectables which are prepared as sterile solid compositions and dissolved, emulsified or suspended when used. When the solubility of the compound of the present invention is low, solubilization treatment may be performed.

The treatment may be a known method applicable to pharmaceutical preparations, for example, a method of adding a surfactant (polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan higher fatty acid esters, sucrose fatty acid esters, etc.), or a drug. Soluble agents such as polymers (water soluble polymers such as polyethylene glycol (PEG), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose phthalate (HPMCP), methyl methacrylate-methacrylic acid And a method of forming a solid dispersion with a polymer (an enteric polymer such as Eudragit L, S (TM); manufactured by Rohm and Haas). Furthermore, if necessary, a method of forming an inclusion complex using a-, β- or γ-cyclodextrin, hydroxypropyl cyclodextrin and the like can also be mentioned. Also, “Pharmaceutical Monograph No. 1, Bioavailability”, Tsuneji Nagai et al., Soft Science, 78-82 (1988) or “Recent formulation technology and its application”, Isao Utsumi et al., Pharmaceutical Journal 15 With reference to 7-159 (1983), the solubilization method can be appropriately changed according to the target drug. Of these, a method of improving the solubility by forming a solid dispersion of a drug and a solubilizing agent can be preferably employed (Japanese Patent Laid-Open Nos. 56-49314 and FR2460667).

The desired dose may conveniently be expressed as a single dose or as divided doses administered at appropriate intervals (eg, 2, 3, 4 or more sub-doses per day). This sub-dose itself can be further divided (eg, into a number of discretely spaced administrations; eg, by multiple inhalations from an injector, or by applying multiple drops to the eye).

The clinical dose of the compound of the present invention for humans is appropriately determined in consideration of the patient's symptoms, body weight, age, sex, etc., and is generally 0.001 to 50 mg orally per day for an adult.

Zkg, preferably 0.01 to 25 mgZkg, more preferably 0.05 to 5 mgZkg.

<Examples of formulation> The following are examples of the pharmaceutical composition of the present invention.

(a) Tablet (lmg)

Compound of Example 6 1. Og

Lactose 90. Og

Sodium carboxymethylcellulose 7. Og

Corn starch paste (5% WZV paste) 1. Og

Magnesium stearate 1. Og

The above ingredients are weighed and compressed into tablets by conventional methods to make lOOmg tablets.

(b) Tablet (lOmg)

10 g of the compound of Example 3

Lactose 140g

Croscarmellose sodium 7. Og

Cornstarch 37. 5g

Polybulol pyrrolidone 2.5 g

Magnesium stearate 3g

The above ingredients are weighed and tableted by a conventional method to give a 200 mg tablet, which is then coated with cellulose acetate phthalate to form an enteric solvent.

(c) Tablet (lOOmg)

100 g of the compound of Example 6

Lactose 180g

Croscarmellose sodium I3g

Corn starch (5% WZV paste) 4g

Magnesium stearate 3g

The above ingredients are weighed and compressed into a 300 mg tablet by a conventional method.

(d) Capsule (50mg)

100 g of the compound of Example 11

Rattan 395. 5g

Magnesium stearate 4.5g Weigh each of the above ingredients and mix evenly. Enclose the mixed powder in a No. 1 hard capsule in an amount of 250 mg.

[0079] [Synthesis Examples]

Next, synthesis examples are given to describe the present invention in more detail, but the present invention is not limited thereto.

For the measurement of nuclear magnetic resonance spectrum (NMR), use ίO EOL JNM ΕΧ270 (manufactured by JEOL Ltd.) or ¾JEOL JNM—LA300 (manufactured by JEOL Ltd.) and TMS (tetramethylsilan) as an internal standard. Expressed in δ (ppm). NMR ^ Vector data marked with * are data measured with JEOL JNM-EX270 (manufactured by JEOL Ltd.). None, JEOL JNM-LA300 (JEOL Ltd. made) ). Liquid chromatography Z mass spectrometry (LCZMS) was measured using the FractionLynx—MS system (Waters), column: SunFire—C18 (4.6 × 50 mm; Waters), temperature: room temperature, flow rate: 3. OmlZ, elution solvent: (A) 0.05% acetic acid aqueous solution, (B) acetonitrile, gradient: 0 min 90% AZB → 6 min 50% AZB → 9 min 10% AZB The measurement was performed under the following conditions: gradient: 0 min 90% AZB → 5 min 10% AZB → 7 min 10% AZB.

[0080] (Example 1)

3 Cyclohexyl 5 -— (4 Fluorobenzyloxy) 4-methyl 4H— 1, 2, 4 Synthesis of triazole

Process 1> 3 Synthesis of cyclohexyl 4-methyl-5 (methylthio) -4Η-1,2,4-triazole

3 Cyclohexyl 5-mercapto 4-methyl 4H-1,2,4-triazole (4. Og) was dissolved in N, N dimethylformamide (44 ml), and cooled with ice water, sodium hydride (containing 60% oil) 1. Og) was added and stirred at the same temperature for 15 minutes. To this, oodomethane (1.4 ml) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture while cooling with ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. Ether was added to the residue, followed by filtration to obtain the title compound (3.6 g). Process 2> Synthesis of 3-cyclohexyl-4-methyl-5- (methylsulfol) 4H— 1, 2, 4 triazole

Dissolve the compound obtained in Step 1 (3.5 g) in methylene chloride (200 ml), slowly add 3-benzoate perbenzoic acid (containing 35% water; 6.3 g) under ice water cooling, and stir overnight at room temperature. did. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. Ether was added to the residue and filtered to obtain the title compound (2.3 g).

Process 3> 3-Cyclohexyl 5-(4-Fluorobenzyloxy) 4-methyl 4 H- 1, 2, 4 Triazolene synthesis

4-Fluorobenzyl alcohol (90 1) was dissolved in 1,3 dimethyl-2-imidazolidinone (1. Oml), and sodium hydride (60% oily product; 41 mg) was added under ice water cooling. The mixture was stirred at room temperature for 30 minutes. Here, under ice-water cooling, the compound (0.10 g) obtained in Step 2 was prepared and stirred overnight at room temperature. Water was added to the reaction mixture under ice-water cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (elution solvent; ethyl acetate: hexane = 1: 5-ethyl acetate) to give the title compound (83 mg).

[0081] (Example 2)

Synthesis of 3- (4-chlorobenzyloxy) 5 cyclohexyl 4-methyl 4H—1, 2, 4-triazole

The title compound (90 mg) was obtained in the same manner as in Step 3 of Example 1 using the compound (0.10 g) obtained in Step 2 of Example 1 and 4-clonal benzyl alcohol (0.12 g). It was.

[Example 3]

3 Cyclohexyl 5— (4 Fluorophenethyloxy) 4-Methyl 4H— Synthesis of 1, 2, 4 Triazole

Using the compound obtained in Step 2 of Example 1 (0.10 g) and 4 fluorophenethyl alcohol (0.10 ml), the title compound (64 mg) was prepared in the same manner as in Step 1 of Example 1. It was obtained.

[0083] (Example 4) 3 Cyclohexyl 4-methyl 5— [2— (piperidine mono 1-yl) ethoxy] —4H— 1, 2, 4 Synthesis of triazole

Using the compound (0.10 g) obtained in Step 2 of Example 1 and 2- (piperidine-1-yl) ethanol (0.11 ml) in the same manner as in Step 3 of Example 1, Compound (78 mg) was obtained.

[0084] (Example 5)

3- (adamantane 1-yl) -5- (4 fluorobenzyloxy) 4-methyl 4 H-1, 2, 4 Triazolene synthesis

Process 1> 3 (Adamantane 1-yl) 4-Methyl 5- (Methylsulfol) 4 H-1, 2, 4 Triazolene synthesis

Example 1 using 3- (adamantane-1-yl) -4-methyl-5 (methylthio) -4Η-1,2,4-triazole (1.9 g) and 3-chloroperbenzoic acid (containing 35% water; 4.2 g) In the same manner as in Step 2, the title compound (1.7 g) was obtained.

Process 2> 3— (adamantane 1-yl) 5— (4 fluorobenzyloxy) 4— methyl-4H—1, 2, 4 Synthesis of triazole

The title compound (55 mg) was obtained in the same manner as in Step 3 of Example 1 using the compound (0.10 g) obtained in Step 1 and 4 fluoro-benzyl alcohol (85 mg).

[0085] (Example 6)

3- (adamantane 1-yl) -5- (4 chlorobenzyl) 4-methyl 4H— 1, 2, 4 Synthesis of triazole

The title compound (74 mg) was obtained in the same manner as in Step 3 of Example 1, using the compound (0.10 g) obtained in Step 1 of Example 5 and 4-clonal benzyl alcohol (97 mg).

[0086] (Example 7)

3- (adamantane 1-yl) -5- (4 fluorophenethyloxy) 4-methyl-4H-1, 2, 4 Triazole synthesis

Using the compound (0.10 g) obtained in Step 1 of Example 5 and 4 fluorophenethyl alcohol (85 1), the title compound (42 mg) was obtained in the same manner as in Step 3 of Example 1. [0087] (Example 8)

3- (adadamantane 1-yl) 4-methyl 5- [2- (piperidine 1-yl) ethoxy] -4Η- 1, 2, 4 Synthesis of triazole

Using the compound (0.10 g) obtained in Step 1 of Example 5 and 2- (piperidine-1-yl) ethanol (90 1) in the same manner as in Step 3 of Example 1, The title compound (74 mg) was obtained.

[0088] (Example 9)

3- (Adamantane 1-yl)-5-(4 Fluorophenoxy) 4-Methyl 4H— Synthesis of 1, 2, 4 Triazole

The compound obtained in Step 1 of Example 5 (0.10 g), 4 fluorophenol (0.91 g) and potassium carbonate (68 mg) were heated in a sealed tube at 180 to 200 degrees for 30 minutes. Under ice-water cooling, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (elution solvent; ethyl acetate: hexane = 1: 1 to ethyl acetate) to obtain the title compound (94 mg).

[Example 10]

3- (4-Fluorobenzyloxy) -5- (4-Fluorophenyl) — 4-Methyl— Synthesis of 4H-1, 2, 4 Triazole

Process 1> Synthesis of 3— (4 fluorophenol) -4-methyl-5 (methylsulfol) —4H-1, 2, 4 triazole

3— (4 Fluorophenol) —4-Methyl-5— (Methylthio) — 4H—1, 2, 4 Triazole (1.75 g) and m-cloperbenzoic acid (containing 35% water; 5.2 g) In the same manner as in Step 2 of Example 1, the title compound (1.7 g) was obtained.

Step 2> Synthesis of 3- (4 fluorobenzyloxy) -5- (4 fluorophenyl) -4-methyl- 4H— 1, 2, 4 triazole

The title compound (96 mg) was obtained in the same manner as in Step 3 of Example 1 using the compound obtained in Step 1 (0.10 g) and 4-fluorobenzyl alcohol (85 μ1).

[0090] (Example 11) 3- (4 Chlorobenzyloxy) 5— (4 Fluorophenol) 4-Methyl 4H— Synthesis of 1, 2, 4 Triazole

The title compound (87 mg) was obtained in the same manner as in Step 3 of Example 1, using the compound (0.10 g) obtained in Step 1 of Example 10 and 4-clonal benzyl alcohol (0.1 g). It was.

[Example 12]

3— (4 Fluorophenethyloxy) 5— (4 Fluorophenyl) 4-Methyl-4

Synthesis of H- 1, 2, 4 Triazonole

Using the compound (0.10 g) obtained in Step 1 of Example 10 and 4 fluorophenethyl alcohol (98 1), the title compound (49 mg) was obtained in the same manner as in Step 3 of Example 1. It was.

[0092] (Example 13)

3- (4 Fluorophenol) 4-methyl 5- [2- (piperidine mono 1-yl) ethoxy] -4H- 1, 2, 4 Synthesis of triazole

Using the compound (0.10 g) obtained in Step 1 of Example 10 and 2- (piperidine-1-yl) ethanol (0.10 ml) in the same manner as in Step 3 of Example 1, The title compound (90 mg) was obtained.

[0093] (Example 14)

3- (4 Fluorophenoxy) 5— (4 Fluorophenol) 4-Methyl 4H— Synthesis of 1, 2, 4 Triazole

The title compound (62 mg) was obtained in the same manner as in Example 9 using the compound (0.10 g) obtained in Step 1 of Example 10 and 4 fluorophenol (1.1 g).

[Example 15]

3 Cyclohexyl 4 Ethyl 5— (4 Fluorophenoxy) 4H—1, 2, 4 Triazole Synthesis

Process 1> 3 Black mouth 5 Cyclohexyl 4 Ethyl 4H— 1, 2, 4 Triazole synthesis

3 Cyclohexylene 4-ethylol-5 mercapto 4H—1, 2, 4-triazole (0 17 g) was dissolved in acetonitrile (8. Oml), potassium nitrate (0.24 g) was added, sulfuryl chloride (0.31 ml) was added under ice-water cooling, and the mixture was stirred for 1 hour. Under ice-water cooling, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. Methylene chloride was added to the residue, and insoluble materials were removed by filtration. The filtrate was concentrated to give the title compound (0.17 g).

Process 2> 3 Cyclohexyl 4 Ethyl 5— (4 Fluorophenoxy) 4H— Synthesis of 1, 2, 4 Triazole

The title compound (57 mg) was obtained in the same manner as in Example 9 using the compound (50 mg) obtained in Step 1 and 4 fluorophenol (0.63 g).

(Example 16)

3- (adamantane 1-yl) 4-ethyl 5- (4 fluorophenoxy) 4H— synthesis of 1, 2, 4 triazole

<Step 1> 3 (adamantane 1yl) 4 ethyl 5 hydroxy 1 4H— 1, 2, 4-triazole

Ethyl isocyanate (0.58 ml) was dissolved in methanol (13 ml), 1-adamantane carboxylic acid hydrazide (1.3 g) was added, and the mixture was heated to reflux for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added 2N aqueous sodium hydroxide solution (50 ml), and the mixture was heated to reflux for 7 hours. 2N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.2 g).

Process 2> 3— (adamantane 1-inore) 1 5 black mouth 4 ethinole 4H— 1, 2, 4— Synthesis of triazole

The compound obtained in step 1 (0.50 g) and phosphorus pentachloride (0.55 g) were charged with salt and phosphoryl (0.94 ml) and heated at 140 to 150 ° C. for 4 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (elution The title compound (0.34 g) was obtained by purification with a medium; ethyl acetate: hexane = 1: 1 to ethyl acetate).

<Process 3> 3 (adamantane 1yl) 4 ethyl 5— (4 fluorophenoxy) — 4H— 1, 2, 4 Synthesis of triazole

The title compound (57 mg) was obtained in the same manner as in Example 9 using the compound (0.10 g) obtained in Step 2 and 4 fluorophenol (0.63 g).

[Example 17]

3- (adamantane 1-yl) 4 ethyl 5- (4 fluorobenzyloxy) 4 H-1, 2, 4 Triazolene synthesis

Process 1> 3 (adamantane-1-yl) —4 ethyl-5- (methylsulfol) —4 H- 1, 2, 4 Synthesis of triazolene

Example 1 using 3- (adamantane-1-yl) -4-ethyl-5-methylthio-4） -1,2,4-triazole (6.7 g) and 3-cloperbenzoic acid (containing 35% water; 14 g) In the same manner as in Step 2, the title compound (4.5 g) was obtained.

Process 2> 3— (adamantane 1-yl) 4 ethyl 5— (4 fluoro-benzyloxy) — 4H— 1, 2, 4 Triazole synthesis

The title compound (16 mg) was obtained in the same manner as in Step 3 of Example 1 using the compound obtained in Step 1 (0.10 g) and 4-fluorobenzyl alcohol (71 μ1).

[Example 18]

3- (adamantane 1-yl) 4-ethyl 5- (4 fluorophenethyloxy) 4H- 1, 2, 4 Synthesis of triazole

Using the compound (0.20 g) obtained in Step 1 of Example 17 and 4 fluorophenethyl alcohol (0.18 g), the title compound (27 mg) was obtained in the same manner as in Step 3 of Example 1. It was.

[0098] [Table 4] Table 2 (Part 1) mmm ι Actual-2

Example 3 Example j

Example 5 Example 6

Example 7 Example ¾

Example 9 Example ίθ

κ-κ

襄 2 (Part 2) Example i Example 12

/ sssosvuosfcld 8 inch / 66Ϊ8909 O00ΖAV

[¾SI / sssosoovuifcld 266Ϊ89 / O0900ΖAV7

(δ2 ε0

[] [] 820ΐο / vu sssososfcld 09 / O 66Ϊ890900ΖAV

^ u6εοΐο Table 3 (Part 4)

0] Table 3 (Part 5)

[0105] (Examples 19 to 272)

The following compounds are also synthesized in the same manner as in the above examples. The compounds can be synthesized by any combination of the following RR ² and R ³ forces, and the combinations shown in the table are preferred. Here, for example, U1 represented as R ¹ represents a 4-fluorophenyl group, V3 represented as R ² represents a cyclopropyl group, and W4 represented as R ³ represents a cyclohexyl group. .

[0106] [Table 11]

[0107] [Table 12] Table 5 (Part 1)

Ex. No. R, R ² R ³

19 U1 V1 W2

20 U1 V1 W3

21 U1 V1 W4

22 U1 V1 W5

23 U1 V1 W6

24 U1 V2 W2

25 U1 V2 W3

26 U1 V2 W5

27 U1 V2 W6

28 U1 V3 W1

29 U1 V3 W2

30 U1 V3 W3

31 U1 V3 W4

32 U1 V3 W5

33 U1 V3 W6

34 U1 V4 W1

35 U1 V4 W2

36 U1 V4 W3

37 U1 V4 W4

38 U1 V4 W5

39 U1 V4 W6

40 U1 V5 W1] (Part 2)

Ex. No. R ¹ R ² R ³

41 U1 V5 W2

42 U1 V5 W3

43 U1 V5 W4

44 U1 V5 W5

45 U1 V5 W6

46 U2 V1 W2

47 U2 V1 W3

48 U2 V1 W5

49 U2 V1 W6

50 U2 V2 W2

51 U2 V2 W3

52 U2 V2 W4

53 U2 V2 W5

54 U2 V2 W6

55 U2 V3 W1

56 U2 V3 W2

57 U2 V3 W3

58 U2 V3 W4

59 U2 V3 W5

60 U2 V3 W6

61 U2 V4 W1

62 U2 V4 W2

63 U2 V4 W3

64 U2 V4 W4

65 U2 V4 W5 4] Table 5 (Part 3)

Ex. No. R ¹ R ² R ³

66 U2 V4 W6

67 U2 V5 W1

68 U2 V5 W2

69 U2 V5 W3

70 U2 V5 W4

71 U2 V5 W5

72 U2 V5 W6

73 U3 VI W2

74 U3 V1 W3

75 U3 V1 W5

76 U3 V1 W6

77 U3 V2 W2

78 U3 V2 W3

79 U3 V2 W4

80 U3 V2 W5

81 U3 V2 W6

82 U3 V3 W1

83 U3 V3 W2

84 U3 V3 W3

85 U3 V3 W4

86 U3 V3 W5

87 U3 V3 W6

88 U3 V4 W1

89 U3 V4 W2

90 U3 V4 W3 5] Table 5 (Part 4)

Ex. No. R ' ² R ³

91 U3 V4 W4

92 U3 V4 W5

93 U3 V4 W6

94 U3 V5 W1

95 U3 V5 W2

96 U3 V5 W3

97 U3 V5 W4

98 U3 V5 W5

99 U3 V5 W6

100 U V1 W2

101 U4 V1 W3

102 U4 V1 W5

103 U4 V1 W6

104 U4 V2 W1

105 U4 V2 W2

106 U4 V2 W3

107 U4 V2 W4

108 U4 V2 W5

109 U4 V2 6

110 U4 V3 W1

111 U4 V3 W2

112 U4 V3 W3

113 U4 V3 W4

114 U4 V3 W5

115 U4 V3 W6 6] Table 5 (Part 5)

Ex. No. R ¹ R ² R ³

116 U4 V4 W1

117 U4 V4 W2

118 U4 V4 W3

119 U4 V4 W4

120 U4 V4 W5

121 U4 V4 W6

122 U4 V5 W1

123 U4 V5 W2

124 U4 V5 W3

125 U4 V5 W4

126 U4 V5 W5

127 U4 V5 W6

128 U1 V2 W7

129 U1 V2 W8

130 U1 V2 W9

131 U1 V2 W10

132 U1 V2 W11

133 U1 V2 W12

134 U1 V2 W13

135 U1 V2 W14

136 U1 V2 W15

137 U1 V2 W16

138 U1 V2 W17

139 U1 V2 W18

140 U1 V2 W19 ] Table 5 (Part 6)

Ex. No. R ¹ R ² R ³

141 U1 V2 W20

142 U1 V2 W21

143 U1 V2 W22

144 U1 V2 W23

145 U1 V2 W24

146 U1 V2 W25

147 U1 V2 W26

148 U3 V2 7

149 U3 V2 W8

150 U3 V2 W9

151 U3 V2 W10

152 U3 V2 W11

153 U3 V2 W12

154 U3 V2 W13

155 U3 V2 W14

156 U3 V2 W15

157 U3 V2 W16

158 U3 V2 W17

159 U3 V2 W18

160 U3 V2 W19

161 U3 V2 W20

162 U3 V2 W21

163 U3 V2 W22

164 U3 V2 W23

165 U3 V2 W24 8] Table 5 (Part 7)

Ex. No. R 'R ³

166 U3 V2 W25

167 U3 V2 W26

168 U5 V2 W1

169 U5 V2 W3

170 U5 V2 W4

171 U6 V2 W1

172 U6 V2 W3

173 U6 V2 W4

174 U7 V2 W1

175 U7 V2 W3

176 U7 V2 W4

177 U8 V2 W1

178 U8 V2 W3

179 U8 V2 W4

180 U9 V2 W1

181 U9 V2 W3

182 U9 V2 W4

183 U10 V2 W1

184 U10 V2 W3

185 U10 V2 W4

186 U11 V2 W1

187 U11 V2 W3

188 U11 V2 W4

189 U12 V2 W1

190 U12 V2 W3 9] Table 5 (Part 8)

Ex. No. R ¹ R ² R ³

191 U12 V2 W4

192 U13 V2 W1

193 U13 V2 W3

194 U13 V2 W4

195 U14 V2 W1

196 U14 V2 W3

197 U14 V2 W4

198 U15 V2 W1

199 U15 V2 W3

200 U15 V2 W4

201 U16 V2 W1

202 U16 V2 W3

203 U16 V2 W4

204 U17 V2 W1

205 U17 V2 W3

206 U17 V2 W4

207 U18 V2 W1

208 U18 V2 W3

209 U18 V2 W4

210 U19 V2 W1

211 U19 V2 W3

212 U19 V2 W4

213 U20 V2 W1

214 U20 V2 W3

215 U20 V2 W4 ] Table 5 (Part 9)

Ex.No.R ¹ R ^{2 3}

216 U21 V2 W1

217 U21 V2 W3

218 U21 V2 W4

219 U22 V2 W1

220 U22 V2 W3

221 U22 V2 W4

222 U23 V2 W1

223 U23 V2 W3

224 U23 V2 W4

225 U24 V2 W1

226 U24 V2 W3

227 U24 V2 W4

228 U25 V2 W1

229 U25 V2 W3

230 U25 V2 W4

231 U26 V2 W1

232 U26 V2 W3

233 U26 V2 W4

234 U27 V2 W1

235 U27 V2 W3

236 U27 V2 W4

237 U28 V2 W1

238 U28 V2 W3

239 U28 V2 W4

2 0 U29 V2 W1 1] Table 5 (Part 1 0)

Ex. No. R 'r ³

241 U29 V2 W3

242 U29 V2 W4

243 U30 V2 W1

244 U30 V2 W3

245 U30 V2 W4

246 U31 V2 W1

247 U31 V2 W3

248 U31 V2 W4

249 U32 V2 W1

250 U32 V2 W3

251 U32 V2 W4

252 U33 V2 W1

253 U33 V2 W3

254 U33 V2 W4

255 U34 V2 W1

256 U34 V2 W3

257 U34 V2 W4

258 U35 V2 W1

259 U35 V2 W3

260 U35 V2 W4

261 U36 V2 W1

262 U36 V2 W3

263 U36 V2 W4

264 U37 V2 W1

265 U37 V2 W3 [0117] [Table 22] Table 5 (Part 1 1)

Ex. No. R ^{1 2} R ³

266 U37 V2 W4

267 U38 V2 W1

268 U38 V2 W3

269 U38 V2 W4

270 U39 V2 W1

271 U39 V2 W3

272 U39 V2 W4

[0118] (Example 273)

3— (2 Kuroguchi Fuenore) 1 5— (4 Funoleorophenoxy) 4-Methinore 4H—1, 2, 4 Synthesis of triazole hydrochloride

Process 1> 3 Black mouth 5— (2 Black mouth) One 4-Methyl 4H— 1,2,4 Triazole synthesis

3- (2 Chlorophenyl) 5-Mercapto-4-methyl 4H— 1,2,4 Triazole (5.0 g), potassium nitrate (6.7 g) and sulfuryl chloride (8.5 ml) In the same manner as described above, the title compound (0.80 g) was obtained.

Process 2> 3— (2 Black Mole) 5— (4 Fluorophenoxy) 4-Methyl 4 H- 1, 2, 4-Triazole Hydrochloride Synthesis

Using the compound (0.10 g) obtained in Step 1 and 4 fluorophenol (2.8 g), the compound obtained in the same manner as in Example 9 was dissolved in methanol (1. Oml). Normal hydrogen chloride-ethyl acetate solution (2.0 ml) was added. The title compound (0.12 g) was obtained by adding ether to the residue obtained by concentration under reduced pressure and filtering.

[0119] (Example 274)

3- (4 Fluorophenoxy) -4-methyl-5- (2-phenolpropane-2-yl) Synthesis of 4H-1,2,4-triazole hydrochloride Step 1> 3-Mercapto- 4-Methyl-5- (2 Phenol-2-yl) —4H-1, 2, 4 Synthesis of triazole

2-Methyl-2 phenolpropionic acid (4. Og) was dissolved in toluene (230 ml), thionyl chloride (3.6 ml) was added, and the mixture was heated to reflux for 1.5 hours. The reaction mixture was concentrated, and methyl chloride (46 ml) was added to the residue, followed by 4-methylsemicarbazide (2.6 g). Pyridine (3.9 ml) was added dropwise thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, 2N aqueous sodium hydroxide solution (180 ml) was added to the residue, and the mixture was heated under reflux for 2.5 hr. 1N Hydrochloric acid was added to the reaction solution to adjust to pH 4-5, and the precipitated crystals were collected by filtration. Washing with ethanol gave the title compound (2.lg).

<Step 2> Synthesis of 4-methyl-3-methylthio 5- (2-phenolpropane 2-yl) -4 H— 1, 2, 4 triazolene

In the same manner as in Step 1 of Example 1, using the compound obtained in Step 1 (1.5 g), sodium hydride (60% oily substance; 0.31 g) and sodomethane (0.44 ml), Compound (0.95 g) was obtained.

<Step 3> Synthesis of 4 Methyl 3 Methylsulfol 5— (2 Phenolpropane-2-yl) 4H— 1,2,4 Triazolene

The title compound (0.92 g) was prepared in the same manner as in Step 2 of Example 1, using the compound (0.95 g) obtained in Step 2 and m-cloperbenzoic acid (containing 35% water; 1.5 g). was gotten.

Process 4> 3— (4 Fluorophenoxy) —4—Methyl—5— (2 Phenolpropane—2-Inole) mono 4H— 1, 2, 4 Synthesis of triazole hydrochloride

Using the compound obtained in Step 3 (0.10 g), 4 fluorophenol (0.96 g) and potassium carbonate (72 mg), the title compound (73 mg) was obtained in the same manner as in Step 2 of Example 19. It was.

(Example 275)

3— (2, 6 Dimethylphenoxy) 4—Methyl 5— (2 Phenylpropane-2-yl) — 4H— 1, 2, 4 Synthesis of triazole hydrochloride

Example 20 Using the compound obtained in Step 3 (0.10 g), 2, 6 dimethylphenol (1. lg) and potassium carbonate (72 mg), in the same manner as in Step 2 of Example 19, Title compound (68 mg) was obtained.

[0121] (Example 276)

3— (4-Fnorolerophenoxy) 4 Isopropinoleole 5 -— (2-Methoxy-4-trophyl) —4Η-1,2, 4 Triazole Synthesis

Process 1> 4-Isopropyl-1-3-mercapto-1-5- (2-Methoxy-1-tetraphenyl) -4H- 1, 2, 4 Synthesis of triazole

2-Methoxy-4-trobenzoic acid (5. Og), thiol chloride (5.6 ml), 4-isopropyl semicarbazide (3.7 g) and 2N aqueous sodium hydroxide solution (200 ml) were used. The title compound (5.3 g) was obtained in the same manner as in Step 1 of Example 20.

Process 2> 4-Isopropyl-3- (2-Methoxy-1-tetraphenol) 5-Methylthio-4H-1,2,4 Triazole Synthesis

In the same manner as in Step 1 of Example 1, using the compound obtained in Step 1 (2. Og), sodium hydride (60% oily substance; 0.33 g) and sodomethane (0.47 ml), Compound (1.63 g) was obtained.

Process 3> 4-Isopropyl 3- (2-Methoxy-1-4-phenol) 5-Methylsulphoninole 4H— 1, 2, 4 Triazolene synthesis

Using the compound obtained in Step 2 (1.5 g) and m-chloroperbenzoic acid (containing 35% water; 1.9 g) in the same manner as in Step 2 of Example 1, the title compound (1.6 g) was gotten.

Step 4> 3— (4 Fluorophenoxy) 4-Isopropyl 5- 5- (2-Methoxy 4-nitrophenol) —4Η-1, 2, 4 Triazole synthesis

Using the compound (1.2 g) obtained in Step 3, 4 fluorophenol (9.49 g) and potassium carbonate (0.71 g) in the same manner as in Example 9, the title compound (1. Og) was obtained.

[0122] (Example 277)

3— (4 Amino-2-methoxyphenol) 5— (4 Funololophenoxy) 4-Isopropyl— 4H— 1, 2, 4 Triazole Synthesis

The compound (1. Og) obtained in Step 4 of Example 22 was dissolved in methanol (10 ml), 10% -palladium carbon (0.10 g) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. did. The reaction mixture was filtered through celite, and the mother liquor was concentrated to give the title compound (0.90 g). [0123] Table 2 shows the structures of the compounds of the present invention obtained in the above Examples. In addition, Table 3 shows physical property data of the Example compounds and intermediates thereof. In Table 3, “Example No. 1-1” means the compound obtained by “Step 1 of Example 1”. Note that in each example, for example, step 1 and step 2, the product of step 1 is an intermediate of step 2 and is not included in the compound of formula (I). .

[0124] [Table 23]

Example 277

Claims

Claim Formula (I)

[Chemical 1]

R ² (i)

(Where R ¹ is

I ^ a) hydrogen atom,

R ^ C Linear or branched aliphatic hydrocarbon group

1-6

R '^ Q ¹

I ^ cD Q ¹ (CO) — linear or branched aliphatic hydrocarbon group represented by C or m 丄 to o

Is

1-6

Q'D C

6-10

Q '^ C alicyclic hydrocarbon group,

3-10

Q ¹ may be further substituted with 1 to 4 groups arbitrarily selected from the substituent group A. R ² is

R may be substituted with a hydroxyl group or a C alkoxy group.

1 "" ^ '6 1

A branched aliphatic hydrocarbon group or C alicyclic hydrocarbon group, or

3-10

R ² b) C linear or branched aliphatic hydrocarbon group substituted by Q ²

1-6

Q ²

Q ² 1) C aryl group,

6-10

Q ² 2) C alicyclic hydrocarbon group,

3-10

Q ² may be further substituted with 1 to 4 groups arbitrarily selected from Substituent Group B. R ³ is

R ³ a) C

1-6 straight or branched aliphatic hydrocarbon groups

R ³ b) Q ³

R ³ c) Q ³ — C replaced by Y—

1-6 straight or branched aliphatic hydrocarbon groups or c 3-10 alicyclic hydrocarbon groups

Q ³

Q ³ 1) C aryl group,

6-10

Q ³ 2) C alicyclic hydrocarbon group,

3-10

R ⁶ and

z is an integer 1 or 2, R ⁶ is hydrogen atom, C alkyl group, C aryl group, nitrogen atom, oxygen atom, sulfur source

1-6 6-10

6 ~: L0 1 ~ 6

A 5- to 10-membered heteroaryl C alkyl group containing 1 to 4 heteroatoms,

1-6

Substituent groups A, B, C are independently

Halogen atom, hydroxyl group, C alkoxy group, C aryloxy group, amino group, C

6-10

6 ~: L0 1 ~ 6

3-10

A saturated or partially unsaturated monocyclic or condensed 3- to 10-membered alicyclic hydrocarbon group containing 1 to 4 heteroatoms arbitrarily selected from elemental atoms, oxygen atoms and sulfur atoms, C

6 aryl group, nitrogen atom · oxygen atom · sulfur nuclear power arbitrarily selected hetero atom 1-4

~Ten

5- to 10-membered heteroaryl group, nitrogen atom 'oxygen atom' 5- to 10-membered heteroaryl C alkyl optionally containing 1 to 4 heteroatoms selected from sulfur atoms

1-6

Mono- or di-substituted with a group, C alkylsulfonyl group, C alkyl group

1 to 3 1 to 6

May be mono- or di-substituted by an aminosulfol group or C aryl group.

6-10

May be mono- or di-substituted by an aminosulfol group, a C aryl group

6-10

Aminosulfinyl group, including 1 to 4 heteroatoms arbitrarily selected from nitrogen atom, oxygen atom and sulfur atom! /, 5- to 10-membered heteroaryl aminosulfol group, nitrogen atom and oxygen atom 'Contains 1 to 4 heteroatoms arbitrarily selected from sulfur atoms 5 to: L0 member Teraryl aminosulfier group, heteroatoms arbitrarily selected from nitrogen atoms, oxygen atoms, sulfur atoms 1 to 5 to 10-membered heteroaryloxy group containing 4 atoms, 1 to 4 heteroatoms arbitrarily selected from nitrogen atom 'oxygen atom' and sulfur atom 5 to: L0-membered heteroaryl group Minocarbon group, C aryl C alkoxy group, C alkyl group

6 "" ^ 10 1 "^ · 丄" "^ 6

Rubonyl, C arylylcarbonyl, C aryl C alkylcarbonyl

6 ~: L0 6 ~: L0 1 ~ 6

Group, C arylamine carbo group, Ν-methyl-N—C arylaminocarbo

6 ~ 10 6 ~ 10

Group, C alkoxy carbo group, C alkyl carboamino group, C ally Roxycarbonyl group, C alkylsulfo-lumino group, c-arylsulfo-

1-3 3-10

Luamino group, including 1 to 4 heteroatoms arbitrarily selected from nitrogen, oxygen, and sulfur atoms! /, 5- to 10-membered heteroarylsulfo-luamino groups, hydroxyl groups, halogen atoms, C alkoxy groups '' C alkyl carbo group 'C alkyl amino group · carboxyl group

~ 3 1 ~ 3 1 ~ 3

• C alkoxy carboxy group · Carboxy C aryl 'C alkylsulfol

1-3 6-6: L0 1-3

Group · trihalogenomethylsulfonyl group · c alkylsulfinyl group · C aryls

1-36 6: L0 sulfonyl group 'consisting of a C alkyl group optionally substituted with a C alkylalkylthio group)

1 to 3 1 to 6

Or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient,

1) 11 j8 -HSD1 inhibition or

2) Regulation of 11 18 -HSD1 activity

A pharmaceutical composition for administration to a patient in need.

[2] A compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 for the manufacture of an inhibitor of U-HSD1 or a modulator of the activity of 11 β-HSD1; Or use of solvates thereof.

[3] The object is to use the compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof.

1) 11 j8 -HSD1 inhibition or

2) Regulation of 11 18 -HSD1 activity

A method for preventing or treating the disease, which is administered to a patient in need.