JPS61236773A - Bis-benzofuran derivative, production thereof and remedy for diabetic complication containing said derivative as active constituent - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (A is amino acid residue of glycine, sarcosine, alanine, N-methylalanine beta-alanine or proline; R1 is alkoxy or alkyl; R2 is H, halogen or linked with R1 to form methylenedioxy) or a salt thereof. EXAMPLE:Bis[4-(N-carboxysulfamoyl)-7-methoxy-2-benzofuranyl]ketone. USE:A remedy for diabetic complications, having inhibitory action on both aldose reductase and blood platelet agglutination, and capable of exhibiting improved effect on prevention and treatment of subjective and autonomic disorder, diabetic renopathy, and eye diseases, e.g. retinopathy or cataract. PREPARATION:A compound expressed by formula II (R3 is alkyl) is hydrolyzed to give the compound expressed by formula I. The compound expressed by formula II is novel, and obtained by chlorosulfating a compound expressed by formula III, and reacting the resultant compound expressed by formula IV with a compound expressed by the formula H-A-OR3.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel subenzofuran derivative useful as a therapeutic agent for diabetic complications, a method for producing the same, and uses thereof.

[Conventional technology]

In recent years, the number of diabetic patients has increased dramatically due to the Westernization of dietary habits, and there is an urgent need for countermeasures to treat the disease.

Insulin and hypoglycemic agents have traditionally been widely used as antidiabetic drugs, but diabetes is not just a disorder of glucose metabolism, but also a disease accompanied by various complications, so these medicinal effects alone are insufficient. It is.

The main complications are cerebrovascular and coronary artery vascular disorders, and approximately 50% of the causes of death in diabetes are due to these vascular disorders. [Yoshio Goto et al.: Comprehensive Clinical Practice, Vol. 22, 779
~785 pages (1973)).

Platelets play an important role in the etiology of such vascular disorders. In other words, in a diabetic state, platelet function is enhanced, which causes thrombosis and causes arteriosclerosis [H, Hess et al.: Diabetology.
(1971), Vol. 7, pp. 308-315 (1971)
) ). Therefore, platelet aggregation inhibitors are useful in the treatment of the vascular disorders mentioned above.

On the other hand, eye diseases such as retinopathy and cataracts are also serious diabetic complications and are the biggest cause of blindness in the elderly. Vascular disorders such as retinal blood vessels, ie microangiopathies, are important for its onset, but also certain glucose metabolic abnormalities are associated with it [K, H, Gabay: Advances in Metabolic Disorders]. Orders (Adv, Metab, Disord, )
, Vol. 2 (2), p. 424 (1973)), that is, in diabetic conditions, polyols such as sorbitol accumulate abnormally, causing an increase in osmotic pressure and water retention, which causes ocular tissue damage. Therefore, by inhibiting aldose reductase, which synthesizes polyols, it is possible to prevent or treat the eye diseases mentioned above [Earl, G., Szirmitsch, et al.: New England Journal of Medicine (New Eng, J.

Med, ), volume 308, pages 119-125 (198
3) Rainbow ray.

H, Kinoshita et al.: Metapolis
s■).

28 (1), pp. 462-469 (1979)).

[Problem that the invention seeks to solve]

The present invention was made to solve the problem that effective therapeutic drugs have not been replaced for eye diseases such as sensory perception, autonomic neuropathy, diabetic nephropathy, retinopathy, and cataracts, which are the main complications of diabetes. It is.

[Means for Solving the Problems] The present invention relates to the general formula (I): (wherein A is an amino acid residue of glycine, sarcosine, alanine, N-methylalanine, β-alanine or proline, and R1 is a carbon A linear or branched alkoxy group having 1 to 4 carbon atoms, or a linear or branched alkyl group having 1 to 4 carbon atoms, R2 is a hydrogen atom, a halogen atom, or is bonded to R1 to form a methylenedioxy group. Expression, SO2A
-OH group, R1 group and R☆ group are substituted at any position of the 4, 5, 6 or 7 position of the benzofuran ring) or a non-toxic salt thereof, and a method for producing the same. and its use as a therapeutic agent for diabetic complications.

The present invention will be explained in detail below.

In the general formula (1), the number of carbon atoms represented by Rx is 1 to
Examples of the straight chain or branched alkoxy group of 4 include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy and t-butoxy groups, and straight chain or branched chain alkoxy groups having 1 to 4 carbon atoms represented by R1. Examples of the alkyl group having a branched chain include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl and t-butyl groups, and examples of the halogen atom represented by R2 include fluoro, chloro, bromo and iodo groups. . Examples of non-toxic salts of the compound represented by general formula (1) include sodium salt, potassium salt, magnesium salt,
Metal salts such as calcium salts or ammonia or ethanolamine.

Addition salts with amines such as ethylamine, diethylamine, triethylamine, diisopropylamine, etc.
Examples include salts that can be used medicinally.

Suitable compounds of the present invention include, for example, the bis-benzofuran derivatives shown in Table 1 and their non-toxic salts.

In the following explanation, when compounds in Table 1 are indicated, they are indicated by compound number.

The compound of the present invention has a general formula (■): group, R2 group and SO2A
The bisbenzofuranyl ketone derivative (n) represented by (the OR3 group is substituted at any position of the 4°, 5.6 or 7 position of the benzofuran ring) is prepared by adding, for example, sodium hydroxide,
It is easily produced by hydrolysis in a conventional manner using an alkali or acid catalyst such as potassium hydroxide, sodium carbonate, hydrochloric acid or sulfuric acid.

That is, the bisbenzofuranyl ketone derivative (II)
with a 1-4N aqueous sodium hydroxide solution or a 1-4N aqueous potassium hydroxide solution, or, if it is difficult to dissolve, with an appropriate solvent such as a saturated alcohol having 1 to 3 carbon atoms, acetone, acetonitrile, dimethylformamide (hereinafter referred to as D).
(hereinafter referred to as MF), dimethyl sulfoxide (hereinafter referred to as DMSO), etc., or with 1 to 4 N hydrochloric acid water or 1 to 4 N sulfuric acid water at 10 ° C. for 10 minutes under reflux.
After reacting for 5 hours, make it acidic when using an alkaline solution and collect the deposited precipitate by filtration. This is suitably carried out by recrystallization from a solvent such as a mixed solution of.

The bisbenzofuranyl ketone derivatives (II) used as starting materials in the present invention are all novel compounds, and are produced, for example, as follows.

That is, general formula (■): (wherein, R1 and R2 mean the same as above, and R
1 group and R2 group are substituted at any position of the 4, 5, 6 or 7 position of the benzofuran ring) is chlorosulfated with, for example, chlorosulfuric acid. .

Or sulfonate with concentrated sulfuric acid, then make a sulfonate with sodium hydroxide etc., and then chlorinate with phosphorus oxychloride etc. to form the general formula (■): (in the formula, ]R1 and R
2 means the same as above, 502CI2 group is substituted at any position of the 4, 5, 6 or 7 position of the benzofuran ring) Chlorosulfonyl compound (IV) of a bisbenzofuranyl ketone derivative I get it.

The chlorosulfonyl compound (IV) of the bisbenzofuranyl ketone derivative obtained above is represented by the general formula (V): H-A-OR
3(V) (wherein A and R3 have the same meanings as above) or its hydrochloride (V) by condensation reaction with the starting material bisbenzofuran. Nylketone derivative (II) can be easily obtained.

Specifically, when chlorosulfating a compound represented by general formula (m), it is mixed with 5 to 20 times the amount of chlorosulfuric acid without a solvent or in an aprotic solvent such as chloroform, carbon tetrachloride, dichloromethane, or dichloroethane. The reaction may be carried out at 0° C. to room temperature for 15 minutes to 2 hours, and the precipitate deposited by pouring the reaction product into ice water may be collected by filtration or extracted with a solvent such as ethyl acetate.

Alternatively, a compound represented by the general formula (m) may be used for 2 to 3
The sulfonate was reacted with twice the amount of concentrated sulfuric acid at 70°C to 110°C for 30 minutes to 2 hours, cooled, dissolved in a saturated alcohol having 1 to 3 carbon atoms, and made alkaline with sodium hydroxide or potassium hydroxide to precipitate the sulfonate. is collected by filtration, either as it is or recrystallized with water etc., and then excess phosphorus oxychloride,
70℃~30℃ under reflux with phosphorus chloride and phosphorus oxychloride etc.
The reaction may be carried out for 7 hours to 7 hours, and after cooling, the reaction product may be poured into ice water and the precipitate may be collected by filtration or extracted with a solvent such as ethyl acetate.

When reacting the compound represented by general formula (IV) with various amino acid esters represented by general formula (V),
A compound represented by the general formula (mV) is dissolved or suspended in a suitable solvent, for example, an aprotic solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.
2 to 4 times the molar amount of various amino acid esters represented by general formula (V) or their hydrochlorides at ℃ to 30℃, such as glycine, sarcosine, alanine, N-methylalanine, β-
A lower alkyl ester such as alanine or proline or its hydrochloride is added, and then an organic amine such as diethylamine or triethylamine is added in an amount of 2 to 5 times the mole.

After reacting for 1 to 24 hours at room temperature, it is concentrated and the residue is poured into water to form a precipitate. After filtering the precipitate or extracting it with ethyl acetate, chloroform, dichloromethane, etc., the obtained precipitate can be mixed with acetone and petroleum benzene, acetone and ethanol, ethanol, ethyl acetate and petroleum ether, ethanol, etc. It is recrystallized from a solvent such as a mixture of petroleum ether and petroleum ether, or fractionated using a silica gel TLC plate manufactured by Merck. The developing solvent was chloroform:ethyl acetate = 4
= 1 or benzene:ethanol = 9 = 1, etc., and extraction is performed with ethyl acetate or acetone, the general formula (
The compound shown in II) can be changed.

In addition, the compound represented by the general formula (m) is disclosed in JP-A-59-
It can be manufactured by the method described in No. 190985.

Furthermore, as will be described later, the compound of the present invention is a therapeutic agent for diabetic complications that can be safely used as a medicine, and for example, for oral administration, it is used in the form of tablets, capsules, powders, and granules. It can also be used as an injection, eye drops, or suppository. The dosage of the compounds of the invention is about 0.05-500 mg/day for adults. The compound of the present invention can be formulated in any conventional manner without any particular limitation, using commonly used carriers. Examples of carriers include binders.

Examples include solid diluents, liquid diluents, fillers, etc., specifically starch 5-lactose, microcrystalline cellulose, sucrose, magnesium stearate, silicic anhydride, talc,
Examples include physiological saline.

[Effect]

The bis-benzofuran derivative of the present invention was orally tested for its inhibitory effect on aldose reductase obtained from rat crystalline lenses (Test Example 1), rabbit platelet aggregation inhibitory effect (Test Example 2), and acute toxicity in mice (Test Example 3). did.

Test example 1 Regarding the bis-benzofuran derivatives of the present invention.

The inhibitory activity against aldose reductase obtained from rat lens was tested.

(1) Test method The method of Hyman et al. (Niss, Hyman, J.

H, Kinoshita: Journal of Biological Chemistry, (J, Biol. Chew, )
, 240 volumes.

877-882 (1965).

After killing male Wistar rats by decapitation, the lens was removed and homogenized in 0.1M phosphate buffer (pH 6, 8, containing 1mM mercaptoethanol and 1mM nicotinamide adenine dinucleotide phosphate (NADP)). The mixture was centrifuged at ,000×g for 15 minutes, and the supernatant was prepared as a crude enzyme solution.

0.1 containing separately 0.104mM NADPH (reduced NADP) and 10mM DL-glyceraldehyde.
M phosphate buffer (pH 6.2) was prepared, 15 μl of various concentration solutions of the test compound were added to this solution, and then 25 μl of the crude enzyme solution prepared in advance was added to start the reaction. The decrease in absorbance at 340 nm was measured using a high-sensitivity self-recording spectrophotometer 5M-401 manufactured by Union Giken.

(2) Test results The results obtained using the test compounds corresponding to the compound numbers listed in Table 1 were calculated using the 50% inhibitory concentration (I Cso (M)
) and shown in Table 2, 1
5 for aldose reductase at 0-m to 10-' M.
0% inhibitory activity was observed.

Table 2 Test Example 2 The bis-benzofuran derivative of the present invention was tested for inhibiting effect on rabbit platelet aggregation.

(1) Test method Blood was collected from the ear blood vessels of domestic rabbits (white native species), and the method of Bensiger et al.

Double, Majieras: Method Enzymology (M
methods Enzy+so1. ), Volume 31, 1
Washed platelets were prepared according to p. 49-155 (1974). Platelets were diluted in 15 mM Tris-HCl buffer to a final concentration of 6 x 10" cells/mu, test compounds were added and incubated for 2 minutes at 37°C. Thrombin [final concentration 0.2 units/mu] was then added.
(1, manufactured by Mochida Pharmaceutical Co., Ltd.) was added for stimulation, and the agglutination reaction was observed using an Alibometer (manufactured by Briston) to determine the aggregation-inhibiting activity of the test compound.

(2) Test results The results obtained using the test compounds corresponding to the compound numbers listed in Table 1 and dipyldamole were compared to the 50% inhibitory concentration (
I Cso (M)) and shown in Table 3. The compound of the present invention exhibited a platelet aggregation inhibitory effect that is equivalent to or about 5 times stronger than dipyridamole, a known platelet aggregation inhibitor.

Table 3 Test Example 3 Acute toxicity tests on mice were conducted orally for the bis-benzofuran derivatives of the present invention.

(1) Test method A test compound suspended in 10% gum arabic (1,2°4 g/kg body weight) was forcibly administered orally to 4 male ddY mice (5 weeks old) in 1 group. Death cases were observed over a period of weeks.

(2) Test results Compound numbers 1, 2, 3, 4, 6 and 1 listed in Table 1
When tests were conducted using test compounds corresponding to LD5.4, no deaths were observed for any of the compounds up to a dose of 4 g/kg body weight. One compound of the present invention with a value of 4 g/kg or more had extremely low toxicity.

〔Example〕

Next, the present invention will be explained with reference to reference examples and examples, but the present invention is not limited to these examples.

Among the symbols indicating the physical and chemical properties of the products in Reference Examples and Examples, mp is the melting point, IR is the infrared absorption spectrum, and M
S represents a mass spectrum, NMR represents a proton nuclear magnetic resonance spectrum, and EA represents an elemental analysis value. Note that NMR was measured as a dimethyl sulfoxide solution in which all six hydrogen atoms were deuterium.

Further, IR was measured by the KBrBr method.

Reference Example 1 30 mQ of bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7-medoxy 2-benzofuranylkoketone chlorosulfonic acid) was cooled to -15°C to -10°C, and while stirring, bis(7- 2.9 g (0,009 M) of methoxy-2-penzofuranyl)ketone was added little by little.Then, the temperature was gradually raised, and after stirring at 0°C for 1 hour, the reaction solution was poured into ice water.

When the deposited precipitate is collected by filtration, washed with water, and dried, m p 22
4.67 g (yield 100%) of chlorosulfonyl compound was obtained at 8-230°C (decomposition).

MS; m/e 519 (M+), m/e 52
1(M'+2).

rrr/e 484 (MCQ) -tale 42
0 (M” 502 CQ) NMR (ppm);
3.85 (6H,S, -0CH3X2).

6.87 (2H, d, HX2 at position 6).

7.25 (2H, d, 5th HX 2).

7.83 (21(,s, H at position 3 x 2) 4.67 g (0,009M) of the chlorosulfonyl compound obtained above
was suspended in 200 mQ of dichloromethane, and L-
Glycine ethyl ester hydrochloride 3.8g (0,027
M) was added, and then 3.6 g of triethylamine (0,
03GM) and further stirred at room temperature overnight. After the completion of the reaction, the reaction solution was concentrated, the residue was poured into water, acidified with 2N hydrochloric acid, the precipitate was collected by filtration, and recrystallized from a small amount of acetone, yielding 2.85 g of the target product with a mp of 204-206°C (decomposition). (yield 47.5%).

MS; race 652 (M), rac
e 579 (M”-COOE7).

tale 493(M-COOEt CH2
C00Et).

m/e 487 (M-502NHCH2C00Et)
IR(c+a-'); 3300~3230 (v
NH).

3000-2850 (νCH).

174θ (乍Coo), 1640 (νCO).

1350-1320 and 1170-1160 (ν509
) (alternative method) 2 g of bis(7-medoxy 2-benzofuranyl) ketone
(0,0062M) and 2g of concentrated sulfuric acid,
React at ℃ (external temperature) for 1 hour. Stirring gradually becomes difficult, so stir it by hand from time to time. After cooling, dissolve in ethanol, 2
The mixture was made alkaline with ~4N sodium hydroxide, and the deposited precipitate was collected by filtration.

After drying, recrystallization from water yielded 2.9 g (yield: 87.9%) of the sulfonate with a mp of 280°C or higher, which was suspended in 10 m Q of phosphorus oxychloride and heated under reflux for 7
The reaction was stirred for a period of time, and after cooling, the precipitate was poured into ice water, collected by filtration, washed with water, dried, and then recrystallized from a mixture of chloroform and petroleum benzene.
2.28 g of chlorosulfonyl compound (yield: 80.0
%) Changed.

Its MS and NMR were the same as above.

Chlorosulfonyl compound obtained above 1. og(0-00
19M) was suspended in 50ml of dichloromethane.

L-glycine ethyl ester hydrochloride 0.85g (0,0
061M), then 0.8 g of triethylamine
(0,008M) and reacted at room temperature with stirring overnight. After the reaction was completed, the reaction solution was concentrated, and the residue was poured into water.
Acidify with N hydrochloric acid, collect the precipitate by filtration, and recrystallize from a small amount of acetone or a mixture of acetone and petroleum benzine to obtain the desired product with a mp of 204-206°C (decomposition) of 0.8
5g (yield 69.1%) was returned. MS and IR of it
was the same as above.

Reference Example 2 Bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7-nitoxy-2-benzofuranylkoketone Instead of bis(7-medoxy-2-benzofuranylkoketone) used in Reference Example 1, -Nitoxy-2-benzofuranyl) ketone was used.

In the same manner as in Reference Example 1, a chlorosulfonyl compound (yield: 87.1%) with m p of 203 to 205°C (decomposition) was obtained.

MS; w/e 547 (M), ttr/e
549 (M+2).

ie/e 512 (M-CQ).

■To483 (cod-CQ-Cx Hs) NMR (pp
m) ; 1.43 (6H,t, -CH2CFr
aX2).

4.15 (4H, q, -C Chichi 2 CH3X2).

6.82 (2H, d, HX2 at position 6).

7.20 (2H, d, HX2 in 5th position).

7.83 (2H,s, H at position 3 x 2) The chlorosulfonyl compound obtained above was recrystallized from a mixture of acetone and ethanol in the same manner as in Reference Example 1 to obtain mp188-1.
The target product at 90°C (yield: 88.3%) was recovered.

+ MS; m/e 680 (M), w+/e 6
07(M+C00Et).

m/e 521(M+ C00Et-CI(2C0
0Et).

trr/e 515 (M” 502 NHCH2CO
OEtCooEt)IR(;3400~3270 (v
NH).

3050-2900 (νCH).

1740 (νCoo), 1650 (νCO).

1335-1315 and 1170-1160 (ν502
) Reference Example 3 Bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7-n-propoxy-2-benzofuranylkoketone Reference Example 1 Bis(7-medoxy 2-
A sulfonate form with a mp of 280°C or higher (yield 80.8%) was produced in the same manner as in Reference Example 1 (alternative method) except that bis(7-n-propoxy-2-benzofuranyl) ketone was used instead of benzofuranyl) ketone. ), this is reference example 1
(alternative method) to prepare yellow powder m p 139-1
Chlorosulfonyl compound (yield 72.4%) at 40°C (decomposition)
) was obtained.

MS: ale 575 (M), ale 577 (
M+2).

ale 540 (M-C1), wI/e 532 (
M-C3H? ) tale 489 (M+-C3H7
X2) ale 454 (MC3H? X2)
C1) The chlorosulfonyl compound obtained above was used in Reference Example 1.
Recrystallized from ethanol in the same manner as (alternative method) to obtain the desired product (yield: 5
0.0%) changed.

MS; Vale 708 (M), +a/e
665 (MC3H7).

mle 635 (M”-COOEt).

tale 548 (M, C00Et-CH2
C00Et).

tale 543 (M 502 NHCH2C00E
t).

it/e 501(M”-502NHCH2C00Et
-C3H7)IR(am-'); 3350~32
00 (yNH).

3050-2850 (νCl).

1750 (Ya C00), 1645 (Rent CO).

1340-1315 and 1170-1150 (9SO2
) Reference Example 4 Bis[4-(N-ethoxycarbonylmethylsulfamoyl)-7-n-butoxy-2-benzofuranylkoketone Instead of bis(7-medoxy-2-benzofuranyl)ketone used in Reference Example 1 The reaction was carried out in the same manner as in Reference Example 1 except that bis(7-n-butoxy-2-benzofuranyl)ketone was used at -20°C to -15°C for 1 hour, and the chlorosulfonyl compound (yield: 93°9%) was converted. Ta.

MS; ale 603 (M+), ml
e 605 (M +2).

ale 568 (M CQ), tale
554 (M+C4HQ).

ale 505 (M+-C4HQ X2).

ale 470 (M+ C4Ha X2 Cf1
) The chlorosulfonyl compound obtained above was recrystallized from a mixture of ethyl acetate and petroleum ether in the same manner as in Reference Example 1 to obtain the desired product with a mp of 148 to 150°C (yield 50.2%).
It was returned.

MS; mle 736 (M”), ale 67
9 (M+-C4Ha).

trr/e 663 (M-COOEt).

ale 623 (M” C4Ha X2).

mle 576 (M C00Et CH*
C00Et).

ale 571(M” 502 NHCH2C00E
Et)IR(c+o-'); 3400-3200
(yNH).

3050-2900 (νCH).

1760-1740 (νCoo), 1655 (νC
O).

1340-1320 and 1170-1160 (502
) Reference Example 5 Bis[4-methoxy-7-(N-ethoxycarbonylmethylsulfamoyl)-2-benzofuranylkoketone Reference Example 1 Bis(7-medoxy-2-
Bis(4-methoxy-) instead of benzofuranyl) ketone
Reference Example 1 except that 2-benzofuranyl) ketone was used.
In the same manner as (alternative method), the soluble portion in methanol is collected and concentrated, resulting in a sulfonate with a m p of 280°C or more (yield: 8
0.0%) changed.

This was reacted for 1.5 hours in the same manner as in Reference Example 1 (alternative method) to convert the chlorosulfonyl compound (yield: 80.0%) with m p of 185 to 186°C (decomposed).

MS; ale 519 (M), ale 52
1(K”+2).

ale 484 (M+-CQ), ale 420
(M+-502CQ) The chlorosulfonyl compound obtained above was recrystallized from acetone or a mixture of acetone and petroleum benzine in the same manner as in Reference Example 1 (alternative method) to mP19.
The target product (yield 65.8%) at 1-193°C was recovered.

MS; ale 652 (M+), a+/e 5
79 (M+-COOEt).

10 race 493 (M -COOEt-CH2C00
Et, ).

ale 487(M”-502NHCH2C00Et)
.

IR (cm-1); 3350-3250 (VN
H).

3050-2850 (vC)l).

1740 (v C00), 1650 (9Co)
.

1350-1320 and 1180-1160 (ν502)
Reference Example 6 Bis[4-(N-methyl-N-methoxycarbonylmethylsulfamoyl-7-methoxy-2-benzofuranylkoketone) L-sarcosine was used in place of monoglycine ethyl ester hydrochloride used in Reference Example 1. In the same manner as in Reference Example 1 except that methyl ester hydrochloride was used, recrystallization was performed from a mixed solution of ethanol and petroleum ether to give a m p of 134 to 136°C (
The desired product was obtained (yield: 60.0%).

MS; Vale 652 (M”), al
e593(M-COOCH3).

ale 522(M”-COOCHa CH2C00
C■3).

ale 478(M -N (CH3) CH2C00
CHaCH2COCooCH 3)IR(a'); 3050~2850(νCH
).

1760 (νC00), 1655 (νCO).

1340-1310 and 1170-1150 (ν502)
Reference Example 7 Bis(4-(N-methyl-N-methoxycarbonylmethylsulfamoyl)-7-nitoxy-2-benzofuranylkoketone) L-sarcosine methyl was used in place of monoglycine ethyl ester hydrochloride used in Reference Example 2. Recrystallized from acetone or a mixture of acetone and ethanol in the same manner as in Reference Example 2 except that ester hydrochloride was used - mP 190-192°C
The desired product (yield 75.0%) was obtained.

MS; ale 680 (M+), ale 62
1 (M+-COOCH3).

ale 550 (M+COOCH3-CH2COOCH
3).

ale 506 (M±-N (C)13) CH2C
OOCH3CH2C00CI(3) IR(cm-'); 3050~2850(9C8
).

1745 (νCoo), 1650 (νCO).

1340-1328 and 1170-1155 (ya 502)
Reference Example 8 Bis(4-[N-(1-ethoxycarbonylethyl)sulfamoyl]-7-medoxy 2-benzofuranyl koketone L-alanine ethyl ester hydrochloride used in Reference Example 1 instead of monoglycine ethyl ester hydrochloride) Recrystallized from ethanol or a mixture of ethanol and petroleum ether in the same manner as in Reference Example 1 except that salt was used to obtain a mp of 68 to 70°C.
The desired product (yield 77.0%) was obtained.

10 MS; ale 680 (M), ale 6
07(M-COOEt).

ale 507(M”-COOEt-CH(CH3)C
OOEt).

ale 464(M NHCH(CH3)COO
Et-CH(C)fa)COOBm)IR(cm-1); 3350-3250(VN
H).

3050-2850 (νCH).

1750 (νC00), 1650 (YaCO).

1340~1320 and 1170~ttso (ν502)
Reference Example 9 Bis(4-[N-methyl-N-(1-methoxycarbonylethyl)sulfamoyl]-7-medoxy 2-benzofuranyl koketone Instead of monoglycine ethyl ester hydrochloride used in Reference Example 1, N -Methyl-thi-alanine methyl ester hydrochloride was used, but the reaction was carried out in the same manner as in Reference Example 1, and separated end II (developing solvent: chloroform: ethyl acetate = 4:1, extraction A portion (solvent acetone) L, Rf = 0.74 was collected and recrystallized from ethanol or a mixture of ethanol and petroleum ether to obtain the desired product (yield 53.0%) with a mp of 117 to 119°C.

MS; ale 680 (M), ale 62
1(M-COOC)+3).

ttr/e 535(M -COOCH3C11(CH
3) COOCH3).

mle 478(M÷-N (CH3) CH(CHa
) C00CH3CH(C)13 ) C00C)+
3) IR (cm-1); 3000-2850 (
vCH).

1745 (Ya Coo), 1650 (vCH).

1335-1320 and 1170-1150 (ν502)
Reference Example 10 Bis[4-[N-(2-ethoxycarbonylethyl)sulfamoyl]-7-medoxy 2-benzofuranyl koketone Instead of monoglycine ethyl ester hydrochloride used in Reference Example 1, β-alanine ethyl ester In the same manner as in Reference Example 1 except that hydrochloride was used, the desired product (mp 160-162°C) was recrystallized from a mixture of acetone and petroleum benzine.
Yield: 82.4%).

MS; tale 680 (M), ale 6
07 (M+-COOEt).

tale 501 (M+502 NHCH2CH2CO
CooEt)IR(a'); 3330-3230
(νNH).

3050-2850 (vCH).

1740 (v Coo), 1640 (V Co)
.

1335-1315 and 1170-1155 (Ya SOri
) Reference Example 11 Bis(4-[N-(2-ethoxycarbonylpyrrolidino)sulfonyl]-7-medoxy2-benzofuranyl]
Ketone was recrystallized from acetone and petroleum benzene in the same manner as in Reference Example 1 except that L-proline ethyl ester was used in place of monoglycine ethyl ester hydrochloride used in Reference Example 1. A product (yield 78.3%) was obtained.

MS; ale 732 (M), ale 65
9(M-COOEt)IR(am-'); 30
50-2850 (v CH).

1740 (v Coo), 1650 (v Co)
.

1340-1325 and 1170-1150 (v SO*
) Reference Example 12 Bis(4-chloro-6-(N-ethoxycarbonylmethylsulfamoyl)-7-medoxy 2-benzofuranyl koketone) Reference Example 1 Bis(7-medoxy 2-
Instead of benzofuranyl koketone, bis(4-chloro-
When reacting for 30 minutes in the same manner as in Reference Example 1 (alternative method) except that 7-medoxy (2-benzofuranyl) ketone was used, a sulfonic acid salt form with m p of 280°C or higher (yield 79.6
When this was reacted for 4 hours in the same manner as in Reference Example 1 (alternative method), a chlorosulfonyl compound (yield 94.9%) with m p of 123 to 125°C (decomposed) was converted.

MS; rrr/e 587 (M+),
Tale 589 (M++2).

ll1le 552 (M+-CQ), ale
448 (M+-502CQ).

The chlorosulfonyl compound obtained above was reacted in the same manner as in Reference Example 1, and purified using a silica gel column (eluent: dichloromethane:ethyl acetate = 4:1).
The target product at 181°C (yield 50.0%) was recovered.

MS; ale 719 (M), ale 72
1(M”+2).

ale 646 (M” C00Et).

tale 554(M-5O12NHCH2C0
0Et,)IR(am-1); 3400-330
0 (wNH).

3050-2850 (v CH).

1760-1745 (νCoo), 1655 (vCH
).

1335-1320 and 1170-1150 (V SO2
) Reference Example 13 10 ml of bis(4-(N-ethoxycarbonylmethylsulfamoyl)-5,6-methylenedioxy-2-benzofuranylkoketone chlorosulfonic acid) was cooled to -15°C to -10°C, and (5,6-methylenedioxy-2-benzofuranyl)ketone O-9g (0,00258M) was suspended in chloroform 10rnQ and gradually added, and then -10℃
After reacting for 1 hour at 0°C and 1 hour at 0°C, pour into ice water.
The deposited precipitate was collected by filtration and dried to obtain a sulfonic acid form, to which 10ml of phosphorus oxychloride was added and the mixture was heated to 90~
React at 100°C for 45 minutes, cool, pour into ice water, extract with ethyl acetate, and concentrate to obtain a chlorosulfonyl compound of 0°4.
2g (yield 30.0%) was exchanged.

MS; tale 545 (M), tale
547 (M+2).

ale 446 (M”-3O2CQ).

ale 350 (M+-502CQ , extraction solvent;
Ethyl acetate, Rf value = 0.61) mp227-229°C
The target product (yield: 40.3%) of (decomposition) was obtained.

MS; rtr/e 679 (M).

tale 513 (M 502 NHCH2C00E
t).

ale 347(M+-5Ox NHCH2C00Et
X2) IR (c+s-'): 3300-3200
(vNH).

3000-2850 (νCH).

1750 (vCoo), 1625 (νCO).

1310-1290 and 1190-1185 (乍SOri)
Reference Example 14 Bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7-methyl-2-benzofuranylkoketone) Bis(7-medoxy2-benzofuranyl)ketone used in Reference Example 1 was replaced with -Methyl-2-benzofuranyl)ketone (mp131-133°C (decomposition), (ethanol recrystallization), MS; + ale 290 (M), ll1le 262
When reacting at room temperature for 2 hours in the same manner as in Reference Example 1 except for using (M''-CH2
(Decomposition) A nochlorosulfonyl compound (yield 98%) was obtained.

MS; ale 485 (M), t
ale 487 (M +2).

ale 450 (M-CQ), tale 38
7(M-502CQ)NMR (ppm);
2-57 (6Ht se CFI3
2) +7.15 (2H, d, HN3 in 6th position).

7.35 (2H, d, HN3 at position 5).

8.06 (2H,s, H at position 3 x 2) The chlorosulfonyl compound obtained above was prepared in the same manner as in Reference Example 1, and mp
Target product at 193-195°C - (Yield 80.0%) Replaced.

MS; tale 619 (M), t
ale 546 (M-COOEt).

ale 488 (M OC2H5CH2C00
Et).

ale 460(M+ C00Et CH2C00
Et).

W/6 454 (M” 502 NHCH2C0
0Et)IR(c+w-'): 3300~325
0(vNH) −3000 to 2850(νCH).

1740 (νC00), 1640 (νCO).

1340-1320 and 1170-1150 (ν5O2)
Reference Example 15 Bis(4-(N-methyl-N-methoxycarbonylmethylsulfamoyl)-7-methyl-2-benzofuranylkoketone Instead of monoglycine ethyl ester hydrochloride used in Reference Example 14, L- In the same manner as in Reference Example 14 except that sarcosine methyl ester hydrochloride was used, the developing solvent was separated using a Merck silica gel thin layer chromatography plate: Chloroform:
Ethyl acetate = 4:1 Extraction solvent: ethyl acetate, Rf value = 0
．． 68), m2 170-172°C target product (yield 50.
0%) Changed.

MS; ale 619 (M+), ale 56
0(M”-COOCH3).

tale 488(M±-COOCH3-C)+2C
OOCH3).

ale 446(M N (CH3) CH2COO
CH3CH2COOCH3) IR (cm"'): 3000~2850 (v C
l1).

1750 (vCoo), 1645 (VCO).

1340-1320 and 1170-1150 (ν502)
Reference Example 16 3 mQ of bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7-s-butyl-2-benzofuranylkoketone chlorosulfonic acid) was cooled to -15°C to -10°C to form bis(7 -5-butyl-2-benzofuranyl)ketone (mp 50°C-52°C, MS; m/e374 (M
), m/e345(M-C2Hs)) 1゜0
Dissolve g (0,0026M) in 3 mQ of chloroform and gradually add it. After reacting at 0°C for 1 hour, pour into ice water.
Extract with ethyl acetate, make the residue alkaline with 2N sodium hydroxide, add a small amount of ethanol, and concentrate to dryness. 5 mQ of heoxyphosphorus chloride was added thereto, the mixture was refluxed for 1 hour, poured into ice water, extracted with ethyl acetate, and concentrated, yielding 1.5 g (yield: 90.0%) of the chlorosulfonyl compound.

MS; rIlce 569 (M”), ale
571 (M++2).

Ten tales 504 (MCQ-C2Hs)
-tale 471 (M” 502 C1l).

tale 442 (M 502 C1l
C2[5] The chlorosulfonyl compound obtained above was fractionated using a silica gel thin layer chromatography plate manufactured by Merck Co., Ltd. in the same manner as in Reference Example 1 (developing solvent: ethanol: benzene = 1 = 9
, Extraction solvent: ethyl acetate, Rf value = 0゜51) L, when recrystallized from a mixture of ether and petroleum ether, mpHo
The target product (yield 50.8%) was obtained at a temperature of 112°C to 112°C.

MS; ll1e 703 (M),
tale 630 (M-COOEt).

tale 543(M CH2C00Et
C00Et).

tale 537 (M-502NHC) I2COOE
t,)IR(am-'): 3300~3230(
νN11).

3000-2850 (V CH).

1760 (νCoo), 1645 (νCO).

1350-1340 and 1135-1110 (ν502)
Example 1 Bis(4-(N-carboxymethylsulfamoyl)-
7-Medoxy 2-benzofuranyl koketone bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7-medoxy 2-benzofuranyl koketone 1
．． 3 g (0,002M) and 1 part of 2N sodium hydroxide
When mixed with 0 m Q and stirred at room temperature for 1 hour, it gradually dissolves and becomes a clear red liquid. After completion of the reaction, the reaction solution was acidified with 2N hydrochloric acid or 10% citric acid, and the precipitate precipitated was collected by filtration, washed with water, and dried.
1.2 g (yield: 100%) of the target product (decomposition) was recovered.

IR (cm-”) = 3300~3200 (9NH
).

3000-2800 (νCH).

1720 (νC00), 1635 (v CO)
.

1335-1310 and 1170-1150 (νS02)
NMR (ppm); 3.39 (4He br-
sr CH* C00X2)4.00 (68,s,
OCH3X2).

5.2 (2H, br, s, C00HX2).

7.10 (2H, d, lX2 at position 6).

7.59 (2H, d, 5th position) lX2).

8.10 (2H+ br-s-NlX2).

8.22 (2H,s, lX2 at position 3) EA; shown in Table 4.

In addition, 0.9 g of the above ester (0,00127M
) and 20 mQ of 4N hydrochloric acid, reacted under reflux for 30 minutes, cooled, filtered to collect precipitate, and washed with water.

When dried, 0.81% (yield 97.0%) of the target product of m p 281-283°C (decomposition) was returned, and its IR
, NMR was the same as above.

Example 2 Bis(4-(N-carboxymethylsulfamoyl)-
7-Nitoxy 2-benzofuranyl koketone Instead of bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7-medoxy 2-benzofuranyl koketone used in Example 1, bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7-medoxy 2-benzofuranyl koketone m p
The desired product (yield 100%) was obtained at 272-274°C (decomposition).

IR(c+a-'): 3350~3250(v
NH).

3030-285Q (vcH).

1730 (YaC00H), 1640 (νCO).

1335-1310 and 1175-1160 (v 502
) NMR (ppm); 1.50 (611,
t,, -CH2C几3X2).

3.60 (4H, br, s, -CH-2COOH
X2) 4.30 (4H, q, -C ratio 2 C) +3
X2).

6.20 (2B, br, s, -COOlX2).

7.10 (28, d, 6th position) lX2).

7.60 (2H, d, lX2 at position 5).

8.00 (2H,br,s,N)lX2).

8.20 (2H,s, 3rd position lX2)EA; Shown in Table 4.

Example 3 Bis(4-(N-carboxymethylsulfamoyl)-
7-n-propoxy-2-benzofuranyl coketone Instead of bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7-medoxy 2-benzofuranyl coketone) used in Example 1, bis(4- Example 1 except that (N-ethoxycarbonylmethylsulfamoyl)-7-n-propoxy-2-benzofuranyl coketone was used.
In the same manner as above, the desired product (yield 96.2%) with mp 256-257°C (decomposition) was obtained.

IR (cm-'); 3350-3150 (9NH
).

3000-2850 (νC)l).

1740 (νC00H), 1645 (νCO).

1330~131O and 1170~1150 (νS02)
NMR (pp carbon dioxide); 1.10 (6H,t,
-CH2CH2CH3X2).

1.65-2.10 (4H, ■, CH2C ratio 2CH3
X2).

3.53 (4H= br-se CH2C00X2
) -3,80(2H,br,s, -COOlX2)
.

4.18 (4H, t, -oc and CH2CH3X2).

7.05 (2H, d, lX2 at position 6).

7.53 (21(, d, lX2 at position 5).

7.90 (2H, br, s, NlX2).

8.10 (2H,s, 3rd position)lX2)EA; 4th
Shown in the table.

Example 4 Bis(4-(N-carboxymethylsulfamoyl)-
7-n-Butoxy-2-benzofuranyl coketone Instead of the bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7-medoxy 2-benzofuranyl coketone used in Example 1), bis[4- (N-ethoxycarbonylmethylsulfamoyl)-7-n-butoxy-
The desired product (mp 213-215°C (decomposition)) was prepared in the same manner as in Example 1 except that 2-benzofuranyl coketone was used.
A yield of 100% was obtained.

IR (cm-'); 3350-3200 (v N
H).

3000-2850 (νCH).

1730 (νC00H), 1650 (νCO).

1340-1310 and 1180-1160 (νS02)
NMR (pp+m); 1.00 (68,t,
CI(2C)+2 CH2C and 3×2).

1.35-2.00 (81,ts, CH2C and COCH2CH3X2).

3.58 (4H,br,se CH2C00X2
).

4.00 (2H, br, s, C00HX2).

4.10 (4H,t,, -QCC20CH2CH
2CH3X2).

7, LO (2H, d, lX2 at position 6).

7.55 (2H, d, 5th position) lX2).

7.90 (2H, br, s, NlX2).

8.10 (2H,s, 3rd position lX2)EA; 4th
Shown in the table.

Example 5 Bis[4-methoxy-7-(N-carboxymethylsulfamoyl)-2-benzofuranylkoketone Bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7-) used in Example 1 Bis[4-methoxy-7-(N
-ethoxycarbonylmethylsulfamoyl)-2-benzofuranyl coketone was used in the same manner as in Example 1, and recrystallized from a mixture of methanol, ethyl acetate, and petroleum ether. ) was obtained (yield 78.9%).

IR(c+s-'); 3350~3250(νN
H).

3000-2850 (νCH).

1735 (yaC00H), 1640 (νCO).

1340-1325 and 1170-1160 (ν502)
NMR (ppi+); 3.75 (4H, br,
s, -CH2C00X2).

3.80 (211,br,s, -COOlX2)
.

3.97 (6H, s, 0C113X2).

6.87 (21(, d, lX2 at 5th position).

7.65 (2 summer 1. d, 6th place lX2).

7.90 (2H, br, s, NlX2).

8.05 (2)! , s, lX2) EA at position 3;
It is shown in Table 4.

Example 6 Bis(4-(N-methyl-N-hydroxymethylsulfamoyl)-7-medoxy 2-benzofuranyl coketone Bis(4-(N-ethoxycarbonylmethylsulfamoyl) used in Example 1) Bis[4-(N-methyl-N-
It was recrystallized from acetone or a mixture of acetone and ethanol in the same manner as in Example 1 except that methoxycarbonylmethylsulfamoyl)-7-medoxy-2-benzofuranyl coketone was used. The desired product (yield 73.0%) was obtained.

IR(c+m-'); 3050~2850(v
C)I).

1730 (YaC00H), 1655 (SCO).

1335-1310 and 1170-1150 (ν502)
NMR (ppm); 2.85 (68,s, -
N (CH3) x2).

3.80 (2H, br, s, -COOlX2).

3.95 (4H, s, CH2C00X2).

4.05 (6H,S, -0CI!3 x2) -7
, 15 (28, d, 6th position) lX2).

7.60 (2L d, 5th position lX2).

7.93 (2H,s, lX2 at position 3) EA; shown in Table 4.

Example 7 Bis(4-(N-methyl-N-hydroxymethylsulfamoyl)-7-nitoxy 2-benzofuranyl coketone Bis(4-(N-ethoxycarbonylmethylsulfamoyl) used in Example 1) bis(4-(N-methyl-N
-Methoxycarbonylmethylsulfamoyl)-7-nitoxy-2-benzofuranyl coketone was used in the same manner as in Example 1, and a 1:1 mixture of water and methanol was added, and the mixture was heated for 10 to 20 minutes at 50 to 60°C. React for minutes. The desired product (yield 75.5%) with m p 249-251°C (decomposed) was obtained by recrystallization from ethanol.

IR(am-'); 3050~2850(νCH
).

1720(vCOOI(), 1650(vCo)
.

1340-1320 and 1170-1160 (νS02)
NMR (ppm); 1.5Q (61(,t,
-CH2CH3X2).

2.83 (6)1. s, N (CH3)
x2).

3.50 (2B, br, s, -COOlX2).

3.90 (4H, s, C)+2 C00X2
).

4.30 (2 C for 4H, q, -C) 13 X2
).

7.10 (2H, d, 6th position) lX2).

7.57 (2H, d, lX2 at position 5).

7.95 (2H,s, lX2 at position 3) EA; shown in Table 4.

Example 8 Bis(4-[N-(1-carboxyethyl)sulfamoyl]-7-medoxy 2-benzofuranylkoketone Bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7 used in Example 1) - The same procedure as in Example 1 was used except that bis[4-[N-(1-ethoxycarbonylethyl)sulfamoyl]-7-medoxy 2-benzofuranyl coketone was used instead of medoxy 2-benzofuranyl coketone. Recrystallization from a mixture of ethanol and petroleum ether gave the desired product (yield: 81.4%) with a m p of 220-222°C (decomposition).

IR (cm-'); 3350-3,200 (v
NH).

3050-2850 (νCH).

1730 (v COOH), 1640 (v CO)
.

1335-1315 and 1170-1155 (v SO2
) NMR (ppm); 1.20 (6H, d,
-CH(CI+3)Cool(X2).

3.40 (211,br,s, -COO1lX2)
.

3.50-3.90 (2H,m, -NHCH(CH
3)COOlX2).

4.30 (6H, s, -0CH3X2).

7.08 (28, d, 6th position lX2).

7.53 (2H, d, 11X2 at position 5).

8.00 (2H, br, s, NlX2).

8.10 (2H,s, lX2 at position 3) EA; shown in Table 4.

Example 9 Bis(4-[N-methyl-N-(1-carboxyethyl)sulfamoyl]-7-medoxy 2-benzofuranyl coketone Bis(4-(N-ethoxycarbonylmethylsulfamoyl) used in Example 1) bis[4-[N-methyl-N-
(1-methoxycarbonylethyl)sulfamoyl]-
In the same manner as in Example 1 except that 7-medoxy 2-benzofuranyl coketone was used, a mixture of water and acetone (l:1) was added and the reaction was carried out at 60 to 70°C for 30 minutes, resulting in m p 2
IR (cm-'); 3000-2
850 (νCH).

1720 (νC00H), 1650 (νCO).

1330-1310 and 1170-1150 (νS02)
NMR (ppm); 1.20 (6H, d, -
CH(Cba3) C00X2).

2.75 (6H,s, -N(CH3) CH(CH
3)×2).

3.40 (2H, br, s, -C0OH x 2).

3.97 (6H, s, -0CH3X2).

4.55 (21(,q, -岨(CH3) C00
X2).

7.08 (2)! , d, 6th place 1 (X2).

7.53 (2+1.d, 5th place) IX2).

7.90 (2H,s, 3rd place H x 2) EA; Shown in Table 4.

Example 10 Bis[4-[N-(2-carboxyethyl)sulfamoyl]-7-medoxy 2-benzofuranylkoketone Bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7 used in Example 1) Example 1 except that bis[4-[N-(2-ethoxycarbonylethyl)sulfamoylco-7-methoxy-2-benzofuranyl coketone was used instead of medoxy 2-benzofuranyl coketone.
In the same manner as above, the target product (yield 70.0%) with m p 240-242°C (decomposition) was obtained.

IR(c+n-'); 3300~3170(v
NH).

3000-2850 (νCH).

1720-1710 (v C00H).

1640 (νCO).

1335-1310 and 1170-1155 (v 502
) NMR (Ppm); 2.10-2.55 (
4FI, ra, NHCH2C) (2COO)I
X2).

2.90 (48,t, NHCH2C)12
C0OH×2).

4.05 (6H, s, -0CH3X2).

6.90 (2H, br, s, -C0OH×2)
.

7.18 (2H, d, HX2 at position 6).

7.40 (2H, br, s, NHX2).

7.62 (2H, d, HX2 at position 5).

8.18 (2H,s, 3rd position llX2)EA; 4th
Shown in the table.

Example 11 Bis(4-[N(2-carboxypyrrolidino)sulfonylcochi-methoxy-2-benzofuranyl]ketone Bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7-medoxy used in Example 1) Example 1 was repeated in the same manner as in Example 1, except that bis(4-[N-(2-ethoxycarbonylpyrrolidino)sulfonyl]-7-medoxy 2-benzofuranyl]ketone was used instead of 2-benzofuranylkoketone. The desired product (yield 92.6%) was obtained at 260-263°C (decomposition).

IR (am-1); 3000-2800 (vcl
I).

1720 (νC00I+), 1645 (νCO).

1340-1325 and 1170-1155 (νS02)
NMR (ppm); 1.50-2.00 (81
1,ff+.

N ClI2 C 2C ratio 2 cox2).

3.10-3.53 (411, m.

N　C112C112C112C1 (X2).

3.90-4.20 (211, br, t.

N　CR2Cl12　CH2CboyX2).

4.05 (6H, s, 0CH3x2).

6.60 (2+I, br, s, -COO1lX2
).

7.18 (211, d, HX2 at position 6).

7.68 (2+1.d, 5th place 1IX2).

8.80 (2H,s, 3rd place H x 2) EA; Shown in Table 4.

Example] 2 Bis[4-chloro-6-(N-ethoxycarbonylmethylsulfamoyl)-7-medoxy 2-benzofuranyl coketone Bis(4-(N-ethoxycarbonylmethylsulfamoyl) bis[4-chloro-6-(N-
The target product (yield: 100%) with m p of 260 to 262°C (decomposition) was obtained in the same manner as in Example 1 except that ethoxycarbonylmethylsulfamoyl)-7-medoxy-2-benzofuranyl coketone was used. .

IR (cm-'); 3380-3280 (vNH
).

3000-2850 (v CH).

1730 (νCool), 1655 (νCO).

1350-1325 and 1175"1155 (v 502
) NMR (ppm): 3.30 (2H, br
, s, -COOHx2).

3.65 (4H,br,s, -CH2COOx2
).

4.25 (6)1. s, -0CH3N2)
.

7.45 (2H, s, HX2 in 5th position).

7.80 (2tl, br, s, -NHX2)
.

7.95 (2)1. s, HX2) EA at position 3; shown in Table 4.

Example 13 Bis(4-(N-carboxymethylsulfamoyl)
-5,6-Methylenedioxy-2-benzofuranyl coketone Instead of bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7-medoxy 2-benzofuranyl coketone) used in Example 1, bis[ Purpose of m p 276-278°C (decomposition) in the same manner as in Example 1 except that 4-(N-ethoxycarbonylmethylsulfamoyl)-5,6-methylenedioxy-2-benzofuranyl coketone was used. The product was changed (yield 100%).

IR (cm-'); 3300-3200 (ν
N)l).

3000-2850 (νC1().

1730 (νC00H), 1620-1610 (vco
).

1310~I290 and 1190~1180 (νS02)
NMR (ppm); 3.60 (2H, b
r, s, C00HX2).

3.75 (48,br,s,-C)+2 C00x
2).

6.15 (4H, s, OCH20-N2).

7.35 (2H, s, 7th position 1lX2).

7.90 (2H, s, 3rd position llX2).

8.15 (2H, br, s, -NHX2)EA;
It is shown in Table 4.

Example 14 Bis(4-(N-carboxymethylsulfamoyl)-
7-Methyl-2-benzofuranyl]ketone Instead of bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7-methoxy 2-benzofuranyl) ketone used in Example 1, bis(4-( N-ethoxycarbonylmethylsulfamoyl)-7-methyl-2-
The desired product (yield: 95.6%) with m p of 235 to 237°C (decomposition) was obtained in the same manner as in Example 1 except that benzofuranyl coketone was used.

IR (cm-'); 3300-3150 (v N
1().

3000-2850 (νCH) 1725(νCoo)l), 1630(νCO).

1330-1320 and 1160-1145 (v502
) NMR (ppm): 2.68 (6H,s,
-CH3N2).

3.65 (4)1. br, s, -CH2C00X
2).

7.20 (2H,br,s, -Cool(N2)
.

7.43 (2H, d, HX2 at position 6).

7.63 (211, d, HX2 in 5th position).

8.10 (2)1. br, s, -NIIX2)
.

8.33 (28,s, 3rd place HX2) EA; shown in Table 4.

Example 15 Bis(4-(N-methyl-N-carboxymethylsulfamoyl)-7-methyl-2-benzofuranyl)ketone Bis(4-(N-ethoxycarbonylmethylsulfamoyl) used in Example 1) -7-Medoxy 2-benzofuranyl koketone was replaced with bis(4-(N-methyl-N
-methoxycarbonylmethylsulfamoyl)゛-7-
In the same manner as in Example 1 except that methyl-2-benzofuranyl]ketone was used, a mixture of water and methanol (1:1) was added, and the mixture was reacted at 60 to 70°C for 30 minutes to give m p 260.
The desired product (yield: 85.7%) was obtained at ~262°C (decomposition).

IR (am”): 3000-2850 (v CH
).

1730 (νC00H), 1640 (v Co)
.

1340-1320 and 1165-1150 (v 502
) NMR (ppm); 2.65 (6H,
s, -CH3X2).

2J5 (68, s, N (CH3) x2).

3.95 (4)1. s, CH2C00X2)
-5,00(28,br,s,-COOHX2).

7.43 (2H, d, HX2 at position 6).

7.61 (2H, d, HX2 in 5th position).

8.05 (2H,s, 3rd place H x 2) EA; Shown in Table 4.

Example 16 Bis(4-(N-carboxymethylsulfamoyl)-
7-s-Butyl-2-benzofuranyl coketone Instead of bis(4-(N-ethoxycarbonylmethylsulfamoyl)-7-medoxy 2-benzofuranyl coketone used in Example 1), bis[4 -(N-Ethoxycarbonylmethylsulfamoyl)-7-s-butyl-2-benzofuranyl coketone was used, but the same procedure as in Example 1 was repeated, and recrystallization from ethanol resulted in an mp of 240 to 2.
The desired product (yield: 81.1%) was obtained at 42°C (decomposition).

IR (cm-'): 3300-3200 (tN
H).

3000-2850 (νC8).

1720 (9C00H), 1640 (νCO).

1350-1335 and 1170-1160 (ν502)
NMR (ppm): 0.87 (6H,t,,
-CH(CH3) -CH2-CH3X2).

1.40 (6H, d, -CH(CH3) CH'
2-CH3X2).

1-80 (4H, m, CH(CH3) CH2
CH3X2).

3.30 (28,tx, CH(C)la)
CH2CH3X2).

3.50 (4)! , br, s, CH2C00
X2).

5.60 (2H, br, s, -COOHX2)
.

7.25 (2) 1. d, 6th place HX2).

7.50 (2) 1. d, 5th place HX2).

7.80 (28, br-st NHX2).

8.17 (2H,s, 3rd position H x 2) EA; shown in Table 4.

Example 17 Bis(4-(N-carboxymethylsulfamoyl)-
7-Medoxy 2-benzofuranyl coketone disodium salt 238.4 mg (0,0004 M) of bis(4-(N-carboxymethylsulfamoyl)-7-medoxy 2-benzofuranyl coketone) obtained in Example 1 was added. The target compound was quantitatively obtained by dissolving in 8 mm of 0.IN aqueous sodium hydroxide solution and freeze-drying. mp280~
The disodium salts of compounds No. 2-16 were converted in a similar manner at 283° C. (decomposition).

Example 18 Bis(4-(N-carboxymethylsulfamoyl)-
7-Medoxy 2-benzofuranyl coketone dipotassium salt 238.4 mg (0,0004 M) of bis(4-(N-carboxymethylsulfamoyl)-7-medoxy 2-benzofuranyl coketone) obtained in Example 1 was The target compound was quantitatively obtained by dissolving in 8 mQ of IN potassium hydroxide aqueous solution and freeze-drying. m p 283
℃ or higher, the dipotassium salts of compounds Nos. 2 to 16 were changed in the same manner.

Example 19 Tablets each weighing 100 mg were prepared according to the following formulation.

Ingredients mg bis[4-
(N-Carboxymethylsulfamoyl)-7-Medokki 100C2-
Benzofuranylcoketone lactose 25 Corn starch 45 Crystalline cellulose
15 methylcellulose
3 Calcium stearate 2
Example 20 100 mg of mixed ingredients were added to 5 ml according to the following recipe.
Capsules were prepared by filling No. 2 capsules.

Ingredients mg bis(4
-(N-carboxymethylsulfamoyl)-7-nitoki 10C2-
Benzofuranylcoketone lactose 45 Cornstarch 35 Crystalline cellulose
8 Calcium stearate
2 Example 21 Each component was mixed according to the following recipe, a core was made using a slang machine, and then pulverized and sized.

Next, mask with TC-5R (film coating agent) and align 20 to 40 meshes for 500m.
A granule of g was prepared.

Ingredients mg bis(4-
(N-carboxymethylsulfamoyl) -7-n-propo 10xy-
2-Benzofuranylcoketone lactose 355 Calcium hydrogen phosphate 80 Crystalline cellulose
40 Calcium stearate
5TC-5R10 Example 22 Bis(4-(N-ruboxymethylsulfamoyl)-
Dissolve 1 mg of 7-n-butoxy-2-benzofuranylkoketone disodium salt in 1 mQ of physiological saline, and
The solution was adjusted to H7.0 to prepare an injection.

〔Effect of the invention〕

Claims (1)

[Claims] 1 General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A is an amino acid residue of glycine, sarcosine, alanine, N-methylalanine, β-alanine or proline, R_1 is a linear or branched alkoxy group having 1 to 4 carbon atoms, or a linear or branched alkyl group having 1 to 4 carbon atoms; Represents an oxy group, S
O_2-A-OH group, R_1 group and R_2 group are substituted at any position of the 4, 5, 6 or 7 position of the benzofuran ring) or a non-toxic salt thereof. 2. The bis-benzofuran derivative or non-toxic salt thereof according to claim 1, which is bis[4-(N-carboxymethylsulfamoyl)-7-methoxy-2-benzofuranyl]ketone. 3. The bis-benzofuran derivative or non-toxic salt thereof according to claim 1, which is bis[4-(N-carboxymethylsulfamoyl)-7-ethoxy-2-benzofuranyl]ketone. 4. The bis-benzofuran derivative or non-toxic salt thereof according to claim 1, which is 4-bis[4-(N-carboxymethylsulfamoyl)-7-n-propoxy-2-benzofuranyl]ketone. 5. The bis-benzofuran derivative or non-toxic salt thereof according to claim 1, which is bis[4-(N-carboxymethylsulfamoyl)-7-n-butoxy-2-benzofuranyl]ketone. 6 Bis[4-(N-methyl-N-carboxymethylsulfamoyl)-7-methoxy-2-benzofuranyl]
The bis-benzofuran derivative or non-toxic salt thereof according to claim 1, which is a ketone. 7 Bis[4-(N-methyl-N-carboxymethylsulfamoyl)-7-ethoxy-2-benzofuranyl]
The bis-benzofuran derivative or non-toxic salt thereof according to claim 1, which is a ketone. 8. The bis-benzofuran derivative or non-toxic salt thereof according to claim 1, which is bis[4-[N-(1-carboxyethyl)sulfamoyl)-7-methoxy-2-benzofuranyl]ketone. 9. The bis-benzofuran derivative or non-toxic salt thereof according to claim 1, which is bis[4-[N-methyl-N-(1-carboxyethyl)sulfamoyl]-7-methoxy-2-benzofuranyl]ketone. . 10. The bis-benzofuran derivative or non-toxic salt thereof according to claim 1, which is bis[4-chloro-6-(N-carboxymethylsulfamoyl)-7-methoxy-2-benzofuranyl]ketone. 11. The bis-benzofuran derivative or non-toxic salt thereof according to claim 1, which is bis[4-(N-carboxymethylsulfamoyl)-7-methyl-2-benzofuranyl]ketone. 12 Bis[4-(N-methyl-N-carboxymethylsulfamoyl)-7-methyl-2-benzofuranyl]
The bis-benzofuran derivative or non-toxic salt thereof according to claim 1, which is a ketone. 13. The bis-benzofuran derivative or non-toxic salt thereof according to claim 1, which is bis[4-(N-carboxymethylsulfamoyl)-7-s-butyl-2-benzofuranyl]ketone. 14 General formula (II): ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, A is an amino acid residue of glycine, sarcosine, alanine, N-methylalanine, β-alanine, or proline, and R_1 is a carbon A linear or branched alkoxy group having 1 to 4 carbon atoms or a linear or branched alkyl group having 1 to 4 carbon atoms, R_2 is a hydrogen atom, a halogen atom, or a methylenedioxy group bonded to R_1, R_3 represents a linear or branched alkyl group having 1 to 4 carbon atoms, and SO_2-A-OR_3, R_4 and R_2 groups are substituted at any position of the 4, 5, 6 or 7 position of the benzofuran ring. General formula (I) characterized by hydrolyzing the bisbenzofuranyl ketone derivative represented by
: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) (In the formula, A, R_1 and R_2 mean the same as above, and SO_2-A-OH group, R_1 group and R_2 group are 4 of the benzofuran ring, A method for producing a bis-benzofuran derivative (substituted at any position of 5, 6 or 7) or a non-toxic salt thereof. 15 General formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, A is an amino acid residue of glycine, sarcosine, alanine, N-methylalanine, β-alanine, or proline, and R_1 is a carbon A linear or branched alkoxy group having 1 to 4 carbon atoms, or a linear or branched alkyl group having 1 to 4 carbon atoms, R_2 is a hydrogen atom, a halogen atom, or a methylenedioxy group bonded to R_1. Representation, S
O_2-A-OH group, R_1 group and R_2 group are substituted at any position of the 4, 5, 6 or 7 position of the benzofuran ring) or a non-toxic salt thereof as an active ingredient. A treatment for diabetic complications.