WO1993017991A1 - DERIVES DE TETRALINE EN TANT QU'INHIBITEURS D'HMG-CoA REDUCTASE - Google Patents

DERIVES DE TETRALINE EN TANT QU'INHIBITEURS D'HMG-CoA REDUCTASE Download PDF

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WO1993017991A1
WO1993017991A1 PCT/JP1993/000266 JP9300266W WO9317991A1 WO 1993017991 A1 WO1993017991 A1 WO 1993017991A1 JP 9300266 W JP9300266 W JP 9300266W WO 9317991 A1 WO9317991 A1 WO 9317991A1
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Prior art keywords
substance
salts
tetralin derivatives
liters
substances
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PCT/JP1993/000266
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English (en)
Inventor
Toshio Goto
Toshihiro Shibata
Masakuni Okuhara
Kazutoshi Sakamoto
Hiroshi Hatanaka
Shigehiro Takase
Tomoko Sato
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Fujisawa Pharmaceutical Co., Ltd.
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Priority claimed from GB929204810A external-priority patent/GB9204810D0/en
Priority claimed from GB929217822A external-priority patent/GB9217822D0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to EP93905607A priority Critical patent/EP0629184A1/fr
Priority to JP5515528A priority patent/JPH07504568A/ja
Publication of WO1993017991A1 publication Critical patent/WO1993017991A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/54—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • 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
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
    • 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
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
    • 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

Definitions

  • This invention relates to novel tetralin derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.
  • the present invention relates to novel tetralin derivatives and pharmaceutically acceptable salts thereof which have inhibitory activity against an enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), to a process for preparation thereof, to a pharmaceutical composition containing the same, to a use of the same as a medicament, and to a method for treating hypercholesterolaemic and hyperlipoproteinaemic states and associated conditions.
  • HMG-CoA reductase 3-hydroxy-3-methylglutaryl-coenzyme A reductase
  • one object of this invention is to provide the tetralin derivatives and pharmaceutically acceptable salts thereof which inhibit the activity of HMG-CoA reductase and therefore are capable of lowering blood serum cholesterol levels and blood lipid levels.
  • Another object of this invention is to provide a process for production of the tetralin derivatives and salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, tetralin derivatives and salts thereof.
  • Still further object of this invention is to provide a use of the tetralin derivatives and salts thereof as a medicament and a method for treating hypercholesterolaemic states, hyperlipoproteinaemic states and associated conditions in human beings or animals.
  • High levels of blood cholesterol and blood lipids are conditions which are involved in the onset of arteriosclerosis. It is well known that inhibitors of HMG-CoA reductase are effective in lowering the level of blood plasma cholesterol, especially low density lipoprotein cholesterol (LDL-C). It has now been established that lowering LDL- C levels affords protection from coronary heart disease.
  • LDL-C low density lipoprotein cholesterol
  • the tetralin derivatives and salts thereof inhibit HMG-CoA reductase and so inhibit cholesterol biosynthesis. They lower concentrations of cholesterol in blood. Thus they are useful for treating hypercholesterolaemic and hyperlipoproteinaemic states (e. g. atherosclerosis) and associated conditions (e. g. angina, myocardial infarction, cerebral vascular occlusion, arterial aneurism, peripheral vascular disease, recurrent pancreatitis and xanthomas).
  • hypercholesterolaemic and hyperlipoproteinaemic states e. g. atherosclerosis
  • associated conditions e. g. angina, myocardial infarction, cerebral vascular occlusion, arterial aneurism, peripheral vascular disease, recurrent pancreatitis and xanthomas.
  • the tetralin derivatives can be represented by the following general formula (I).
  • R ⁇ is hydrogen or acetyl
  • R2 is carboxy and R is hydroxy
  • R2 and Rg may form lactone
  • WF14919B substance can be produced by fermentation.
  • WF14919A substance and WF14919B substance are referred briefly as WF14919 substances.
  • the fermentation can be conducted using WF14919 substances-producing strain such as Agonomycetes strain No. 14919 in a nutrient medium.
  • the production of the WF14919 substances is not limited to the use of the particular organism described herein, which is given for the illustrative purpose only.
  • This invention also includes the use of any mutants which are capable of producing the WF14919 substances including natural mutants as well as artificial mutants which can be produced from the described organism by conventional means such as irradiation of X-ray, ultra-violet radiation, treatment which N-methyl-N'-nitro-N-nitrosoguanidine, 2- aminopurine, and the like.
  • the fungus strain No. 14919 was originally isolated from a soil sample, collected at Mt. Kiyosumi, Chiba-ken, Japan. This organism grew very rapidly on various culture media, and formed white-edged and dark gray colonies. During one month, the strain formed neither teleomorph nor anamorph. The differentiated hyphal structures (e. g. sclelotia, bulbils, chlamydospores and clamp connections) were also not observed. These characteristics showed that strain No. 14919 was classified in the Mycelia Sterilia (Hyphomycetes) Its mycological characteristics were as follows.
  • the vegetative hyphae were smooth, septate, hyaline and branched.
  • the hyphal cells were cylindrical and 1.5 - 5.0 ⁇ m in diameter.
  • Strain No. 14919 was able to grow at the temperature range from 9 to 33 °C with the growth optimum at 24 to 27 °C. These temperature data were determined on potato dextrose agar (made by Nissui).
  • Potato dextrose G Spreading broadly, 6.5 - 7.0 cm agar (Difco 0013) S: Circular, plane, felty, formed no conidial structures, pale gray (1B1) to black, white
  • Czapek's solution G Rapidly, 4.0 - 4.5 cm agar (Raper and S: Circular to irregular, plane, raised, felty, Thorn 1949) formed no conidial structures, yellowish gray (4B2), white (1A1) at the edge
  • Sabouraud dextrose G Spreading broadly, >7.5 cm agar (Difco 0190) S: Raised, felty, formed no conidial structures, brownish gray (6C2), yellowish white (4A2) at the center, produced brown exudations and brown soluble pigment
  • Oatmeal agar G Spreading broadly, >7.5 cm (Difco 0552) S: Felty to cottony, formed no conidial structures, dark gray (1F1) to black R: Brownish gray (5E2), orange gray (5B4) at the center
  • Emerson Yp Ss agar G Spreading broadly, 6.0 - 6.5 cm (Difco 0739) S: Circular, plane, felty, formed no conidial structures, black, white (1A1) at the edge R: Yellowish white (3A2)
  • Com meal agar G Spreading broadly, 5.5 - 6.0 cm (Difco 0386) S: Circular, raised, cottony, formed no conidial structures, yellowish white (4A2), partly dark gray (1F1) R: Yellowish white (4A2), partly dark gray
  • MY20 agar* G Spreading broadly, >7.5 cm
  • G growth, measuring colony size in diameter
  • S colony surface
  • R reverse
  • MY20 agar 5 g peptone, 3 g yeast extract, 3 g malt extract, 200 g glucose and 20 g agar per liter of water
  • the WF14919 substances are produced when the WF14919 substances-producing strain is grown in a nutrient medium containing sources of assimilable carbon and nitrogen under aerobic conditions (e. g. shaking culture, submerged culture, etc.).
  • the preferred sources of carbon in the nutrient medium are carbohydrates such as glucose, sucrose, starch, fructose or glycerin, or the like.
  • the preferred sources of nitrogen are yeast extract, peptone, gluten meal, cotton seed flour, soybean meal, com steep liquor, dried yeast, wheat germ, etc., as well as inorganic and organic nitrogen compounds such as ammonium salts (e. g. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.), urea or amino acid, or the like.
  • ammonium salts e. g. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.
  • urea or amino acid or the like.
  • the carbon and nitrogen sources though advantageously employed in combination, need not to be used in their pure form because less pure materials, which contain traces of growth factors and considerable quantities of mineral nutrients, are also suitable for use.
  • medium mineral salts such as sodium or calcium carbonate, sodium or potassium phosphate, sodium or potassium chloride, sodium or potassium iodide, magnesium salts, copper salts, zinc salts, cobalt salts, or the like.
  • a defoaming agent such as liquid paraffin, fatty oil, plant oil, mineral oil or silicone, or the like may be added.
  • Agitation and aeration of the culture mixture may be accomplished in a variety of ways, such as agitation by a propeller or similar mechanical agitation equipment, by revolving or shaking the fermenter, and the like.
  • the fermentation is usually conducted at a temperature between about 10°C and 40°C, preferably 20°C to 30°C, for a period of about 50 hours to 150 hours, which may be varied according to fermentation conditions and scales.
  • the culture broth is then subjected for recovery of the WF14919 substance to various procedures conventionally used for recovery and purification of biological active substance, for instance, solvent extraction with an appropriate solvent or a mixture of some solvents, chromatography or recrystallization from an appropriate solvent or a mixture thereof.
  • WF14919A substance may be converted to its salt since it is acidic substance.
  • the salt of the WF14919A substance can be prepared by a conventional manner, during or after the recovery and purification of the WF14919A substance.
  • Suitable salts of the WF14919A substance are conventional pharmaceutically acceptable salts and include a metal salt such as an alkali metal salt (e. g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e. g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e. g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N'- dibenzylethylenediamine salt, etc.), and the like.
  • a metal salt such as an alkali metal salt (e. g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e. g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e. g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N'- dibenzylethylened
  • WF14919A substance has the following physico-chemical properties:
  • Soluble methanol, ethyl acetate, acetone
  • WF14919A substance is inferred to have the following chemical formula.
  • WF14919B substance has the following physico-chemical properties: Appearance:
  • Soluble methanol, ethyl acetate, acetone
  • WF14919B substance is inferred to have the following chemical formula.
  • WF14919A substance and WF14919B substance can be introduced to their corresponding deacylated compound, respectively and they are referred to as FR152415 substance and FR152416 substance, respectively.
  • FR152415 substance can be obtained from WF14919A substance by a conventional chemical deacetylation.
  • obtained FR152415 substance has the following physico- chemical properties:
  • Soluble methanol, ethyl acetate, acetone
  • FR152415 substance is inferred to have the following chemical formula.
  • FR152416 substance can be obtained from FR 152415 substance by a conventional lactonization.
  • FR152416 substance has the following physico- chemical properties: Appearance: colorless needles Molecular formula :
  • Soluble methanol, ethyl acetate, acetone
  • FR152416 substance is inferred to have the following chemical formula.
  • the tetralin derivatives and salts thereof are potent inhibitors of an enzyme HMG-CoA reductase and are capable of inhibiting cholesterol biosynthesis. Therefore, they can lower blood serum cholesterol levels and blood lipid levels and are useful for the treatment of hyperlipemia and atherosclerosis.
  • HepG2 cells (HB 8065, a human hepatoma cell line) were obtained from the American Type Culture Collection. Cholesterol synthesis in HepG2 cells was determined according to the method of Brown et al. (J. Biol. Chem. 253, 1121-1128, 1978) with some modifications. HepG2 cells were grown in flasks containing Eagle's modified imnimum essential medium with non-essential amino acids supplemented with pyruvate (1 mM), penicillin G (100 units/ml), streptomycin (100 units/ml), and 10% fetal bovine serum (FBS) in a humidified incubator (5% C0 2 ) at 37 °C.
  • FBS fetal bovine serum
  • the cells On day 0, the cells (3 x 10 5 cells/well) were seeded into 35 mm 6-well plastic culture dishes (2 ml/well). On day 4, the medium was replaced with 1 ml of fresh medium containing 10% human, lipoprotein-deficient serum instead of FBS and the cells were preincubated for 2 hours at 37 °C with WF14919A substance (or WF14919B substance or FR152415 substance) dissolved in 2 ⁇ l of dimethylsulfoxide (DMSO). DMSO (2 ⁇ l) was added to the control culture. Then, 1 mM [1- C]acetic acid, sodium salt (37 MBq/mmol, DuPont/NEN Research Products) was added to the medium and incubated at 37 °C for 2 hours.
  • DMSO dimethylsulfoxide
  • HMG-CoA reductase activity was determined as described according to the method of Brown et al. (J. Biol. Chem. 249, 789-796, 1974) with some modifications. HepG2 cells (2 x 10 cells) were seeded into
  • the tetralin derivatives or salts thereof are used in the form of conventional pharmaceutical preparation which contains said substance, as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external(topical) administration.
  • pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external(topical) administration.
  • the pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, suppository, solution, suspension, syrup, emulsion, lemonade, lotion, ointment, gel, and the like.
  • auxiliary substances stabilizing agents, wetting agents and other commonly used additives such as lactose, stearic acid, magnesium stearate, terra alba, sucrose, com starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, tartaric acid, citric acid, fumaric acid, and the like.
  • the dosage of the tetralin derivatives may vary from and also depend upon the age, conditions of the patient, a kind of diseases, etc. In general, amount between about 0.1 mg and about 1,000 mg or even more, preferably between about 1 mg and about 200 mg per day may be administered to a patient. An average single dose of about 0.1 mg, 1 mg, 10 mg, 20 mg, 30 mg, 50 mg, 100 mg, 200 mg, 250 mg of the tetralin derivatives may be used in treating hypercholesterolaemic and hyperlipoproteinaemic states and associated conditions.
  • aqueous seed medium 60 ml containing sucrose 4%, cotton seed flour 2%, dried yeast 1%, peptone 1%, KH 2 P0 4 1%, Tween 80
  • the resultant seed culture was inoculated to 20 liters of sterile production medium (pH 6.5) consisting of glucose 0.5%, glycerin 0.5%, soluble starch 4%, dried yeast 0.5%, corn steep liquor 0.5%, potato protein 1.5%, Adekanol LG-109 (defoaming agent, Asahi Denka Co., Ltd.) 0.05% and Silicone KM-70 (defoaming agent, Shin-Etsu Chemical Co., Ltd.) 0.05% in a 20-liter jar fermenter. Fermentation was carried out at 25 °C for 4 days under aeration of 20 liters/min and agitation of 300 rpm.
  • sterile production medium pH 6.5
  • sterile production medium consisting of glucose 0.5%, glycerin 0.5%, soluble starch 4%, dried yeast 0.5%, corn steep liquor 0.5%, potato protein 1.5%
  • Adekanol LG-109 defoaming agent, Asahi Denka Co.,
  • the production of active compounds in the fermentation broth was monitored by measuring its enzyme inhibitory activity and HPLC analysis.
  • the ethyl acetate fraction was discarded and the residual aqueous solution was adjusted to pH 2.0 with 1 N HC1 and extracted with an equal volume of ethyl acetate.
  • the ethyl acetate extract was concentrated under reduced pressure to give an oily residue.
  • the oily residue was mixed with twice its weight of acidic silica gel ( silicar CC-4 special, Mallinckrott Inc ), and this mixture was slurried in dichloromethane. After the solvent was evaporated, resultant dry powder was subjected to a column chromatography of the same acidic silica gel (640 ml) which was packed with dichloromethane.
  • the column was developed with dichloromethane (3.2 Hters), mixed solutions of dichloromethane and methanol (100:1, 3.2 liters; 50:1, 3.2 liters; 25:1, 3.2 liters; 10:1, 3.2 liters).
  • the fractions containing objective compounds were collected and concentrated under reduced pressure to give an oily residue.
  • the oily residue was dissolved in 50% aqueous acetonitrile containing 0.1% of phosphoric acid and subjected to a column chromatography (300 ml) of YMC gel (ODS-AM 120-S50, YMC Co., Ltd) packed and developed with the same solvent system. Fractions containing objective compounds were collected and evaporated to give residual aqueous solution.
  • This solution was adjusted to pH 4.0 with 1 N NaOH and extracted with an equal volume of ethyl acetate.
  • the ethyl acetate layer was concentrated under reduced pressure to give an yellowish oil.
  • This oil was dissolved in 30% aqueous acetonitrile and subjected to a column (350 ml) of YMC gel (ODS-AM 120-S50, YMC Co., Ltd.) which was packed with 30% aqueous acetonitrile containing 0.1% of phosphoric acid.
  • WF14919A substance was eluted with 40% aqueous acetonitrile containing 0.1% of phosphoric acid and WF14919B substance was eluted with 50% aqueous acetonitrile containing 0.1% phosphoric acid.
  • the objective compounds were finally isolated with high performance liquid chromatography using an YMC pre-packed column (D-ODS-5, S5 12 ⁇ A , 30mmID x 250mm, YMC Co., Ltd.) with 50% aqueous acetonitrile containing 0.1% phosphoric acid. After all, 7.9 mg of WF14919A substance and 5.5 mg of WF14919B substance were obtained as colorless crystals.
  • aqueous seed medium 60 ml containing sucrose 4%, cotton seed flour 2%, dried yeast 1%, peptone 1%, KH 2 P0 4 1%, Tween 80 0.1% and CaC0 3 0.2% was poured into a 250-ml Erlenmeyer flask and sterilized at 120 °C for 30 minutes.
  • a loopful of Agonomycetes strain No. 14919 was inoculated from a slant culture into the flask.
  • the flask was shaken on a rotary shaker (220 rpm, 5.1 cm-throw) at 25 °C for 4 days and then transferred at the rate of 2% to 160 ml of the same sterile seed medium in each of twenty 500-ml Erlenmeyer flasks.
  • the flasks were shaken on a rotary shaker (220 rpm, 5.1 cm-throw) at 25 °C for 3 days.
  • the resultant seed culture was inoculated to 150 liters of sterile production medium consisting of glucose 0.5%, glycerin 0.5%, soluble starch 4%, dried yeast 0.5%, corn steep hquor 0.5%, potato protein 1.5%, Adekanol LG-109 (defoaming agent, Asahi Denka Co.) 0.05% and Silicone KM-70 (defoaming agent, Shin-Etsu Chemical Co.) 0.05% in a 200-liter jar fermenter. Fermentation was carried out at 25 °C for 3 days under aeration of 150 liters/min and agitation of 200 rpm.
  • the production of active compound in the fermentation broth was monitored by measuring its enzyme inhibitory activity and HPLC analysis.
  • the cultured broth (155 liters) was extracted with 140 liters of acetone by intermittent mixing.
  • the acetone extract was filtered with an aid of diatomaceous earth and 265 liters of water was added.
  • the mixture was passed through a column (30 liters) of Diaion HP-20 (Mitsubishi Chemical Ind. Co.).
  • the column was washed with 30% aqueous acetone and 40% aqueous acetone, and then eluted with 60% aqueous acetone.
  • To the eluate (43 liters) was added 37 liters of water and passed through a column (4 liters) of Diaion SP-207 (Mitsubishi Chemical Ind. Co.).
  • the column was developed with 35% aqueous acetonitrile containing 0.1% of phosphoric acid and 40% aqueous acetonitrile containing 0.1% of phosphoric acid. Active fractions (11 liters) were combined, concentrated in vacuo to an aqueous solution, adjusted to pH 4.0 with 1 N NaOH and extracted with an equal volume of ethyl acetate. The extract was concentrated in vacuo to give WF14919A substance in the form of colorless crystals (2.8 g).
  • WF14919A substance (200mg) was suspended in a distilled water (1 liter), and agitated for 45 hours at room temperature. After incubation, this aqueous solution was subjected to a preparative HPLC column of YMC pre-packed ODS-AM (S-5, 12 ⁇ A, 20mm_D x 250mm, YMC CO., Ltd.), which was packed and developed with 30% aqueous acetonitrile containing 0.1% phosphoric acid. Active fractions (116 ml) were combined, adjusted to pH 5.0 with IN NaOH and concentrated in vacuo to an aqueous solution. The concentrate was adjusted to pH 4.0 and extracted with an equal volume of ethyl acetate. The extract was concentrated in vacuo to give FR152415 substance
  • FR 152415 substance 232 mg
  • 1-hydoxybenzotriazole 47 mg
  • 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 150 mg
  • the solution was stirred at room temperature for 5 hours.
  • the solution was evaporated to give the residue, which was dissolved with ethyl acetate.
  • the organic layer was washed with water, aqueous 0.01N hydrogen chloride, aqueous saturated sodium bicarbonate and water, and dried. Evaporation of the solvent followed by recrystallization from hexane-ethyl acetate afforded FR152416 substance (153 mg).
  • Fig. 1 H Nuclear magnetic resonance spectrum of WF14919A substance.
  • Fig. 2 13 C Nuclear magnetic resonance spectrum of W ⁇ 14919A substance.
  • Fig. 3 H Nuclear magnetic resonance spectrum of WF14919B substance.
  • F Fiigg.. 77 H Nuclear magnetic resonance spectrum of FR152416 substance ⁇ ..

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Abstract

L'invention porte sur de nouveaux dérivés de tétraline ayant une activité inhibitrice contre la réductase de 3-hydroxy-3-méthylglutaryl-coenzyme A, représentés par la formule générale (I) dans laquelle R1 est hydrogène ou acétyle, R2 est carboxy et R3 est hydroxy, ou R2 et R3 peuvent former un lactone, et sels acceptables sur le plan pharmaceutique. L'invention se rapporte également à des procédés de production de ces composés, ainsi qu'à une composition pharmaceutique en renfermant.
PCT/JP1993/000266 1992-03-04 1993-03-03 DERIVES DE TETRALINE EN TANT QU'INHIBITEURS D'HMG-CoA REDUCTASE WO1993017991A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP93905607A EP0629184A1 (fr) 1992-03-04 1993-03-03 DERIVES DE TETRALINE EN TANT QU'INHIBITEURS D'HMG-CoA REDUCTASE
JP5515528A JPH07504568A (ja) 1992-03-04 1993-03-03 ＨＭＧ−ＣｏＡレダクターゼ阻害物質としてのテトラリン誘導体

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB929204810A GB9204810D0 (en) 1992-03-04 1992-03-04 Wf14919 substances
GB9204810.7 1992-03-04
GB9217822.7 1992-08-21
GB929217822A GB9217822D0 (en) 1992-08-21 1992-08-21 Tetralin derivatives

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WO1993017991A1 true WO1993017991A1 (fr) 1993-09-16

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EP (1) EP0629184A1 (fr)
JP (1) JPH07504568A (fr)
WO (1) WO1993017991A1 (fr)

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US8877221B2 (en) 2010-10-27 2014-11-04 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising calcium phosphate particles and statins and methods of using the same
US9107983B2 (en) 2010-10-27 2015-08-18 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising statins
US9308190B2 (en) 2011-06-06 2016-04-12 Warsaw Orthopedic, Inc. Methods and compositions to enhance bone growth comprising a statin

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FR2449685A1 (fr) * 1979-02-20 1980-09-19 Sankyo Co Agent antihypercholesterolemique prepare par culture de microorganismes du genre monascus et son procede de preparation
EP0022478B1 (fr) * 1979-06-15 1983-02-23 Merck & Co. Inc. Polyhydro-3,7-diméthyl-8-(2-(tétrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-éthyl)-1-naphtylényl-2-méthylbutanoates, les hydroxy-acides correspondants, procédé de préparation et compositions pharmaceutiques les contenant
US4997849A (en) * 1989-06-23 1991-03-05 Merck & Co., Inc. Microbial transformation of simvastatin

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Publication number Priority date Publication date Assignee Title
FR2449685A1 (fr) * 1979-02-20 1980-09-19 Sankyo Co Agent antihypercholesterolemique prepare par culture de microorganismes du genre monascus et son procede de preparation
EP0022478B1 (fr) * 1979-06-15 1983-02-23 Merck & Co. Inc. Polyhydro-3,7-diméthyl-8-(2-(tétrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-éthyl)-1-naphtylényl-2-méthylbutanoates, les hydroxy-acides correspondants, procédé de préparation et compositions pharmaceutiques les contenant
US4997849A (en) * 1989-06-23 1991-03-05 Merck & Co., Inc. Microbial transformation of simvastatin

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8877221B2 (en) 2010-10-27 2014-11-04 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising calcium phosphate particles and statins and methods of using the same
US9107983B2 (en) 2010-10-27 2015-08-18 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising statins
US9308190B2 (en) 2011-06-06 2016-04-12 Warsaw Orthopedic, Inc. Methods and compositions to enhance bone growth comprising a statin
US10363238B2 (en) 2011-06-06 2019-07-30 Warsaw Orthopedic, Inc. Methods and compositions to enhance bone growth comprising a statin

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EP0629184A1 (fr) 1994-12-21
JPH07504568A (ja) 1995-05-25

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