WO1994004520A1 - Ascofuranone, and hypolipidemic agent, hypoglycemic agent and glycation inhibitor each containing ascofuranone derivative as active ingredient - Google Patents

Abstract

An ascofuranone derivative represented by general formula (II) (wherein R1 represents lower alkylcarbonyl, pyridylcarbonyl, benzoyl substituted by one lower alkyl or alkoxy group, toluenesulfonyl, carbamoyl substituted by one or two lower alkyl groups, or lower alkyl substituted by lower alkoxycarbonyl); a hypolipidemic agent containing the same as the active ingredient; and a hypoglycemic agent or a glycation inhibitor each containing an ascofuranone derivative represented by general formula (I) (wherein R represents hydrogen, lower alkylcarbonyl, pyridylcarbonyl, benzoyl substituted by one lower alkyl or alkoxy group, toluenesulfonyl, carbamoyl substituted by one or two lower alkyl groups, or lower alkyl substituted by lower alkoxycarbonyl) as the active ingredient. The compounds represented by the above general formulae (I) and (II) are excellent in hypoglycemic, hypolipidemic and glycation-inhibiting effects, thus being remarkably useful for preventing and treating diabetes, arteriosclerosis and so forth.

Description

 Specification

 Lipid-lowering agents, hypotensive agents, and glycation inhibitors containing m-ascofuranone and ascofuranone derivatives as main components

Technical field

 The present invention provides a hypoglycemic agent and a glycation inhibitor containing ascofuranone represented by the following general formula (I) and a derivative thereof as an active ingredient, and a compound represented by the following general formula (II) TECHNICAL FIELD The present invention relates to an ascofuranone derivative and a blood lipid lowering agent containing these as an active ingredient.

(Wherein, R is a hydrogen atom, a lower alkylcarbonyl group, a pyridylcarbonyl group, a benzoyl group substituted with one lower alkyl group or a lower alkoxy group, a toluenesulfonyl group, and one Or lower alkyl group substituted with two lower alkyl groups or lower alkoxycarbonyl lower alkyl group, and R 'is low! ^ Alkylcarbonyl group, pyridylcarbonyl group, 1 Low Benzyl, toluenesulfonyl, substituted with one or two lower alkyl groups, or rubamoyl, or lower alkoxy groups substituted with lower alkyl or lower alkoxy groups Means a loweryl lower alkyl group. )

Background art

 Among the compounds represented by the above general formula (I), those in which R is a hydrogen atom are compounds known as ascofuranone invented by the present inventors. Ascoflanonone is an isoprenoid antibiotic produced by the filamentous fungus Ascochyta visiae, and its specific production method is Japanese Patent Publication No. 56-255. It is described in No. 10 publication. The biological activity of ascoflanon has been described as a serum lipid-lowering effect (Journal of Antibiotics, Vol. 26, p. 681, p. 1973). And "Japan Journal 'ob' Pharmaceuticals", Vol. 25, p. 35, 1979.

 Also, the blood sugar lowering effect of ascochlorin produced from the above-described filamentous fungi during the production of ascofuranone and its derivatives are already known (see Japanese Patent Publication No. 3-61838). .

Disclosure of the invention

The present inventors have conducted intensive studies in an attempt to explore the new usefulness of ascofuranone as a drug. As a result, it has been found that ascofranone has an excellent blood glucose lowering effect. I found In addition, it has been discovered that the novel aspcoflanonone derivative represented by the above general formula (II) also has an excellent hypoglycemic effect similarly to aspcoflanonone. In addition, glycemic acid was one of the causes of diabetic complications. The increase in glycated protein tissue and lipoprotein has been noted. It has been discovered that the compound represented by the general formula (I) exhibits a potent glycation inhibitory action. In addition, it has been found that the compound represented by the above general formula (I), which contains ascofuranone, has lower toxicity compared to ascochlorin and its derivatives. Furthermore, they have also found that the novel ascofuranone derivative represented by the general formula (II) has an excellent blood lipid lowering action. The present invention has been completed based on these findings.

 The present invention has the general formula (D)

(In the formula, R ′ is a lower alkylcarbonyl group, a pyridyl carbonyl group, a benzoyl group substituted with one lower alkyl group or a lower alkoxy group, and a toluenesulfonyl group. Or a lower alkoxy group substituted with one or two lower alkyl groups, or a lower alkoxycarbonyl lower alkyl group). It relates to a blood Φ lipid-lowering agent possessed as an active ingredient.

Further, the present invention provides a compound represented by the general formula (I):

(Wherein R is a hydrogen atom, a lower alkylcarbonyl group, a pyridylcarbonyl group, a benzoyl group substituted with one lower alkyl group or a lower alkoxy group, a toluenesulfonyl group, Or a lower alkyl group substituted with two or more lower alkyl groups, or a lower alkoxycarbonyl lower alkyl group) as an active ingredient. And glycation inhibitors.

 In the above substituents of the compound of the present invention, lower alkyl and lower alkoxy mean alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons, respectively.

 In the pyridylcarbonyl group, the substitution position of the carbonyl on the pyridin ring is 2-position (that is, picolinol) and 3-position.

(That is, nicotinol) or 4th place (that is, isonicotinol).

 The position of the alkyl group or lower alkoxy group on the benzene ring of the benzyl group may be any of the ortho, meta and para positions.

In the present invention, the tonolenth sulfonyl group refers to any one of an ono-toluene-sulfonyl group, a metha-no-lenos-norre-honisle group, and a norat-no-lens-nore-honyl group. Or mean. In the present invention, the compound represented by the general formula (Π) is a novel compound, and these compounds are obtained by using ascofuranone as a raw material, for example, an acid halide, an acid anhydride, and in some cases, a cyanate, A reactive derivative of an acid such as an isocyanate is used in the presence of a condensing agent (a tertiary amine such as pyridines, triethylamine, dimethylaniline, alkaline base, etc.) or It is produced by reacting without adding a condensing agent.

 Among the compounds of the present invention represented by the general formula (Π), the following compounds can be mentioned as typical ones.

 4 — 0 — acetylascofuranone (compound of Example 15)

4 — 0 — Propionylasco frannon

 4 — 0 — Butyri Noreasco Flanonon

 4 — 0 — Isonico Chinolulasco Flanonone (Compound of Example 1)

 4 1 0 _ Nico Chino Luasco Flanon

 4 — 0 — Picolinoleuscoflanonone (compound of Example 15) 4 — 0 — Picolinenolascoflanonone

 4 1 0 —Echinorekka

 4 1 0 — dimethylcarbamoylascoflanonone

 4 _ 0 — Jetylcarbamoylascofuranone (Compound of Example 12)

 4 — 0 — methoxycarbonylmethylascofuranone (compound of Example 1)

 4 1 0 —Methoxycarbonylethylascofuranone

4 — 0 — Methoxycanolevonilpropyrasco furanone 4 — 0 — ET Sika Norrebonilmetilus Cofuranon

 4 1 0 — ET Sika

 4 — 0 — Ethoxycarboxylic carbonyl provircofuranone (compound of Example 13)

 4 — 0 — No. Lame Chilbenzoy Noreas Skofuranon

 4 1 0 — Paramethoxybenzoylascofuranone (Compound of Example 15)

 4 — 0 — ヽ ラ

 4 1 0 — NO ヽ ラ エ エ エ

 4 — 0 — Orthomethylsilylascofuranone

 4 ◦ ◦ One-way metrology

 4 — 0 — Onore Tetinore Benzoi Noreaskofuranon

 4 — 0 — ONORETTO

 4 — 0 — No, 'Latraensulfonylascofuranone (compound of Example 15)

 4 — 0 ノ レ レ レ レ ゾ ゾ ゾ ゾ ゾ ゾ ゾ

 4 _ 0 — Metaphoric noise

 Ascofuranone is a compound represented by the general formula (I) wherein R is a hydrogen atom.

When the compound of the present invention is used as a drug, it may be used alone. It is desirable to make it. Excipients or auxiliaries include lactose, sucrose, various types of powder, glucose, cellulose, methylsenorelose, canoleboxime, methylsenololose, magnesium stearate, magnesium Sulphate, talc, vegetable oil, It can be manufactured using lecithin or the like.

BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail with reference to Examples, but this does not limit the present invention in any way.

Example 1 Example 1 1

 Dissolve 1.68 g (3.999 mmol) of ascofuranone in dry pyridine 50 ^ and stir with stirring while stirring 1.1 g (6.18 mmol) of isonicotinic acid chloride hydrochloride. ) Was added and the mixture was heated at 80-90 and heated for 24 hours, and the reaction solution was concentrated under reduced pressure to dryness. The residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid and water, dried, concentrated under reduced pressure, and the remaining oil was separated and purified by silica gel chromatography. 1.8 g of the desired product represented by the following formula was obtained as an oil.

Proton nuclear magnetic resonance <400 MHz, CDCf ₃ , internal standard TMS> δ: 1.21 (3H, s), 1.28 (3H, s), 1.54 (3H, s), 1.62 (3H, s), 1.93 (2H, m), 2.17 (2H, m), 2.40 (2H, m), 2.69 (3H, s), 3.50 (2H, m), 4.52 (lH, dd, J = 6.2, 9.9Hz), 5.09C1H , t J = 7.0Hz), 5.48 (lH, t J = 7.0Hz), 8.04 (2H, dd, J = 1.5, 4.4Hz), 8.91 (2H, dd, J = 1.5, .4H ₂ ), 10.34 (lH, s), 12.61 (lH, s)

m- 2

m-2

 2.25 g (5.99 millimoles) of Ascoflanonone was dried with 50 raU of pyridinium, and then added with N, N—Jetylcarbamoylc π-lide 1 .5 g (10.84 mmol) was added, and the mixture was heated and stirred at 80-90 mm for 24 hours. The residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid and water, dried, and concentrated under reduced pressure. The remaining oily substance was separated by silica gel chromatography, and the oily target substance was dissolved in ethanol and allowed to stand at room temperature to precipitate 1.0 g of the target substance crystal represented by the following formula. did. A sample recrystallized from ethanol showed a melting point of 69-70.

Proton nuclear magnetic resonance <400 MHz, CDCf 3, internal standard TMS> δ: 1.21 (3Η, t J = 7.0 Hz), 1.21 (3H, s), 1.28 (3H, s), 1.31 (3H, t J = 7.0Hz), 1.63 (3H, s) ヽ 1.74 (3H, s), 2.02 (2H, m), 2.13C2H, m), 2.40C2H, br m), 2.64 (3H, s), 3.24dH br s), 3.40 (3H, q, J = 7.0 Hz), 3.50 (2H, m), 4.51 (1 H, dd, J = 6.6, 9.5), 5.15 (1H, dd, J = 5.5, 7.0) , 5.5K1H, t, J = 7.0) .10.28 (1H _; s), 12.53 (1H s)

卖施例一 3

卖 Example 1 3

Dissolve 2.52 g (5.99 milliliters) of Ascofuranone in 50 jsfi of dimethylformamide. This is followed by 60% hydrogenated sodium 0.2 Add g little by little. To the resulting sodium salt solution is added 1.8 g (9.3 millimoles) of 4-bromoacetic acid ethyl ester, and the mixture is heated to 90 to 100'C for 3 hours. Then add 0.5 g of 60% sodium hydride and 0.5 g of 4-bromomethyl acid ester and heat for another 10 hours. The reaction solution is concentrated to dryness under reduced pressure, and the residue is separated between 1% hydrochloric acid (40) and black hole form (40 ml).

 Concentrate the clot form solution to dryness under reduced pressure. The remaining oil was separated and purified by silica gel chromatography to obtain 1.2 g of the desired product represented by the following formula as an oil.

 Proton nuclear magnetic resonance 400 MHz, CDCf 3, internal standard TMS> 6: 1.03 (3H, brs), 1.76 (3H, brs), 2.03 (2H, m), 2.17 (4H, m) , 2.34 (lH, dd, J = 9.9Hz, 18.3Hz), 2.41 (1H, dd, J = 6.2Hz, 18.3Hz), 2.62 (2H, m), 2.62 (3H, s), 3.35 (2H, d , J = 6.6Hz). 3.97 (2H, t J = 6.0Hz), 4.16 (2H, q J = 7.0Hz), 4.51 (lH, dd J = 6.2Hz, 9.9Hz), 5.17 (1H, dd J = 6.6Hz, J = 5.5Hz), 5.50 (1H, t J = 6.6Hz) 10.24 (lH, s), 12.51 (lH, s)

実施例一 4

Example 1 4

Dissolve 2.52 g (5.99 mimol) of Ascoflanonone in dimethylformamide 30. To this, 0.2 g of 60% sodium hydride is added little by little. Bromine vinegar is added to the obtained sodium salt solution. Add 1.5 g (9.8 mmol) of the acid methyl ester. After standing at room temperature overnight, 0.02 g of 60% sodium hydride and 0.15 g of methyl bromoacetate are added. After standing overnight, concentrate under reduced pressure. To the remaining oil, 1% hydrochloric acid (100%) Rfi and 100% formaldehyde are added, and the mixture is stirred with a separatory funnel. After adding methanol to the remaining oily substance and allowing it to stand overnight, 1.9 g of crystals of the target substance were deposited. A sample recrystallized from methanol showed a melting point of 77'C.

Proton nuclear magnetic resonance <400 MHz, CDCi 3, internal standard TMS> δ: 1.21 (3H, s), 1.27 (3H, s), 1.63 (3H, s), 1.76 (3H, s) _N 2.03 (2H, m), 2.14 (2H, m), 2.35 (1H, dd J = 10.3Hz, 18.3Hz), 2.43 (1H, dd J = 6.2Hz, 18.3Hz), 2.64 (3H, s), 3.45 ( 3.84 (3H, s), 4.52 (1H, dd J = 6.2Hz, J = 10.3Hz), 4.58 (2H, s), 5.16 (1H, dd J = 5.5Hz, J = 7.0Hz), 5.50 (lH, t J = 7.0Hz), 10.26 (1H, s), 12.52 (lH, s)

実施例一 5

Example 1 5

 In the same manner as in each of the above Examples, the following compounds were produced from ascofuranones and the corresponding acid chlorides or sulfo-yuric-openings.

(a) 4 — 0—paramethoxybenzoylascofuranone (tan Oil)

 (b) 40_Acesulascoflanonone (tan oil)

 (c) 40-picolino luasco furanone (tan oil)

(d) 4 — 0—no, 'La-toluenesulfonylascoflanonone (brown oil)

 In vivo and in vitro experiments were performed in order to examine the Dariketion inhibitory effect and the blood glucose lowering effect of the ascofuranones and derivatives thereof of the present invention. The glycemic acid inhibitory effect is obtained by adding ascofuranone and its derivatives to a reaction solution containing bovine serum albumin and glucose, culturing for a long time, and producing the acid hydrolysis product of fructose-lysine. In addition to measuring the amount of oral synthase, the reaction mixture containing ribose, arginine, and lysine was added with ascofuranone and its derivatives, followed by cultivation. We measured the amount of pentosidine, one of which was used to study the glycemic inhibition effect of ascofuranone and its derivatives. The hypoglycemic effect is measured by orally administering ascofuranone and its derivatives to hereditary diabetic db / db mice and streptozotocin-diabetic mice and measuring blood glucose levels. The blood glucose lowering effect was examined.

 m-6

の牛血清アルブミ ン と 4 0 O mMのグルコ ースを舍 む反応液に 0. 1 , 0. 4 , 1. 6 mg/ のァスコ フラノ ンを添加し 3 7 てで 1 4 日間培養した。 生成したフロ シ ンを高速液体ク ロ マ トグラフ ィ ー （ 2 8 0 nm， 0. 7 mM リ ン酸） で測定し、 その 面積で表示した。 その結果を表 1 に示した。 フ ロ シ ン 阻害率 ） ァスコ フ ラ ノ ン 0 mg/m£ 373437 ± 20444 twenty five

0.1, 0.4, 1.6 mg / ascofuranone was added to a reaction solution containing 40 mM of bovine serum albumin and glucose at 40 OmM, and cultured at 37 for 14 days. The generated furocin was measured by high-performance liquid chromatography (280 nm, 0.7 mM phosphoric acid), and the area was displayed. Table 1 shows the results. Frosin inhibition rate) Asco flavonone 0 mg / m £ 373437 ± 20444

 0.1 351979 ± 10845 5.8% MS

0.4 318517 ± 17772 14.7% *

1. 6 276 718 ± 15091 2 5.9 ** Average soil standard error * P <0.05 ** P <0.01 As shown in Table 1, addition of ascofuranone 0.4, 1.S mgZmfi Thus, the production of flocin was significantly inhibited.

卖 Example 1 7

To a reaction solution containing 25 mg / ml of bovine serum albumin and 40 OmM of glucose, add l mg of ァ scofuranone and its derivative, and add And cultured for 12 days. The generated fluorin was measured by high-performance liquid chromatography and the area was displayed as _c.

The results are shown in Table 2.

Flosin inhibition rate (¾) Not added 237926 ± 6192

 -0-I Sonico Chinoil 258 355 ± 16901 0

Asco Franconon

 4-0-Ethoxycanolebonil 198542 ± 4238 16.6% * Propilasco flamenone

 4-0-METHOLIC VOLUME 196 292 ± 2784 17.5% * Methylasco Flanon

 4-0-Jetinoreka Noreno Mo I Nore 198644 ± 9458

Asco Flanon

 4-0-Dimethylenocanoleno Moine No.185431 ± 10611 22.6% ** asco flanon tasco flanonone 178829 ± 13411 24.8% **

 Mean soil standard error * P <0.05 ** P <0.0 * 1 * As shown in Table 2, the results show that ascofuranone and its derivatives significantly inhibited the production of flocin.

Example 1 8

To each reaction solution containing 10 mM ribose, arginine, and lysine, 20 100, 500, 1000 ns of ascofuranone was added, and cultured for 37 days _; 8 days. The generated pentosidine was measured by high-performance liquid chromatography (excitation 335, fluorescence 385, 7 mM phosphoric acid), and the area was displayed. The results are shown in Table 3. 3 Pentosidine (inhibition rate%)

 4 days 8 days

Asco frannon 0/310 249 ± 6061 507 788 ± 18683

 20 58 405 ± 2401 91 195 ± 7067

 (81.2% **) (82.0% **)

100 0 22 942 ± 1894

 (100% **) (95.5% **) 500 0 0

 (100¾ **) (100 **) 1000 0 0

 (100% **) (100¾ **) Mean ± standard error ** 1 <0.01 As shown in Table 3, the result is 100% with addition of 1000, 500 iig / πά However, the addition of 100, 20 also significantly inhibited the production of pentosidine.

Example 1 9

To each reaction solution containing 10 mM ribose, arginine, and lysine, each lmZ ascofuranone and its derivative were added, and the cells were cultured for 37 to 8 days. The pentosidine produced was measured by high performance liquid chromatography and the area was displayed. The results are shown in Table 4. Pentosidine (inhibition rate%) Not added 608457 ± 24314

 4-0-METHOSHICA NOREVONIL (100% **) METHYLASSCOFRANON

 Ascofuranone (100% **)

4-0-Dimethylcarbamoyl 703972 ± 3317 (0% ns)

 4-0-Jetilka Lubamoyl 883578e 10048 (0% ns) Ascofuranonon

 4-0-Etoxy Carbine 58801 ± 5650 (90.3% **) Mouth Pinorea Sco Flanonon

 4-0-SONCO CHINOIL (100¾ **)

 Mean ± standard error * P 0.01 The results are ascofuranones and 4 — ◦ as shown in Table 4, and the results are as shown in Table 4. TOKYO CARBON LF. Mouth Pinoreas coflanonone, 40-10—Isonicotinolulas coflaranone inhibited the production of pentosidine by more than 90%.

Example 1 10

8-week-old male contagious diabetes db / db mice were fed a diet (0.3% Nippon Claire, CE-2) containing 0.3% of cascofranone or a derivative thereof for 7 days. Eyes were sacrificed and blood sugar and blood neutral fat were measured. The results are shown in Table 5. δ compound blood sugar triglyceride rng / dk control group 594.1 soil 12.δ 331.9 ± 15.8 ascofuranone 458.4 ± 39.5 271.6 ± 12.8

 (-22.8% *) (-18.2% *)

4-0-Isonico Chinoru 504.7 48.8 28.4 ± 19.5 asco frannon (-15.0% *) (-14.0% *)

4-0-Jetinole Canoleno Moy 463.7 ± 40 202.6 ± 23.0 Lusco furanone (-21.9¾ *) (-39.0 * *) 0

 4-0-Paramethoxy benzo 470.4 ± 33 • 8 218.3 ± 12.8 Iraseco furanone (-20 *) (-34.2% * *)

4-0-ヽ ラ ノ 8.4 8.4 8.4 3.1 488.4 ± 30 293.1 ± 20 Ninorescoflanone (-17.8% *) (-11.7% *) Mean ± Standard error * Ρ <0.0c ** P <0.0 i As shown in Table 5, all the compounds used in the experiment showed blood, glucose and triglyceride lowering effects.

 Example 1 I 1

 16 nig / kg of streptozotocin was administered intraperitoneally to d d Y0 mice, and 8 rag / kg of ascofuranone and its derivatives were administered for 7 days.

 Oral administration and blood glucose levels were measured.

Five 6 Body weight (g) Blood sugar (mg / ίίβ) tm¾

 Control group 30.1 ± 0.5 430.9 ± 47.5 Ascoff phono 30 * 1 ± 0.7 348.4 ± 30.8

 -丄) «丄 *

 4 Q

 — U—No ^ 7 No / No * U U, 357.0 ± 42.5 Ma * 7-^

 Λ NOFNO-17.2% *

4-0,,:>--,,, J "

 29.8 0.9 0.93.8 ± 26.2

/ Scos Funon

 4-0-Sony J

5 323.8 ± 30.2 Asco frannon

 4-0-Ethoxycarbonyl 31.1 ± 0.6 305.6 ± 20.9 Provirasco Flanonone-t29.1% **

 Average soil standard error * p <0.05 ** P <0.01 As shown in Table 6, the results were as shown in Table 6 for mice treated with streptozotocin for both ascoflanonone and its derivatives. Blood glucose level significantly decreased.

卖 Example 1 1 2

Eight-week-old male hereditary diabetic db / db mice and their normal littermates were fed 0.3% ascoflavonone (Clea Japan, CE-2) for 1 week and killed on the 7th day. Blood glucose and triglyceride in blood were measured, and the results are shown in Table 7. Weight blood sugar neutral fat

 dbZdb mass

 Control group 4 6 ± 1 5 2 3 ± 2 4 2 8 8 ± 1 8 Asco frannon 4 8 ± 1 4 0 5 ± 4 8 2 3 9 ± 1 1 ns-2 3 *-17% * Normal Litter

 Control group 2 5 ± 1 1 6 7 ± 1 5 2 1 6 Sat 8 Vasco frannon 2 3 ± 1 1 6 3 ± 1 5 1 6 7 ± 1 8 nsns-2 3% * Average soil standard error * P <0.05 As shown in Table 7, the blood glucose and triglyceride levels in the db / db mice were significantly reduced by the addition of ascofuranone to the diet.

卖 Example 1 1 3

8-week-old male hereditary diabetic db / db mice were orally administered ascoflanonone 391, 156, 63 mg Zk suspended in 2% Arabic gum for 7 days. The results are shown in Table 8. Asco flavonone Blood sugar Neutral fat

 Dosage mg / ύίβ

 0 (control group) 6 1 5 Sat 1 6 3 3 2 ± 1 6

 39 1 mg / kg 4 0 5 ± 3 1 2 0 3 ± 2 3

 ― 34%-39%

 1 5 6 mg / kg 4 3 3 ± 4 1 2 1 8 ± 1 8

 3 2% *-3 4% **

63 mg / kg 5 3 0 Sat 1 2 2 7 2 ± 1 3

 1 5%-22% * Mean soil standard error * P <0.05 ** p <0.01 Oral administration of suspension of ascofuranone for 7 days as shown in Table 8 As a result, blood glucose and triglyceride in blood significantly decreased.

 m-ι

Ascofuranone or a derivative thereof was orally administered to ddY mice at 8 mg / kg for 7 days. The results are shown in Table 9.

Blood sugar neutral fat cholesterol compound

Control group 244.1 ± 9.6 190.7 ± 16.9 190.5 ± 7.8 Vasco frannon 253.7 ± 12.5 189.1 ± 11, 202.0 ± 7.8 ns ns ns

4-0-Jetyl carbamo 236.4 ± 21.9 157.3 ± 23.2 163.0 ± 10.6 illusco frannon ns -17.5% * ns

4-0-dimethylcarbamo 288.3 ± 18.0 231.0 ± 24.8 173.1 ± 7.2 irsco furanone ns ns ns

4-0-Sonico Chinoil 283.3 ± 11. 164.3 ± 14.0 166.7 ± 8.1 ASCF Flanon ns ns ns

4-0-Methoxycarbine 250.6 ± 14.1 140.3 ± 8.3 164.0 ± 6.6 Lume Tilasco Flanonon ns -26.4% * -14.0% * Mean soil standard error * P <0.05

 As shown in Table 9, the results show that in the group treated with 410-methoxycarbonylmethylascofuranone, 26.4% of triglycerides, 14.0% of cholesterol and 4-4% of cholesterol were observed. — In the group treated with getylcarbamoy-cleascofuranone, neutral fat was 17.5%, which was significantly lower than the control group.

 Industrial applicability

 Ascofuranone and the novel iscofuranone derivative represented by the formula (II) have excellent hypoglycemic, hypolipidemic and glycemic inhibitory effects, and thus prevent diabetes, arteriosclerosis, etc. It is extremely useful as a therapeutic drug.

Claims

The scope of the claims  1. General formula (Π)

(In the formula, R ′ is a lower alkylcarbonyl group, a pyridylcarbonyl group, a benzoyl group, a toluenesulfonyl group, or a benzoyl group substituted with one lower alkyl group or a lower alkoxy group. A squafuranone derivative represented by the formula: a carbamoyl group substituted by two lower alkyl groups, or a lower alkoxycarbonyl lower alkyl group). 2. General formula (Π)

(In the formula, R ′ is a lower alkylcarbonyl group, a pyridylcarbonyl group, a benzoyl group, a toluenesulfonyl group, or a benzoyl group substituted with one lower alkyl group or a lower alkoxy group. (2) a blood lipid having an ascofuranone derivative represented by the formula (1) as an active ingredient: a carbamoyl group substituted by a lower alkyl group or a lower alkoxycarbonyl lower alkyl group). Lowering agent 3. General formula (I)

(Wherein, R is a hydrogen atom, a lower alkylcarbonyl group, a pyridyl propyl group, a benzoyl group substituted with one lower alkyl group or a lower alkoxy group, a toluenesulfonyl group, and at least one Or a lower alkyl group substituted with two lower alkyl groups, or a lower alkoxycarbonyl lower alkyl group) as an active ingredient. Agent.