WO2008044656A1

WO2008044656A1 - Imidazolidinone derivative

Info

Publication number: WO2008044656A1
Application number: PCT/JP2007/069616
Authority: WO
Inventors: Hiroshi Fukushima; Ryo Suzuki; Ayako Mikami; Hiroaki Tanaka
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 2006-10-06
Filing date: 2007-10-05
Publication date: 2008-04-17

Abstract

Disclosed is an imidazolidinone derivative represented by the formula (1), a pharmaceutically acceptable salt thereof, or a hydrate of the derivative or the salt, which has a satisfactory therapeutic effect that relies on a 11β-HSD1-inhibiting activity. (1) wherein A represents an aromatic hydrocarbon ring; R1 and R2 and R3 independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a C1-4 alkyl group, a trifluoromethoxy group, or a C1-4 alkoxy group; R4 represents a C1-4 alkyl group; and X represents a hydroxyl group, a C2-5 alkoxycarbonyl group, acarboxyl group, or a carbamoyl group.

Description

Specification

Imidazolidinone derivatives

Technical field

The present invention relates to an imidazolidinone derivative useful as an 11 β -hydroxysteroid dehydrogenase type 1 (11 / 3-HSD1) inhibitor.

Background art

[0002] 11 β -HSD1 is an enzyme that converts cortisone (inactive darcocorticoid) to cortisol (darcocorticoid), and is expressed mainly in liver, visceral fat and the like. 11 β -HSD1 plays a local role, and is thought to function as a factor that increases the intracellular cortisol concentration in each organ. It is responsible for gluconeogenesis in the liver and is related to the accumulation of visceral fat. Inhibiting the activity of this enzyme has the effect of reducing blood sugar by suppressing gluconeogenesis in the liver and suppressing fat accumulation in visceral fat. Wait. Therefore, the 11 β -HSD1 inhibitor can be expected to be effective against obesity, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertension and metabolic syndrome (see Patent Document 1).

In addition, inhibition of 11 / 3-HSD1 can suppress the increase in local darcocorticoid concentrations, and the diseases that are expected to improve the pathological conditions are neurodegenerative diseases, cognitive impairment, dementia, depression. Diseases such as psychiatric diseases, osteoporosis, glaucoma-induced intraocular pressure disorders (see Patent Document 1), arteriosclerosis, cardiovascular lesions, cerebral infarction, peripheral vascular lesions, hypertension, diabetic nephropathy, retinopathy, Vascular lesions such as diabetic neuropathy and complications of diabetes (see patent document 2), Cushing syndrome (see patent document 3), muscle fatigue (see patent document 4), cellular immunity presumed to be more involved than humoral immunity Tuberculosis, leprosy, psoriasis and the like (see Patent Document 5).

As inhibitors of 11 / 3-HSD1, various compounds such as thiazole derivatives, triazole derivatives, pyrrolidinone derivatives have been reported (see Patent Documents 6 to 19). As for the imidazolidinone derivative having a substituted adamantyl group in the side chain related to the compound of the present invention, a tricyclic compound (see Patent Document 16) is disclosed, but a monocyclic imidazole is disclosed. Zolizinone derivatives are not known. In addition, the activity of these known 11 / 3-HSD1 inhibitors is not sufficient, and it is desired to develop compounds that have therapeutic effects by 11 / 3-HSD1 inhibitory action and are satisfactory as pharmaceuticals! .

[0003] Patent Document 1: International Publication No. WO06 / 055752 Pamphlet

Patent Document 2: International Publication No. WO06 / 068992 Pamphlet

Patent Document 3: International Publication No. WO06 / 066109 Pamphlet

Patent Document 4: International Publication No. WO06 / 040329 Pamphlet

Patent Document 5: International Publication No. WO05 / 110980 Pamphlet

Patent Document 6: International Publication No. WO01 / 90090 Pamphlet

Patent Document 7: International Publication No. WO01 / 90091 Pamphlet

Patent Document 8: International Publication No. WO01 / 90092 Pamphlet

Patent Document 9: International Publication No. WO01 / 90093 Pamphlet

Patent Document 10: International Publication No. WO01 / 90094 Pamphlet

Patent Document 11: International Publication No. WO03 / 065983 Pamphlet

Patent Document 12: International Publication No. WO03 / 104207 Pamphlet

Patent Document 13: International Publication No. WO05 / 108360 Pamphlet

Patent Document 14: International Publication No. WO05 / 108361 Pamphlet

Patent Document 15: International Publication No. WO06 / 024627 Pamphlet

Patent Document 16: International Publication No. WO06 / 024628 Pamphlet

Patent Document 17: International Publication No. WO06 / 049952 Pamphlet

Patent Document 18: International Publication No. WO06 / 068991 Pamphlet

Patent Document 19: International Publication No. WO06 / 068992 Pamphlet

Disclosure of the invention

Problems to be solved by the invention

[0004] An object of the present invention is to provide an imidazolidinone derivative having excellent 11β-HSD1 inhibitory activity.

Means for solving the problem

[0005] As a result of intensive studies to achieve the above object, the present inventors have expressed the following equation (1). It was found that imidazolidinone derivative S, which has a superior 11 β -HSD1 inhibitory activity, completed the present invention.

That is, the present invention refers to the following formula (1)

[0007] [Chemical 1]

[Where

示し indicates an aromatic hydrocarbon ring,

RR ² and R ³ are the same or different and each represents a hydrogen atom; a no, a rogen atom; a trifluoromethyl group; a C 1-4 alkyl group; a trifluoromethoxy group; or a C 1-4 alkoxy group,

R ⁴ represents a C ^1-4 alkyl group,

X represents a hydroxyl group; a C2-5 alkoxycarbonyl group; a carboxyl group; or a strong rubamoyl group. Or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0008] Another aspect of the present invention is the above formula (1).

A represents an aromatic hydrocarbon ring,

R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom; a norologene atom; a trifluoromethyl group; a methyl group; a trifluoromethoxy group;

R ⁴ represents a methyl group,

X is a hydroxyl group; a methoxycarbonyl group; a carboxyl group; or an imidazolidinone derivative which is a strong rubamoyl group, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. Another aspect of the present invention is the above formula (1).

A represents a benzene ring, naphthalene ring or anthracene ring,

RR ² and R ³ are the same or different and each represents a hydrogen atom; a norologene atom; a trifluoromethyl group; a methyl group; a trifluoromethoxy group; or a methoxy group;

R ⁴ represents a methyl group,

X is a hydroxyl group; a methoxycarbonyl group; a carboxyl group; or an imidazole group A dazolidinone derivative or a pharmaceutically acceptable salt thereof or a hydrate thereof. The invention's effect

[0009] According to the present invention, an imidazolidinone derivative having an unprecedented new skeleton and exhibiting excellent 11β-HSD1 inhibitory activity could be provided.

BEST MODE FOR CARRYING OUT THE INVENTION

[0010] In the following, the imidazolidinone derivative of the present invention is not particularly limited to those exemplified in more detail for explaining the imidazolidinone derivative.

[0011] The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Yes

[0012] The C1-4 alkyl group represents a linear or branched alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an η-butyl group, Examples include s-butyl group and t-butyl group.

[0013] The aromatic hydrocarbon ring refers to a skeleton ring excluding a substituent in a monocyclic or condensed polycyclic aromatic hydrocarbon compound having 6 to 15 carbon atoms, such as a benzene ring, a naphthalene ring, Anthracene ring may be mentioned.

[0014] The C1-4 alkoxy group refers to a linear or branched alkoxy group having 1 to 4 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n-butoxy group. Ci group, s-butoxy group, t-butoxy group.

[0015] The C2-5 alkoxycarbonyl group refers to a straight or branched alkoxycarbonyl group having 2 to 5 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, or a propoxycarbonyl group. , Isopropoxycarbonyl group, n-butoxycarbonyl group, s-butoxycarbonyl group, t_butoxycarbonyl group.

[0016] The imidazolidinone derivative of the present invention may be a pharmaceutically acceptable salt thereof or a hydrate thereof. Hereinafter, the imidazolidinone derivative of the present invention or a pharmaceutically acceptable salt thereof or a hydrate thereof is also referred to as “the compound of the present invention”.

[0017] In the present invention, the pharmaceutically acceptable salt is, for example, a mineral salt such as hydrochloride, hydrobromide, hydrofluoride, phosphate, sulfate, nitrate; Sulfonic acids such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate Organics such as oxalate, tartrate, citrate, maleate, succinate, acetate, benzoate, mandelate, ascorbate, lactate, darconate, malate Acid addition salts such as acid salts, glycine salts, lysine salts, arginine salts, ornithine salts, amino acid salts such as glutamate salts, aspartates, or lithium salts, sodium salts, potassium salts, calcium salts , Inorganic salts such as magnesium salts, or salts with organic bases such as ammonium salts, triethylamine salts, diisopropylamine salts, cyclohexylamine salts, preferably hydrochlorides, hydrobromides, phosphates , Sulfate, methanesulfonate, P-toluenesulfonate, oxalate, tartrate, citrate, acetate, lactate, dartrate, aspartate, naphthalate Potassium salts, potassium salts, Anmoniumu salt or Toryechirua Min salts and the like, preferably sodium salts, hydrochlorides or sulfates, more preferably the hydrochloride salt. In the present specification, the compound of the present invention includes a compound that is metabolized in vivo and converted into the compound of the present invention, so-called prodrug. The hydrate in the present invention is a pharmaceutically acceptable hydrate of the compound of the present invention or a salt thereof. The compound of the present invention and the salt thereof may absorb water or become adsorbed water or become a hydrate when exposed to the atmosphere or recrystallized. The compound in the present invention includes such a hydrate.

[0018] The compound of the present invention may have an asymmetric center, in which case there are various optical isomers or arrangements. Thus, the compounds of the present invention may exist as separate optically active forms of (+) and (one) and as racemates or (soil) mixtures. In addition, in the case of a compound having two or more asymmetric centers, diastereomers due to their respective optical isomerism also exist. The compounds of the present invention include all these forms in any proportion. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemical techniques well known for this purpose. . Further, the compound of the present invention may have isomers such as cis isomer and trans isomer. The compounds of the present invention include those isomers and those containing these isomers in an arbitrary ratio.

[0019] The compound of the present invention has 11 β -HSD1 activity inhibitory action, and diseases involving 11 β -HSD1, such as diabetes, metabolic syndrome, obesity, hypertension, arteriosclerosis, It can be used effectively for hyperlipidemia. That is, the compound of the present invention is used as an inhibitor of 11 / 3-HSD1, for example, in diabetes, metabolic syndrome, obesity, hypertension, arteriosclerosis, hyperlipidemia, dementia, dementia, diabetic complications. Diabetic nephropathy, neurosis, retinopathy, cardiovascular disease and cerebral infarction, glaucoma and diseases based on elevated intraocular pressure, neurodegenerative diseases and cognitive impairment, osteoporosis, Cushing syndrome, muscle fatigue, tuberculosis, leprosy, psoriasis It can be used as a therapeutic or prophylactic agent. The compounds of the present invention can be administered as a medicament alone or together with a pharmaceutically or pharmaceutically acceptable carrier or diluent. When the compound of the present invention is used as an 11β-HSD1 inhibitor or the like, the compound of the present invention may be administered orally or parenterally as it is. Moreover, it may be administered orally or parenterally as an agent containing the compound of the present invention as an active ingredient. Parenteral administration includes intravenous administration by injection.

[0020] When the above agents are administered orally, diluents, excipients, disintegrants, binders, lubricants, antioxidants, coating agents, surfactants, plasticizers, colorants, flavoring agents. Or the like, and may be administered as a preparation such as granules, capsules, tablets, medicinal drops, troches, hard candy, powders, sprays and the like containing the compound of the present invention as an active ingredient. Moreover, you may perform sweetening or flavoring suitably. For parenteral administration of the above-mentioned agents, injections, drops, eye drops, creams, salves, suppositories, jelly, jewels, pastes, lotions, ointments, aqueous suspensions, etc. containing the compounds of the present invention as active ingredients It may be administered as a formulation. In formulating, a normal formulation method can be used.

[0021] The compound of the present invention can be administered orally or parenterally, for example, 1 mg to 1000 mg, preferably 10 mg to 200 mg per dose, for example, once to 3 times per day. The dosage of the compound of the present invention can be appropriately adjusted depending on the age, weight and symptoms of the patient.

[0022] The 11 β -HSD1 activity inhibition of the compound of the present invention can be evaluated according to a known method such as the method described in Examples.

[0023] The method for producing the compound according to the present compound will be described in detail, but it is not particularly limited to those exemplified. Further, the solvent used for the reaction is not particularly limited as long as it does not inhibit each reaction. [Scheme 1]

[Chemical 2]

(Where A,

R ² , R ³ , R ⁴ , and X are as defined above. )

Scheme 1 shows a step of converting a diamine derivative (11) into an adamantylamine derivative (15) by reductive amination, followed by conversion to an imidazolidinone derivative (1), an amide derivative (12), (1 3 ) Or (14) is reduced to an adamantylamine derivative (15) and then converted to an imidazolidinone derivative (1).

For example, in the step of converting the diamine derivative (11) to the adamantylamine derivative (15) by reductive amination, the diamine derivative (11) can be converted using various reducing agents. Examples of the reducing agent to be used include lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, diborane, borane tetrahydrofuran complex, borane dimethylsulfide complex, titanium chloride and the like. It is done. In this reaction, a catalytic reduction method using a metal catalyst such as palladium or platinum can also be used. Solvents used in this reaction include methanol, ethanol, chloroform, tetrahydrofuran. , Dioxane, toluene, N, N-dimethylformamide and the like. These reactions can be carried out at 0 to 150 ° C.

[0026] Further, for example, in the step of reducing the amide group of the amide derivative (12), (13) or (14) to convert it to the adamantylamine derivative (15), conversion can be performed using various reducing agents. The Examples of the reducing agent used include lithium aluminum hydride, diborane, borane dimethyl sulfide complex, borane tetrahydrofuran complex, sodium borohydride, lithium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. I can get lost. Examples of the solvent used in this reaction include ethanol, methanol, tetrahydrofuran, dioxane, toluene, xylene and the like. These reactions can be carried out at 0 to 150 ° C.

[0027] In addition, in the step of converting the adamantylamine derivative (15) into the imidazolidinone derivative (1), phosgene, triphosgene {bis (trichloromethinole) carbonate}, benzenechloroformate, etc. It can be used and converted. In this case, the reaction can be carried out using an appropriate base. Examples of the base include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate and sodium hydrogen carbonate. Examples of the solvent used in this reaction include black mouth form, ethyl acetate, jetyl ether, tetrahydrofuran, dioxane, toluene, xylene and the like. These reactions can be carried out at 20 to 50 ° C.

[0028] Further, the adamantylamine derivative (15) is converted to the imidazolidinone derivative (1). This step can also be performed using carbodidiimidazole urea or the like. Examples of the solvent used in this reaction include black mouthform, ethyl acetate, tetrahydrofuran, dioxane, toluene, xylene, acetonitrile, methanol, ethanol, N, N-dimethylphenolamide, water, and the like. It can be carried out at 20 to 200 ° C.

[Scheme 2]

[0029] [Chemical 3]

(Where A,

R ² , R ³ , and R ⁴ are each as defined above. R ⁵ represents a CL_ ⁴ alkyl group. )

Scheme 2 shows a process in which the ester derivative (16) is hydrolyzed to be converted to a carboxylic acid derivative (17) and then converted to a strong rubamoyl derivative (18) by condensation with ammonia.

[0030] For example, the step of hydrolyzing the ester derivative (16) to convert it to the carboxylic acid derivative (17) can be performed using sodium hydroxide, potassium hydroxide, lithium hydroxide or the like. As a solvent to be used, water, methanol, ethanol, tetrahydrofuran, dioxane or the like can be used. The reaction can be carried out at a temperature between 20 ° C and 100 ° C.

[0031] In addition, in the step of converting the carboxylic acid derivative (17) and the ammonia into the strong rubamoyl derivative (18), the rubamoylation can be performed using a dehydrating condensing agent. Examples of dehydrating condensing agents include 1-ethyl _3- (3-dimethylaminopropyl) carpositimide 'hydrochloride, dicyclohexyl carpositimide, diphenyl phosphoryl azide, and carbonyl diimidazole. Activating agents such as 1-hydroxybenzotriazole and hydroxysuccinimide can be used. Examples of the reaction solvent include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, ethyl acetate and the like. At this time, the reaction can be performed using a base. Examples of the base include amines such as triethylamine, N, N-diisopropylethylamine, sodium 2-ethylhexanoate, 2-ethylhexanoic acid. Examples thereof include organic acid salts such as potassium, and inorganic bases such as potassium carbonate. The reaction can be carried out at a temperature between 50 ° C and 50 ° C.

[Scheme 3]

[0032] [Chemical 4]

(In the formula, A, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are each as defined above.)

Scheme 3 shows the step of converting the amine derivative (19) to the diamine derivative (11).

[0033] For example, the conversion from the amine derivative (19) to the amide derivative (20) by amidation includes a method using an acyl chloride, an acid bromide such as an acid chloride, and a method using an ester amide exchange reaction using an ester. Etc.

[0034] Further, for example, in the amidation reaction, the corresponding carboxylic acid or ester can be converted to an acyl halide such as acyl chloride bromide and then condensed with the amine, and the corresponding carboxylic acid or ester acyl halide. For the conversion into thioyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride and the like can be used. Examples of the solvent used in these reactions include solvents that do not participate in the reaction, such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, ethyl acetate, and the like. Can be performed at ° C. The condensation reaction of amine and acylamine can be carried out using an appropriate base. Examples of the base include amines such as triethylamine, N, N-diisopropylethylamine, sodium 2-ethylethylhexanoate, 2-ethylyl. Examples include organic acid salts such as potassium hexanoate or inorganic bases such as potassium carbonate. Examples of the solvent used in these reactions include dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, ethyl acetate, and the like. Can be carried out at 100 ° C.

[0035] Further, as a method using an ester amide exchange reaction using a corresponding ester, An example is a method in which the amine derivative (19) and the ester are heated in a solvent that does not participate in the reaction. Examples of the solvent used in this reaction include black mouth form, tetrahydrofuran, dioxane, toluene, xylene, acetonitrile, methanol, ethanol, N, N-dimethylformamide, etc., and this reaction is carried out at 50 to 200 ° C. be able to.

For example, the amide derivative (20) force and the conversion to the carbamoyl derivative (21) can be carried out by a method using an ester amide exchange reaction using ammonia. Examples of the solvent used in this reaction include black mouthform, tetrahydrofuran, dioxane, toluene, xylene, acetonitrile, methanol, ethanol, N, N-dimethylformamide, and this reaction is performed at 50 to 200 ° C. be able to.

[0037] For example, the step of converting the rubamoyl derivative (21) into the diamine derivative (11) is performed in the same manner as the method for obtaining the diamine derivative (15) from the amide derivative (14) shown in Scheme 1. The power of S

[Scheme 4]

[0038] [Chemical 5] Method>

( twenty five )

(Where A,

R ² , R ³ , R ⁴ , R ⁵ and X are as defined above. R ⁶ represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group. )

[0039] Scheme 4 shows a step of converting an aminoadamantyl derivative (22) or oxoadamantyl derivative (23) into an amide derivative (12).

[0040] For example, an ester derivative having an N-substituent introduced from an aminoadamantyl derivative (22)

In the step of obtaining (24), compound (25) can be used and the reaction can be carried out in the presence of a base. for

Examples of V and base include amines such as triethylamine and diisopropylethylamine, and inorganic substances such as sodium hydride, potassium hydride, n-butyllithium, sodium hydroxide, potassium hydroxide, potassium carbonate and sodium hydrogen carbonate. A base. Examples of the solvent used in this reaction include black mouth form, jetyl ether, tetrahydrofuran, dioxane, toluene, xylene, acetonitrile, methanol, ethanol, N, N-dimethylformamide, water and the like. 50 ~; can be carried out at 150 ° C.

[0041] For example, in the step of obtaining an ester derivative (24) having an oxoadamantyl derivative (23) force N-substituent introduced, reductive amination with the compound (26) can be carried out. Examples of reducing agents used include lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, diborane, borane tetrahydrofuran complex, borane dimethylsulfide complex, and titanium chloride. Can be mentioned. In this reaction, a catalytic reduction method using a metal catalyst such as palladium or platinum can also be used. Examples of the solvent used in this reaction include methanol, ethanol, chloroform, tetrahydrofuran, dioxane, toluene, N, N-dimethylformamide and the like. These reactions can be performed at 0 to 150 ° C.

[0042] Further, for example, the conversion from the ester derivative (24) to the amide derivative (12) involves a condensation reaction between the carboxylic acid obtained by hydrolyzing the ester derivative (24) and the amine derivative (19). for

V, or a method using an ester amide exchange reaction between the ester derivative (24) and the amine derivative (19).

[0043] For example, the step of hydrolyzing the ester derivative (24) can be performed using sodium hydroxide, potassium hydroxide, lithium hydroxide or the like. Solvents used include water and methanol. , Ethanol, tetrahydrofuran, dioxane and the like can be used. The reaction can be carried out at 20 ° C to 100 ° C. In the subsequent condensation reaction with the amine derivative (19), amidation can be carried out using a dehydrating condensing agent. Examples of the dehydrating condensing agent to be used include 1-ethyl-3- (3-dimethylaminopropyl) carpositimide 'hydrochloride, dicyclohexyl carpositimide, diphenylphosphoryl azide, carbonyldiimidazole and the like. Activating agents such as 1-hydroxybenzotriazole and hydroxysuccinimide can be used. Examples of the reaction solvent include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, ethyl acetate and the like. In this case, the reaction can be performed using a base. Examples of the base include amines such as triethylamine, N, N-diisopropylethylamine, sodium 2-ethylhexanoate, 2-ethylhexane. Examples thereof include organic acid salts such as potassium acid and inorganic bases such as potassium carbonate. The reaction can be carried out at a temperature between 50 ° C and 50 ° C.

[0044] Further, for example, a method using an ester amide exchange reaction includes a method in which the ester derivative (24) and the amine derivative (19) are heated in a solvent not involved in the reaction. Examples of the solvent used in this reaction include black mouthform, tetrahydrofuran, dioxane, toluene, xylene, acetonitrile, methanol, ethanol, N, N-dimethylformamide, and the like. The reaction should be performed at 50 to 200 ° C. Can do.

[Scheme 5]

[0045] [Chemical 6]

(In the formula, A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and X are as defined above.)

[0046] Scheme 5 shows a step of converting an amine derivative (19) to an amide derivative (13).

For example, the step of converting the amine derivative (19) to the ester derivative (27) can be carried out by the same method as the method A for obtaining the ester derivative (24) shown in Scheme 4.

Further, for example, the step of converting the ester derivative (27) to the amide derivative (13) can be performed by the same method as the method for obtaining the amide derivative (12) shown in scheme 4.

[Scheme 6]

[0047] [Chemical 7]

(In the formula, A, R ¹ , R ² , RR ⁴ , R ⁵ , and X are each as defined above.)

[0048] Scheme 6 shows a step of converting an ester derivative (28) to an amide derivative (14).

For example, the step of converting the ester derivative (28) to the amide derivative (14) can be performed by a method similar to the method for obtaining the amide derivative (12) shown in Scheme 4.

[0049] The present invention will be specifically described below with reference examples, examples and test examples. It is not particularly limited to those made.

[0050] Reference Example 1 Synthesis of N-[(1S) -1_ (3-methoxypheninole) ethinole] ethanediamide (A-1-1)

Triethylamine (1.2 ml) was added to a solution of (S)-(-)-l_ (3-methoxyphenyl) ethylamine (873 mg) in chloroform (10 ml), and then chloroglyoxylic acid ether with ice cooling. A black mouth form solution (5 ml) of stealth (788 mg) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted with black mouth form, and washed sequentially with 1M aqueous hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethanol (10 ml), 28% aqueous ammonia (3.5 g) was added, and the mixture was stirred overnight at room temperature. The precipitated crystals were collected by filtration, the filtrate was concentrated, and the crystals were further collected by filtration. The obtained crystals were washed with a 1: 1 mixture of methanol and n-pentane. The title compound (1.42 g) was obtained as a colorless powder by drying under reduced pressure at room temperature. The structure and NMR data are 5 and 7 in Table 11.

(S) -l- [3- (trifluoromethyl) phenyl] ethylamine, (S) -l_ [4- (trifluoromethyl) phenyl] ethylamine, (S)-(-)-l_ (4- Using (methylphenyl) ethylamine and (1S) -1_ [4- (trifluoromethoxy) phenyl] ethylamine, (A-12) to (A-15) were obtained in the same manner as described above. The structure and NMR data of the obtained compound are shown in Table 11.

[0051] Reference Example 2 Synthesis of N-[(1S) -1_ (3-methoxyphenyl) ethyl] ethane-1,2-diamin (A—2-1)

Under an argon atmosphere, N-[(1S) -1_ (3-methoxyphenyl) ethyl] ethanediamide (A—1-1) (1.42 g) described in Table 1-1 and borane-tetrahydrofuran complex (1. A mixture of 03M tetrahydrofuran solution (45 ml) was heated to reflux for 6 hours. Once the solvent was distilled off under reduced pressure, 6 M aqueous hydrochloric acid solution was added, and the mixture was heated to reflux for 1 hour. After returning the reaction solution to room temperature, water and sodium hydroxide were added under ice cooling, followed by extraction with black mouth form. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 3:;! ~ 1: 1 ~ black form: methanol = 50:;! ~ 10: 1) The title compound (990 mg) was obtained as a pale yellow oil. Table 12 shows the structure and NMR data of the obtained compound. Compounds (A2-2) to (A-2-5) were synthesized in the same manner as described above using (A-12) to (A-15) synthesized in Reference Example 1. Table 12 shows the structures and NMR data of (A-2-2) to (A-2-5).

[0052] Reference Example 3 Synthesis of ethyl N- (5-hydroxy-2-adamantyl) glycina 1 HA-3-1)

(Method A)

Potassium iodide (1.5 g) was added to an ethanol (15 ml) solution of black ethyl acetate (1. lg) and stirred at 70 ° C. for 0.5 hour, and then 4-aminoadamantan-1-ol (1. 5 g, synthesized by the method described in Khim. Farm. Zh • 810-815 (1986)) and potassium carbonate (1.2 g) were added and stirred at room temperature for 4 hours. After the reaction, the solvent was distilled off under reduced pressure, water was added, the mixture was extracted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying the organic layer with anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: black-form: methanol = 49: 1) to obtain the title compound (1.2 g) as a pale yellow oily substance. Table 13 shows the structure and NMR data of the obtained compound.

[0053] (Method B)

Glycineethyl ester hydrochloride (4.30 g) is suspended in 1,2-dichloroethane (100 ml), and molecular sieve 4A (5 · Og) and 5-hydroxy-2-adamantanone (5. l lg) are cooled on ice. After stirring for 2 hours under ice cooling, the mixture was returned to room temperature and stirred overnight. Thereafter, sodium triacetoxyborohydride (15.2 g) was added, and the mixture was further stirred at room temperature for 5 hours. The reaction solution was filtered through celite, the filtrate was concentrated, diluted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, black-form: methanol = 20: 1) to obtain the title compound (6. l lg) as a colorless oily substance.

[0054] Reference Example 4 Synthesis of N-((1S) _1-phenylethyl) -N '-(5-hydroxy-2-adamantyl) glycine amide (A- 4 1)

Ethyl N- (5-hydroxy-2-adamantyl) glycina mono-HA-3-1) (2.58g) obtained in Reference Example 3 was added with sodium hydroxide (2M methanol solution) (7.5ml) at room temperature. 2 days stirring Stir. After distilling off the solvent under reduced pressure, the resulting residue was dissolved in N, N-dimethylformamide (25 ml) and (1S) _1-phenylethylamine (1.30 ml) and 1-hydroxybenzotriazol (2 · 03 g), 1-ethyl-3- (3_dimethylaminopropyl) carpositimide hydrochloride (2.5 · 4 g) was added and stirred at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform: methanol = 20: 1) to obtain the title compound (1.0 g) as a colorless oily substance. Table 13 shows the structure and NMR data of the obtained compound.

Ethyl N- (5-hydroxy-2-adamantyl) glycinate obtained in Reference Example 3 and (1S) -1-naphthylethylamine, (1S) -1_ (4-fluorophenyl) ethylamine, (1S)- 1_ (4-methoxyphenenoyl) ethylamine, (1S) -1_ (4-chlorophenenole) ethylamine, (1S) -1_ (2-fluorophenenole) ethylamine, (1S) -1_ (2-chromium phenol) Nole) ethylamine (A-6-l) and (1S) -1_ (2-trifluoromethylphenyl) ethylamine were used in the same manner as above, but compounds (A-4 2) to (A-4) 8) was obtained. The structures and NMR data of the obtained compounds are shown in Tables 13 to 14.

Reference Example 5 Synthesis of methyl 4-oxoadamantane-1-carboxylate (A-5-1)

A solution of 4-oxoadamantan-1-ol (5.0 g) in formic acid (25 ml) was added dropwise over 1.5 hours to fuming sulfuric acid (50 ml) heated and stirred at 50 ° C. After completion of dropping, the mixture was stirred at 80 ° C for 10 hours. After the reaction, saturated brine was added under ice cooling, and the mixture was extracted with black mouth form. 4N sodium hydroxide was added to the extracted organic layer, and the aqueous layer was separated. The separated aqueous layer was charged with 12N hydrochloric acid, adjusted to pH 1-2, extracted with black mouth form, and washed with saturated brine. After the organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. A colorless solid and the compound obtained here (3.0 g) were mixed with chloroform (40 ml) and methanol (8 ml). 1-Ethyl-3- (3_dimethylaminopropyl) carpositimide hydrochloride (4.4 g) was added to the solution, and the mixture was stirred at room temperature for 3 days. After the reaction, the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with chloroform, and washed with saturated brine. The organic layer is anhydrous magnesium sulfate After drying with shim, the desiccant was filtered off and the solvent was distilled off under reduced pressure to give the title compound (2.9 g) as a pale yellow oil.

1H NMR (300 MHz, CHLOROFORM—D) σ 1.84-2.28 (m, 11 H), 2.54-2.64 (m, 2 H), 3.69 (s, 3 H).

[0056] Reference Example 6 Synthesis of (1S) -1_ (2-chlorophenyl) ethylamine (A-6- 1)

To a solution of (1S) -1-phenylethylamine (400 g) in jetyl ether (35 Oml) under ice-cooling was added n-butyllithium (2.6M n-hexane solution, 14. Oml). The solution was added dropwise and stirred for 15 minutes. Subsequently, trimethylsilyl chloride (4.30 ml) was added dropwise and stirred for 30 minutes. Further, n_butyl lithium (2.6M n-hexane solution, 40. Oml) was added dropwise and stirred for 1 hour, then the temperature was raised to room temperature and the mixture was stirred overnight. Next, the reaction solution was cooled to -78 ° C, and a solution of hexachloroethane (16.41g) in jetyl ether (50.0ml) was added dropwise, then the temperature was raised to 45 ° C and stirred for 1 hour. . The reaction solution was added dropwise to an ice-cooled 3M aqueous hydrochloric acid solution (90 ml) and stirred for 1 hour. The organic layer was separated and washed with 3M aqueous hydrochloric acid. Potassium hydroxide was added to the aqueous layer to adjust the pH to 12, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate: methanol = 1: 0 to 4: 1) to obtain the title compound (2.02 g) as a pale yellow oily substance.

1H NMR (300 MHz, CHLOROFORM—D) σ 1.40 (d, J = 6.6 Hz, 3 H), 1.57 (s, 2 H), 4.55 (q, J = 6.6 Hz, 1 H), 7.12-7.20 (m , 1 H), 7.23-7.36 (m, 2 H), 7.53 (d, J = 7.8 Hz, 1 H).

Example 1 Synthesis of Compounds (1 la) to (; 15a) and (1 lb) to (; 15b)

(l) Synthesis of 4-[(2-{[(lS) -l_ (3-methoxyphenyl) ethyl] amino} ethyl) amino] adamantane-1-oneore (1A-1)

N-[(1S) -1_ (3-methoxypheninole) ethinole] ethane-1,2-diamine (A—2—1) (990 mg) obtained in Reference Example 2 was added to the black mouth form solution (20 ml). _Hydroxy-2-adamantanone (931 mg) was added and stirred at room temperature for 1 hour, sodium triacetoxyborohydride (3.24 g) was added, and the mixture was stirred at room temperature for 4 hours. Water and 1M aqueous hydrochloric acid solution were added to the reaction mixture, and the mixture was extracted with black mouth form. Sodium hydroxide was added to the aqueous layer and extracted with black mouth form. Organic layer with saturated salt Washed with water and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain the title compound (1.59 g) as a colorless oily substance. The structure and NMR data are listed in Table 2-1.

Compounds (11-2) to (1A-5) were synthesized in the same manner as described above using (Α-2-2) to (Α-2-5) synthesized in Reference Example 1. The structures and NMR data of (1A-2) to (1A-5) are shown in Table 21.

[0058] (2) Ζ-1- (5-Hydroxy-2-adamantyl) -3-[(lS) -l_ (3-methoxyphenyl) ethyl] imidazolidin-2-one (1 la) and El- Synthesis of (5-Hydroxy-2-adamantyl) -3-[(lS) -l_ (3-Methoxyphenyl) ethinole] imidazolidin-2-one (1 lb)

Example 1 4-[(2-{[(lS) -l_ (3-methoxyphenyl) ethyl] amino} ethyl) amino] adamantan-1-ol (1A-1) (1A-1) ( 1. 59 g) of a black mouth form solution (25 ml) was cooled to 15 ° C, triethylamine (1 · 4 ml) and triphosgene (549 mg) were added, and the mixture was stirred for 3 hours while gradually warming. The reaction mixture was diluted with chloroform and washed successively with 0.1 M aqueous hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 1: 1 to 1: 4) to give the title compound (1 1 a) as a colorless powder (540 mg). (1 lb) was obtained as a colorless oil (790 mg). The structure and NMR data are listed in Table 31.

Example 1 Using (1 A-2) to (; 1A-5) synthesized in (1), compounds (12a) to (; 15a) and (12b) to (; 15b) were Synthesized in the same way. The structure and NMR data of the obtained compound are shown in Tables 3-1 to 3-2.

Example 2 Synthesis of Compounds (2-la) to (2-8a) and (2-lb) to (2-8b)

(l) Synthesis of 4-[(2-([(lS) _l-phenylethyl] amino) ethyl) amino] adamantan-1-ol (2A 1)

Borane tetrahydrofuran complex (32 · Oml) was added to (A-4-1, 1.00 g) obtained in Reference Example 4 under ice-cooling, and the mixture was heated to reflux for 14 hours. After the solvent was distilled off under reduced pressure, 3M hydrochloric acid aqueous solution (10 ml) was added to the obtained residue, and the mixture was heated to reflux for 1 hour. Sodium hydroxide was added to adjust the pH to 12, followed by extraction with black mouth form and washing with saturated brine. Organic layer with anhydrous sodium sulfate After drying, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, black mouth form: methanol: 28% aqueous ammonia = 95: 5: 0.1 to 90: 10: 1.0.1), and the title was obtained as a colorless oily substance. Compound (0.70 g) was obtained. The structure and NMR data of the obtained compound are shown in Table 2-2.

Compounds (2A-2) to (2A-8) were obtained in the same manner as described above using the compounds (A-42) to (A-48) obtained in Reference Example 4. The structures and NMR data of the obtained compounds are shown in Tables 2-2 to 2-3.

[0060] (2) Z-1-[(1S) _1-phenylethyl] -3- (5_hydroxy-2-adamantinore) imidazolidin-2-one (2-la) and E-1-[(1S) _1-phenylethyl] -3- (5_hydroxy-2-adamanthinore) imidazolidin-2-one (2-lb)

Example 1 4-[(2-([(lS) _l-phenylethyl] amino) ethyl) amino] adamantan-1-ol (2A—1) (0 · 70 g), triphosgene (0.23 g) and triethylamine (0.68 ml) were used to obtain the title compound (2-la) as a colorless powder (21 lmg) and (2-1 b) as a colorless powder (285 mg). . The structure and NMR data are shown in Table 3-3.

Using compounds (2A-2) to (2A-8), compounds (2-2a) to (2-8a) and (2-2b) to (2-8b) were obtained in the same manner as described above. The structure and NMR data of the obtained compound are shown in Table 33 to Table 3-5.

[0061] Example 3 Methyl 4- {3-[(lS) -l- (4-methoxyphenyl) ethyl] -2-oxoimidazolidine-1-yl} adamantane-1-carboxylate (3- Synthesis of 1)

(1) Synthesis of methyl 4-[(2-{[(lS) -l_ (3-methoxyphenyl) ethyl] amino} ethyl) amino] adamantane-1-carboxylate (3A-1)

Methyl 4-oxodadamantane-1-carboxylate (A—5—1) (1.2 g) and (S)-(−)-1- (4-methoxyphenyl) ethylamine obtained in Reference Example 5 Compound (3A-1) was obtained as a yellow oil (2. Og) in the same manner as in Example 1 (1). The structure and NMR data are listed in Table 2-3.

[0062] (2) Methyl 4- {3-[(lS) -l_ (4-methoxyphenyl) ethyl] -2-oxoimidazolidine-1-yl} adamantane-1-carboxylate (3 1) Synthesis of

Example 3 Methyl 4-[(2-{[(lS) -l_ (3-methoxyphenyl) ethyl] amino} ethyl obtained in (1) (L) amino] adamantane-1-carboxylate (3A-1) (2. Og) was used in the same manner as in Example 1 (2) to give compound (3-1) as a pale yellow oil (0. 85 g) Got as. The structure and NMR data are shown in Table 3-6.

Example 4 Z-4- {3-[(lS) -l- (4-methoxyphenyl) ethyl] -2-oxoimidazolidine-1-yl} adamantane-1-carbonoxylica Cyd (4 1 a) and E-4- {3-[(1 S) _ 1 _ (4_methoxy phenenole) ethyl] -2-oxoimidazolidine-1-inore} adamantane-1-carboxoxy Synthesis of quasacid (4 lb)

Methyl 4- {3-[(lS) -l_ (4-methoxyphenyl) ethyl] -2-oxoimido zolidine-1-yl} adamantane-1-carboxylate obtained in Example 3 (E and Z To a solution of 0.85 g) in tetrahydrofuran (5 ml) was added 1/6 sodium hydroxide (5 ml), and the mixture was stirred at room temperature. Thereafter, 8N sodium hydroxide (2 ml) was added, and the mixture was heated to reflux and stirred for 2 hours. After the reaction, 6N hydrochloric acid was added to adjust the pH to 1 to 2, followed by extraction with black mouth form and washing with saturated saline. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 4: 1) to give the title compounds (4 la, 0.15 g), (4 lb, 0.14 g). ) Were obtained as colorless solids, respectively. Structure and NMR data are listed in Table 3-6

Yes

Example 5 E-4- {3-[(lS) -l- (4-methoxyphenyl) ethyl] -2-oxoimidazolidine-1-ynole} adamantane-1-carboxamide ( 5—synthesis of la)

To a solution of the compound obtained in Example 4 (4 la, 62 mg) in chloroform (2 ml), N, N_diisopropylethylamine (0 · 08 ml), 1-hydroxybenzotriazole (49 mg), 1- Ethyl-3- (3_dimethylaminopropyl) carpositimide hydrochloride (46 mg) was added, and the mixture was stirred at room temperature for 1 hour. Ammonia (2M methanol solution, 0 · 23 ml) was added thereto and stirred at room temperature for 3 days. After the reaction, water was added and the mixture was extracted with ethyl acetate and washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol = 9: 1) to obtain the title compound (5-la, 42 mg) as a colorless solid. The structure and NMR data are listed in Table 3-6. Using the compound (4 lb) obtained in Example 4, the compound (5-lb) was obtained in the same manner as described above. The structure and NMR data are listed in Table 3-6.

[0065] [Table 1-1]

[0066] [Table 1-2]

-3]

1-4]

1]

2-2]

-3]

-1]

3-2]

3]

Four]

Five]

6]

Test Example [11 / 3HSD1 Inhibition Test] Test compounds were evaluated as follows. The 11 β HSD1 enzyme reaction was performed in 96 μl reaction solution using 96 Well Polypropylene Microplates. The reaction mixture was 30 mM TrisHCl (pH 7.4) / lmM EDTA buffer, final concentration 100 μΜ NADPH, final concentration ImM G6P, final concentration 0.8 μg / ml human liver microsome (enzyme source, Tissue Transformation Technologies), a test compound 101 dissolved in DMSO was added, and the enzyme reaction was started by adding cortisone at a final concentration of 100 nM. After incubation at 20 ° C for 80 minutes, the reaction was stopped by adding 101 non-specific inhibitor ImM 18β glycyrrhetinic acid. Next, the generated conoletin was directly quantified using a detection kit (Nihon Schering Co., Ltd.) based on the HTRF (Homogeneous Time-Resolved Fluorescence) method. This system detects fluorescence resonance energy transfer between anti-cortisol antibody labeled with europium and cortisol labeled with XL665. When unlabeled cortisol is added, the binding signal is attenuated by competitive reaction. To do. At this time, the amount of cortisol produced by the reaction was evaluated using a standard curve obtained from cortisol of known concentration attached to the kit. The HTRF reaction was performed in 96 Well Half Area Microplates by adding the kit anti-cortisol antibody solution 15 ^ 1 and XL665-labeled Conoretizole solution 15 ^ 1 to 30 1 enzyme reaction solution, and stirring at room temperature for 1 hour. Further, it was allowed to stand at 20 ° C for 1 hour. The reaction solution 401 was transferred to 384we 11 Microplates and fluorescence was measured. Before the start of the enzymatic reaction, the amount of cortisol produced by adding 18 β-glycyrrhetinic acid was used as a background, no compound was included! /, The amount of cortisol produced by well was taken as 100% enzyme activity, and the ratio of each compound was 3 The IC50 value was calculated using the dilution series.

[0079] Compound No. IC50

Compound 2— 4b 15nM

Compound 2— 5b 12nM

Industrial applicability

[0080] According to the present invention, it is possible to provide a compound having an excellent 11β-HSD1 inhibitory activity, and the compound of the present invention is used as an active ingredient of a pharmaceutical agent having a sufficient therapeutic effect as an 11 / 3-HSD1 inhibitory action. be able to.

Claims

The following formula (1)

[Chemical 1]

[Where

A represents an aromatic hydrocarbon ring,

R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom; a norologene atom; a trifluoromethyl group; a C 1-4 alkyl group; a trifluoromethoxy group; or a C 1-4 alkoxy group. Show

R ⁴ represents a C ^1-4 alkyl group,

X represents a hydroxyl group; a C2-5 alkoxycarbonyl group; a carboxyl group; or a strong rubamoyl group. ] The imidazolidinone derivative represented by these, its pharmaceutically acceptable salt, or those hydrates.

[2] In the above formula (1)

A represents an aromatic hydrocarbon ring,

R ⁴ represents a methyl group,

The imidazolidinone derivative according to claim 1, wherein X is a hydroxyl group; a methoxycarbonyl group; a carboxyl group; or a strong rubamoyl group, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[3] In the formula (1)

A represents a benzene ring, naphthalene ring or anthracene ring,

R ⁴ represents a methyl group,

X is a hydroxyl group; a methoxycarbonyl group; a carboxyl group; or a strong rubamoyl group. The imidazolidinone derivative according to claim 1, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[4] A medicament comprising, as an active ingredient, the imidazolidinone derivative according to claim 1, 2 or 3, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[5] The medicament according to claim 4, for preventing or treating a disease or condition that can be improved by inhibiting 11β-HSD1.

[6] The disease or condition that can be ameliorated by inhibiting 11 13 -HSD1 is diabetes.

[7] The medicament according to claim 5, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSD1 is metabolic syndrome.

[8] The disease or condition that can be ameliorated by inhibiting 11 13 -HSD1 is obesity.

[9] The medicament according to claim 5, wherein the disease or condition that can be improved with 11 / 3-HSD1 is hypertension.

[10] Inhibits 11 / 3-HSD1: The disease or condition that can be ameliorated in or is atherosclerosis.

5. The medicine according to 5.

[11] The medicament according to claim 5, wherein the disease or condition that can be improved with 11 / 3-HSD1 is hyperlipidemia.

[12] 11/3 -Inhibits HSD1: The disease or condition that can be improved by dementia according to claim 5

[13] The disease or condition that can be ameliorated by inhibiting 11 / 3-HSD1 is: dementia.

[14] The medicament according to claim 5, wherein the disease or condition that can be improved by inhibiting 11β-HSD1 is diabetic nephropathy, neuropathy, retinopathy, cardiovascular disease, or diabetic complications of cerebral infarction.

[15] The medicament according to claim 5, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSD1 is a disease based on glaucoma and increased intraocular pressure.

[16] The medicament according to claim 5, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSD1 is a neurodegenerative disease or a cognitive disorder.

[17] The medicament according to claim 5, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSDl is osteoporosis.

[18] The medicament according to claim 5, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSDl is Cushing's syndrome, muscle fatigue, tuberculosis, leprosy, or psoriasis.