WO2006080406A1

WO2006080406A1 - Tricyclic compounds

Info

Publication number: WO2006080406A1
Application number: PCT/JP2006/301248
Authority: WO
Inventors: Minoru Taguchi; Ryo Suzuki; Ayako Mikami; Koji Yamamoto; Takumi Sekine
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 2005-01-28
Filing date: 2006-01-26
Publication date: 2006-08-03

Abstract

Diseases including hypertriglyceridemia, diabetes, impaired glucose tolerance, obesity and fatty liver are composite syndromes defined as life style-related diseases. It appears that the fundamental cause for these diseases resides in hypermetabolism of fatty acids in the liver or fat tissues due to the accumulation of visceral fat. It is considered that accelerated fatty acid synthesis ability can be generally ameliorated by inhibiting the effect of SREBP-1c which is a transcriptional factor comprehensively controlling the lipogenic enzyme family. Thus, it is expected that fatty acid synthesis can be more efficiently lowered thereby. A novel tricyclic compound or a pharmaceutically acceptable salt thereof which has effects of lowering the triglyceride level in the liver and lowering the blood glucose level by inhibiting the expression of SREBP-1c and, therefore, is useful as a preventive or a remedy for diabetes, hyperlipemia, fatty liver, obesity, impaired glucose tolerance, diabetic complications (for example, nephropathy, nervous disorder, retinopathy, etc.), metabolic syndrome and syndrome X.

Description

Specification

Tricyclic compounds

Technical field

[0001] The present invention relates to a novel tricyclic compound. Specifically, it is a novel tricyclic compound that suppresses the expression of SREBP-lc. More specifically, by suppressing the expression of SREBP-lc, it has the effect of lowering triglycerides in the liver and lowering blood glucose levels, resulting in diabetes, hyperlipidemia, fatty liver, obesity, glucose intolerance, diabetic complications (Eg, nephropathy, neuropathy, retinopathy, etc.), metabolic syndrome, and syndrome X

Background art

[0002] SREBPs are transcription factors belonging to the basic helix loop one helix bite icin zipper (bHLH-Zip) family. At first, by researching cholesterol metabolism, especially in research on transcriptional regulation of LDL receptor gene, by binding to specific sequences such as SRE (sterol regulatory element) sequences on promoters of genes that are subject to transcriptional regulation, It has been reported that it has an action of promoting transcription activity (Non-patent Document 1).

[0003] There are three types of SREBP isoforms: SREBP-la, lc, and 2, and SREBP-1 and SREBP-2 show about 47% amino acid homology. SREBP-lc is a repo-enzyme gene group related to synthesizing a fatty acid such as acety 卜 CoA carb oxylase, fatty acia synthase ^ glycerol- «3-phosphate phosphatetransferase, and SREBP-2 is HMG-CoA reductase, LDL receptor It has been reported that cholesterol metabolism-related genes such as SREBP-la are involved in both of these transcriptional controls (Non-patent Document 2).

[0004] Expression of SREBP-la and SREBP-lc is regulated by different promoters existing in the same gene. Due to this alternative splicing, the first exon is expressed as a different isoform, and SREBP-la has a longer region bound to acidic amino acids, which are transcriptional active domains located on the N-terminal side than SREBP-lc. It has strong transcriptional activity and induces not only fatty acid synthesis system but also cholesterol synthesis system.

[0005] SREBP-la is a highly expressed medium in lymphoid tissues such as spleen and thymus, and mucosal epithelium of the intestinal tract. Expression is elevated in highly proliferative cells such as feeder cells, and it is thought that lipids required for division are supplied. In tissues such as the liver, SREBP-lc is expressed more than REBP-la, and it is known to play a role as a master regulator of the reposienic enzyme responsible for fatty acid synthesis. (Non-Patent Document 3)

[0006] Transgenic mice in which SREBP-lc is expressed specifically in adipose tissue exhibit fat-atrophic diabetes and are known to cause hyperinsulinemia, insulin resistance, and fatty liver (non-) Patent Document 4). It is also reported that SREBP-lc expression increases at high sucrose loading, but the induction is lost in SREBP-1 knockout mice! /! (Non-Patent Document 3).

[0007] Furthermore, it has been reported that when the expression of mouse liver-derived cell line H2.35 is evaluated, the expression level of SREBP-lc increases in a glucose concentration-dependent manner (Non-patent Document 5).

[0008] Nicotinic acid preparations, fibrates and the like exist as compounds having a triglyceride lowering action. However, nicotinic acid preparations are known to rather deteriorate glucose tolerance, and for fibrate drugs, bezafibrate improves insulin resistance, resulting in hypoglycemic effects such as sulfonylurea drugs used in combination. There is a power to strengthen The power itself does not exhibit a hypoglycemic effect.

[0009] As compounds having hypoglycemic activity, sulfo-urea drugs, thiazolidine derivatives, biguanides, darcosidase inhibitors, etc. are present. Other than thiazolidine derivatives have action on lipids! ,. Thiazolidine derivatives are known as compounds having a triglyceride lowering action and a blood glucose level lowering action, but all have a chemical structure different from that of the compound of the present invention.

[0010] Non-Patent Document 1: Brown, M.S., et al., Cell, 89, 331-40 (1997)

Non-Patent Document 2: Horton, J.D., et al., J. Clin. Invest., 101, 2331-9 (1998)

Non-Patent Document 3: Shimano, H "et al, J. Biol. Chem., 274, 35832-35839 (1999) Non-Patent Document 4: Shimomura, I., et al" Genes Dev., 12, 3182-94 ( 1998)

Non-Patent Document 5: Hasty, A.H., et al "J. Biol. Chem., 275, 31069-31077 (2000) Disclosure of the Invention

Problems to be solved by the invention [0011] Diseases such as hypertriglyceridemia, diabetes, impaired glucose tolerance, obesity, and fatty liver are complex syndromes defined as lifestyle-related diseases. The basis of these diseases is visceral fat accumulation, which may be due to increased fatty acid metabolism in the liver or adipose tissue. S REBP-lc is a transcription factor that comprehensively regulates the reposienic enzyme system. By suppressing this action, it is thought that the enhancement of fatty acid synthesis ability can be improved overall. Compared to drugs targeting the inhibition of single enzymes in complex lipid metabolism pathways, it is expected to be more effective in reducing fatty acid synthesis and there may be less concern about side effects such as accumulation of intermediate metabolites. Therefore, it is to provide a novel compound that suppresses the expression of SREBP-lc and has less side effects.

Means for solving the problem

[0012] As a result of diligent research to achieve the above-mentioned problems, the present inventors have found that certain tricyclic compounds suppress the expression of SREBP-lc and completed the present invention.

That is, the present invention relates to the formula (I)

[0013] [Chemical 1]

(Wherein R ¹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

A ring is represented by the following formula:

[0015] [Chemical 2]

^Haha

A- 1 A- 2 Α-3

(Wherein R ² is a hydroxyalkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 6 carbon atoms, an amide group having 1 to 10 carbon atoms (provided that N, O-dimethylhydroxy And a nitrile group, an alkyl group having 1 to 6 carbon atoms, an amino group, an acylamino group having 2 to 6 carbon atoms, or a hydroxyiminoalkyl group having 1 to 6 carbon atoms.) And ring B is represented by the following formula: [0017] [Chemical 3]

[In the formula, R ³ and R ⁴ independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a substituted alkoxy having 1 to 6 carbon atoms. Group, an acyloxy group having 2 to 6 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group, an alkylsulfo-loxy group having 1 to 6 carbon atoms, a phenol sulfo group, a p-tolyl sulfo-oxy group or Represents a trifluoromethanesulfol group), and W represents the formula -CH- or the formula-(CH)-.

2 2 2 Where A ring represents Formula A-1, R ² represents an alkyl group having 1 to 6 carbon atoms or an acyl group having 2 to 6 carbon atoms, W represents the formula —CH—, and R ¹ represents hydrogen. An atom and the B ring is of the formula B-

2

In the case of 1, R ³ and R ⁴ are not hydrogen compounds, alkyl groups having 1 to 6 carbon atoms, and compounds having 1 to 6 carbon atoms. Ring A represents Formula A-1, R ² represents an amide group having 1 to 10 carbon atoms (excluding N, O-dimethylhydroxycarboxamide group) or -tolyl group, and W is- CH-, R ¹ represents a hydrogen atom, and ring B represents formula B-1.

2

And R ³ and R ⁴ are not hydrogen compounds. Or a pharmaceutically acceptable salt thereof.

[0019] Preferably, the A ring is the formula A-1, R ² is a hydroxyalkyl group having 1 to 6 carbon atoms, W is the formula -CH ^2- , and the B ring is the formula B-1. R ¹ is a hydrogen atom or a carbon atom number 1 to 6

2

When R ¹ is a hydrogen atom, R ³ and R ⁴ are substituted alkoxy groups having 1 to 6 carbon atoms, and R ¹ is an alkyl group having 1 to 6 carbon atoms, R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a substituted alkoxy group having 1 to 6 carbon atoms, represented by the above formula (I). Compound or a pharmaceutically acceptable salt thereof.

More preferably, the A ring is the formula A-1, R ² is an acyl group, W is —CH 2 —, and the B ring.

2

Is Formula B-1, R ¹ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ¹ is a hydrogen atom, R ³ and R ⁴ are independently a cetoxy group or a carbon atom. When R ¹ is a substituted alkoxy group having 1 to 6 carbon atoms and R ¹ is an alkyl group having 1 to 6 carbon atoms, R ³ and R ⁴ are independently A tricyclic compound represented by the above formula (I), which is an elementary atom, an alkyl group having 1 to 6 carbon atoms, an acetoxy group, or a substituted alkoxy group having 1 to 6 carbon atoms, or a pharmaceutically acceptable product thereof. It is a salt.

[0021] Further, the present invention is a SREBP-lc expression inhibitor comprising as an active ingredient a tricyclic compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof.

[0022] Further, the present invention is a triglyceride lowering agent comprising as an active ingredient a tricyclic compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof.

[0023] The present invention is also a blood glucose level-lowering agent comprising as an active ingredient a tricyclic compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof.

[0024] Further, the present invention provides diabetes, hyperlipidemia, fatty liver, obesity, which comprises a tricyclic compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Glucose intolerance, diabetic complications

It is a preventive or therapeutic agent for metabolic syndrome and syndrome X.

[0025] The present invention is also a triglyceride lowering agent that also has a compound power having an SREBP-lc expression inhibitory action.

[0026] The present invention is also a hypoglycemic agent that also has a compound ability to suppress SREBP-lc expression.

[0027] The present invention also relates to the prevention or prevention of diabetes, hyperlipidemia, fatty liver, obesity, glucose intolerance, diabetic complications, metabolic syndrome, syndrome X comprising a compound having a SREBP-lc expression inhibitory action. It is a therapeutic agent.

The invention's effect

[0028] The tricyclic compound of the present invention that suppresses the expression of SREBP-lc has a triglyceride lowering action and a blood sugar level lowering action in the liver, and it has diabetes, hyperlipidemia, fatty liver, obesity. Syndrome, glucose intolerance, diabetic complications (eg nephropathy, neuropathy, retinopathy, etc.), metabolic syndrome, syndrome X prevention and Z or therapeutic effects.

BEST MODE FOR CARRYING OUT THE INVENTION

[0029] In the present invention, the alkyl group having 1 to 6 carbon atoms means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, Propyl group, t-butyl group, cyclopentyl group, cyclohexyl group, cyclopentylmethyl group Can be mentioned.

[0030] The acyl group having 2 to 6 carbon atoms refers to a linear, branched or cyclic acyl group having 2 to 6 carbon atoms such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group. And cyclopentyl carbo yl group.

[0031] The amide group having 1 to 10 carbon atoms refers to a linear, branched or cyclic amide group having 1 to 10 carbon atoms, for example, a rubamoyl group, a methylamide group, a propylamide group. , T-butylamide group, cyclopentylamide group, dimethylamide group, and arylide group.

[0032] The acyl group having 2 to 6 carbon atoms is a linear, branched or cyclic acyl group having 2 to 6 carbon atoms, and includes, for example, an acetylamino group, a propio-lamino group, an isobutylylamino group, And a cyclopentylcarbo-lamino group.

[0033] The hydroxyiminoalkyl group having 1 to 6 carbon atoms represents a linear, branched or cyclic hydroxyiminoalkyl group having 1 to 6 carbon atoms, such as a hydroxyiminomethyl group, Examples include 1-hydroxyiminoethyl group, 1-hydroxyiminopropyl group, and (hydroxyimino) monocyclopentylmethyl group.

[0034] The alkoxy group having 1 to 6 carbon atoms refers to a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, such as methoxy group, ethoxy group, propoxy group, t- Examples include butoxy, cyclopentyloxy, cyclohexyloxy, and cyclopentylmethyloxy.

[0035] The substituent of the substituted alkoxy group having 1 to 6 carbon atoms includes a halogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, an unsubstituted or substituted amino group, an amide group, a cyano group, and the number of carbon atoms. It may be substituted with a 2 to 6 acyl group, a carboxy group, a C2 to C6 alkoxycarbonyl group, a phenoxy group, a phenolthio group, a C1 to C6 alkyl group, or a halogen atom. Examples include phenyl, pyridyl, chenyl, furyl, pyrrolyl, isoxazol, tetrahydrofuryl, tetrahydrobiral, 2-oxoxazolidinyl, or 1,3-dioxal. The substituted amino group refers to an amino group substituted with an alkyl group having 1 to 6 carbon atoms, and examples thereof include a methylamino group, an ethylamino group, and a dimethylamino group. Further, a methanesulfonamino group, an acetylamino group, a pyrrolidi- Group, piperidyl group or morpholinyl group. The amide group is as described above. In addition to an amide group having 1 to 10 carbon atoms, an amide group that is substituted with an alkyl group having 1 to 6 carbon atoms that may be substituted with a hydroxyl group, such as (hydroxymethyl) amide group, ) Amido group, and (N, O dimethylhydroxycarboxamide group, t-butoxycarboxamide group, and amide group) Alkoxycarbonyl group having 2 to 6 carbon atoms is linear or branched. A linear or cyclic C2-C6 alkoxy carbonyl group is exemplified, and examples thereof include a methoxy carbo ol group, an ethoxy carbo ol group, a propoxy carbo ol group and a t-butoxy carbo ol group.

[0036] The acyloxy group having 2 to 6 carbon atoms means a linear, branched or cyclic acyloxy group having 2 to 6 carbon atoms, such as an acetoxy group, a propio-loxy group, isobutyryl. An oxy group, and a cyclopentylcarbo-loxy group.

[0037] The alkylsulfonyloxy group having 1 to 6 carbon atoms refers to a linear, branched or cyclic alkylsulfoxy group having 1 to 6 carbon atoms, such as a methanesulfoxy group. Propylsulfoxyloxy group, t-butylsulfoloxyl group, and cyclohexylsulfoloxyl group.

[0038] The pharmaceutically acceptable salt in the present invention is an acid or alkali addition salt. Acids include salts with mineral acids such as sulfuric acid, hydrochloric acid, and phosphoric acid, and salts with organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, and benzenesulfonic acid. Examples of the alkali include metal ions such as sodium and potassium, and ammonium ions such as alkyl ammonium.

[0039] The compound of the present invention may be a single compound or a mixture of stereoisomers. In addition, the compound of this invention can exist also as various solvates. It may also be a surface hydrate of applicability as a medicine.

[0040] The compounds of the present invention also include compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, sulfur atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful for metabolic and pharmacokinetic studies, or for biological analysis as receptor ligands.

[0041] The compound of the present invention can be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical preparation. The above carrier, excipient and diluent Examples include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, methyl cellulose , Polybulurpyrrolidone, alkyl parahydroxybenzosorbate, tanolec, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil, and other oils.

[0042] In addition, additives such as extenders, binders, disintegrants, pH adjusters, and solubilizers that are generally used as necessary are mixed with the above carriers, excipients, or diluents, so that usual preparations are mixed. Depending on the technology, it can be prepared as an oral or parenteral pharmaceutical such as tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, injections, skin patches and the like. The compound of the present invention can be administered orally or parenterally to an adult patient in an amount of 0.001 to 500 mg once or several times a day. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.

[0043] The compound of the present invention can be produced, for example, according to the method shown below. In the following, WSC 'HCl is 1-ethyl 3- (3 dimethylaminopropyl) carbodiimide hydrochloride, DCC is dicyclohexylcarbodiimide, HOBt is 1-hydroxybenzotriazole, and DEAD is jetyl. Azodicarboxylate, Boc represents a t-butoxycarbonyl group.

[0044] In the compound of the present invention, R ¹ represents a hydrogen atom, A ring represents Formula A-1, R ² represents an acyl group having 2 to 6 carbon atoms, and B ring represents Formula B-1. Compound (2) in which R ³ represents a hydrogen atom, R ⁴ represents a substituted alkoxy group having 1 to 6 carbon atoms, and W represents the formula —CH 2 —

2

As shown in Scheme 1, Method A: a method in which a phenol intermediate (1) and a substituted alkyl halide are reacted in the presence of a base, or Method B: a method in which a phenol intermediate (1) and a substituted alcohol are reacted by Mitsunobu. This can be synthesized.

Reaction scheme 1

[0045] [Chemical 4]

(Wherein R ⁵ is an acyl group having 2 to 6 carbon atoms, and R ⁶ represents a substituted alkoxy group having 1 to 6 carbon atoms.)

In the compound of the present invention, R ¹ represents a hydrogen atom, A ring represents Formula A-1, R ² represents an acyl group having 2 to 6 carbon atoms, and B ring represents Formula B-1. R ³ represents a hydrogen atom, R ⁴ represents the formula [0048]

0

[0049] The compound (4) in which W represents the formula -CH 2-represents a compound (3)

2

It can be obtained by hydrolysis.

Reaction scheme 2

[0050] [Chemical 6]

[0051] (wherein R ⁵ has the same meaning as described above, and R ⁷ has the formula

[0052] [Chemical 7] Ύ

0

[Wherein R ⁹ represents an alkyl group having 1 to 6 carbon atoms], and R ⁸ represents a formula

[0054] [Chemical 8]

[0055] is shown. )

[0056] In the compound of the present invention, R ¹ represents a hydrogen atom, the heel ring represents Formula A-1, and R ² represents carbon. An acyl group having 2 to 6 atoms, ring B represents formula B-1, R ³ represents a hydrogen atom, R ⁴ represents a formula [0057] [Chemical 9]

,. ,

0

(In the formula, R ^1Q is an alkyl group having 1 to 6 carbon atoms which may be substituted with a hydrogen atom or a hydroxyl group, and R ¹¹ is an alkyl group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group. Compound (5) in which W represents the formula -CH 2-is a compound of the compound (4) as shown in Reaction Scheme 3.

2

It can be obtained with Amido. Here, as a method for converting to amide, a method using a condensing agent such as WSC 'HC1, DCC, or a method via acid chloride can be used.

Reaction scheme 3

[0059] [Chemical 10]

[0060] (wherein R ⁵ and R ⁹ are as defined above, and R ¹² represents the formula

[0061] [Chemical 11]

, 0 R,

0

[0062] (R ^1Q and R ¹¹ are as defined above). )

[0063] In the compound of the present invention, R ¹ represents a hydrogen atom, A ring represents Formula A-1, R ² represents an acyl group having 2 to 6 carbon atoms, and B ring represents Formula B-1. R ³ represents a hydrogen atom, R ⁴ represents the formula [0064] [Chemical 12]

, 0 ^^ 瞧 13

(Wherein R ¹³ represents an acyl group having 2 to 6 carbon atoms or an alkylsulfonyl group having 1 to 6 carbon atoms), and a compound in which W represents the formula —CH 2 — (7 ) As shown in Reaction Scheme 4.

2

Further, the compound (6) can be obtained by deprotection and then amidation. Reaction scheme 4

[0066] [Chemical 13]

[In the formula, R ⁵ has the same meaning as described above, and R ¹⁴ represents the formula

[0068] [Chemical 14]

[0069] R ¹⁵ is the formula

[0070] [Chemical 15]

, 0 ^^ 隱 13

Wherein R ¹³ is as defined above. )

In the compound of the present invention, R ¹ represents a hydrogen atom, A ring represents Formula A-1, R ² represents an acyl group having 2 to 6 carbon atoms, and B ring represents Formula B-1. R ³ represents a hydrogen atom, R ⁴ represents the formula [0073]

[0074] Compound (8) in which W represents the formula -CH 2-represents a compound (8) as shown in Reaction Scheme 5

2

Can be obtained by hydrolysis. Examples of the hydrolysis method include a method using t-butyl alcohol in potassium butyl alcohol and a method of heating in hydrochloric acid. Reaction scheme 5

[0075] [Chemical 17]

[In the formula, R ⁵ has the same meaning as described above, and R ¹⁶ represents the formula

[0077] [Chemical 18] [0078] where R ¹⁷ is the formula

[0079] [Chemical 19]

[0080] )

[0081] In the compound of the present invention, R ¹ represents a hydrogen atom, A ring represents Formula A-1, R ² represents an acyl group having 2 to 6 carbon atoms, and B ring represents Formula B-1. R ³ represents a hydrogen atom, R ⁴ represents the formula [0082] [Chemical 20]

[0083] Compound (11) in which W represents the formula -CH 2-represents a compound (1

2

0) can be obtained by clotting. Here, as a clotting agent, thiolucyl lide, methanesulfol sulfide, carbon tetrachloride triphenylphosphine, phosphoryl chloride and the like can be used.

Reaction scheme 6

[0084] [Chemical 21]

[In the formula, R ⁵ has the same meaning as described above, and R ¹⁸ represents the formula

[0086] [Chemical 22]

[0087] R ¹⁹ is the formula

[0088] [Chemical 23]

[0089] ) [0090] In the compound of the present invention, R ¹ represents a hydrogen atom, the A ring represents Formula A-1, and R ² represents an amide group having 1 to 10 carbon atoms (provided that Ν, Ο-dimethylhydroxycarboxamide group) The ring represents formula B-1, R ³ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, and R ⁴ represents carbon. Compound (13), which represents an alkyl group having 1 to 6 atoms or an alkoxy group having 1 to 6 carbon atoms, and wherein W represents the formula —CH 2 — is represented by Reaction Scheme 7

2

As shown in the above, it can be obtained by amidating compound (12). Here, the method described above can be used as a method for conversion to amide.

Reaction scheme 7

[0091] [Chemical 24]

[0092] (In the formula, R ° represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, and R ²¹ represents an alkyl group having 1 to 6 carbon atoms or carbon. An alkoxy group having 1 to 6 atoms is represented, and R ²² represents an amide group having 1 to 10 carbon atoms (excluding Ν, ヒドロキシ -dimethylhydroxycarboxamide group).

[0093] In the compound of the present invention, R ¹ represents a hydrogen atom, the heel ring represents Formula A-1, R ² represents a -tolyl group, the B ring represents Formula B-1, and R ³ represents A hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms; R ⁴ represents an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms; , W represents the formula -CH 2-(14)

2

As shown in Chem. 8, compound (12) can be obtained by subjecting compound (12) to a condensation reaction with aqueous ammonia to convert it into strong rubamoyl and dehydrating it. Here, dianhydride pentalin, phosphorus pentachloride, thionyl chloride, methanesulfonyl chloride, salt cyanur and the like can be used as dehydrating agents for amides.

Reaction scheme 8

[0094] [Chemical 25]

[In the formula, R ^{A 1} is as defined above.]

In the compound of the present invention, R ¹ represents a hydrogen atom, the A ring represents Formula A-1, and R ² represents the formula

[0096] [Chemical 26]

0

[In the formula, represents an alkyl group having 1 to 6 carbon atoms.], Ring B represents formula B-1, and R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or A compound (15) in which R 1 represents an alkoxy group having 1 to 6 carbon atoms, R ⁴ represents an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, and W represents the formula —CH 2 — As shown in Reaction Scheme 9, compound (1

2

2) can be obtained by curty-use rearrangement reaction, deprotection to convert to amine, and then amidation. Here, the method described above can be used as a method for converting to amide.

Reaction scheme 9

[0098] [Chemical 27]

twenty three

[In the formula, R ² °, R ²¹ is as defined above, and represents an alkyl group having 6 carbon atoms,

)

[0100] In the compound of the present invention, R ¹ represents a hydrogen atom, A ring represents Formula A-1, R ² represents an alkyl group having 1 to 6 carbon atoms, and B ring represents Formula B-1. R ³ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, and R ⁴ represents an alkyl group having 1 to 6 carbon atoms or an alkyl group having 1 to 6 carbon atoms. Represents an alkoxy group, W represents the formula -CH-

As shown in Reaction Scheme 10, compound (17) reduces the carbo group of compound (16). You can get it by doing. Here, hydrazine, triethylsilane, zinc amalgam, or the like can be used as the reducing agent.

Reaction scheme 10

[0101] [Chemical 28]

[In the formula, ί is as defined above, and represents an acyl group having 2 to 6 carbon atoms, and R ′ ^b represents an alkyl group having 1 to 6 carbon atoms.]

[0103] In the compound of the present invention, R ¹ represents a hydrogen atom, A ring represents Formula A-1, R ² represents a hydroxyiminoalkyl group having 1 to 6 carbon atoms, and B ring represents Formula B Wherein R ³ represents an elementary atom or an alkyl group having 1 to 6 carbon atoms, R ⁴ represents an alkyl group having 1 to 6 carbon atoms, and W represents a formula —CH 2 — (18 ) Is a compound (16) as shown in Reaction Scheme 11.

2

I can gain power.

Reaction scheme 11

[0104] [Chemical 29]

[In the formula, ί R ^z R is as ^defined above, and represents a hydroxyiminoalkyl group having 1 to 6 carbon atoms.]

[0106] In the compound of the present invention, R ¹ represents a hydrogen atom, the Α ring represents Formula A-2, R ² represents an acyl group having 2 to 6 carbon atoms, and the B ring represents Formula B-1. Wherein R ³ and R ⁴ independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, and W represents a compound represented by the formula —CH 2 — (20 ) Is 2-acetyltetra, as shown in Reaction Scheme 12.

2

Ron derivative (19)

Reaction scheme 12 [0107] [Chemical 30]

[Wherein R ^{z represents} independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, and R ²⁹ represents 2 to 6 carbon atoms. Represents the acyl group.)

[0109] In the compound of the present invention, R ¹ represents a hydrogen atom, the Α ring represents Formula A-3, R ² represents an acyl group having 2 to 6 carbon atoms, and the B ring represents Formula B-1. R ³ and R ⁴ independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, and W represents a compound represented by the formula —CH 2 — (23 ) Is obtained by the method shown in Reaction Scheme 13. Ie

2

Bromination of the α-position of the carboxyl group of the tetralone derivative (21), reaction with ethylthioxamate to form a thiazole ring, and hydrolysis of the ester yields the compound (22). . Next, the compound (23) can be obtained by alkylation after conversion to the amide of Winelev. A metal lithium reagent such as methyl reagent or methyl lithium can be used.

Reaction scheme 13

[0110] [Chemical 31]

[In the formula, R ²⁸ and R ²⁹ are as defined above.]

[0112] In the compound of the present invention, R ¹ represents a hydrogen atom, A ring represents Formula A-1, R ² represents an acyl group having 2 to 6 carbon atoms, B ring represents Formula B-2, Formula B-3 or Formula B-4 is shown, W is formula- Compound (26) showing CH 2-is obtained by the method shown in Reaction Scheme 14. Tetra

2

The Ron derivative (24) is subjected to Vilsmeier reaction, reacted with thioglycolic acid ethyl ester, and the ester is hydrolyzed to obtain the compound (25). Next, the compound (26) can be obtained by converting to amide of wine lev and alkylating. Here, the above-mentioned reagents can be used as the alkylating agent.

Reaction scheme 14

[0113] [Chemical 32]

(Wherein the ring B represents the formula B-2, the formula B-3 or the formula B-4, and is as defined above.

)

[0115] In the compound of the present invention, R ¹ represents a hydrogen atom, A ring represents Formula A-1, R ² represents an acyl group having 2 to 6 carbon atoms, and B ring represents Formula B-1. R ³ and R ⁴ independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, and W represents — (CH 2) 2 — 29) is a tetralone derivative (27) as shown in Reaction Scheme 15.

twenty two

Can be obtained in the same manner as described above.

Reaction scheme 15

[0116] [Chemical 33]

[In the formula, R ²⁸ and R ²⁹ are as defined above.]

[0118] In the compound of the present invention, R ¹ represents an alkyl group having 1 to 6 carbon atoms, A ring represents formula A -1, R ² represents an acyl group having 2 to 6 carbon atoms, B The ring represents Formula B-1, R ³ and R ⁴ 1S independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, and W represents the formula -CH Compound (32) indicating-is as shown in Reaction Scheme 16.

2

Furthermore, the tetralone derivative (30) force can also be obtained using the same method as described above.

Reaction scheme 16

[0119] [Chemical 34]

[In the formula, R ^z R ^z is as ^defined above, and represents an alkyl group having 1 to 6 carbon atoms.]

In the compound of the present invention, R ¹ represents a hydrogen atom, the Α ring represents Formula A-1, R ² represents an acyl group having 2 to 6 carbon atoms, the B ring represents Formula B-1, and R Compound (35) in which ³ represents a hydrogen atom, a trifluoromethyl group or a trifluoromethoxy group, R ⁴ represents a trifluoromethyl group or a trifluoromethoxy group, and W represents the formula —CH 2 — is shown in Reaction Scheme 17. Te Tolonone derivative (33) force Can be obtained using the same method as described above.

Reaction skies

[0122] [Chemical 35]

(Wherein R ² is as defined above, R ³¹ represents a hydrogen atom, a trifluoromethyl group or a trifluoromethoxy group, and R ³² represents a trifluoromethyl group or a trifluoromethoxy group. Show.)

[0124] In the compound of the present invention, R ¹ represents a hydrogen atom, A ring represents Formula A-1, R ² represents an acyl group having 2 to 6 carbon atoms, and B ring represents Formula B-1. R ³ represents a hydrogen atom, R ⁴ represents an acyloxy group having 2 to 6 carbon atoms, an alkylsulfooxy group having 1 to 6 carbon atoms, a phenylsulfo-loxy group, or p-tolylsulfo-oxyloxy. Compound (36), which represents a group and W represents the formula —CH 2 —, can be obtained from phenol derivative (1) as shown in Reaction Scheme 18.

Reaction scheme 18

[0125] [Chemical 36]

(Wherein R ⁵ is as defined above, and R ³³ is an acyloxy group having 2 to 6 carbon atoms, an alkylsulfo-oxy group having 1 to 6 carbon atoms, a phenylsulfo-loxy group, or p-tolyl sulfo-loxy group.)

[0127] In the compound of the present invention, R ¹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, A ring represents Formula A-1, and R ² represents a hydroxyalkyl group having 1 to 6 carbon atoms. The ring B is Formula Bl, Formula B-2, Formula B-3 or Formula B-4, wherein R ³ and R ⁴ forces are independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, and 1 to 6 carbon atoms. An alkoxy group, a substituted alkoxy group having 1 to 6 carbon atoms, a trifluoromethyl group or a trifluoromethoxy group, wherein W is a compound represented by the formula —CH 2 — or a formula — (CH 2) — (38) Represents Formula A-1, R ² is the number of carbon atoms 1

2 2 2

Represents a hydroxyalkyl group of ˜6, W represents the formula —CH—, R ¹ represents a hydrogen atom, ring B

2

When R represents Formula B-1, R ³ and R ⁴ exclude a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, and an alkoxy group having 1 to 6 carbon atoms. ) Can be obtained by reducing the carbonyl group of compound (37) as shown in Reaction Scheme 19. Here, sodium hydrogen hydride, lithium aluminum hydride, or the like can be used as the reducing agent.

Reaction scheme 19

[0128] [Chemical 37]

[0129] (where,

W is as defined above, and ring B represents formula Bl, formula B-2, formula B-3 or formula B-4, and R ³ and R ⁴ independently represent a hydrogen atom, a carbon atom number of 1 Represents an alkyl group having ˜6, an alkoxy group having 1 to 6 carbon atoms, a substituted alkoxy group having 1 to 6 carbon atoms, an acetoxy group, a trifluoromethyl group, or a trifluoromethoxy group, and R ³⁴ has 1 carbon atom. Represents a hydroxyalkyl group of ~ 6. However, in compound (38), ring A represents formula A-1, R ² represents a hydroxyalkyl group having 1 to 6 carbon atoms, ring B represents formula B-1, and R ³ and R ⁴ represent , Independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, W represents the formula -CH-, and R ¹ represents a hydrogen atom. Excluding things. )

2

[0130] Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.

Example

[0131] Example 1

(Method A)

2 — [(2—Acetyl 4,5—Dihydronaphtho [1,2—b] Chen 7—yl) oxy] aceto Manufacture of mid

1- (7-Hydroxy-4,5-dihydronaphtho [1,2-b] chen-2-inole) ethanone Add 0.50 g of 2-bromoacetamide 0.25 g and potassium carbonate 0.43 g to a solution of 0.5 g of dimethylformamide 80 The mixture was stirred at ° C for 2 hours. After the reaction, water was added, and the crystals were collected by filtration, washed with water and ethyl acetate, and then dried. 2-[((2 acetyl 4,5 dihydronaphtho [1,2, b] chen-7yl) oxy] 0.65 g of yellow acetoamide crystals were obtained.

[0132] Example 2

(Method B)

1— [7— (2 Fluoroethoxy) 4, 5 Dihydronaphtho [1, 2— b] Chain 1 2-yl] Production of ethanone

Under nitrogen substitution, trifluorophosphine was added to a solution of 0.20 g of 2 fluoroethanol in 50 ml of tetrahydrofuran. Next, under ice-cooling, 1- (7-hydroxy-1,4,5 dihydronaphtho [1,2, -b] chen-2-yl) ethanone 0.50 g was added, and DEAD1.4 ml of tetrahydrofuran 1 Oml was added dropwise. Thereafter, the mixture was stirred overnight at room temperature. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (50% ethyl acetate-hexane) and recrystallized from ethanol. 1— [7— (2 Fluoroethoxy) 4, 5 0.22 g of yellow crystals of dihydronaphtho [1,2-b] chen-2-yl] ethanone was obtained.

[0133] Examples 3-36

The compounds shown in Tables 11 to 18 were obtained in the same manner as in Example 1 (Method A) or Example 2 (Method B).

[0134] [Table 1-1] Example Method Structure Data

1 A MS m / z: 324 (M + Na) ⁺

¾ NMR (300 MHz, dmso-d6) 5 (ppm):

H ₂ N 丫 0 A> _S `` 2.50 (s, 3 H), 2.72-2.98 (m, 4 H), 4.47 (s, 2

H), 6.86 (dd, J = 2.6, 8.4H¾ 1 H), 6.94 (d, 7 = 2.6 Uz, 1 H), 7.43 (d, J = S .4 Hz, 1 H), 7.54 (brs, 2 H), 7.80 (s, 1 H)

2 B MS m / z: 31 3 (M + Na) ⁺

¾NM (200MHz, CDC1 ₃ ) 5 (ppm): 2.54 (s, 3H), 2.73-3.03 (m, 4 H), 4. 13-4.36 (m, 2H), 4.60-4.93 (m, 2H), 6.73 -6.87 (m, 2H), 7.35-7.45 (m, IH), 7.48 (s, IH)

3 A MS m / z: 31 1 (M + Na) ⁺

¾ NMR (300 H¾ CDC1 ₃ ) 5 (ppm): 2.54 (s, 3 H), 2.73-3.00 (m, 4 H), 3.49 (s, 3 H), 0 5.20 (s, 2 H), 6.85- 6.99 (m, 2 H), 7.40 (d, 7 = 9.3 1 H) ₃ 7.48 (s, 1 H)

4 A MS m / z: 31 1 (M + Na) ⁺

^ NMR (200MHz, CDC S (ppm): 2.54 (s,

H. 1 ₃ )

3H), 2.72-3.02 (m, 4H), 3.89-4.04 (m, 2H) _: 4.06- 4.19 (m, 2H), 6.73-6.86 (m, 2H), 7.32-7.47 (m, IH), 7.48 (s, IH)

5 A MS m / z: 380 (M + Na) ⁺

¾ NMR (300 MHz, CDC1 ₃ ) S (ppm): 2.54 (s, 3 H), 2.56-2.62 (m, 4 H), 2.77-2.87 (m, 4 H), 2.88-2.99 (m, 2 H ), 3.69-3.78 (m, 4 H), 4.14 (t, J = 5.8 Hz, 2 H), 6.70-6.84 (m, 2 H), 7.33-7.43 (m, 1 H), 7.48 (s , 1 H) 1-2] Example Method Structure Data

6 A MS m / z: 31 6 (M + H) ⁺

¾ NMR (300 MHz, CDC1 ₃ ) 6 (ppm): 2.34 (s, 6 ¥), 2.55 (s, 3 H), 2.75 (t, J = 5.8 Hz, 2 H), 2.68-2.79 (m, 4 H), 4.06 (t, J = 5.8 Hz, 2 H), 6.75-6.83 (m, 2 H), 7.20 (d, 7 = 8.4 Hz, 1 H), 7.48 (s, 1 H)

7 A MS m / z: 343 (M + H) ⁺

¾ NMR (300 MHz, CDC1 ₃ ) 5 (ppm): 1.35-1.77 (m, 5 H), 1.82-1 .98 (m, 1 H), 0 2.55 (s, 3 H), 2.64-2.96 (m , 4 H), 3.45-3.59

(m, 1 H), 3.63-3.77 (m, 1 H), 3.834. 14 (m, 3 H), 6.65 -6.86 (m, 2 H), 7.38 (d, J = 8.3 H¾ 1 H), 7.48 (s, IH)

8 A MS m / z: 336 (M + H) ⁺

¾ NMR (300 MHz, CDC1 ₃ ) 5 (ppm): 2.55 (s, 3 H), 2.70-3.03 (m, 4 H), 5.07 (s, 2 H), 6.83-6.92 (m, 2 H), 7.30-7.45 (m, 2 H), 7.49 (s, 1 H), 7.69-7.87 (m, 1 H), 8.60 (dd, • 7 = 1.5, 4.6Hz, 1 H), 8.69 (s, 1 H )

9 A MS m / z: 329 (M + H) ⁺

¾ NMR (200 MHz, CDC1 ₃ ) 5 (ppm): 1.69-2.21 (m, 4 H), 2.55 (s, 3 H), 2.58-2.99 (m, 4 H), 3.69-4.02 (m, 4 H ), 4. 194.37 (m, 1 H), 6.65 -6.86 (m, 2 H), 7.39 (d, J = 7.9 H¾ 1 H), 7.49 (s _: 1 H)

1 0 A MS m / z: 301 (M + H) ⁺

'HNMR (200MH¾ CDC) 5 (ppm): 2.29 (s, 3H), 2.54 (s, 3H), 2.69-3.07 (n¾ 4H), 4.57 (s, 2H) 6.62-6.89 (m, 2H), 7.40 ( d, J = 7.9H¾ IH), 7.48 (s, IH) 1-3]

/ O 90 8090SAV

? so

1-5]

1-6]

1-7]

8 O £ / 900Zdf / e :) d 83 90t080 / 900Z OAV

[0142] Example 37

Production of [(2-acetylene 4,5-dihydronaphtho [1,2-b] chen-6-yl) oxy] acetic acid

10 ml of an aqueous solution of 0.96 g of potassium hydroxide was added dropwise to a mixed solution of the compound 2.7 g of 2.7 g of ethanol 40 ml and tetrahydrofuran 40 ml under ice-cooling and stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, 2N hydrochloric acid was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (2% methanol / chloroform form), and [(2-acetyl- 4,5-dihydronaphtho [1,2-b] [Chen-6-yl) oxy] Acetic acid yellow powder 1. 9g was obtained.

[0143] Examples 38 to 39

The compounds shown in Table 2 were obtained in the same manner as in Example 37.

[0144] [Table 2]

Example Structural data

3 7 MS m / z: 301 (M-H) "

NMR (200 MHz, dmso-d6) 6 (ppm):

OH

2.49 (s, 3H), 2.74-3.02 (m, 4H), 4.76 (s, 2H), 6.89 (d, J = 7.9Hz, 1H), 7.14 (d, J = 7.9Hz, 1H), 7.24 ( t, J = 7.9Hz, 1H), 7.84 (s _: 1 H)

3 8 MS m / z: 301 (M-H) "

o

'H NMR (300 MHz, dmso-d6) (ppm): 2.51 (s, 3H), 2.74-3.03 (m, 4H), 4.74 (s, 2 H), 6.85 (dd, J = 2.9, 8.5H¾ 1 H), 6.99 (d, J = 2.9Hz, 1 H), 7.24 (d, J = 8.5H¾ 1H), 7.84 (s, 1H)

3 9 MS m / z: 303 (M + H) ⁺

lK NMR (300 MHz, dmso-d6) 6 (ppm): 2.50 (s, 3 H), 2.65-2.99 (m, 4 H), 4.56 (s, 2 H), 6.78 (dd, 7 = 2.5, 8.4 Hz, 1 H), 6.86 (d, 7 = 2.5 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 1 H), 7.79 (s, 1 H)

[0145] Example 40

2 — [(2 acetylenore 4,5 dihydronaphtho [1, 2— b] Chen 7 inore) oxy] N— Preparation of methylacetamide

0.47 g of the compound obtained in Example 39 and methylamine (40% aqueous solution) 0.13 g, 1-hydroxybenzotriazole 0.23 g of dimethylformamide in 5 ml of 1-ethyl-3- (3 dimethylaminopropyl) To the reaction mixture, 0.30 g of carpositimide hydrochloride was added and stirred at room temperature for 2 days. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate-hexane, 2% methanol chloroform) to give 2-[(2 acetyl-4,5 dihydro Naphtho [1,2-b] chain-7-yl) oxy] -N-methylacetamide yellow powder 0.40 g was obtained.

[0146] Examples 41 to 44

The compounds shown in Table 3 were obtained in the same manner as in Example 40.

[0147] [Table 3]

Example 45

N— {3— Preparation of [(2 acetyl 4,5 dihydronaphtho [1, 2— b] chain-7-yl) oxy] propyl} acetoamide

Compound obtained in Example 35 2. 20 g of ethyl acetate in 20 ml solution of 4N hydrochloric acid 20 ml of the solution was added dropwise and stirred overnight at room temperature. After the reaction, it was filtered and washed with ethyl acetate. 1- [7- (3-Aminopropoxy) -4,5-dihydronaphtho [1,2-b] chen-2-yl] ethanone hydrochloride yellow 1.8 g of powder was obtained.

[0149] 5 ml of triethylamine and 0.20 ml of acetic anhydride were added dropwise to a solution of 0.50 g of the compound obtained here in 5 ml of black mouth form under ice cooling, and the mixture was stirred overnight at room temperature. After the reaction, water was added, and after stirring for 30 minutes, the organic layer was isolated and washed successively with a saturated aqueous ammonium chloride solution and saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (10% methanol / chloroform) and recrystallized from ethanol to give N— {3 — [(2-acetylyl 4, There were obtained 0.25 g of colorless crystals of 5-dihydronaphtho [1,2-b] chen-7-yl) oxy] propyl} acetamide.

[0150] Examples 46 to 47

The compounds shown in Table 4 were obtained in the same manner as in Example 45.

[0151] [Table 4]

[0152] Example 48

4 — [(2 acetylyl 4, 5 dihydronaphtho [1, 2— b] chain 7-yl) oxy] butanamide

A solution of 0.55 g of the compound obtained in Example 17 and 0.55 g of potassium hydroxide in 5 ml of t-butanol was heated to reflux for 1 hour. After the reaction, the reaction solution was returned to room temperature, poured into a saturated saline solution (10 ml), and extracted with black mouth form. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (35% methanol / chloroform form) to give 4-[(2 acetyl-4,5 dihydronaphtho [1 , 2-b] Chen-7-yl) oxy] butanamide, 0.18 g of a yellow powder was obtained.

[0153] [Table 5]

[0154] Example 49

1 Production of [7- (2 Chloroethoxy) -4,5 Dihydronaphtho [1,2—b] Chen 2-Inole] ethane

To a solution of the compound obtained in Example 4 (1.7 g) in 20 ml of black mouth form, 0.55 ml of methanesulfonyl chloride and 0.97 ml of triethylamine were added dropwise under ice cooling, followed by stirring at room temperature for 1.5 hours. After the reaction, water was added under ice-cooling, and the mixture was stirred for 30 minutes. The organic layer was isolated and washed with saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (5% ethyl acetate-hexane) and then recrystallized from ethanol. 1-[7 — (2 black ethoxy) There was obtained 0.21 g of yellow powder of 4,5 dihydronaphtho [1,2-b] chen-2-yl] ethanone.

[0155] [Table 6] Example Structural data

4 9 MS m / z: 307 (M + H) ⁺

^ NMR (200 MH¾ CDC1 ₃ ) 5 (ppm): 2.54 (s, 3H), 2.70-3.05 (m, 4H), 3.83 (t, J = 5.8Hz, 2H), 4.26 (t, J = 5. Mz , 2H), 6.71-6.84 (111, 2H), 7.30-7.45 (m, 1H), 7.48 (s, 1H)

[0156] Example 50

Preparation of N, N, 6,8-tetramethyl-1,4,5-dihydronaphtho [1,2-b] thiophene 2-carboxamide

6,8-dimethyl-4,5-dihydronaphtho [1,2-b] thiophene 2-carboxylic acid 0.50 g and dimethylolamine (50% aqueous solution) 0.21 g, 1-hydroxybenzotriazolene 0.36 g To a 7 ml solution of dimethylformamide was added 0.45 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and the mixture was stirred at room temperature for 14 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, hexane was added to the residue, and the mixture was stirred and washed at room temperature for 30 minutes. The crystals were collected by filtration and dried to obtain 0.41 g of colorless powder of N, N, 6,8-tetramethyl-4,5-dihydronaphtho [1,2-b] thiophene-2-carboxamide.

[0157] Examples 51-52

The compounds shown in Table 7 were obtained in the same manner as in Example 50.

[0158] [Table 7]

Example 53

6,8-Dimethyl-4,5-Dihydronaphtho [1,2—b] thiophene—Manufacturing 2-carbo-tolyl

6,8-Dimethyl-4,5-Dihydronaphtho [1,2-b] thiophene-2-Strong Rubonic acid 2.5g and Ammonia (28% aqueous solution) 2.6ml, 1-Hydroxybenzotriazole 1.8ml Dimethylformamide 30ml To the solution, 2.2 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added and stirred overnight at room temperature. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, followed by stirring and washing at room temperature for 30 minutes. The crystals were collected by filtration and dried to obtain 1.86 g of colorless powder of 6,8-dimethyl-4,5-dihydronaphtho [1,2-b] thiophene-2-carboxamide.

A solution of 0.89 g of the compound obtained above and 0.3 ml of cyanuric chloride in 10 ml of dimethylformamide was stirred at room temperature for 3 hours, further 0.39 g of salt cyanuric was added, and the mixture was stirred at room temperature for 2 hours. After the reaction, water was added under ice-cooling, followed by extraction with ethyl acetate, and the organic layer was washed successively with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. Purification by column chromatography (30% ethyl acetate) gave 0.73 g of colorless powder of 6,8 dimethyl-4,5 dihydronaphtho [1,2-b] thiophene-2-carbo-tolyl.

[Table 8]

[0161] Example 54

Preparation of N- (6,8 Dimethinole 4,5 Dihydronaphtho [1,2-b] Chen 2-ynole) acetamide

6, 8 Dimethyl-4,5 Dihydronaphtho [1,2-b] thiophene-2-strong rubonic acid 1. Add 0.42 ml of thioluculide to a mixed solution of Og in 20 ml of chloroform and 40 ml of tetrahydrofuran, and heat to reflux for 5 hours. . After returning to room temperature, the solvent was distilled off under reduced pressure, and 30 ml of tetrachloroammonium bromide 15 ml was added, and 5 ml of an aqueous solution of 0.76 g of sodium azide was added dropwise under ice cooling, followed by stirring for 1 hour. After the reaction, it was poured into water and extracted with black mouth form, and the organic layer was washed successively with water and saturated brine. After drying with magnesium sulfate, 5.8 g of t-butyl alcohol was added and heated to reflux for 9 hours. After the reaction, the reaction mixture was poured into water and extracted with black mouth form, and the organic layer was washed successively with water and saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.lg of tertbutyl (6,8 dimethyl-4,5 dihydronaphtho [1,2-b] chen-2-yl) strength rubamate.

[0162] 20 ml of 4N hydrochloric acid-acetyl acetate solution was added dropwise to a 10 ml solution of 1.lg of the compound obtained here in 1 ml of ethyl acetate, and the mixture was stirred overnight at room temperature. After the reaction, it was collected by filtration and washed with ethyl acetate to obtain 0.41 g of a light brown powder of 6,8-dimethyl 4,5 dihydronaphtho [1,2-b] thiophene 2-amine hydrochloride.

[0163] 0.14 ml of acetic anhydride and 5 ml of triethylamine were added dropwise to a 10 ml solution of 0.23 g of the compound obtained here in 10 ml of black mouth form, and the mixture was stirred overnight at room temperature. After the reaction, add ice-cold water and add 3 After stirring for 0 minute, the organic layer was isolated and washed with saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (50% ethyl acetate-hexane), recrystallized from ethanol, and N- (6,8-dimethyl-4, A brown powder of 75 mg of 5-dihydronaft [1,2-b] chen-2-yl) acetamide was obtained.

[0164] [Table 9]

[0165] Example 55

2-Ethyl-6,8 Dimethyl-4,5 Dihydronaphtho [1,2-b] thiophene 1- (6,8 Dimethyl-4,5 Dihydronaphtho [1,2-b] Chen-2yl) ethanone 1. Og To a 10 ml solution of ethylene glycol were added 10 ml of hydrazine monohydrate and 0.66 g of potassium hydroxide, and the mixture was heated to reflux for 3 hours. After the reaction, the reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (20% ethyl acetate), 2-ethyl 6,8 dimethyl 4,5 dihydronaphtho [1,2-b 0.10 g of yellow oily substance of thiophene was obtained.

[0166] [Table 10]

[0167] Example 56

1— (6,8 dimethyl-4,5 dihydronaphtho [1,2—b] chain 2 yl) ethanonoxy Sim manufacturing

1- (6,8-Dimethyl-4,5-dihydronaphtho [1,2-1]] Chen-2-yl) ethanone 1.4 ₈ and hydroxylamine hydrochloride 1. 70% sodium hydroxide in 2 g ethanol in 30 ml solution 3 ml of an aqueous solution was added dropwise and stirred at room temperature for 1 hour. After the reaction, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to diastereomer mixture 1- (6,8 dimethyl-4,5 dihydronaphtho [1,2-b] chain— Yl) Yellow powder of ethanone oxime 1. 4g was obtained.

[0168] [Table 11]

[0169] Example 57

Preparation of 2-acetyl 3 methyl 4, 5 dihydro 2H benzo [g] indazole 2-acetyl 3,4 dihydronaphthalene mono 1 (2H) -one 1. Hydrazine monohydrate in 0.3 ml of Og in ethanol 0.34 ml, Acetic acid (0.40 ml) was added and stirred at room temperature. After the reaction, the solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. — 0.98 g of a colorless oily substance of methyl-4,5 dihydro-2H benzo [g] indazole.

To a solution of 0.50 g of the compound thus obtained in 10 ml of tetrahydrone, 0.16 g of sodium hydride was added under ice-cooling and stirred for 30 minutes. Then, 0.28 ml of acetic anhydride was added and stirred at room temperature for 2 hours. After the reaction, water was added, extracted with ethyl acetate, and the organic layer was saturated aqueous sodium hydrogen carbonate solution, After washing with saturated brine and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by force column chromatography (5% ethyl acetate-hexane) to give 2-acetyl-1-methyl 4, 5 A colorless powder of dihydro 2H benzo [g] indazole 0.5 g was obtained.

[0170] [Table 12]

[0171] Example 58

Preparation of 1- (8-methoxy 4,5 dihydronaphtho [1,2-d] [l, 3] thiazol-2-yl) ethanone

To a 150 ml solution of 7-methoxy-1-tetralone 10 g of tetrasalt and carbon, 2.9 ml of bromine was added dropwise and stirred at room temperature for 2.5 hours. After the reaction, water was added under ice-cooling, and the mixture was stirred for 30 minutes. The organic layer was isolated and washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (20% ethyl hexane) to give a colorless powder of 2 bromo-7 methoxy 3,4 dihydronaphthalene 1 (2H) one. 9. 4g was obtained.

[0172] To a 50 ml solution of the compound 2. Og obtained in this manner and dimethylformamide was added 1.3 g of ethylthioxamate, and the mixture was stirred at 130 ° C overnight. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, 10% aqueous sodium hydroxide solution, saturated aqueous ammonium chloride solution and saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by force chromatography (5% ethyl acetate-hexane). Ethyl 8-methoxy-1,4-dihydronaphtho [1, 2-d] 0.26 g of a yellow oily substance of [l, 3] thiazole 2 carboxylate was obtained.

[0173] 52 mg of sodium hydroxide was added to a mixed solution of the compound obtained here (0.26 g) in ethanol (5 ml) and water (0.5 ml), and the mixture was heated to reflux overnight. After the reaction, the solvent was distilled off under reduced pressure, 1N hydrochloric acid was added, and the precipitated crystals were collected by filtration to give 8-methoxy-4,5 dihydronaphtho [1,2-d] [l, 3] thiazole. — 0.18 g of 2-carboxylic acid brown powder was obtained.

[0174] 0.118 g of the carboxylic acid obtained here and 81 mg of N, O dimethylhydroxylamine hydrochloride, 120 mg of 1-hydroxybenzotriazole, 120 mg of triethylamine in 0.1 ml of dimethylformamide in 10 ml of 1-ethyl 3- ( 3) Dimethylaminopropyl) carbodiimide hydrochloride (170 mg) was added, and the mixture was stirred at room temperature for 5 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying with magnesium sulfate, the solvent was distilled off under reduced pressure, and N, 8-dimethoxy-N-methyl-4,5-dihydronaphtho [1,2, -d] [l, 3] thiazole-2-carboxamide brown oily substance Got.

[0175] To a 10 ml solution of the obtained compound in tetrahydrofuran was added 0.57 ml of a 3M methylmagnesium bromide jetyl ether solution under ice-cooling, and the mixture was stirred at the same temperature for 2 hours. After the reaction, 10% hydrochloric acid was added under ice-cooling, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate-hexane), recrystallized from ethanol, and 1- (8-methoxy 4,5 dihydro 55 mg of brown crystals of naphtho [1,2-d] [l, 3] thiazol-2-yl) ethanone were obtained.

[0176] [Table 13]

Example 59

1— (4,5, 5a, 6, 7,8, 9, 9a—octahydronaphtho [1,2—b] chain 2) Manufacture of ethanone

Under ice cooling, dimethylformamide (5.1 ml) was added dropwise with phosphorus oxychloride (4. Oml), and the mixture was warmed to room temperature and stirred for 30 minutes. Thereto was added a solution of Octahydronaphthalen-1 (2H) -one 1.Og in 20 ml of chloroform at room temperature, and the mixture was heated to reflux overnight. After the reaction, add water and stir for 30 minutes The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a brown solid of 1-black mouth 3,4,4a, 5,6,7,8,8a-octahydronaphthalene 2-carbaldehyde.

[0178] To a solution of the compound thus obtained in acetonitrile of 0.8 ml were added ethyl thioglycolate 0.88 ml and potassium carbonate 2.4 g, and the mixture was stirred overnight at room temperature. After the reaction, ethyl acetate was added, and the organic layer was washed successively with water, 10% aqueous sodium hydroxide and saturated brine. After drying with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a brown solid of 1-black mouth 3,4,4a, 5,6,7,8,8a-octahydronaphthalene 2-carbaldehyde.

[0179] 0.42 g of sodium hydroxide sodium salt was added to a mixed solution of 30 ml of ethanol and 3 ml of water obtained here, and the mixture was stirred at 80 ° C overnight. After the reaction, the solvent was distilled off under reduced pressure, 1M hydrochloric acid was added, and the precipitated crystals were collected by filtration. 4,5,5a, 6,7,8,9,9a-octahydronaphtho [1,2-b] thiophene 1. 0.5 g of colorless crystals of 2-carboxylic acid was obtained.

[0180] 0.5 g of the carboxylic acid obtained here and 0.25 g of N, O dimethylhydroxylamine hydrochloride, 0.37 g of 1-hydroxybenzotriazole, 0.3 ml of triethylamine, 20 ml of dimethylformamide in 20 ml 0.53 g of 1-ethyl 3- (3 dimethylaminopropyl) carbodiimide hydrochloride was added and stirred at room temperature for 5 hours. After the reaction, ethyl acetate was added and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and N-methoxy-1-N-methyl 4,5, 5a, 6, 7,8, 9, 9a-octahydronaphtho [1,2 b] thiophene 2-carboxamide Of a brown solid was obtained.

[0181] Under nitrogen substitution, add 8 ml of 3M methylmagnesium bromide in ethyl acetate to 10 ml of tetrahydrofuran solution of the compound obtained here under ice-cooling, and stir at the same temperature for 3 hours. did. After the reaction, 10% hydrochloric acid was added under ice-cooling, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine. After drying with magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate-hexane), recrystallized with ethanol, and 1- (4,5,5 &, 6, 7.29 g of yellow crystals of 7,8,9,9 & -octahydronaphtho [1,2-1]] chen-2-ynole) ethanone were obtained.

[0182] Examples 60-66

The compounds shown in Table 14-1 to Table 14-2 were obtained in the same manner as in Example 59. [0183] [Table 14-1]

[0184] [Table 14-2] Example Structural data

6 5 MS m / z: 319 (M + Na) ⁺

^ NMR (200MHz, CDC1 ₃ ) 6 (ppm): 2.57 (s, 3H), 2.83-2.96 (m, 2H), 2.98-3.09 (m, 2H),

CF ₃ 7.45 (d, J = 7.9Hz, 1 H), 7.48 (dd, J = \. \, 7.9H¾ m), 7.67 (d ₃ J = l. LHz, 1H), 7.64 (s, 1H)

6 6 MS m / z 335 (M + Na) +

'HNMR (200MHZ, CDC1 ₃ ) S (ppm): 2.56 (s, 3H), 2.78-3.07 (m, 4H), 7.00-7.16 (m, 2H) _:

0GF ₃ 7.42-7.49 (m, ΊΗ), 7.50 (s, ΊΗ)

[0185] Example 67

2-acetyl 4,5 dihydronaphtho [1,2-b] chain 1 7-yltrifluoromethanesulfonate production

1- (7-hydroxy-4,5-dihydronaphtho [1,2-b] chen-2-inole) ethanone 5. Add 50 ml of trifluoroacetic anhydride under ice-cooling to 50 ml of Og in pyridine, and add 2 ml at the same temperature for 2 hours. Stir. After the reaction, water was added under ice-cooling, followed by extraction with ethyl acetate, and the organic layer was washed successively with 3M hydrochloric acid and saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate) to give 2-acetyl 4,5 dihydronaphtho [1,2-b] chen 7 yl. 6.2 g of yellow powder of trifluoromethanesulfonate was obtained.

[0186] Example 68 69

The compounds shown in the table were obtained in the same manner as in Example 67.

[0187] [Table 15]

[0188] Example 70

2— Preparation of {[2- (1-hydroxyethinole) -4,5 dihydronaphtho [1,2-b] chen 7-ynole] oxy} acetoamide

95 mg of sodium borohydride was added to a mixed solution of 0.3 g of the compound obtained in Example 1 (30 g) in ethanol (40 ml) and tetrahydrofuran (80 ml) under nitrogen-cooled ice-cooling and stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, a saturated aqueous solution of ammonium chloride was added under ice cooling, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate-hexane) to give 2-{[2- (1 hydroxyethyl) -4,5-dihydro 0.23 g of a light yellow powder of naphtho [1,2-b] chen-7-yl] oxy} acetamide was obtained.

[0189] Examples 71-102

The compounds shown in Table 16-1 to Table 16-7 were obtained in the same manner as in Example 70.

[0190] [Table 16-1]

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[0197] Test example SREBP-lc mRNA expression suppression test

Human liver derived Chang Liver (ATCC # CCL-13) was used. Chang Liver cells were cultured for 24 hours in the presence of 10% FBS in Dulbecco's modified Eagle medium in the presence of 5% carbon dioxide at 37 ° C in the presence of the specimen. After completion of the culture, RNA was collected from the cells using an RNeasy 96 kit (Qiagen), and the expression level of SREBP-lc mRNA was quantified from real-time RT-PCR.

[0198] Using the TaqMan EZ RT-PCR kit (Applied by Systems), reverse transcription reaction and SREBP-lc specific amplification reaction were performed in one step. The primer for amplification was designed using commercially available software (Primer Express, Applied Biosystems) based on the SREBP-1 sequence (Genbank Accession # ° AH004383, U00968), and forward 5'-ACGCCCCAAGGGCG-3 ', Reverse 5'-GAAGCATGTCTTCGAAAGTGCA-3 ', and TaqMan probe, 5,-CGCAGATCGCGGAGCCATGG -3, were used.

[0199] ABI PRISM7700 (Applied Biosystems) was used for the reaction. First, a reverse transcription reaction at 60 ° C for 30 minutes, an inactivation reaction at 95 ° C for 5 minutes, and then at 94 ° C for 20 minutes. Second, the reaction for 1 minute at 62 ° C was repeated 40 cycles. Usually modified at the 5 'end of the TaqMan probe The fluorescent dye FAM is also quenched by the fluorescent dye TAMRA modified at the 3 'end. The fluorescent dye FAM is released by the exonuclease activity accompanying the amplification reaction with the thermostable DNA polymerase. Since the amount depends on the amount of template mRNA, SREBP-lc expression can be quantified. Using the above method, the SREBP-lc expression inhibitory action of the compounds of Examples 70, 72, 74, 80, and 81 was evaluated.

[0200] The results are shown in Table 17.

[0201] [Table 17]

[0202] The compound of each Example of the present invention exhibited SREBP-lc expression inhibitory action.

Industrial applicability

[0203] By suppressing the expression of SREBP-lc, it has the effect of lowering triglycerides in the liver and lowering blood glucose levels. Diabetes, hyperlipidemia, fatty liver, obesity, glucose intolerance, diabetes complications ( (For example, nephropathy, neuropathy, retinopathy, etc.), metabolic syndrome, syndrome X can be used as a prophylactic treatment.

Claims

Claim Formula (I)

[Chemical 1]

A ring is represented by the following formula:

[Chemical 2]

(In the formula, R ² is a hydroxyalkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 6 carbon atoms, an amide group having 1 to 10 carbon atoms (provided that N, O-dimethylhydroxycarboxamide group is A nitrile group, an alkyl group having 1 to 6 carbon atoms, an amino group, an acylamino group having 2 to 6 carbon atoms, or a hydroxyiminoalkyl group having 1 to 6 carbon atoms. Ring B has the following formula

[Chemical 3]

(Wherein R ³ and R ⁴ are independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a substituted alkoxy group having 1 to 6 carbon atoms, C2-C6 acyloxy group, trifluoromethyl group, trifluoromethoxy group, C1-C6 alkylsulfo-loxy group, phenol sulfol group, p-tolylsulfo-loxy group or trifluoro L represents a methanesulfuryl group.) W represents a formula -CH- or a formula-(CH)-

2 2 2 Provided that ring A represents formula A-1 and R ² represents an alkyl group having 1 to 6 carbon atoms or a carbon atom. A 2 to 6 acyl group, W represents the formula -CH-, R ¹ represents a hydrogen atom, and the B ring represents the formula

2

In the case of B-1, R ³ and R ⁴ are not hydrogen compounds, alkyl groups having 1 to 6 carbon atoms, and compounds having 1 to 6 carbon atoms and alkoxy compounds. Ring A represents Formula A-1, R ² represents an amide group having 1 to 10 carbon atoms (excluding N, O-dimethylhydroxycarboxamide group) or -tolyl group, and W is- CH-, R ¹ represents a hydrogen atom, and the B ring represents the formula B-1

2

In this case, R ³ and R ⁴ are not hydrogen compounds. Or a pharmaceutically acceptable salt thereof.

[2] Ring A is Formula A-1, R ² is a hydroxyalkyl group having 1 to 6 carbon atoms, W is Formula -CH-, Ring B is Formula B-1, and R ¹ Is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms

2

When R ¹ is a hydrogen atom, R ³ and R ⁴ are substituted alkoxy groups having 1 to 6 carbon atoms, and when R ¹ is an alkyl group having 1 to 6 carbon atoms, R ³ and R ⁴ 2. The tricyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a substituted alkoxy group having 1 to 6 carbon atoms.

[3] Ring A is Formula A-1, R ² is an acyl group having 2 to 6 carbon atoms, W is —CH 2 —, B

2 ring is formula B-1, R ¹ is an alkyl group having 1 to 6 carbon hydrogen atom or a carbon atom, when R ¹ is water atom, R ³ and R ⁴ are independently Asetokishi group Or a substituted alkoxy group having 1 to 6 carbon atoms, and when R ¹ is an alkyl group having 1 to 6 carbon atoms, R ³ and R ⁴ are independently a hydrogen atom, The tricyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, which represents a 6 alkyl group, an acetoxy group or a substituted alkoxy group having 1 to 6 carbon atoms.

[4] An SREBP-lc expression inhibitor comprising the tricyclic compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.

[5] A triglyceride reducing agent comprising the tricyclic compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.

[6] A blood sugar level-lowering agent comprising the tricyclic compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.

[7] Diabetes, hyperlipidemia, fatty liver, obesity, impaired glucose tolerance, comprising the tricyclic compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient, Preventive or therapeutic agent for diabetic complications, metabolic syndrome, syndrome X.

[8] A tridalylide reducing agent comprising a compound having an action of suppressing SREBP-lc expression.

[9] A hypoglycemic agent comprising a compound having an action of suppressing SREBP-lc expression.

[10] A prophylactic or therapeutic agent for diabetes, hyperlipidemia, fatty liver, obesity, glucose intolerance, diabetic complications, metabolic syndrome, syndrome X comprising a compound having an inhibitory action on SREBP-lc expression.