JPS5869860A - Ascochlorin derivative - Google Patents

Abstract

NEW MATERIAL:A compound of the formula (R is pyridyl, amino, substituted amino, phenoxyalkyl or phenyl that may have substituents on the nucleus). USE:It is used for treating and preventing human and animal diabetes, arteriosclerosis, and ischemic cardiopathies. This compound improves hypercaloriemia accompanied by diabetes and arteriosclerosis to maintain normal metabolism in a living body. PREPARATION:An acid reactive derivative such as an acid halide, acid anhydride, when necessary, cyanate or isocyanate is made to act on ascochlorin, preferably in a solvent in the presence of a condensation agent such as pyridine or dimethylaniline to produce 4-0-acyl derivative of ascochlorin of the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION Diabetes is a typical metabolic disease that develops due to genetic predisposition and the involvement of complex environmental factors. Since the onset of diabetes is directly triggered by the involvement of a wide variety of factors, there is a view that the name diabetes only refers to a single syndrome.

However, in general, there are two types of diabetes: juvenile diabetes, which mainly develops in older people and can lead to serious disorders if exogenous insulin is not supplied, and adult-type diabetes, which develops in adults and requires little insulin supplementation. It is classified as. The latter is known to be closely related to obesity in its onset. Despite these differences in whether insulin injections are necessary or unnecessary for treatment, the underlying cause, which is common to all types of diabetes, is a lack of insulin action in the body. This is due to the fact that

Insulin is an essential peptide hormone in vertebrates that promotes the synthesis of glycogen, protein and fat, suppresses gluconeogenesis in the liver, suppresses lipolysis in adipose tissue,
It is known to exhibit a variety of physiological effects, including the promotion of proliferation in cell culture.

However, its most essential function is that it is the only hormone that acts to store energy from the food an animal ingests in the body in preparation for the intermeal or fasting period. In this respect, it is in sharp contrast to other hormones, such as catecholamines, glucagon, AOTEH, and glycocordecoids, which are stored in the body and act to release nine energy.

It is natural that insulin injections have a specific effect on diabetes caused by insufficient insulin action. However, excessive use of insulin is not desirable as it disrupts the balance with other hormones.Therefore, if a drug existed that could enhance the action of insulin in the body, it would be useful not only for non-insulin-dependent diabetes but also for insulin-dependent diabetes. In normalizing metabolism even in sexually transmitted diseases -
This is desirable.

On the other hand, it is known from various epidemiological studies that ischemic heart disease occurs at a high rate not only in diabetes but also in cases where decreased glucose tolerance and hyperinsulinemia coexist.

In this case, deterioration of glucose tolerance is caused by insulin-dependent tissues becoming insulin insensitive. Since the body is unable to maintain homeostasis with normal insulin secretion, the pancreas attempts to compensate for the lack of insulin secretion by increasing insulin secretion. That is, the seemingly contradictory coexistence of hyperinsulinemia and worsening of glucose tolerance is a compensatory response associated with insulin insensitivity. In such pathological conditions, improving the insulin sensitivity of one tissue)
Drugs that enhance the action of endogenous and exogenous insulin must be extremely meaningful for the prevention and treatment of ischemic heart disease and the cause of it, coronary artery sclerosis.

As a result of many years of searching for substances that enhance diinsulin action, the present inventors discovered a new derivative obtained by acylating the 4-hydroxyl group of ascotaroline, which has the property of specifically enhancing insulin action. This led to the completion of the present invention.

Ascocu-a-sin, along with congeners of species A including asco-7lanone, is present in the filamentous fungi Ascoquita and Visiae (Asco-7lanone).
(Kaifeng et al., J., Aatlblot).
Mucs, 21:539 pages, 196$JIE) @ Ascochlorin tf 7 x Ko1 key? Besides Viche, there are also some other filamentous fungi, such as Heptosarum, II lp.
, (Fm5s+r!um up, ) R@H,H
v 誼n* et al., U, 8. pat@at 3,546,1
078 m lf 8, 1973)・Netatoria Coccunea (Nec*rl Maro coccla axis visit, O,
Aldricb et al., J. Ohem, 8oc., P.
Erkin I, 2136 pages.

1972), Klindogastric Taladiumuli, (Oyl
la-drecladlam mp,, Kato et al., J.
Aatlbiotlcm, 24: 16g pages, 1970) and Cylindroclmdlmm illclc
a1m Minato et al.

J. Amtlbiot Ics 25:315, 1972). When ascochlorin is administered to mammals in a form that is rapidly absorbed into the body, severe symptoms of poisoning occur, and in extreme cases, death. It is known that one way to specifically weaken the benign toxicity of ascochlorin without impairing its physiological effects is to modify the hydroxyl group at the 4-position of the aromatic ring (Hosokawa et al., Agr, Blol, Oham, 45:5).
31 pages, 1980, Hosokawa et al., Bur, J.
pkarmmcol.

69:42G page, 1981*), 4-0-methylascocrine, which was used by L. Kashijinko, has poor water solubility, and when administered systemically or orally, it is difficult to increase the blood concentration of roundness. There were a lot of flaws.

The present inventors investigated with the aim of improving the above-mentioned drawbacks, and found that the hydroxyl group at the 4-position of the aromatic ring was modified with an acyl group and a carbamoyl group, and found that the nine novel derivatives had excellent action and safety, resulting in the present invention. 4-0-acyl derivatives of ascochlorin, 4-0-acyl derivatives of ascochlorin. .

The O-reaction, which is produced by reacting in the presence of tertiary dimethylaniline (such as triethylamine, alkali bases, etc.) or without the addition of a condensing agent, proceeds without a solvent, but it does not affect the O-perspectives such as yield and operability. The reaction is usually carried out in a solvent, and the solvent is one that does not cause any reaction with the reactive derivative of the acid.Usually, benzene, dimethylformamide, ethers, phosphorium, acetone, etc. are used. In addition, there is no problem even if the condensing agent is used also as a solvent.The temperature range for the reaction can be wide from room temperature to the boiling point of the solvent. However, the use of large excesses of acid-reactive derivatives should be avoided as this may result in the formation of λ4-bis-lowacyl derivatives of buscocutetraline. However, under the reaction conditions shown in the Examples, the production of bis isomers is almost suppressed. Purification of the desired product can be carried out by common means such as recrystallization, columnar chromatography, and solvent extraction.

The physiological action of the novel compound of the present invention is as follows: When administered orally to healthy animals continuously for one week, blood sugar and blood lipids are significantly lowered. Which fact improves the hypercaloric syndrome that accompanies diabetes and arteriosclerosis,
It is suitable for maintaining normal metabolic homeostasis in living organisms.

In fact, the compound of the present invention can be used for diabetes 4! ! A remarkable improving effect is observed when orally administered to model animals.0 For example, hereditary obese diabetic mice 057 B
The db+) system is said to be a pathological model similar to adult diabetes, including hyperglycemia, hyperlipidemia, obesity, hyperinsulinemia, insulin resistance, polyuria, urinary sugar excretion, and vascular disorders. For these diabetic mice, conventional antidiabetic drugs, such as sulfonylureas and Biguanai compounds, have been shown to be ineffective.
This drug significantly improved the abnormalities characteristic of diabetes without decreasing t. In other words, in addition to the reduction in blood sugar and urinary sugar excretion, what is especially noteworthy is that the symptoms of diabetes such as polydipsia and polyuria are markedly improved. It also showed a lowering effect on blood sugar and serum lipids as well as on the original apparatus in diabetic animals induced by i&a tetraxane and streptocytosine.

Using the compounds of the present invention, we investigated the mechanism of action in malo-reK, and from the results of experiments, it is clear that these compounds not only enhance the action of insulin, but also act as a partial substitute for insulin. Specifically, when the compound of the present invention was applied to normal rat liver slices at a low concentration of 10 M in the presence of insulin, glucose oxidation was clearly promoted. When fed, fatty acid synthesis was restored to normal. On the other hand, when insulin was applied to the hypodermic adipose tissue of diabetic and diabetic animals, the uptake of glucose and the amount of sugar were 9 times, and when added to the sections indicated by the blue line, 4 identical reactions occurred. It was fastened. Furthermore, when the compound of the present invention is applied to the tetrasomal fraction obtained by grinding the accessory adipose tissue tube, the lipoprotein lipase activity is increased and promoted in the same manner as when insulin is added, and conversely, The activity of neutral fat lipase was strongly inhibited.

Effects on diabetic and healthy animals and Kinmaroro
From the experimental results and results in K., it is presumed that the compound of the present invention not only enhances the icisuline effect in vivo, but also partially replaces the effect. This kind of action has not been found in any conventional drug except insulin.
It's a good thing. In particular, the compound of the present invention can be said to have a great advantage in terms of clinical treatment in that it exhibits such effects when administered orally.

Although the compound of the present invention may be used alone, it is usually used as a suspending agent,
Preferably, it is mixed with excipients or other adjuvants to formulate a dosage form suitable for parenteral and oral administration.
Preferred preparations include, for example, one injection, nine tablets, sugar-coated tablets, pills, capsules, and suppositories. These formulations can be manufactured according to conventional methods, for example using royal excipients or adjuvants.

Lactose, mar, various starches, glucose, cellulose, methylcellulose, carboxymethylcellulose, stearic acid! Gnesium, lauryl sulfate, talc, vegetable oil, octyldecyl triglyceride, bicarbonate, various polynorbates.

Polyethylene glycol, lecithin and these two
A mixture of more than one species.

Preparations for oral administration contain 10 to 55% active ingredient (by weight);
The injection preferably contains 1 to 2 ON (weight ratio). The pharmaceutical of the present invention is effective for the treatment and prevention of diabetes, arteriosclerosis, and ischemic heart disease in humans and animals. The toxicity of the compounds of the invention that can be used is quite low;
The acute toxicity of LDI to rats and mice is α5-10. Of/# or more, 150- by intraperitoneal administration!
It is $00'IQ/#.

The dosage of the drug of the present invention varies depending on the type of pathology, symptoms, etc., but for example, in the case of injection, the dosage is 5 to 100 per adult per day.
019. In the case of oral administration, the purpose can be achieved with 30 to 300011P, and in the case of crude drugs, 5 to 1000119. Next, formulation examples are shown.

4-0-nicotinoyl azcochlorin 10019wal
l) Dissolve in a solution of 20 t of corn oil and 200 q of lecithin and inject into a solution containing nitrogen gas.

Tablets for oral administration are formulated as follows.

100 parts of 4-0-nicotinyl ascochlorin O11 powder (particle size approximately 271), 88 parts of lactose, and corn tank flour Zo
o part, HPO-8 part 2 parts, L-) IPO (PO-30)
50 parts of microcrystalline cellulose, 33 parts of calcium stearate, and 10 parts of talc were added, mixed well, and compressed into tablets with a diameter of 11 wm and a weight of 2 soq using a tablet machine.

Dissolve 50 dK of dry pyridine in 50 dK of dry pyridine, cool the surroundings of the container with ice water, and while stirring, 8.8 P of nicotinic acid chloride hydrochloride (37,07
(mmol) little by little.

After the addition is complete, the temperature inside the reaction vessel is gradually returned to room temperature while stirring is continued. - After stirring day and night, the reaction solution is concentrated to dryness under reduced pressure. The residue was separated and extracted with chlorotetraform and water,
After thoroughly washing the aa form layer with water, anhydrous sodium sulfate is added to dehydrate and dry. After dehydration, the resulting filtrate is concentrated under reduced pressure, and the remaining oil is separated and purified using silica gel column chromatography. Fractions of the desired product eluted with amform containing 1 to 2X methanol or benzene containing 5X ethyl acetate are collected and concentrated under reduced pressure to obtain a viscous 7-oil product. If this is dissolved in ethanol and left to stand, crystals of the desired product will precipitate. Target crystal 9.6f (76
3%) was obtained, which was recrystallized from ethanol and had a standard mark point of 159-160C. The elemental analysis value of this thing is 0 false H
Theoretical value as 3,05OjN; 08&29%, I(&3
2N, N175! Actual value: 068.23X, H6.3
6X, N18ON structural formula; 40.5t of ascochlorin (α
1 mol), dry benzene 500d, dry pyridine 24d
((1297 mm) is mixed and shaken to uniformly dissolve the solution. While stirring this solution on a magnetic stirrer, nicotinic acid loride salt scale, salt 25.22F (0,14
2 mol). The mixture was stirred at room temperature for 3 hours, and the precipitated and suspended pyridine hydrochloride was removed by filtration. m'WLK
The operation of adding 500 m of water, shaking, and removing the aqueous layer was repeated three times. After shaking and distilling off the solvent under reduced pressure, a viscous oil was obtained.

When this was dissolved in ethanol 80011jK and discharged, the target crystal 4LOf (8α4N) was obtained. When recrystallized from ethanol, it shows a melting point of 159-160°C, and the elemental analysis value is 0 deHslO, 0JLN, and the theoretical value (transformation): 0
6&29. H&32. N2L75 actual measurement value 4306&21
．． H&32. Nλ76・Proton nuclear magnetic resonance 1 value < 1
00MH1, solvent 0DOAs, internal standard TM8>0.
69 (3H, s), N80 (3H, d) #0.82 (9
H, d) , 1.70 (30, a) @ 3.55 (2H,
d) , 5.37 (IH, d) , 5.54 (IH, 1
),! ;,84(1)(,d),7.49(11(
, sacrifice), N55 (1m (, d), N96 (IH, d)
), 9.42 (1M, m), 10.34 (IH, a),
12.80 (IH, s) Structural formula; Example 1 Amekokutetraline 20 f (49,4 mol) was dissolved in 100 sII of dry pyridine and diethylcarbamoyl chloride & 11f (49,9 mol) was added to it, and the heating rate was increased. After about 5 hours, 6.9f of diethylcarbamoyltalolide was added and heating under reflux was continued. When it is confirmed that ascochlorin has disappeared from the reaction system, the reaction solution is concentrated under reduced pressure to dryness. The residue is separated between water and benzene, and the benzene layer is thoroughly washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off. Remove the remaining oily substance through a silica gel column! Separate and purify using Togelahui. 5%
A viscous oil is obtained by collecting a fraction of the target product eluted with benzene containing ethyl acetate and concentrating to dryness. When this is dissolved in ethanol and left in a cold place, the target substance 16f (64%) is precipitated as crystals9. When the crude crystals are recrystallized from ethanol, they show a melting point of 125-127°C.
The elemental analysis value is OuH@osanN and the theoretical value is 411: 06a72. Hfu JO, N17g actual value: 06 & 85. H7,67, Nl! 10 proton nuclear magnetic resonance < 100 M 1 (!, anons
, internal standard TM8> - value: 0.67 (3) (, Lu)
,0.79(3)T,d) ,0.82(3H,d)
, L12-L36 (6) [4).

186 (3H-s) e 120-250 (31(
, 愼).

λ6B (3H, s), 3.30-3.60 (6) I, Tsuru).

5.35 (IH, d), 5.42 (IH, t), 5.
89 (i H= d ) -10,28 (I H-@)
e 12.53 (i H-8) Example table Ascochlorin lOf<24.7<limole) was dried and dissolved in 9-pyridine 100M1K, and bara aa phenoxyacetyl chloride &0f (39.0 mol) was added. Heat and stir at 60-70°C for 5 hours. TsutK! ! Packed into 4-phenoxyacetyl chloride Lot (4,
9 mmol) and stirred while heating at 60-70°C for 5 hours. Next, the reaction solution was concentrated to dryness under reduced pressure and treated in the same manner as in Example 3. Separated and purified using silica gel column coomadography, the target product in the form of an oil was dissolved in ethanol, and when left at room temperature, crystals 47F (312%) of the target product precipitated.
The standard product recrystallized from methanol has a melting point of 122-124℃.
The elemental analysis value is the theoretical value as ost)ls4oson*; 06491)! &9g Actual value (2); 064.86.1 (5,95 proton nuclear magnetic resonance <100 MI (x, O″ DOA3 e internal standard〒M8> - value: O6γ0 (31 (, s), 0.
80 (38°d), 0.83 (3H, d), N87
(3H,s)eλ86 (3H* 5)-140(2H
, d), Table 93 (2H= a ) -5, 20 (I H
-t)e! a38 (iH-d)-5,84(
IH, d) , 6.92 (!H, d) , 7.30 (2
M, d), 10.30 (IH, s), IL
56 (18° easy) Example & Dry ascochlorin 7f (17.3f rimole) and dissolve it in 9-pyridine 70d, add this (paramethoxypenzoyl tetratide & 0F (46.9f rimole) and heat under reflux for 5 hours. Thereafter, the desired product was treated in the same manner as in Example 3, and the obtained target product was dissolved in ethanol and left at room temperature. Crystals of the desired product with a concentration of 3.8 fC4 (1.8%) were precipitated. When recrystallized from ethanol, the melting point is 1.
It shows 55-156℃, and the elemental analysis value is 03lH3iO@
Theoretical value -E 069.07. HfL54 actual value (1f%: 06&82.) 1456 proton nuclear magnetic resonance <100MHz, ODO photovoltaic 1. Internal standard TM&＞
-value: 0.6g (3H-i) *a79 (3H.

d) , 0.82 (3H, d) , 1.70 (3) f,
*).

λ67 (30, s), N55 (2H, d), N91 (3
H*m)e 35 (1) 1. d), 5.50 (IH.

1), 5.818 (II (, d), 7.01 (2H, d
).

&16 (2H, d), 10.32 (IH, s), 115
? (IH9 temperature) Structural formula of target product = Example & Dissolve aspchlorin 10f (247 mmol) in dry pyridine 100d, add K 15 methoxycarbonylbenzoyl tetralide & 9ff291S mmol), and stir at 60 to 70°C for 7 hours. Heat and stir for an hour, then add K A
Ramethoxylic is i Benzoyl chloride 5.9 f
(29,6 mmol) and 60-70°C for 7 hours.
Heat and stir. Thereafter, the target product in the form of an oil obtained by the same treatment as in Example 3 is dissolved in ethanol and left at room temperature. Crystals of the target product 13f (216%) are precipitated. When the crude crystals are recrystallized from ethanol, the melting point 147-148
℃ is the theoretical value -: og:, ys, H6, 22 actual measurement (5
1: 067.78, T (8,30 proton nuclear magnetic resonance < 100MHz, 0DOj3. Internal standard〒M
J value of 8〉: 0.68 (3H, @), 0.78 (3H
.

d), 0.81 (3H, d), 1.59 (3H, 5) =
269(31(,s), 155(2)1.d), 3
．． 99 (3H, l), 5.35 (1M, d) $5.
53 (IH, t).

5.84 (IH, d), 10.34 (1) 1. s),
116G (IH, s) - & 14 (48, s) Example 7゜Askokulin 209 (49,4 olimoflu) was mixed with 100 dKIIj of dry pyridine, and to this was added isonicotine acid gastric acid hydrochloride 1 & 2 mF (717 mol). Add 7
The mixture was heated and stirred at 0° C. for 4 hours, and after 9 hours, inonicotinic acid a-ride hydrochloride 5F (2 & 1 mmol) was added, and heating and stirring was continued for 7 hours.

Thereafter, the oily residue obtained by processing in the same manner as in Example 3 is dissolved in ethanol and left in a cold place to obtain crystals 7.2F (2 & 6X) of the desired product. When the crude crystals are recrystallized from ethanol, they show a melting point of 111-113°C,
The elemental analysis value is onnuosOjN and the theoretical value ■: 06 & 30. H & 2g Actual measurement information: 06 & 2γ, ) I & 31 Proton nuclear magnetic resonance < 100MHg, 0DOJ1
3, -value of internal standard TM8>: 0.68 (3M
, s ) e O, 78 (38-d), 0J1 (3)
f, d), L67 (3F(, s).

! 69(3H,s)-&45(2H,d), &2g(
18, d), 翫$5 (1)1. t), 5.8
3 (IH, t).

&00(2)! , d) i80 (2H, d), IQ, 34
<IH, Lu), 12fJ1 (IH, m) Example color Ascochlorin 5 f (1135i II mol>tt
tt Dry pyridipyridine 5K was dissolved, 4.4fC24,'1 mmol of picolinic acid tallolide hydrochloride was added thereto, and the mixture was heated and stirred at 80'CK for 3 hours, and then 15f picolinic acid tallolide hydrochloride (&43t 43°C was added). Heat and stir at 60°C for 7 hours.Then, process in the same manner as in Example 3 to obtain an oily target substance.Dissolve in ethanol and leave at room temperature to form crystals of the target substance at 2.0F (32N).
get. When this crude crystal is recrystallized from ethanol, it shows a melting point of 150 to 152°C and a single element analysis value of FiO,...
Theoretical value (2) 306 & 30.1 (6,28 actual value ■i
06&30. I (6,25 tetraton nuclear magnetic resonance <100
MHz, 0DOAs *-value of internal standard 'rM8>:
0.6g (3H, s), 0.77 (3H.

J), 0.79 (3H, d), L7g (3M, s)
.

! 88 (3M, s), 155 (2H, l), &26
(IH, d), 5.41 (IH, t) #113 (1B
, d).

7.62 (1M, s), 7.96 (IH, s), &26
(IH, d), &87(1m(,d), 1(L33(1
8°s), 1159 (IH, s) Example hypergenic obesity diabetes Max 057 B L /Ksj (d
b"/ab">K4-o-2-tchi/Iruasukoku Shisun Aoss containing feed (Nippon Talea, 0R-2) 1 to 1
I gave it a week. 1 week immediately before drug administration and 1 week after drug administration
Food intake, water consumption, urine output, and urinary sugar excretion were measured daily for a week, and the effects of the drug were examined.

Table 1 (s-5) Values are Mean±8EIF<0.05
**P<0.01 As is clear from the table, 4-0-ecotinoyl ascochlorin significantly suppressed polydipsia, polyuria and urinary sugar excretion in genetically obese diabetic mice.

Example 1 (L) The novel compound α0 of the present invention was administered to 5-week-old ddY male mice.
Feed feed containing 5% (Nippon Talea, O'B-2) for one week, kill one at the 78th day, and measure blood lipids and blood sugar. ! The results are shown in Table 2.

As shown in the table above, all compounds have hypoglycemic effects. 4-0-nicotinoyl asgochlorin, 4-O
-(P-Chlotetraphenoxy)acetylascochlorin and 4-0-isonicotinoyl ascochlorin exhibit serum lipid-lowering effects.

Example 11 Streptocytosine 150~/# was intraperitoneally administered to 5-week-old ddY male mice (%-7), and 24 hours later, 4
-0-Nicotinoyl ascotetraline was fed for one week with feed containing 0.05%. The control group was given the same diet (Nippon Talea, 0E-2) containing no drug. On the 7th day, the cells were layered and blood sugar and plasma lipids were measured, and the results are shown in Table 3.

Table 3 Values are Mean ± 8 g Adjustment P < 0.05 As shown in the table, 4-〇-nicotinoyl ascochlorine significantly suppressed the increase in blood sugar and plasma triglycerides in the streptocytosine diabetic model.

Example 12 Genetic obese diabetic mouse 057 B L /Ksj
(db"/db") K Feed containing 0.05% of 4-0-nicotinoyl ascochlorin was given for one week. The control group mice were fed the same drug-free diet (Nippon Talea, 0B).
-2) was given. One week later, Kl was killed and blood sugar and blood lipids were measured and the results are shown in the Queen's table.

Table 4 (s=7) Numerical value FiMemn±sgop<αos
imp<αO1 As shown in the table, 4-0-nicotinoyl ascochlorine significantly improved hyperlipidemia and high face m in these hypertrophic 7111 sugar mound disease mice.

Applicant: Chugai Pharmaceutical Co., Ltd. Continuation of page 1 0 shots clear person Kaifeng Gakuzo 2-17-12 Sanno, Ota-ku, Tokyo Procedural amendment (formality) %formula% 1.Display of the incident 1981 Patent Application No. 168821 2 Name of the invention Ascochlorin derivative 1. Person making the amendment Relationship to the case Patent applicant 5-5-1 Ukima, Kita-ku, Tokyo゛ (331) Chugai Pharmaceutical Co., Ltd. Representative Kimio Ueno 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 5. Date of amendment order & Target of correction Specification 7. Contents of correction Attachment) Engraving of the statement (no changes to the contents)

Claims (1)

[Claims] General formula (wherein 8 is a pyridyl group, an optionally substituted amino group, a phenoxyalkyl group that may have a substituent on the nucleus, or a 7EL woodwind that may have a substituent on the nucleus) ) is an ascochlorin derivative represented by