[go: up one dir, main page]

WO2006126654A1 - Un nouveau composé : l'acide collétoïque - Google Patents

Un nouveau composé : l'acide collétoïque Download PDF

Info

Publication number
WO2006126654A1
WO2006126654A1 PCT/JP2006/310497 JP2006310497W WO2006126654A1 WO 2006126654 A1 WO2006126654 A1 WO 2006126654A1 JP 2006310497 W JP2006310497 W JP 2006310497W WO 2006126654 A1 WO2006126654 A1 WO 2006126654A1
Authority
WO
WIPO (PCT)
Prior art keywords
salt
compound
culture
obesity
hypertension
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2006/310497
Other languages
English (en)
Japanese (ja)
Inventor
Azusa Aoyagi
Mariko Kobayashi
Yasunori Ono
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sankyo Co Ltd
Daiichi Sankyo Co Ltd
Original Assignee
Sankyo Co Ltd
Daiichi Sankyo Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sankyo Co Ltd, Daiichi Sankyo Co Ltd filed Critical Sankyo Co Ltd
Publication of WO2006126654A1 publication Critical patent/WO2006126654A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
    • C12P7/42—Hydroxy-carboxylic acids
    • 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
    • A61P3/08—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30—Unsaturated compounds
    • C07C62/32—Unsaturated compounds containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/50—Spiro compounds

Definitions

  • the present invention relates to a novel compound having an inhibitory action on 11 j8-hydroxysteroid dehydrogenase typel (hereinafter referred to as "11 j8- HSD1”), a medicine containing the compound as an active ingredient (preferably diabetes, obesity , Treatment of hyperlipidemia, hypertension, or metabolic syndrome that develops these pathological conditions in combination ”, a method for producing the compound, a novel microorganism that produces the compound, and the like.
  • 11 j8- HSD1 11 j8-hydroxysteroid dehydrogenase typel
  • Non-patent Document 1 Any treatment! / Food therapy and exercise therapy are used at first and are less effective! / Pharmacotherapy is combined with epilepsy or severe cases.
  • Diabetes is classified into insulin-dependent (type I, IDDM) and insulin-independent (type II, NIDDM), and more than 90% of diabetics are the latter.
  • Insulin injection is used to treat IDDM, and sulfo-urea drugs that promote insulin secretion, thiazolidinedione drugs that improve insulin resistance, and daricosidase inhibitors that inhibit digestion and absorption of sugars.
  • biguanide drugs that suppress gluconeogenesis in the liver are used (Non-patent Document 2).
  • Non-patent Document 2 Non-patent Document 2
  • none of these drugs is always effective, and the effectiveness of these drugs decreases over time, increasing the number of patients who have serious complications.
  • Hyperlipidemia treatment includes HMG Co A reductase inhibitor that inhibits cholesterol synthesis in the liver, fibrate drugs that inhibit synthesis of neutral fat in the liver, and promotes bile acid excretion Anion exchange resin is used.
  • the ultimate goal of hyperlipidemia treatment is to prevent arteriosclerotic diseases such as coronary artery disease and cerebral infarction, but arteriosclerosis is not only hyperlipidemia but also hypertension, diabetes, obesity Since various risk factors, such as aging, overlap, it is important to keep an eye on these other risk factors, and multifaceted efforts are required (Non-patent Document 3).
  • Glucocorticoids cortisol in humans and corticosterone in rodents release amino acids from muscle and promote the release of fatty acid and glycerol into blood through the expression of various proteins
  • it promotes gluconeogenesis in the liver using these substrates, which in turn promotes an increase in blood sugar.
  • it matures immature adipocytes in adipose tissue and leads to obesity, and in the kidney, it acts on mineralocorticoid receptors to increase blood pressure.
  • 11 j8-hydroxysteroid dehydrogenase in target organs such as liver, adipose and tissue, and lung
  • 11 — HSD1 inhibitors suppress the action of glucocorticoids in these tissues, thereby suppressing hyperglycemia, obesity, hyperlipidemia and epilepsy or hypertension, and combining these pathologies It is expected to exert multifaceted effects on metabolic syndrome that has developed spontaneously.
  • Non-Patent Document 5 In adipose tissue-specific 11 ⁇ HSD1 high-expressing mice, visceral fat obesity, impaired glucose tolerance, insulin resistance and increased blood pressure have been reported and support these possibilities (Non-Patent Document 5, Or non-patent document 6).
  • 11 Aminothiazol sulphonamide derivatives (Non-patent Document 7) and triazole derivatives (Patent Document 1) are known as 18-HSD1 inhibitors, but are not yet in practical use.
  • Patent Document 1 International Patent Publication Number WO03Z065983 Pamphlet
  • Non-patent document 1 “Nature”, 414 ⁇ , p. 782 (2001)
  • Non-Patent Document 2 "The American Journal of”
  • Non-Patent Document 3 “The Journal of Clinical Endocrinology & Metabolism”, 89, 2601 (2004)
  • Non-Patent Document 4 “Endocrinology”, 142 ⁇ , 1371 (2001)
  • Non-Patent Document 5 “Science”, 294 ⁇ , 2166 (2001)
  • Non-Patent Document 6 “The Journal of Clinical Investigation”, 112 ⁇ , 83 (2003)
  • Non-Patent Document 7 “Journal of medicinal chemistry”, 45 ⁇ , page 3813 (2002)
  • the present inventors have conducted extensive research for the purpose of searching for a substance having 11 ⁇ -HSD1 inhibitory activity, and that a novel compound isolated and purified from a microorganism culture has the activity.
  • the present invention was completed.
  • the present invention provides:
  • the infrared absorption spectrum measured by the thin film method shows the following maximum absorption.
  • the 13 C-nuclear magnetic resonance spectrum measured in deuterated dimethyl sulfoxide using the deuterated dimethyl sulfoxide signal (39.5 ppm) as an internal standard is shown below. 19.2 (q), 19.6 (q), 23.7 (t), 25.2 (q), 26.1 (t), 27.1 (d), 27.3 (t), 45.8 (t), 47. l (s), 55. 17 (d), 55. 19 (d), 66.8 (d), 122. 6 (d), 135.9 (s), 17 6.1 (s ) ppm,
  • the compound producing the compound according to (1) or (2) belonging to the genus Colletotricum is Colletotrichum gloeosporioid s SANK 21404 (FERM BP-10309), ( 3) the production method according to
  • a pharmaceutical comprising the compound according to (1) or (2) or a pharmaceutically acceptable salt thereof as an active ingredient
  • the medicament according to (7) which is a therapeutic drug for diabetes, a therapeutic drug for obesity, a therapeutic drug for hyperlipidemia, a therapeutic drug for hypertension or a drug for improving metabolic syndrome,
  • choletoic acid (English name: “colletoic acid”) refers to a compound represented by the above formula (I) or a compound having the physicochemical properties described in the above (2).
  • the compound of the present invention can be converted to a salt by a method well known to those skilled in the art using a base.
  • the present invention also includes salts of these compounds.
  • the salt of the compound of the present invention is used as a pharmaceutical, it is not particularly limited as long as it is medically used and pharmacologically acceptable. Moreover, when using for uses other than a medicine, if it can be used for this use, it will not specifically limit.
  • salts include alkali metal salts such as sodium salts, potassium salts and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts and iron salts. , Zinc salt, copper salt, nickel salt, cobalt salt, etc .; inorganic salt such as ammonium salt; toctylamine salt, dibenzylamine salt, morpholine salt, darcosamine salt, vinylglycine alkyl ester salt, ethylenediamine salt, N —Methyl darcamine salt, guazine salt, jetylamine salt, triethylamine salt, dicyclohexylamine salt, N, N, -dibenzylethylenediamine salt, black pro-in salt, pro-in salt, diethanol Amine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxy Organic amine salts such as chill) Aminomet
  • the compound of the present invention and a salt thereof may be left in the air or mixed with water or an organic solvent to combine with water or a solvent to form a hydrate or a solvate.
  • hydrates and solvates are also included in the present invention.
  • the choretic acid of the present invention has various steric structures.
  • equal and unequal mixtures of these stereoisomers are all represented by a single structural formula.
  • the compound of the present invention also includes these isomers and mixtures of these isomers. Everything is included.
  • Choletoic acid can be isolated and purified according to a conventional method for culturing microorganisms that produce the substance.
  • the microorganism producing colletic acid is not particularly limited, but is preferably a fungus, more preferably a fungus belonging to the genus Colletotricum, and most preferably Colletotrichum gloeosporioides (Colletotrichum gloeosporioides).
  • S ANK 21404 (hereinafter referred to as “SANK 21404 shares”! /).
  • SANK 21404 strain is isolated from a plant in Okagaki-machi, Onga-gun, Fukuoka.
  • the SANK 21404 strain has the following mycological properties.
  • the color indications are: “Kornerup and Vanceyer, Metune Handbook of Color, 3rd Edition, Ellie Metune, London, UK, 1—252 (1978); (Kornerup A, Wanscher JH : Methuen handbook of color. 3rd ed., Eyre Methuen, London, UK., 1—252 (1978))
  • Potato Dextrose Agar Medium (hereinafter referred to as “PDA” medium): Dissolve 39 g of Nissi Potato Dextrose Agar Medium (manufactured by Nissui Pharmaceutical Co., Ltd.) in 100 ml of distilled water. Prepare plates after sterilization at ° C for 15 minutes.
  • WSH medium eclipse oatmeal 10 g, magnesium sulfate heptahydrate lg, potassium dihydrogen phosphate lg, sodium nitrate lg and agar 20 g are dissolved in 1000 ml of distilled water. Prepare plates after sterilization at ° C for 15 minutes.
  • PCA medium Potato Carrot Agar medium
  • the lesion is round to irregular, light brown, and forms a conidia layer on the front or back surface.
  • the conidia layer is superficial to integumental, discoid and forms bristles, and conidia appear as white to pale pink conidia.
  • the conidia pattern is parallel to the surface of the conidia layer, is colorless and does not branch, and forms conidia at the tip.
  • the SANK 21404 strain exhibits the following mycological properties on each medium.
  • Colonies in PDA medium have a diameter of 82-88 mm when cultured for 1 week at 25 ° C.
  • Koguchi-1 is fluffy and has a greenish gray (29B2) to white color with abundant aerial hyphae. No exudate, sclerotia, or conidia are observed.
  • the back side is dark green (28F4) to greenish gray (28C2) at the center and white at the edge. No soluble dye is observed.
  • Colonies in WSH medium have a diameter of 75-85 mm after 1 week of culture at 25 ° C. Colonies range from wooly to velvety, from gray (lEl) to white. No exudate, nuclei, or conidia are observed. The back side is brownish gray (8F2) at the center and reddish gray (8C2) and white at the edge. No soluble pigment is observed.
  • Colonies in PCA medium have a diameter of 65-67 mm when cultured for 1 week at 25 ° C.
  • the mouth is fluffy and has a gray (grey (lEl)) to white color. No exudate, mycorrhiza, or conidial mass is observed.
  • the back surface is gray yellow (4C3) to gray (grey (4 B1)) at the center and white at the edge. No soluble pigment is observed.
  • the SANK 21404 strain includes all the mutant strains.
  • the mutant strain included in the SANK 21404 strain of the present invention is a strain characterized by producing cholate acid.
  • mutant strains include those obtained by genetic methods such as recombination, transduction, transformation and the like. That is, SANK 21404 strain producing cholate, mutants thereof and strains not clearly distinguished from them are all included in SANK 21404 strain.
  • choletic acid can be produced by culturing a bacterium that produces the substance.
  • the culture of SANK 21404 strain can be carried out using a medium usually used for producing secondary metabolites of microorganisms.
  • a medium usually used for producing secondary metabolites of microorganisms.
  • Such a medium contains a carbon source, a nitrogen source and an inorganic salt that can be assimilated by the microorganism.
  • Examples of the carbon source include glucose, fructose, maltose, sucrose, man-toll, glycerin, dextrin, oats, rye, starch, potato, corn flour, cottonseed oil, molasses, citrate, tartaric acid and the like. These can be used alone or in combination.
  • the amount of carbon source added is usually in the range of 1 to 10% by weight of the medium.
  • the nitrogen source a substance or an inorganic salt containing a protein and a hydrolyzate thereof is usually used.
  • nitrogen sources include soy flour, bran, peanut flour, cottonseed flour, casein hydrolyzate, pharmamine, fish meal, corn steep liquor, peptone, meat extract, yeast, yeast extract, malto extract, gelatin.
  • the amount of nitrogen source added is usually in the range of 0.2 to 10% by weight of the medium.
  • the nutrient inorganic salt for example, salts capable of obtaining ions such as sodium ion, ammonium ion, calcium ion, phosphate ion, sulfate ion, salt ion, and carbonate ion are used. .
  • salts containing trace amounts of metals such as potassium, calcium, conoleto, manganese and magnesium can also be used.
  • an antifoaming agent can be used as necessary, and as such an antifoaming agent, for example, silicon oil, vegetable oil, a surfactant or the like is used.
  • Choleto acid can be obtained by aerobic culture of SANK 21404 strain.
  • a culture method for example, a solid culture method, a shaking culture method, an aeration stirring culture method, or the like is used.
  • shaking culture is preferably performed at 9 to 35 ° C (preferably 15 ° C to 33 ° C, optimally 23 ° C). Incubation begins in a conical flask with one or more stages of seed development. The seed culture is performed by adding a sterilized seed culture medium to the flask, inoculating the SANK 21404 strain, and then shaking in a constant temperature incubator for several days or until it has grown sufficiently.
  • Part or all of the obtained seed culture solution is used to inoculate the seed culture medium or production culture medium in the next stage.
  • the culture should be sterilized
  • the seed culture solution can be inoculated into a flask containing the production culture medium and shaken at a constant temperature for several days or until it has grown sufficiently.
  • Mass culture is preferably performed in a suitable jar or tank equipped with a stirrer and a ventilator.
  • Media can be made in jars or tanks, sterilized by heating to 121 ° C, and cooled before use.
  • For cultivation inoculate the seed culture medium in the production culture medium in the jar or tank and agitate at 9 to 35 ° C (preferably 15 ° C to 33 ° C, optimally 23 ° C). Can be done. This method is suitable for obtaining large amounts of compounds.
  • the target culture can be obtained by extracting and purifying the obtained culture, the supernatant obtained from the culture by centrifugation or filtration, or the whole culture.
  • a compound can be obtained.
  • the amount of choletic acid produced with the progress of culture is determined by collecting a part of the culture solution, extracting the compound, performing high performance liquid chromatography, and measuring the compound. It's possible to quit.
  • choletic acid present in the liquid part of the culture liquid, in the microbial cells, or both uses the whole culture ending liquid or the microbial cells and other solid parts as diatomaceous earth as a filter aid. It is possible to extract and purify from the filtrate or supernatant obtained by filtration or centrifugation, and bacterial cells, using high-performance liquid chromatography as an index, and using their physical and physical properties.
  • Choletic acid present in the filtrate or supernatant is not miscible with water under acidic conditions, and is an organic solvent such as ethyl acetate, chloroform, ethylene chloride, methylene chloride, butanol alone or , And can be extracted and purified by a combination thereof.
  • an adsorbent for example, Amberlite XAD-2, XAD-4 (manufactured by Rohm 'and' Haas Co., Ltd.), which is activated carbon or an adsorbent resin, Diaion HP-10, HP-20 CHP20P, HP-50, Sepabeads SP-207 (manufactured by Mitsubishi Chemical Corporation) and the like can also be used for extraction and purification.
  • the liquid containing the target compound is removed by passing through the adsorbent layer and adsorbing the impurity to the adsorbent, or the target compound is adsorbed and washed away. Thereafter, the target compound can be extracted and purified by eluting the target compound with methanol water, acetone water, butanol water or the like.
  • Choletic acid present in the microbial cells is extracted with 50 to 90% aqueous acetone or aqueous methanol, and after removing the organic solvent by concentration, the extraction and purification operation is performed in the same manner as described above. Obtainable.
  • the target compound can be extracted by adding an appropriate amount (preferably a final concentration of 50%) of acetone or methanol after completion of the culture. After completion of the extraction, the target compound can be extracted and purified by performing a filtration operation using diatomaceous earth as a filter aid and subjecting the obtained extract to the same extraction and purification operation as the filtrate.
  • an appropriate amount preferably a final concentration of 50%
  • the target compound can be extracted and purified by performing a filtration operation using diatomaceous earth as a filter aid and subjecting the obtained extract to the same extraction and purification operation as the filtrate.
  • the solution containing choletic acid extracted and purified by the above method is a carrier such as silica gel, Cefadex LH-20 (manufactured by Amersham Biosciences), florisil, cosmosyl (manufactured by Nakarai Tesque).
  • a carrier such as silica gel, Cefadex LH-20 (manufactured by Amersham Biosciences), florisil, cosmosyl (manufactured by Nakarai Tesque).
  • the above-mentioned separation and purification means can be separated or purified by using the above-mentioned separation and purification means alone or in combination as appropriate, and repeatedly in some cases.
  • the choretic acid or a salt thereof of the present invention has 11 ⁇ -HSD1 inhibitory activity.
  • Glucocorticoids cortisol in humans and corticosterone in rodents
  • various physiological activities that regulate blood sugar levels, blood pressure, and the like. For example, it promotes the release of amino acids from muscles and the release of fatty acids and glycerol from adipose tissue into the blood, and promotes gluconeogenesis in the liver using these substrates, resulting in an increase in blood sugar levels.
  • Physiological activity that promotes elevation is known.
  • Glucocorticoids are also known to have the activity of maturating immature adipocytes in adipose tissue to lead to obesity and the activity of acting on mineralocorticoid receptors in the kidney to increase blood pressure. Being Yes.
  • HSD1 is an enzyme that is mainly expressed in tissues such as liver, adipose tissue, and lung, and has an activity to convert inactive glucocorticoids into active forms.
  • 11 — HSD1 inhibitors are By suppressing the action of glucocorticoids in tissues, hyperglycemia, obesity, hyperlipidemia, and sputum or hypertension are suppressed. It also exerts multifaceted effects on metabolic syndrome, which is a condition with these symptoms. “Metabolic syndrome” is a symptom in which the metabolic functions of carbohydrates and lipids in the living body are abnormal.
  • the present invention also relates to a medicament containing as an active ingredient choletic acid or a pharmaceutically acceptable salt thereof. Since cholate has the activity described above, the drug is useful as an 11 j8-HSD1 inhibitor or a therapeutic or prophylactic agent for diabetes, obesity, hyperlipidemia, hypertension, and Z or metabolic syndrome. It is.
  • the present invention also provides a method for inhibiting 11 ⁇ -HSD1 in vivo by administering the medicament, or the treatment or prevention of diabetes, obesity, hyperlipidemia, hypertension, and epilepsy or metabolic syndrome. Regarding the method.
  • the present invention relates to 11 ⁇ -HSD1 inhibitor or choletic acid or a pharmaceutically acceptable salt thereof for producing a therapeutic or prophylactic agent for diabetes, obesity, hyperlipidemia, hypertension, and epilepsy or metabolic syndrome.
  • Use of the salt for producing a therapeutic or prophylactic agent for diabetes, obesity, hyperlipidemia, hypertension, and epilepsy or metabolic syndrome.
  • the choletic acid of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms.
  • the administration form include tablets, capsules, granules, emulsions, pills, powders, syrups (solutions) or the like, or injections (intravenous, intramuscular, subcutaneous or intraperitoneal administration), Examples include parenteral administration such as instillation and suppository (rectal administration).
  • parenteral administration such as instillation and suppository (rectal administration).
  • These various preparations are usually used in the pharmaceutical formulation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. It can be formulated with adjuvants that can be used.
  • lactose When used as a tablet, for example, lactose, sucrose, sodium chloride salt, dalcose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, key acid, etc. are used as carriers.
  • Agents Water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polypyrrolidone, etc .; dry starch, sodium alginate, agar powder, lamina lan Powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc .; disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil; Absorption accelerators such as quaternary ammonium salts and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal key acid; purified talc and stearate , Boric acid powder, polyester It can be used lubricants
  • a tablet with a normal coating such as a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet.
  • excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, talc; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol, etc. ; Disintegrants such as laminaran agar can be used.
  • carriers that are conventionally known in this field can be widely used as carriers, such as polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like. Can do.
  • solutions, emulsions or suspensions are preferably sterilized and isotonic with blood.
  • the solution used for the production of these solutions, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, Examples thereof include polyoxylated isostearyl alcohol and polyoxyethylene sorbitan fatty acid esters.
  • the preparation may contain a sufficient amount of sodium chloride, glucose or glycerin to prepare an isotonic solution, and it also contains ordinary solubilizing agents, buffers, soothing agents, etc. May be
  • coloring agents in the above-mentioned preparations, coloring agents, preservatives, fragrances, flavoring agents, sweetening agents, etc., as necessary. Can also be included, and other pharmaceuticals can also be included.
  • the amount of the active ingredient compound contained in the above-mentioned preparation is not particularly limited, and can be appropriately selected over a wide range.
  • the amount used varies depending on symptoms, age, body weight, administration method, dosage form, etc., but is usually 2000 mg or 40 mg / kg (preferably lOOmg or 2 mg / kg) per day for adults.
  • the lower limit is 0. lmg or 0.002mg / kg (preferably lmg or 0.02mg / kg, more preferably lOmg or 0.2mg / kg) once or several times a day depending on the symptoms. Can be administered.
  • the present invention provides a novel compound having 11 ⁇ -HSD1 inhibitory activity.
  • the compound or a pharmacologically acceptable salt thereof is considered to have an effect of treating or ameliorating diabetes, obesity, hyperlipidemia, and hemorrhoids or hypertension. Furthermore, the compound is considered to have a therapeutic or ameliorating effect on metabolic syndrome in which these symptoms are combined.
  • the first type culture was performed by culturing at 23 ° C, 210 rpm for 5 days in a rotary shaker. Aseptically remove 1 ml of the obtained first-type culture solution, aseptically pour into a 2 ml cryotube containing lml of 20% glycerin solution, suspend, and store frozen at 100 ° C as a final concentration of 10% glycerin solution. (Hereinafter referred to as frozen first-class culture) The nutrient solution is called “frozen seed”).
  • Sterilization Sterilized at 121 ° C for 20 minutes.
  • the culture broth was cultured at 23 ° C, 210 rpm for 7 days in a rotary shaker (main fermentation culture) to obtain a culture end solution.
  • Sterilization Sterilized at 121 ° C for 20 minutes.
  • the active fraction was monitored by using HPLC under the following conditions.
  • the ram was washed with the same solvent (250 ml) and then developed with the same solvent (200 ml), and the eluate was fractionated every 20 ml (Fr. 1 to 11). Then, similarly, containing 0.3% triethylamine-phosphate, 35% acetonitrile water adjusted to PH3 (200 ml, Fr. 12 to 21), containing 0.3% triethylamine-phosphate, adjusted to pH 3 40% acetonitrile water (200 ml, Fr. 22 to 31) was developed in this order, and the eluate was fractionated every 20 ml, and the fractions (600 ml) of Fr. Obtained.
  • the obtained fraction was concentrated to distill off acetonitrile, followed by extraction with ethyl acetate (300 ml).
  • the aqueous layer was extracted again with ethyl acetate (200 ml), and the organic layers obtained by the two extraction operations were combined.
  • the organic layer 500 ml was washed with saturated brine (400 ml), dried over anhydrous sodium sulfate (60 g) and dehydrated for 1 hour. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness under reduced pressure to obtain a crude product (14 mg).
  • a plasmid in which cDNA encoding the full length of human 11 ⁇ - HSD1 was incorporated into the mammalian cell expression vector pCIneo was introduced into HEK293 cells using Lipofectamine plus reagent (Invitrogen) according to the package insert. To collect Frozen at 80 ° C. As a control, cells into which the pCIneo vector was introduced were similarly prepared. Cells are thawed, suspended in buffer containing 20 mM final concentration of Hepes, ImM ethylenediaminetetraacetic acid, 2 mM magnesium chloride, and protease inhibitor cocktail (Roche), and placed on ice with N2 cavity. 4. Pressure was applied for 30 minutes to disrupt the cells.
  • the cell lysate was centrifuged at 1,000 X g for 10 minutes at 4 ° C, and the supernatant was recovered. The resulting supernatant was further centrifuged at 10, 5000 Xg for 30 minutes at 4 ° C, and the resulting precipitate was suspended in Atsey buffer (50 mM Tris buffer, 10% glycerol) as a microsomal fraction.
  • Atsey buffer 50 mM Tris buffer, 10% glycerol
  • cortisone with a final concentration of 500 nM was added to start the reaction, and the reaction was performed at room temperature for 60 minutes.
  • the plate was heated at 99 ° C for 10 minutes to stop the reaction, and the amount of cortisol produced was measured with Discovery (Packard) using a Cortisol prototype kit (CIS Bio International) according to the attached document.
  • Coretic acid showed 99% inhibition at 10 ⁇ against the production of I l j8 — HSD1-expressing cortisol, which was not seen in the microsomal fraction derived from similarly treated control cells.
  • this powder After mixing the powder of the above formulation and passing it through a 60 mesh sieve, this powder is put into a gelatin force capsule to form a capsule.
  • the compound of the present invention or a salt thereof is useful as an effective component of a therapeutic or ameliorating agent for diabetes, obesity, hyperlipidemia, hypertension, and Z or metabolic syndrome that develops them in combination. It is.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Hematology (AREA)
  • Zoology (AREA)
  • Obesity (AREA)
  • Wood Science & Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Cardiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention porte sur un nouveau composé présentant un effet inhibiteur vis-à-vis de la 11β-hydroxystéroïde déshydrogénase type 1 (désignée ci-après par l'abréviation « 11β-HSD1 ») ; un produit pharmaceutique comprenant ledit composé au titre de principe actif (préférentiellement un agent thérapeutique ou soulageant vis-à-vis du diabète, de l'obésité, de l'hyperlipémie, de l'hypertension ou du syndrome métabolique, qui développe ces états pathologiques de concert) ; une méthode de synthèse dudit composé ; un nouveau micro-organisme capable de produire ledit composé ; etc.
PCT/JP2006/310497 2005-05-26 2006-05-25 Un nouveau composé : l'acide collétoïque Ceased WO2006126654A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2005-153348 2005-05-26
JP2005153348 2005-05-26

Publications (1)

Publication Number Publication Date
WO2006126654A1 true WO2006126654A1 (fr) 2006-11-30

Family

ID=37452077

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2006/310497 Ceased WO2006126654A1 (fr) 2005-05-26 2006-05-25 Un nouveau composé : l'acide collétoïque

Country Status (2)

Country Link
TW (1) TW200722522A (fr)
WO (1) WO2006126654A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024257791A1 (fr) * 2023-06-12 2024-12-19 グリーンケミカルズ株式会社 Composition de composés aromatiques et polymère

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003065983A2 (fr) * 2002-02-01 2003-08-14 Merck & Co., Inc. Inhibiteurs de la 11-beta-hydroxysteroide deshydrogenase 1 utiles pour le traitement du diabete, de l'obesite et de la dyslipidemie
WO2006053024A2 (fr) * 2004-11-10 2006-05-18 Incyte Corporation Composes de lactame et leur utilisation en temps que substances pharmaceutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003065983A2 (fr) * 2002-02-01 2003-08-14 Merck & Co., Inc. Inhibiteurs de la 11-beta-hydroxysteroide deshydrogenase 1 utiles pour le traitement du diabete, de l'obesite et de la dyslipidemie
WO2006053024A2 (fr) * 2004-11-10 2006-05-18 Incyte Corporation Composes de lactame et leur utilisation en temps que substances pharmaceutiques

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BARF T. ET AL.: "Arylsulfonamidothiazoles as a New Class of Potential Antidiabetic Drugs. Discovery of Potent and Selective Inhibitors of the 11beta-Hydroxysteroid Dehydrogenase Type 1", J. MED. CHEM., vol. 45, no. 18, 2002, pages 3813 - 3815, XP002993387 *
HUANG Q. ET AL.: "Studies on metabolites of mycoparasitic fungi. III. New sesquiterpene alcohol from Trichoderma koningii", CHEM. PHARM. BULL., vol. 43, no. 6, 1995, pages 1035 - 1038, XP003002767 *
RASCHER W. ET AL.: "Synthese von spiroverbindungen-V (plus or minus)-Acorenon aus (plus or minus)-acorenon-B durch konfigurationsinversion am spirochiralitätszentrum", TETRAHEDRON, vol. 33, no. 5, 1977, pages 575 - 577, XP003002766 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024257791A1 (fr) * 2023-06-12 2024-12-19 グリーンケミカルズ株式会社 Composition de composés aromatiques et polymère

Also Published As

Publication number Publication date
TW200722522A (en) 2007-06-16

Similar Documents

Publication Publication Date Title
JP2007291075A (ja) 新規化合物ステレニン及びその製造方法
JP3111470B2 (ja) 新規ポリペプチド化合物およびその製造法
Wang New novel α–glucosidase inhibitors produced by microbial conversion
JP5275337B2 (ja) 環状化合物を生産する微生物
CN104159910B (zh) 一种甾醇类衍生物及其制备方法与应用
CA2315796C (fr) Nouvelles substances kf-1040 et leur procede de fabrication
WO2004020460A1 (fr) Nouveau compose depsipeptide
WO2009113661A1 (fr) Composé cyclique et son sel
WO2006126654A1 (fr) Un nouveau composé : l'acide collétoïque
CN103172693B (zh) 一种甾醇类衍生物、其制备方法及用途
CN103211822B (zh) 一种甾醇类衍生物的抑制脂肪酶的用途
WO2009141786A2 (fr) Composés anti-inflammatoires
CN118852187B (zh) 深海吲哚生物碱与聚酮杂合体及其制备与在抑制细胞铁死亡和防治铁死亡相关疾病中的应用
CN103242417B (zh) 一种甾醇类衍生物及其制备方法与应用
US20240409572A1 (en) Compound for treating neurodegenerative diseases and its isolation method thereof
RU2184740C2 (ru) Вещество kf-1040, способ его получения и штамм gliocladium sp., обладающий способностью его продуцировать
JP2006176438A (ja) Ｆ−１９８４８ａ及びその製造方法
WO1993017991A1 (fr) DERIVES DE TETRALINE EN TANT QU'INHIBITEURS D'HMG-CoA REDUCTASE
JP5718450B2 (ja) 抗悪性腫瘍剤およびその製造方法と用途
JPH07506332A (ja) 医薬としての複素環化合物のリン酸エステル
JPH1129561A (ja) 新規化合物ａｍ６１０５及びその製法
EP3937931A1 (fr) Macrocycles présentant des activités antioxydantes et neuroprotectrices
JP2006056806A (ja) Ｆ−９１４９５ａおよびその製造方法
JPH06135982A (ja) 新規生理活性物質ｈｒ０４
JP2001122846A (ja) スフィンゴシンキナーゼ阻害剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 06746876

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP