WO2003094912A1

WO2003094912A1 - Bislactone derivative and use thereof in medicinal composition

Info

Publication number: WO2003094912A1
Application number: PCT/JP2003/005754
Authority: WO
Inventors: Seiichi Sato; Takayuki Kajiura; Noriyuki Okusa; Eiko Hayashi; Yukio Nihei
Original assignee: Ajinomoto Co.,Inc.
Priority date: 2002-05-09
Filing date: 2003-05-08
Publication date: 2003-11-20
Also published as: JP2005320250A; AU2003235887A1

Abstract

A preventive and/or therapeutic agent for diabetes, obesity, hyperlipemia, fatty liver, and complications of diabetes, which contains a bislactone derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. (I) (In the formula, R1 represents C1-12 alkyl; R2 represents hydrogen, aryl, optionally substituted aryl, heteroaryl, or optionally substituted heteroaryl; X-Y represents CR3-CH2 or C=CH; R3 represents hydrogen, hydroxy, or C1-12 alkoxy; Z represents an interatomic bond, -O-, -NH-, -S-, or -(CH2)n-; and n is 1 to 12.)

Description

Bislactone derivatives and their use as pharmaceutical compositions Background of the invention

The present invention relates to a bislactone derivative, and more particularly, to a bislactone derivative having acetyl CoA carboxylase (hereinafter sometimes abbreviated as ACC) inhibitory activity, and a pharmaceutical composition containing the bislactone derivative.

In recent years, obesity has emerged as a major risk factor for atherosclerotic disease, especially coronary artery disease. That is, in an obese individual, accumulated visceral fat releases various factors such as fatty acids and TNF-fiber, which cause insulin resistance in skeletal muscle, liver and adipose tissue, and neutral fat in liver. It has been reported to promote the synthesis of liposomes, leading to hyperlipidemia. Furthermore, insulin in the blood, which is compensated by insulin resistance, not only causes impaired glucose tolerance and diabetes, but also enhances renal Na ion absorption and activates sympathetic nerves in the kidney. Increase peripheral vascular resistance, and eventually form a hypertensive state. Hyperlipidemia, diabetes, and hypertension caused by fertility are thought to cause vascular disorders based on arteriosclerosis such as cerebrovascular disorder and coronary artery disease, and have a serious impact on life prognosis. Have been.

Exercise therapy and diet are the basis of obesity treatment.However, due to various factors such as conflict with fundamental human needs, work time, and increased stress, it is enormous to achieve the set goals. With difficulty. Surgical treatments such as gastric reduction and gastric bypass may be indicated for patients with extreme obesity.However, obese patients often have infections, fat melting and other wound complications during laparotomy. At present, it is lossy and painful. Therefore, a doctor who can safely and easily supplement dietary exercise There is a need for a combination of drugs. At present, drugs used as anti-obesity drugs include central appetite suppressants such as mazindol and cyptramine, and orlythate, a Teng lipase inhibitor. Cerebral agonists may cause severe side effects, such as bile, constipation, stomach discomfort, and sometimes hallucinations, and in Orulis evening, digestion of diarrhea, incontinence, flatus, etc. Vascular side effects have been observed. In general, the effects of these antiobesity drugs are moderate at doses that do not produce side effects, the safety of long-term use has not yet been established, and their beneficial effects on insulin resistance, which is closely related to obesity, are not significant. At present, it is rarely recognized.

Regarding insulin resistance, treatment with the agonist of the biguanide drug, peroxisome proliferator-related receptor (hereinafter abbreviated as PPAR) gamma is widely used. It has been reported that biguanides exhibit a hypoglycemic effect and a ameliorating effect on hyperlipidemia, mainly in patients with non-insulin-dependent diabetes mellitus, in addition to improving insulin resistance. However, the therapeutic effect of the drug alone is insufficient, and it has been shown that in addition to gastrointestinal symptoms such as upper abdominal discomfort, nausea, and diarrhea, it also has life-threatening side effects such as lactic acidosis. I have. PPM gamma agonists, like biguanides, improve insulin resistance, hyperglycemia, hyperlipidemia and hypertension in patients with non-insulin-dependent diabetes, but still have side effects (obesity, fulminant hepatitis) It is hardly satisfactory.

ACC is an enzyme that catalyzes the synthesis of Malonyl CoA from Acetyl CoA, and is the rate-limiting enzyme in the synthesis of long-chain fatty acids. It is also known that Malonyl CoA itself synthesized from Acetyl CoA by ACC negatively controls Carnitine acy ransf erase involved in the consumption of free long-chain fatty acids as an energy source. Furthermore, it is thought that the activation of fatty acid synthesis in visceral adipose tissue involves the activation of ACC. Therefore, drugs that inhibit ACC are not suitable for long-chain fatty acids and It is thought to be based on obesity and obesity-induced hyperlipidemia, fatty liver and insulin resistance by reducing existing adipose tissue as well as inhibiting new synthesis of triglycerides and triglycerides It has potential as a therapeutic and prophylactic agent for various diseases. As existing ACC inhibitors, for example, articles (The Journal of Antibiotics, 38, 599, 1985) and patents (International Publication No.W002 / 02101) have been reported. No ACC inhibitory activity has been reported for bislactone derivatives such as the compounds of the invention. Also, for example, a dissertation (The Journal-Ob Antibiotics, Vol. 47, p. 112, 1994, journal off ', The Chemical Society, p. 5385, 1963, journal' ob The Chemical Society, Section C, pp. 2431, 1971, Chemistry 1st, p. 1311, 1980, The Journal of Organik 'Chemistry, Vol. 57, 2228, 1992 ) Discloses a skeleton compound included in the present invention, but does not disclose the pharmacological activity intended in the present invention. Disclosure of the invention

An object of the present invention is to provide a bislactone derivative having an ACC activity inhibitory effect and a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical composition containing the bislactone derivative or a pharmaceutically acceptable salt thereof.

The present invention also relates to obesity and hyperlipidemia induced by obesity, fatty liver, and impaired glucose tolerance considered to be based on insulin resistance containing the bislactone derivative or a pharmaceutically acceptable salt thereof. ACC activity inhibitor or pharmaceutical composition effective for the treatment of diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), hypertension and atherosclerosis The purpose is to provide a product or a treatment method using it. The present inventors have conducted intensive studies in order to solve this problem, and as a result, the following general formula

It has been found that the bislactone derivative represented by (I) has excellent ACCP and harmful activity, and the present invention has been completed.

The present invention relates to a diabetes, obesity, hyperlipidemia, fatty liver, diabetic complication characterized by containing a bislactone derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. Provide prophylactic and / or therapeutic agents.

(Wherein, R ¹ is an alkyl group having 1 to 12 carbon atoms, R ² is a hydrogen atom, an aryl group, an optionally substituted aryl group, a heteroaryl group, and an optionally substituted heteroaryl group. XY represents CR ³ -C¾ and C 2 CH. R ³ represents a hydrogen atom, a hydroxyl group, an alkoxyl group having 1 to 12 carbon atoms, Z represents an interatomic bond, -0-, -NH -, - S -, - ( CH 2) n- shown n is 1;. is 12)..

The present invention also provides a bislactone derivative represented by the following general formula (II) or a pharmaceutically acceptable salt thereof.

(Wherein, R ¹ is an alkyl group having 1 to 12 carbon atoms; R ² is a hydrogen atom, an aryl group, an optionally substituted aryl group, a heteroaryl group, and an optionally substituted heteroaryl group. Represents an alkyl group and an alkyl group which may be substituted, and XY represents CR ³ —CH ₂ and C 及び CH. R ³ represents a hydrogen atom, a hydroxyl group, or an alkoxyl group having 1 to 12 carbon atoms. Z represents an interatomic bond, -0-, -NH-, -S-,-(C¾) n-, wherein n is 1 to L2. However, when R ² is a hydrogen atom, XY is C 2 CH, and Z is an interatomic bond, R ¹ is not a methyl group, an ethyl group, an n-octyl group or an n-decyl group. When R ² is a phenyl group, X—Y is CH—C¾, and Z is —S—, R ¹ is not an ethyl group or an n-octyl group. When R ¹ is an n-octyl group, is a hydrogen atom and Z is -0-, XY is not C (0H) -C¾. When R ¹ is an n-octyl group, R ² is a methyl group, and Z is −0-, XY is not CH—C¾. When R ¹ is an n-octyl group, R ² is a hydrogen atom, and Z is an interatomic bond, X—Y is not CH—CH ₂ . )

The present invention also provides a pharmaceutical composition comprising a bislactone derivative represented by the above formula (II) or a pharmaceutically acceptable salt thereof.

The present invention also provides a diabetes, obesity, hyperlipidemia, fatty liver, diabetic complication, which comprises a bislactone derivative represented by the above formula (II) or a pharmaceutically acceptable salt thereof. To provide prophylactic and / or therapeutic agents for diseases (such as diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, glycemic diabetic macrovascular disease, hypertension, and arteriosclerosis).

The present invention also provides an ACC activity inhibitor comprising a bislactone derivative represented by the above formula (I) or (II) or a pharmaceutically acceptable salt thereof. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

The present invention is a substance (composition) containing, as an active ingredient, a bislactone derivative (including a salt form) represented by the above general formulas (I) and (II). Further, it is considered that the bislactone derivative is in an equilibrium state between the lactone body and the hydroxy acid salt in the living body. Further, a hydroxy acid salt obtained by hydrolyzing this bislactone derivative with an alcohol can also be a lactone in vivo, so that a hydroxy acid salt can also be used as an active ingredient.

In the present invention, the enzyme inhibitory action means an action of inhibiting the enzyme activity of ACC, which catalyzes the synthesis of malonyl CoA from acetyl CoA.

The active ingredient used in the ACC inhibitor of the present invention is a bislactone derivative contained in the general formula (I) or (II), and will be described in detail below.

In the formula, the alkyl group preferably represents a linear, branched or cyclic alkyl group having 1 to 12 carbon atoms, and specifically includes, for example, a methyl group, an ethyl group, an n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-pentadecyl group, n-dodecyl group, isopropyl group, isoptyl Group, sec-butyl group, tert-butyl group, isopentyl group, tert-pentyl group, neopentyl group, 2-pentyl group, 3-pentyl group, n-hexyl group, 2-hexyl group, tert-octyl group, A cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a trifluoromethyl group, and the like, preferably an ethyl group, an n-octyl group, an n-decyl group, and more preferably an n-octyl group. No. The aryl group indicates a 5- to 12-membered aromatic substituent composed of 1 to 3 rings composed of carbon atoms. The aryl group in the present invention may be a substituted or unsubstituted aryl group. Specific examples include a phenyl group and a naphthyl group, and a phenyl group is preferable.

The heteroaryl group refers to a 5- to 7-membered heteroaromatic substituent consisting of 1 to 3 rings composed of carbon, nitrogen, oxygen, sulfur and the like, specifically, for example, a pyridyl group, a pyridazinyl group, a pyrimidinyl group , Virazinyl group, pyrrolyl group, furanyl group, chenyl group, oxazolyl group, isooxazolyl group, pyrazolyl group, imidazolyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, indolyl group Soindolyl, benzofuryl, isopenzofuryl, benzochenyl, benzopyrazolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolyl, etc. And preferably a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 1-birazolyl group and the like.

The substituent of the aryl group or the heteroaryl group includes a halogen atom, a hydroxyl group, a carboxyl group, an alkyloxy group having 1 to 12 carbon atoms, and 1 to carbon atoms; an alkyloxycarbonyl group, an alkyl group, an amino group, and a nitro group having L2. Group, a cyano group. Of these, a carboxyl group, an amino group and a phenyl group are preferred. The substitution position of the aryl group is not particularly limited, but is preferably substituted at the 4-position. In addition, although it may be monosubstituted or polysubstituted, monosubstituted one is preferable.

The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The alkoxy group is an alkoxy group having a linear, branched or cyclic alkyl group having 1 to 12 carbon atoms, and specifically, for example, a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group , N-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy, n-nonyloxy, n-decyloxy, n-pentadecyloxy, n-dodecyloxy, isopropoxy, isobutoxy Group, sec-butoxy group, tert-butoxy group, cyclopropyloxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, 2-cyclohexylethoxy group, and the like. Preferably methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy n- Dodeshiruokishi group, Kishiruokishi group cyclohexylene, etc. Puchiruokishi group can be mentioned cyclohexylene, more preferably methoxy group, ethoxy alkoxy group, n- propoxy group, n- butoxy group, and Kishiruokishi group to n- Examples of the alkyl group in the alkyloxy group having 1 to 12 carbon atoms and the alkyloxycarbonyl group having 1 to 12 carbon atoms include a branched or cyclic alkyl group. Examples of the alkyl group include those described in the above alkoxy group. The same is true.

In the present invention, as the compound according to claim 1 represented by the general formula (I) or a pharmaceutically acceptable salt thereof, the following are preferable.

R ¹ is preferably an alkyl group, more preferably an n-octyl group.

R ² is preferably a hydrogen atom, an alkyl group, an aryl group, or a heteroaryl group, and more preferably an aryl group. Further, a phenyl group, an aminophenyl, a hydroxyphenyl group, a trifluoromethylphenyl group, and a carboxyphenyl group are preferred. Among these, a phenyl group having a substituent is particularly preferably a 4-aminophenyl, a 4-hydroxyphenyl group, a 4-trifluoromethylphenyl group, and a 4-carboxyphenyl group. Also, 2-aminophenyl, 3-hydroxyphenyl, 3-carboxyphenyl, trifluoromethylphenyl, 3- or 4-chlorophenyl, 4-nitrophenyl, 4-nitrophenyl Also preferred are a cyanophenyl group, a 3-methoxyphenyl group, a 3-methoxycarbonylphenyl group and a 3-methoxycarbonyl-4-aminophenyl group.

The X- Y, C = CH, CH- CH 2, 0 3) - (¾ is preferably, CH-C¾ more preferably ο

R ³ is preferably a hydroxyl group or an alkoxy group having 1 to 12 carbon atoms, and more preferably a hydroxyl group.

Z is preferably an interatomic bond, -NH-, -0-, -S-,-(C¾) n- (iFl-12), and more preferably an interatomic bond.

The pharmaceutically acceptable salt specifically refers to, for example, a sufficiently acidic compound of the present invention, such as an ammonium salt, an alkali metal salt (such as a sodium salt or a potassium salt). And alkaline earth metal salts (calcium salts, magnesium salts and the like are preferred), and organic base salts include, for example, dicyclohexylamine salts, benzathine salts, and arginine. And salts of amino acids such as lysine.

Further, for the compounds of the present invention that are sufficiently basic, acid addition salts thereof, for example, inorganic acid salts such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, or acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, and monomethyl acid Organic acid salts such as sulfuric acid are exemplified.

The bislactone derivative (including the salt form and the hydroxy acid salt) used for the active ingredient can be used in any of the isomeric forms such as all optical isomers and geometric isomers.

Further, it may be in the form of a hydrate, a solvate, or the like, and may be used in the form of an amorphous derivative as well as a crystalline form.

Examples of the skeleton compound included in the present invention include, for example, articles (The 'Journal' of Antibiotics, Vol. 47, p. 112, 1994, Journal of the Chemical Society, p. 5385). , 1963, Journal 'Ob the Chemical Society'; Section C, 2431, 1971, Chemistry 'Letters, 1311, 1980, The Journal of Organic' Chemistry, Vol. 57, 2228, 1992), which is different from the pharmacological activity intended in the present invention.

In the present invention, diabetes, obesity, hyperlipidemia, fatty liver, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hypertension, arteriosclerosis) Regarding the production of bislactone derivatives used as active ingredients of prophylactic and / or therapeutic agents and the bislactone derivatives of the present invention described below, known substances are produced based on the prior art, and new substances are produced by applying the known technique. can do.

The compound of the present invention can be synthesized by the following method. For example, in the compound (I) of the present invention, R ¹ is an n-octyl group, XY is C が CH, Z is an interatomic bond, and R ² is an aryl group (formula IV). It can be synthesized by reacting avenaciolide (Formula III) with aryl iodide as a raw material.

I I I IV

R represents a substituent on the aromatic ring

In the compound (I) of the present invention, R ¹ is an n-octyl group, XY is CH—C¾, Z is an interatomic bond, and R ² is an aryl group. Can be synthesized by reducing.

R represents a substituent on the aromatic ring

0 Avenaciolide as a raw material can be obtained by culturing a microorganism having the ability to produce avenaciolide, for example, an unidentified fungi strain AJ117543.

The above AJ117543 strain was obtained from Tsukuba East 1-chome, Ibaraki Pref., Japan at 1-1-1, Chuo No. 6 National Institute of Advanced Industrial Science and Technology The deposit number is FEM BP-8346 (transferred from FERM P-18836, deposited on April 25, 2002).

The compound of the present invention obtained by the above-mentioned method can be purified by a method usually used in organic synthesis such as extraction, distillation, crystallization, column chromatography and the like.

The obtained compound of the present invention has an ACC inhibitory action, as described later, and is useful for treating a disease mediated by this action. In particular, prevention of diabetes, obesity, hyperlipidemia, fatty liver, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macrovascular disease, hypertension, arteriosclerosis) And / or can be used for therapeutic drugs.

The present invention relates to a drug containing the above bislactone derivative as an active ingredient. Other active ingredients (either having the same or different pharmacological activity from the active ingredient used in the present invention) may be used in combination, It may also contain pharmaceutically useful auxiliaries. In the present invention, any drug that contains the bislactone derivative in an effective amount so as to exhibit an ACC inhibitory effect is included in the drug of the present invention.

Use this compound for diabetes, obesity, hyperlipidemia, fatty liver, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hypertension, arteriosclerosis) When used as a drug for the prevention and / or treatment of thyroid, various administration forms such as oral administration, intravenous administration, and transdermal administration are possible.

The dosage depends on the patient's condition, age, and method of administration. , Are appropriately selected in accordance with them. Usually, for example, in the case of oral administration, preferably 0.001 to about 100 lg / Kg / day may be employed. On the other hand, in the case of parenteral administration such as injection administration, about one-half to one-twentieth of the dose in the case of oral administration is employed.o

In addition to the active ingredient, pharmaceutically acceptable excipients, carriers, diluents, and other formulation aids are appropriately mixed as auxiliaries useful in the formulation, and tablets, capsules, and granules are formed in a conventional manner. It can be administered orally or parenterally in the form of fine granules, powders, pills, syrups, suspensions, emulsions, ointments, suppositories or injections. In the present invention, a pharmaceutical preparation or a pharmaceutical composition containing the bislactone derivative as an active ingredient (active ingredient) and a pharmaceutically acceptable carrier and / or diluent thereof is preferable. Here, examples of the carrier and the diluent include glucose, sucrose, lactose, nylon, silica, cellulose, methylcellulose, starch, gelatin, ethylene glycol, polyethylene glycol, glycerin, ethanol, water and oils and fats.

Hereinafter, the present invention will be described specifically with reference to Examples and Test Examples, but the present invention is not limited to these Examples.

(Example 1)

Isolation of ('-)-apenaciolide

(Process 1)

AJ117543 strain isolated from soil collected in the United States was mashed potato (20 g / L), glucose (5 g / L), NZ-Case (3 g / L), yeast extract (2 g / L), NaCl (2 g / L), was inoculated into Erlenmeyer flasks containing CAC0 ₃ the liquid medium (3 g / L) composition comprising (pH 7.0), they were cultured in shaking for 4 days at 25 ° C (180rpm). This culture was used for rapeseed meal (10 g / L), fish meal (5 g / L), malt extract (5 g / L), soytone (3 g / L), glucose (30 g / L), lactose _{(10g / L), CaC0 3} (4g / L), MgS0 4 (0.5g / L) liquid medium of the composition of (pH 6.4) was inoculated into an Erlenmeyer flask, and cultivated at 25 ° C. by swirling and shaking (180 rpm) for 4 days.

(Process 2)

Cells were obtained by centrifuging the culture solution (2 L) thus obtained, and extracted with acetone (2 L) at room temperature. After separating and removing the cell residue from the extract by filtration, the filtrate was concentrated under reduced pressure. The concentrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The obtained oil (4 g) was dissolved in a 50% aqueous methanol solution and passed through a Diaion HP-20 column. After sufficiently washing the column with a 50% aqueous methanol solution, the column was eluted with methanol. The methanol eluted fraction was passed through a silica gel column and eluted with a black hole form. The thus-obtained form-form-eluting fraction was passed again through a silica gel column, and eluted with n-hexane / ethyl acetate (4: 1) to give avenaciolide (0.8 g).

Preparation of Compound IVa

A DMF solution (0.3 mL) of triphenylphosphine (5 ing), palladium acetate (2 mg), and triethylamine (35 μL) was stirred at 70 ° C for 1 hour, and then avenenalide (50 mg) and iodobenzene (50 mg) were added. 10 L) and stirred for 5 hours. After the reaction solution was filtered through celite, it was concentrated to dryness under reduced pressure. The residue was purified by silica gel preparative TLC [n-hexane / ethyl acetate (4: 1)] to obtain a compound (IVa) IVa (27 mg) as a white solid. 84% yield;

_{^ NMR (300MHz, CDC1 3)} δ 0 · 88 (3Η, t, J = 6.9Hz), 1.22-1.50 (12Η 3 m), 1.59-1 · 85 (2Η, m), 4. 13 (1Η 3 dt , J = 2.7, 8.4Hz), 4 · 40 (1Η, ddd, J = 2.7, 3.0, 11.6Hz), 5.17 (1H 3 d, J = 8.4Hz), 7.47 (5H, s), 7.75 (1H 5 d, J = 2.7Hz).

Three

Example 2 Production of Compound IVb

According to the method of Example 1, compound IVb was synthesized using avenaciolide and 4-odoaniline as starting materials.

63% yield;

Thigh (300 t, DMSO-dJd 0.84 (3H, t, J = 6.6Hz), 1.22 (11H, m) ₃ 1.39 (1H, br), 1.85 (2H, m), 4.30 (1H, m), 4.39 ( 1H, m), 5.44 (1H ₅ d, J = 8.7 Hz), 6.61 (2 H, d, J = 8.7 Hz), 7.31 (2H ₅ d, J = 8.7 Hz) ₅ 7.39 (1H, d, J = 2.1Hz).

Example 3 Production of Compound IVc

According to the method of Example 1, avenacolide derivative IVc was synthesized using avenacolide and 4-phenol as raw materials.

Yield 88%;

^{J H NMR (300MHz, DMS0- 0.83} (3H, t, J = 6.9Hz), 1.19 (11H, s), 1.37 (1H 5 m ), 1.83 (1H, m), 4.35 (2H, m), 5.47 (1H, d, J = 8.7Hz), 6.86 (2H, d, J = 8.7Hz) ₃ 7.48 (2H, d, J = 8.7Hz) ), 7.51 (1H, d, J = 2.4Hz), 10.27 (1H 3 br).

Example 4 Production of Compound IVd

According to the method of Example 1, an avenaciolide derivative IVd was synthesized using avenaciolide and 4-trifluoromethylbenzene as raw materials.

Yield 55%;

Thigh (300 _{Stephen, CDC1 3) δ 0.87 (3H} , t, J = 6.9Hz), 1.21 (11H, s), 1.38 (1H, m), 1.60-1.80 (2H, m) 5 4.11 (1H 3 dt, _{J = 3.0 3 8.4Hz), 4.35} (1H 3 m), 5.20 (1H, d, J = 8.4Hz), 7.59 (2H, d, J = 8.1Hz), 7.75 (1H 3 d, J = 8.1Hz) , 7.77 (1H, s).

(Example 5) Production of compound IVe

According to the method of Example 1, avenacolide and IV-benzoic acid were used as raw materials to synthesize avenacolide derivative IVe.

Five Yield 82%;

^{J H NMR (300MHz, acetone- d} 6) d 0.86 (3H, t, J = 6.6Hz), 1.22 (12H, m), 1.42 (1H, m), 1.87 (2H 5 q, J = 7.2Hz) 3 4.43 (1H, m), 4.59 (1H, dt, J = 2.7, 8.4Hz), 5.4 7 (1H, d, J = 8.4Hz), 7.74 (1H 5 d, J 2.7Hz), 7.83 (2H, d , J = 7.8Hz), 8.18 (2H ₅ d, J = 7.8Hz).

Example 6 Production of Compound IVf

In accordance with the method of Example 1, avenaciolide and IV-benzobenzene were used as raw materials to synthesize avenaciolide derivative IVf.

Yield 70%;

¾ thigh _{(300MHz, CDC1 3) δ 0.87} (3H, t, J = 6.6Hz), 1.23 (11H, m), 1.41 (1H, m), 1.75 (2H, m), 4.10 (1H, m), 4.39 (1H ₅ m), 5.19 (1H, d, J = 9.0Hz), 7.40 (2H, d, J = 8.7Hz), 7.46 (2H, d, J = 8.7Hz) ₃

7.67 (1H ₃ d, J = 2.1 Hz).

IVf Example 7 Production of Compound IVg

According to the method of Example 1, avenaciolide derivative IVg was synthesized using apenaciolide and 1-iodo-1-nitrobenzene as raw materials.

Yield 37%;

Thigh (300MHz, acetone-d6) δ 0.86 (3H, t, J = 6.6Hz), 1.20-1.41 (12H, m), 1.77- 1.89 (2H, m), 4.43 (1H, m), 4.61 (1H, dt, J = 3.0, 6.0Hz), 5.48 (1H, d, J = 8.7Hz), 7.79 (1H, d, J = 3.0Hz), 8.00 (2H, d, J2 9.0Hz), 8.41 (2H, d, J = 9.0Hz).

IVg

Example 8 Production of Compound IVh

According to the method of Example 1, avenaciolide derivative IVh was synthesized using apenaciolide and 4-odopyridine as raw materials.

17% yield;

Thigh (300 _{Stephen, CD 3 0D) δ 0.89 (} 3H, t, J = 6.6Hz), 1.19-1.33 (12H 3 m), 1.69 (2H, m), 4.29 (1H, dt, J = 3.6, 8.7Hz ), 4.39 (1H ₅ m), 5.34 (1H, d, J = 8.7 Hz), 7.59 (2H, d, J = 8.7 Hz), 7.67 (1H ₃ d, J = 2.4 Hz), 8.67 (2H ₅ d, J = 8.7Hz).

7

IVh

Example 9 Production of Compound IVi

According to the method of Example 1, avenaciolide derivative IVi was synthesized using avenaciolide and 4-benzobenzonitrile as raw materials.

Yield 48%;

¾ NMR (300MHz, acetone- d6) δ 0.88 (3H, t, J = 6.6Hz), 1.23- 1.42 (12H, m), 1. 85 (2H 5 m), 4.41 (1H 5 m), 4.59 (1H , dt, J = 3.0, 8.7Hz ), 5.47 (1H, d, J = 8.7Hz), 7.73 (1H, d, J = 2.7Hz), 7.90- 7.98 (4H 5 m).

IVi

Example 10 Production of Compound IVj

According to the method of Example 1, avenaciolide derivative IVj was synthesized using avenaciolide and 3-phenylphenol as raw materials.

Yield 81%;

¾ NMR (300MHz, acetone-d6) δ 0.87 (3H, brs), 1.25-1.55 (12H, m), 1.89 (2H, m), 4.35-4.53 (2H, m), 5.42 (1H ₅ d, J = 7.8Hz), 6.98 (1H, brd, J = 6.6Hz), 7.08 -7.20 (2H, m), 7.37 (1H, m), 7.59 (1H, brs), 8.80 (1H, brs).

ivj

(Example 11) Production of compound IVk

According to the method of Example 1, avenaciolide derivative IVk was synthesized using avenaciolide and 3-phosphodisole as raw materials.

Yield 56%;

Ή NMR (300MHz, acetone-d6) δ 0.88 (3Η, t, J = 6.6Hz), 1.25 (12Η, brs), 1.86 (2Η, m), 3.88 (3Η, s), 4.41 (1Η, m ), 4.54 (1Η, dt, J-3.0, 6.0Hz), 5.42 (1H, d, J = 8.4Hz) ₅ 7.08 (1H ₃ dd, 3 = 2.7, 8.1Hz), 7.22-7.27 (2H, m) , 7.47 (1H ₅ t, J2 8.1 Hz), 7.65 (1H, d, J = 2.7 Hz).

IVk

(Example 12) Production of compound IV1

According to the method of Example 1, avenaciolide derivative IV1 was synthesized using avenaciolide and 3-benzoic acid as raw materials.

Yield 42%;

¾ NMR (300MHz, acetone-d6) δ 0.86 (3H, t, J-6.6Hz), 1.22-1.40 (12H, m), 1. 69-2.00 (2H, m), 4.45 (1H, m) ₃ 4.57 (1H ₃ m), 5.48 (1H, d, J = 9.0Hz), 7.67-7.7 4 (2H, m), 7.94 (1H, d , J = 7.8Hz), 8.15 (1H, d, J = 8.1Hz),, 8.30 (1H, s).

IVI

Example 13 Production of Compound IVm

According to the method of Example 1, avenaciolide derivative IVm was synthesized using avenaciolide and 1-chloro-3-chlorobenzene as raw materials.

86% yield;

¾ NMR (300MHz, acetone-d6) δ 0.88 (3Η, t, J = 6.6Hz), 1.25-1.50 (12Η, m), 1.86 (2Η, m) ₅ 4.43 (1H, m), 4.59 (1H _{, dt, J = 3.0 3 8.7Hz} ), 5.46 (1H, d, J = 8.7Hz), 7.42-7.73 (5H 3 m).

IVm

Example 14 Production of Compound IVn

According to the method of Example 1, avenaciolide and IV-indole were used as raw materials to synthesize avenaciolide derivative IVn.

Yield 72%; ¾ NMR (300MHz, acetone-d6 ) δ 0.85 (3H, t, J = 6.6Hz), 1.22-1.55 (12H, m), 1. 91 (2H, m), 4.50 (1H 5 dt, J = 2.7, 8.7Hz), 4.39 (1H, dt, J = 2A, 8.7Hz), 5.43 (1H, d, J = 9.0Hz), 6.62 (1H, d, J = 3.0Hz), 7.22 (1H, d, J = 6.9Hz), 7.42-7.48 (2H, m), 7.6K1H, d, J = 8.7Hz), 7.78 (1H, d, J = 2.7Hz), 7.96 (1H, s), 10.67 (1H, brs) .

IVn

Example 15 Production of Compound IVo

According to the method of Example 1, avenaciolide derivative IVo was synthesized using avenaciolide and 2-phenyladineline as raw materials.

Yield 50;

¾ NMR (300MHz, acetone-d6) δ 0.88 (3H, t, J = 6.9Hz), 1.1-9-1.0 (12H, m), 1.69 (2H, m) ₃ 4.28 (1H, m) , 4.40 (1H, dt, J = 3.0, 9.0Hz), 5.22 (2H 5 brs), 5.40 (1H, d, J = 9.0Hz), 6.73 (1H, m) 5 6.88 (1H, dd, J = 0.9 , 8.7Hz), 7.20 (1H, m), 7.34 (1H, dd, J = 0.9, 7.8Hz) ₅ 7.69 (1H, d, Jh 3.0Hz).

IVo (Example 16)

According to the method of Example 1, avenaciolide derivative IVp was synthesized using avenaciolide and methyl 2-amino-5-odobenzoate as raw materials.

Yield 11%;

¾ thigh _{(300MHz, CDC1 3) δ 0.87} (3H, t, J = 6.6Hz), 1.26 (11H 3 m), 1.52 (1H 3 m), 2.01 (2H 3 m) 3 3.9K3H, s), 4.43 ( 1H, dt, J = 2.4, 8.7Hz), 4.55 (1H, dt, J = 2.7, 9.3Hz), 5.4K1H, d, J = 8.7Hz), 6.98 (1H, d, J-8.7Hz) , 7.51 (1H ₃ d, J = 2A Hz), 7.59 (1H ₅ dd, J = 2A, 8.7Hz), 8.14 (1H, d, J = 2.4Hz)

IVp

(Example 17) Production of compound Va ■ '.

Compound (IVa) (15 mg) was dissolved in chloroform / methanol (1: 1) (1 mL), palladium carbon (2 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 4 hours. The reaction solution was filtered through celite, and concentrated to dryness under reduced pressure to obtain Compound Va (15 mg) as a white solid. Yield 99%;

! H Anonymous (300 _{Stephen, acetone- d 6) (50.88 (} 3H, t 3 J = 7.2Hz), l.21-1.44 (14H 3 m), 2.96 (1 H, dd 3 J = 10.8,15.6Hz) ₅ 3.28 (lH, dd ₃ J = 7.2 ₅ 15.6Hz), 3.34 (lH ₅ dd ₃ J = 5,15.6Hz), 3.81 (lH, m), 4.70 (lH, m), 5.03 (lH, d, J = 7.2 Hz), 7.27 (lH, t, J = 7.2 Hz), 7.36 (2H, t, J = 7.2 Hz), 7.40 (2H, d, J = 7.2 Hz).

(Example 18) Production of compound Vb

According to the method of Example 17 and using compound IVc as a starting material, an avenaciolide derivative Vb was synthesized.

96% yield;

¾ NM (300MHz, DMS0-d _B ) δ 0.84 (3Η, t, J = 6.6Hz), 1.12- 1.21 (14Η,), 2.73 (1Η, dd, J = ll.l, 15.6Hz), 2.94-3.06 (2H, m), 3.65 ( 1H, m), 4.61 (1H, m), 4.9 5 (1H, d, J = 6.9Hz), 6.67 (2H 3 d, J = 8.4Hz), 7.05 (2H, d , J = 8.4Hz), 9.24 (1H, s).

Vb Pharmacological Test Example 1: Measurement of ACC inhibitory activity

1. Purification of ACC

The male SD rats were fasted for 2 days, then a high sucrose diet (component) was given for 2 days, the inferior vena cava was incised under ether anesthesia, blood was exsanguinated, and the liver was immediately removed. Ice-cold buffer (225 mM mannitoK 75 mM sucrose, 10 mM Tris-HCl (pH 7.5), 0.05 m MEDTA, 5 mM potassium citrate, 2.5 mM MgC12, 10 mg / L pepstatin A, 10 mg / L leupeptin, 1 mM PMSF) were homogenized with a polytron homogenizer. A 9-fold amount of buffer A was added to the liver weight, and the mixture was centrifuged at 1000 g for 10 minutes. Then, the supernatant was collected, and further centrifuged at 17,000 g for 10 minutes.

Ammonium sulfate was added to the obtained supernatant so as to be 35% saturated, stirred for 45 minutes, and then centrifuged at 17,000 g for 10 minutes. Buffer B (100 mM Tris-HCl (pH 7.5), 500 mM NaCl, 1 mM EDTA ヽ 0.1 iM DTT ヽ 10% glycerols 10 mg / L pepstatin A, 10 mg / L leupeptin, 0.5 mM (PMSF) was added and dissolved, followed by centrifugation at 4000 g for 20 minutes. The supernatant was dialyzed against buffer C (100 mM Tris-HCl (pH 7.5), 500 mM NaCK, 1 mM EDTA, 0.1 mM DTT, and 5-glycerol). The dialyzed supernatant was filtered through a 5〃M filter overnight, applied to a monomeric avidin sepharose column, washed with buffer B, and eluted with AC B with buffer B containing 2 mM d-biotin. .

2. Measurement of ACC inhibitory activity

Each of the compounds prepared in the above Examples was dissolved in DMS0, placed in a glass vial, and contained 250 〃 of a reaction solution 1 containing ACC (40 mM Tris-HCl (pH 7.5), 40 mM MgC12, 40 mM sodium citrate, 2 mM DTT), and the mixture was heated in a thermostat at 3 '7 ° C for 30 minutes and then cooled on ice. To reaction solution 1, add 250141 of reaction solution 2 (40 mM Tris-HCl (pH 7.5), 2 mM DTT ヽ 8 mM ATP, 0.5 mM acetyl CoA) containing [14C] -NaHC03, and add After heating for 10 minutes with, the reaction was stopped by adding 100/1 IN HC1. Centrifugal evaporator-After removing the water in the reaction solution in the evening, the scintillation was added overnight to dissolve the solid components, and the radioactivity of 14C was measured in the liquid scintillation counter. The ACC inhibitory activity of each compound was calculated from the following formula, and the concentration (IC50) at which 50% inhibition was obtained was determined. The results are shown in Table 1. ACC inhibition rate (%) = {1-(ac) / (bc)} x 100

a: Radioactivity when the test drug is added

b: Radioactivity without test drug added

c: Blank 氺

* Add 100 jul of IN HC1 to Reaction Solution 1 before mixing Reaction Solution 1 and Reaction Solution 2.

The following table shows the ACCP and harmful activities of the compounds of the present invention.

Compound number C50

III 6.4 jug / ml (24.0 ΛίΜ)

IVa 7.4 ug / ml (2 1.6)

Va 3.8 Aig / ml _ (1 1.0 M)

In the table, compound III is a known compound, avenaciolide.

In addition, the AC C inhibitory activity (P and harm rate) at a 10 μM amount of the compound of the present invention was determined in the same manner. The results are shown in Table-2.

Table-2 Inhibition rate at compound No. 10〃M (%)

9 0

7 3

7 6

5 5

7 3

6 7

8 6

5 1

6 2

4 3

5 8

7 4

7 3 The bislactone derivative of the present invention is considered to be based on obesity and hyperlipidemia induced by obesity, fatty liver and insulin resistance by a different mechanism from conventional anti-obesity drugs and insulin resistance improving drugs. Can treat abnormal glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), hypertension and arteriosclerosis It is extremely useful as a prophylactic and / or therapeutic agent for diseases.

Claims

The scope of the claims

1. Prevention of diabetes, obesity, hyperlipidemia, fatty liver, diabetic complication characterized by containing a bislactone derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. / Or remedy.

(Wherein, R ¹ is an alkyl group having 1 to 12 carbon atoms; is a hydrogen atom, an aryl group, an optionally substituted aryl group, a heteroaryl group, and an optionally substituted heteroaryl group, an alkyl group, Represents an alkyl group which may be substituted, XY represents CR ³ -C¾ and C = CH, R ³ represents a hydrogen atom, a hydroxyl group, an alkoxyl group having 1 to 12 carbon atoms, Z represents an interatomic bond, -0. -, -NH-, -S-,-(C¾) n-, where n is 1 to 12.)

2. The preventive and / or therapeutic agent for diabetes, obesity, hyperlipidemia, fatty liver, and diabetic complication according to claim 1, wherein in the formula (I), Z is an atomic bond.

3. The preventive and / or therapeutic agent for diabetes, obesity, hyperlipidemia, fatty liver, and diabetic complication according to claim ¹ , wherein R ¹ in the formula (I) is an n-octyl group.

In 4. formula (I), the claim 1, wherein the diabetes XY is C = CH or CH-CH _2, obesity, hyperlipidemia, fatty liver, prevention and / or treatment of diabetic complications.

5. In the formula (I), R ² is a phenyl group, an aminophenyl group, a hydroxyphenyl group, a carboxyphenyl group, a trifluoromethylphenyl group, a chlorophenyl group, a nitrophenyl group, a cyanophenyl group, a methoxyphenyl group. 2. The method according to claim 1, wherein the group is selected from the group consisting of an enyl group, a methoxycarbonylphenyl group, a pyridyl group and an indolyl group. The preventive and / or therapeutic agent for diabetes, obesity, hypermentemia, fatty liver, and diabetic complications described in the above.

6. A claim according to claim 1, wherein in the formula (I), E ² is a phenyl group, a 4-aminophenyl group, a 4-hydroxyphenyl group, a 4-carboxyphenyl group, and a 4-trifluoromethylphenyl group. The preventive and / or therapeutic agent for diabetes, obesity, hypertension, fatty liver, and diabetic complications according to 1.

7. In the formula (I), Z is an interatomic bond, R ¹ is an n-octyl group, and XY is C = CH or CH-C¾, diabetes, obesity, hyperlipidemia, fatty liver. Prevention and / or treatment of diabetic complications.

8. In the formula (I), Z is an interatomic bond, R ¹ is an n-octyl group, and X-Y is C = CH or CH-C¾, wherein diabetes, obesity, hyperlipidemia, Prevention and / or treatment of fatty liver, 5fe uremic complications.

9. A bislactone derivative represented by the following general formula (II) or a pharmaceutically acceptable salt thereof.

(Wherein, R ¹ represents an alkyl group having 1 to 12 carbon atoms; R ² represents a hydrogen atom, an aryl group, an optionally substituted aryl group, a heteroaryl group, and an optionally substituted heteroaryl group. And X represents a CR ³ —C¾ or CCHCH, R ³ represents a hydrogen atom, a hydroxyl group, or an alkoxyl group having 1 to 12 carbon atoms. Represents an interatomic bond, -0-, -NH-, -S-,-(C¾) n-, where n is 1 to 12. However, R ² is a hydrogen atom, XY is C = CH, and Z is an atom. In the case of an interbond, R ¹ is a methyl group, an ethyl group, an n-octyl group and And n-decyl group. There phenyl group, XY is CH-C¾, Z is - S- of, H ¹ is not a E methyl group and n- Okuchiru group. When R ¹ is an n-octyl group, R ² is a hydrogen atom, and Z is -0-, XY is not C (0H) -C¾. When R ¹ is an n-octyl group, is a methyl group and Z is −0-, X—Y is not CH—C¾. When R ¹ is an n-octyl group, is a hydrogen atom, and Z is an interatomic bond, X—Y is not CH—CH ₂ . )

10. In the formula (Π), Z is an interatomic bond, R ¹ is an n-octyl group, X-Y is C = CH or CH-C¾, R ¹ is an n-octyl group, and X-Y is CH-CH ₂ or C double CH, R ² is phenyl group, Aminofue two group, hydroxyphenyl group, carboxy off We group, triflate Ruo Russia methyl Hue group, black hole phenyl group, nitrophenyl group, Shianofueniru group, Metokishifu Eniru group, 10. The compound according to claim 9, which is selected from the group consisting of a methoxycarbonylphenyl group, a viridyl group and an indolyl group.

11. In the formula (II), R ¹ is an n-octyl group, R ² is a phenyl group, a 4-aminophenyl group, a 4-hydroxyphenyl group, a 4-trifluoromethylphenyl group, and a 4-carboxyphenyl group. 10. The compound according to claim 9, wherein XY is any of CH-C¾ and (().

12. A pharmaceutical composition comprising the bislactone derivative represented by the formula (II) according to claim 9 or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising the bislactone derivative according to claim 10 or a pharmaceutically acceptable salt thereof.

14. Diabetes, obesity, hyperlipidemia, fatty liver, diabetic complication characterized by containing a bislactone derivative represented by the formula (II) according to claim 9 or a pharmaceutically acceptable salt thereof. Prophylactic and / or therapeutic drug for the disease.

15. An ACC activity inhibitor comprising the bislactone derivative represented by the formula (I) described in claim 1 or a pharmaceutically acceptable salt thereof.

16. A bislactone derivative represented by the formula (Π) according to claim 9 or a pharmaceutically acceptable salt thereof. An ACC activity inhibitor, which comprises a salt acceptable for ACC.

17. An ACC activity inhibitor comprising the bislactone derivative represented by the formula (II) according to claim 10 or a pharmaceutically acceptable salt thereof.