WO2003094912A1 - Derives de bislactone et leur utilisation dans les compositions medicales - Google Patents

Derives de bislactone et leur utilisation dans les compositions medicales Download PDF

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Publication number
WO2003094912A1
WO2003094912A1 PCT/JP2003/005754 JP0305754W WO03094912A1 WO 2003094912 A1 WO2003094912 A1 WO 2003094912A1 JP 0305754 W JP0305754 W JP 0305754W WO 03094912 A1 WO03094912 A1 WO 03094912A1
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group
formula
bislactone
obesity
diabetes
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PCT/JP2003/005754
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English (en)
Japanese (ja)
Inventor
Seiichi Sato
Takayuki Kajiura
Noriyuki Okusa
Eiko Hayashi
Yukio Nihei
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Ajinomoto Co.,Inc.
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Priority to AU2003235887A priority Critical patent/AU2003235887A1/en
Publication of WO2003094912A1 publication Critical patent/WO2003094912A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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.
  • ACC acetyl CoA carboxylase
  • 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.
  • 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.
  • PPAR peroxisome proliferator-related receptor
  • 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.
  • 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.
  • 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.
  • 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
  • diabetes diabetic complications
  • diabetic nephropathy diabetic retinopathy
  • diabetic macroangiopathy 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
  • 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.
  • a bislactone derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof Provide prophylactic and / or therapeutic agents.
  • 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 -C3 ⁇ 4 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.
  • 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 —CH 2 and C ⁇ ⁇ 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-,-(C3 ⁇ 4) n-, wherein n is 1 to L2.
  • R 2 is a hydrogen atom
  • XY is C 2 CH
  • Z is an interatomic bond
  • R 1 is not a methyl group, an ethyl group, an n-octyl group or an n-decyl group.
  • R 2 is a phenyl group
  • X—Y is CH—C3 ⁇ 4
  • Z is —S—
  • R 1 is not an ethyl group or an n-octyl group.
  • R 1 is an n-octyl group
  • Z is -0-
  • XY is not C (0H) -C3 ⁇ 4.
  • R 1 is an n-octyl group
  • R 2 is a methyl group, and Z is ⁇ 0-
  • XY is not CH—C3 ⁇ 4.
  • R 1 is an n-octyl group
  • R 2 is a hydrogen atom
  • Z is an interatomic bond
  • X—Y is not CH—CH 2 .
  • the present invention also provides a pharmaceutical composition
  • 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.
  • a diabetes obesity, hyperlipidemia, fatty liver, diabetic complication
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • Puchiruokishi group can be mentioned cyclohexylene, more preferably methoxy group, ethoxy alkoxy group, n- propoxy group, n- butoxy group, and Kishiruokishi group to n-
  • 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.
  • 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.
  • a phenyl group, an aminophenyl, a hydroxyphenyl group, a trifluoromethylphenyl group, and a carboxyphenyl group are preferred.
  • 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.
  • 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) - (3 ⁇ 4 is preferably, CH-C3 ⁇ 4 more preferably ⁇
  • 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-,-(C3 ⁇ 4) 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.
  • 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.
  • 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.
  • diabetes obesity, hyperlipidemia, fatty liver, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hypertension, arteriosclerosis)
  • diabetic complications diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hypertension, arteriosclerosis
  • 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.
  • R 1 is an n-octyl group
  • XY is C ⁇ CH
  • Z is an interatomic bond
  • R 2 is an aryl group (formula IV). It can be synthesized by reacting avenaciolide (Formula III) with aryl iodide as a raw material.
  • R represents a substituent on the aromatic ring
  • R 1 is an n-octyl group
  • XY is CH—C3 ⁇ 4
  • Z is an interatomic bond
  • R 2 is an aryl group. Can be synthesized by reducing.
  • R represents a substituent on the aromatic ring
  • 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.
  • 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 may be used in combination, It may also contain pharmaceutically useful auxiliaries.
  • 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.
  • this compound for diabetes, obesity, hyperlipidemia, fatty liver, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hypertension, arteriosclerosis)
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • compound IVb was synthesized using avenaciolide and 4-odoaniline as starting materials.
  • avenacolide derivative IVc was synthesized using avenacolide and 4-phenol as raw materials.
  • an avenaciolide derivative IVd was synthesized using avenaciolide and 4-trifluoromethylbenzene as raw materials.
  • avenacolide and IV-benzoic acid were used as raw materials to synthesize avenacolide derivative IVe.
  • avenaciolide and IV-benzobenzene were used as raw materials to synthesize avenaciolide derivative IVf.
  • avenaciolide derivative IVg was synthesized using apenaciolide and 1-iodo-1-nitrobenzene as raw materials.
  • avenaciolide derivative IVh was synthesized using apenaciolide and 4-odopyridine as raw materials.
  • avenaciolide derivative IVi was synthesized using avenaciolide and 4-benzobenzonitrile as raw materials.
  • avenaciolide derivative IVj was synthesized using avenaciolide and 3-phenylphenol as raw materials.
  • avenaciolide derivative IVk was synthesized using avenaciolide and 3-phosphodisole as raw materials.
  • avenaciolide derivative IV1 was synthesized using avenaciolide and 3-benzoic acid as raw materials.
  • avenaciolide derivative IVm was synthesized using avenaciolide and 1-chloro-3-chlorobenzene as raw materials.
  • avenaciolide and IV-indole were used as raw materials to synthesize avenaciolide derivative IVn.
  • avenaciolide derivative IVo was synthesized using avenaciolide and 2-phenyladineline as raw materials.
  • avenaciolide derivative IVp was synthesized using avenaciolide and methyl 2-amino-5-odobenzoate as raw materials.
  • an avenaciolide derivative Vb was synthesized.
  • Vb Pharmacological Test Example 1 Measurement of ACC inhibitory activity
  • 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
  • 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 ⁇ 0.1 iM DTT ⁇ 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. .
  • 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.
  • ACC 40 mM Tris-HCl (pH 7.5), 40 mM MgC12, 40 mM sodium citrate, 2 mM DTT
  • compound III is a known compound, avenaciolide.
  • 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.

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Abstract

L'invention concerne un agent préventif et/ou thérapeutique destiné aux diabètes, à l'obésité, l'hyperlipidémie, la stéatose hépatique et les complications du diabète. Cet agent contient un dérivé de bislactone représenté par la formule générale (I) ou un sel pharmaceutiquement tolérable. Dans la formule (I), R1 représente alkyle C1-12 ; R2 représente hydrogène, aryle, aryle éventuellement substitué, hétéroaryle ou hétéroaryle éventuellement substitué ; X-Y représente CR3-CH2 ou C=CH ; R3 représente hydrogène, hydroxy ou alcoxy C1-12 ; Z représente une liaison interatomique, -O-, -NH-, -S- ou (CH2)n- ; et n vaut 1 à 12.
PCT/JP2003/005754 2002-05-09 2003-05-08 Derives de bislactone et leur utilisation dans les compositions medicales WO2003094912A1 (fr)

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JP2002134054A JP2005320250A (ja) 2002-05-09 2002-05-09 ビスラクトン誘導体及びその医薬組成物としての使用
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Cited By (5)

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WO2005108370A1 (fr) * 2004-04-16 2005-11-17 Ajinomoto Co., Inc. Composés du benzène
WO2008088692A2 (fr) 2007-01-12 2008-07-24 Merck & Co., Inc. Dérivés spirochromanone
WO2008088688A1 (fr) 2007-01-12 2008-07-24 Merck & Co., Inc. Dérivés substitués de spirochromanone en tant qu'inhibiteurs d'acc
EP2189458A1 (fr) 2008-10-30 2010-05-26 Janssen Pharmaceutica, N.V. Composé arylamide en tant qu'inhibiteur de l'acétyl coenzyme A carboxylase
US8524730B2 (en) 2008-07-04 2013-09-03 Msd K.K. Spirochromanone carboxylic acids

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WO2005108370A1 (fr) * 2004-04-16 2005-11-17 Ajinomoto Co., Inc. Composés du benzène
US7402696B2 (en) 2004-04-16 2008-07-22 Ajinomoto Co., Inc. Benzene compounds
WO2008088692A2 (fr) 2007-01-12 2008-07-24 Merck & Co., Inc. Dérivés spirochromanone
WO2008088688A1 (fr) 2007-01-12 2008-07-24 Merck & Co., Inc. Dérivés substitués de spirochromanone en tant qu'inhibiteurs d'acc
US8524730B2 (en) 2008-07-04 2013-09-03 Msd K.K. Spirochromanone carboxylic acids
EP2189458A1 (fr) 2008-10-30 2010-05-26 Janssen Pharmaceutica, N.V. Composé arylamide en tant qu'inhibiteur de l'acétyl coenzyme A carboxylase

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