JPH04128266A - Hydantoin derivative and medicinal composition containing the same hydantoin as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (Q is 1-8C alkyl, biphenyl or heterocycle substitutable with halogen, lower alkyl, nitro, carbamoyl or phenyl, etc.), a salt or a solvate of said compound and a solvate of said salt. EXAMPLE:1-(Benzo[b]thien-2-yl sulfonyl) hydantoin. USE:Useful for therapy and prevention of various complications of diabetes, having aldose reductase-inhibiting action and simultaneously exhibiting cataract- inhibiting action, nervous incompetency inhibiting action and hypoglycemic action. PREPARATION:A sulfonylglycine derivative expressed by formula II is cyclized with halogenated formic acid ester in a solvent such as N,N-dimethylformamide in the presence of a base (e.g., NaH) at a temp. from -20 deg.C to 120 deg.C to afford the compound expressed by formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a sulfonylhydantoin derivative, a method for producing the same, a pharmaceutical composition containing the same as an active ingredient and having an aldose reductase (hereinafter abbreviated as AR) inhibitory effect, and This invention relates to intermediates for the synthesis of derivatives thereof.

[Prior art] Cataracts and peripheral neuropathy as diabetic complications.

Retinopathy and nephropathy result from unnecessary accumulation of corresponding polyols produced from carbohydrates due to AR. For example, in sugar cataracts, the AR present in the lens of the eye converts glucose, galactose, etc. into corresponding sugar alcohols, and the sugar alcohols are unnecessarily accumulated in the lens, causing an increase in osmotic pressure.

It has been reported that this occurs by damaging the crystalline lens [J.
tal, Biochlm.

B i o p h y s , A c t a +
158+472 (1968) and references cited therein]. There have also been reports of various adverse effects caused by sorbitol accumulation in the lens, peripheral nerve cord, and kidney of diabetic animals [A, Pirie
et al,, Exp, Eye Res.

3.124 (1964); L, T, Chylack
Jr. et al., Inves
t, 0phtha1. ．． 8,401 (1969);
J.D.

Ward et al., Diabet
6, 531 (1970)]. Follow me.

In order to prevent, alleviate or treat the above-mentioned complications, it is important to inhibit the activity of AR, which is the cause thereof, as strongly as possible.

Related prior art includes the following.

Okuda et al., JP-A-58-109418, JP-A-62-
No. 67075, JP 62-201873 and JP 1-61485 disclose sulfonylhydantoin derivatives useful as AR inhibitors. Maamas et at, M.S. discloses sulfonylhydantoin derivatives useful as AR inhibitors in JP-A-63-22565.

Also.

Oishi et al. disclose benzofuranylsulfonylglycine derivatives useful as therapeutic agents for diabetic complications in JP-A-62-155269.

[Problems to be Solved by the Invention] Conventionally, many compounds such as arrestatin and turvinil have been provided as AR activity inhibitors.

In addition to still not being fully satisfied with its ability to inhibit AR activity, even if it shows some degree of effective inhibition ability in vitro, it is not sufficiently effective in vivo due to metabolic factors and other factors. In view of the current situation, there has been a desire for a compound that has stronger AR activity inhibiting power and is effective in vivo.

[Means for Solving the Problems] 'The present inventors have conducted intensive research on the effects of various compounds in order to obtain compounds that have stronger and more effective AR activity inhibition ability, and have developed a hydantoin derivative represented by the general formula (+). The present inventors have discovered that these salts have an extremely strong ability to inhibit AR activity, and have completed the present invention.

The present invention is based on the general formula: Alkyl group, nitro group, cyano group, optionally protected carboxyl group, optionally protected carboxymethyl group, halogenated lower alkyl group, lower alkylthio group,
Same or different selected from the group consisting of lower alkylcarbonyl group, lower alkoxy group, lower alkylsulfinyl group, lower alkylsulfonyl group, optionally protected hydroxyl group, optionally protected amino group, carbamoyl group, or phenyl group (represents a monocyclic heterocyclic group or a fused heterocyclic group which may be substituted with one or more groups)
The present invention relates to a hydantoin derivative represented by the above formula, a salt, a solvate thereof, or a solvate of a salt thereof, a method for producing the same, a pharmaceutical composition containing the same, and a synthetic intermediate.

The hydantoin derivatives, salts, solvates, and solvates of salts of the present invention have a strong ability to inhibit AR activity, and also exhibit cataract-preventing action, neuropathy-preventing action, and hypoglycemic action in experimental animal models. It has no central nervous system side effects such as anticonvulsant activity, low toxicity, and high safety, and can be used for the treatment and prevention of diabetic complications. Specifically, neurosis, autonomic neuropathy, cataract, and retinopathy.

It can be used to prevent and treat symptoms associated with diabetes such as nephropathy and microangiopathy.

The hydantoin derivative of the present invention can be produced as follows.

First, general formula (Vl) Q-SO2-Y (Vl) (wherein Q is a straight or branched alkyl group having 1 to 8 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms) , biphenylyl group or halogen atom, lower alkyl group, nitro group, cyano group, optionally protected carboxyl group,
optionally protected carboxymethyl group, halogenated lower alkyl group, lower alkylthio group, lower alkylcarbonyl group, lower alkoxy group, lower alkylsulfinyl group, lower alkylsulfonyl group, optionally protected hydroxyl group, unprotected represents a monocyclic heterocyclic group or a fused heterocyclic group optionally substituted with one or more of the same or different groups selected from the group consisting of an optional amino group, a carbamoyl group, or a phenyl group, and Y represents a halogen atom. The starting material sulfonyl halide represented by amide) and sulfur dioxide, followed by a halogenating agent (e.g. chlorine).

It can be synthesized by reacting bromine, phosphorus pentachloride, thionyl chloride, N-chlorosuccinimide, N-bromosuccinimide, etc.).

Also, formula 9 Q-H (Q and H have the same meanings as above)
The compound represented by is halosulfonic acid.

Desirably, sulfonyl halide can be directly synthesized by reacting with chlorosulfonic acid or the like.

Alternatively, a compound represented by Formula 1 Q 5O3H (Q has the same meaning as above) is treated with, for example, sodium hydrogen carbonate to form a salt, and then a halogenating agent (for example, phosphorus pentachloride, thionyl chloride or bromide) is prepared. thionyl, etc.)
It can be synthesized by reacting.

It can also be synthesized by reacting a halogenating agent (for example, chlorine) with a compound represented by formula 9 Q 5C82C6H5 (Q has the same meaning as above).

In addition, after the compound represented by Formula 9 Q NH2 (Q has the same meaning as above) is treated with a nitrite (e.g., sodium nitrite), sulfur dioxide and a halogenating agent (e.g., copper chloride) are added. It can be synthesized by reacting.

The sulfonyl halide obtained in this way and the general formula (■
) NH,CH2CO-R (■) (wherein, R represents an amino group optionally substituted with a hydroxyl group, an alkoxy group, or an alkoxycarbonyl group)
By reacting with a glycine derivative represented by the general formula (
V) A sulfonylglycine derivative represented by Q-So2NHCH,Co-R (1) (wherein Q and R have the same meanings as above) can be synthesized. The condensation reaction between the sulfonyl halide represented by the general formula (Vl) and the compound represented by the general formula (■) can be carried out in an aqueous solution or in an organic solvent (for example, methylene chloride, chloroform, dioxane, tetrahydrofuran, acetonitrile,
Ethyl acetate.

Acetone, N,N-dimethylformamide, a mixed solvent thereof, etc.) or a mixed solvent thereof, and if necessary, a deoxidizing agent is added thereto. Examples of deoxidizers in organic solvents include:

Organic bases (eg, triethylamine, diethylaniline, pyridine, etc.) are used, and in aqueous solutions, water-soluble bases (eg, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, etc.) are used. The condensation reaction is carried out at a temperature range of -20°C to 80°C, preferably at a temperature range of 0°C to room temperature.

When R in the general formula (V) is an unsubstituted amino group, the sulfonylglycine derivative has the general formula (II) Q-SO, N
It is represented by HCH2CONH2(II) (wherein Q has the same meaning as above).

The sulfonylglycine derivative represented by the general formula (II) is prepared in the presence of a base (eg, sodium hydride, potassium hydride, butyllithium, etc.).

Haloformates (e.g. methyl chloroformate).

cyclized using ethyl chloroformate, etc.) to form the general formula (1)
It can be a hydantoin derivative represented by

The cyclization reaction is generally carried out in an inert solvent (e.g. N,N-dimethylformamide, dimethyl sulfoxide, ethyl ether, tetrahydrofuran, dioxane, methylene chloride, etc.) at a temperature ranging from -20°C to 120°C, but preferably It is carried out at a temperature of 0°C to 80°C.

When R is an amino group substituted with an alkoxycarbonyl group, the sulfonylglycine derivative.

Hydantoin derivatives can be obtained by treatment with the above bases.

When R in general formula (V) is a hydroxyl group or an alkoxy group, the sulfonylglycine derivative is optionally treated with a base (such as pyridine, triethylamine, etc.)
The general formula (IV
) can be a thiohydantoin derivative represented by The cyclization reaction is generally performed in an organic solvent (e.g. pyridine,
triethylamine, N,N-dimethylformamide, dimethyl sulfoxide, etc.).

The temperature range is from 0°C to 120°C, and fE is preferably from room temperature to 100°C. Furthermore, the thiohydantoin derivative is treated with a suitable oxidizing agent (eg, nitric acid).

The hydantoin derivative represented by the general formula (1) can be obtained by oxidation with chlorine, iodine chloride, potassium permanganate, hydrogen peroxide, dimethyl sulfoxide, sulfuric acid, etc.).

In the compound of general formula (1), the linear or branched alkyl group having 1 to 8 carbon atoms is, for example.

Methyl, ethyl, isopropyl, tertiary butyl.

It shows hexyl, octyl, etc., and the cyclic alkyl group having 3 to 6 carbon atoms is, for example, cyclopropyl.

Indicates cyclopentyl, cyclohexyl, etc., and monocyclic heterocyclic groups include, for example, pyrrolyl, pyrrolinyl, imidazolyl,
Pyrazolyl, triazolyl, tetrazolyl, oxasilyl, isoxasilyl, oxadiazolyl, thiazolyl, inthiazolyl, thiazolinyl, thiadiazolyl, thiatriazolyl.

thienyl, furyl, pyrrolidinyl, imidazolidinyl,
Thiazolidinyl, pyridyl and its N-oxyto, pyrazinyl, pyrimidinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl.

triazinyl, preferably thiazolyl, thienyl, furyl, pyridyl, and the fused heterocyclic group is, for example, indolyl, isoindolyl, benzimidazolyl, quinolyl, isoquinolyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, indazolyl, benzotriazolyl, benz Oxacylyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzisoxasilyl, benzisothiazolyl, benzothienyl, tetrahydrobenzothienyl, benzofuranyl, isobenzofuranyl, chromenyl.

Chromanyl, coumarinyl, chromonyl, triazolopyridyl, tetraclopyridyl, purinyl, thiazolopyrimidinyl, triazolopyrimidinyl.

Thiadiazolopyrimidinyl, thiazolopyridazinyl, naphthyridinyl, xanthenyl, phenoxathiinyl, phenoxazinyl, phenothiazinyl.

carbazolyl, preferably indolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl,
Benzisoxasilyl, benzisothiazolyl, benzothienyl, tetrahydrobenzothienyl, benzofuranyl, coumarinyl, chromonyl, more preferably benzo[b-cochenyl or benzo[b]furanyl. The monocyclic heterocyclic group and the fused heterocyclic group include lower alkyl groups (for example, methyl, ethyl, propyl, isopropyl,
tertiary butyl), lower alkylcarbonyl groups (e.g. acetyl, propanoyl, butanoyl, pivaloyl, etc.), lower alkoxy groups (e.g. methoxy, ethoxy,
isopropoxy, tertiary butoxy, etc.)2. Phenyl group, cyano group, optionally protected carboxyl group, optionally protected carboxymethyl group, nitro group, halogenated lower alkyl group (eg trifluoromethyl).

pentafluoroethyl, etc.), an optionally protected hydroxyl group, an optionally protected amino group (such as acylamino), and a lower alkylthio group.

Lower alkylsulfinyl groups, lower alkylsulfonyl groups or halogen atoms (e.g. fluorine, chlorine.

bromine, etc.), etc.), and may be substituted with one or more same or different groups.

Monocyclic MI heterocyclic groups are preferably unsubstituted or substituted with 1 or 2 halogen atoms or phenyl groups, and fused heterocyclic groups are unsubstituted or substituted with halogen atoms, lower alkyl groups, halogenated lower alkyl groups, In the case of a benzo[bfuran-2-yl group which may be substituted with a fused heterocyclic group, which is preferably substituted with 1 to 3 lower alkylthio groups or cyano groups,
The substituent preferably has 1 to 3 halogen atoms.

It is known that in the compound of the present invention represented by general formula (1), the hydantoin moiety has a tautomeric relationship as shown in the following formula. Since these are generally treated as the same substance,9 in the present invention, these isomers are included and expressed as a hydantoin moiety.

Furthermore, due to this tautomerism, the hydantoin moiety exhibits acidity and forms nine different salts. Salts include, for example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, inorganic bases such as ammonium salts, salts with organic bases such as benzylamine salts and diethylamine salts, and Formulation-acceptable salts such as salts with amino acids such as arginine salts and lysine salts are useful and can be easily obtained by conventional methods.

Moreover, the compound represented by -maximum (1) can form an acid addition salt. Examples of acid addition salts include salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, and phosphate, acetate, and citrate.

Salts with organic acids such as maleate, tartrate, benzoate, ascorbate, ethanesulfonate, toluenesulfonate, aspartate.

Pharmaceutically acceptable salts such as salts with amino acids such as glutamate are useful and can be readily obtained by conventional methods.

Some representative compounds of the present invention are illustrated below, and the ability of the compounds to inhibit AR activity is demonstrated through experimental examples.

Compound of Example 1: 1-(benzo[b]chen-2-ylsulfonyl)hydantoin Compound of Example 3: 1-(5-fluorobenzo[b]chen-2-ylsulfonyl)hydantoin Compound of Example 4: 1 -(5-chlorobenzo[b]chen-2-ylsulfonyl)hydantoin Compound of Example 5: 1-(3-chlorobenzo[b]chen-2-ylsulfonyl)hydantoin Compound of Example 6: 1-(4-chlorobenzo[ b] Chen-2-ylsulfonyl)hydantoin Compound of Example 7: 1-(5-bromobenzo[b]furan-2-ylsulfonyl)hydantoin Compound of Example 8: 1-(5-chlorobenzo[bfuran-2 -ylsulfonyl)hydantoin Compound of Example 12: 1-(benzo[blisothiazol-3-ylsulfonyl)hydantoin Compound of Example 15: 1-(Coumarin-6-ylsulfonyl)hydantoin Compound of Example 23: 1 -(2,5-cyclothien-3-ylsulfonyl)
Hydantoin Compound of Example 26: 1-(biphenyl-4-ylsulfonyl)hydantoin Compound of Example 27: 1-(6-chlorobenzo[b]thien-2-ylsulfonyl)hydantoin Compound O1 of Example 28: 1- (7-chlorobenzo[b]chen-2-ylsulfonyl)hydantoin Compound of Example 29: 1-(3-isopropylbenzo[b]chen-2-ylsulfonyl)hydantoin Compound of Example 30: 1-(3-trifluoro Methylbenzo[b]thiene-2
-ylsulfonyl)hydantoin Compound of Example 31: 1-(3-bromobenzo[b]chen-2-ylsulfonyl)hydantoin Compound of Example 33: 1-(4,5-dibromothiethyl-2-ylsulfonyl)
Hydantoin Compound of Example 34: 1-(4,6-dichlorobenzo[bfuran--2-ylsulfonyl)hydantoin Compound of Example 35: 1-(3-bromobenzo[bfuran--2-ylsulfonyl)hydantoin] Compound of Example 37: 1-(3-bromo-7-fluorobenzo[b]thien-2-ylsulfonyl)hydantoin Compound of Example 45: 1-(2-chlorobenzo[b]thien-3-ylsulfonyl)hydantoin Compound of Example 47: 1-(4-iodobenzo[b]furan-2-ylsulfonyl)hydantoin Compound of Example 49: 1-(5-nitrobenzo[b]chen-2-ylsulfonyl)hydantoin Compound of Example 51 : 1-(5-carboxybenzo[b]chen-2-ylsulfonyl)hydantoin Compound of Example 54: 1-(Benzothiazol-2-ylsulfonyl)hydantoin Compound of Example 56: 1-(3-methoxybenzo[ b]Thien-2-ylsulfonyl)hydantoin Compound of Example 60: 1-(3-methylsulfonylbenzo[b]thien-2-
ylsulfonyl)hydantoin Compound of Example 61: 1-(3-cyanobenzo[b]chen-2-ylsulfonyl)hydantoin Compound of Example 65: 1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin Implementation Compound of Example 67: 1-(7-fluorobenzo[bfuran--2-ylsulfonyl)hydantoin Compound of Example 68: 1-(4,5-dichlorobenzo[bfuran-2-ylsulfonyl)hydantoin] Compound of Example 69: 1-(5,6-dichlorobenzo[b]furan-2-ylsulfonyl)hydantoin Compound of Example 70: 1-(3-bromo-7-fluorobenzo[bfuran--
2-ylsulfonyl)hydantoin Compound of Example 75: 1-(3-bromo-4,6-dichlorobenzo[b]furan-2-ylsulfonyl)hydantoin Comparison compound: turvinyl (method of Sarges et al.
t al,, J, Med.

Chem, 28.1716 (1985)] Experimental Example 1 Synthesized by the method of Inagaki et al.
, Arch, Blochem, Bioph
AR inhibitory activity was measured using the AR of bovine lens according to J. Ys., Mata Idan 337 (1982)]. Namely, 0.4M ammonium sulfate, 10mM DL-glyceraldehyde, 0.16mM reduced nicotinamide adenine dinucleotide phosphate, reduced form and 0.
．． 010-0.016unlts 0.1 including AR
Add 10μ1 (
7) A hydantoin derivative solution was added and the decrease in absorbance at 340 nm was measured with a Hitachi model 22OA spectrophotometer.

Below are the 50% inhibitory concentrations (IC50) of representative example compounds of the present invention and comparative compound turvinil against AR.
are shown in Table 1.

The compound of the present invention exhibited a stronger AR inhibitory effect than the conventional comparative compound turvinil, which has a strong ability to inhibit AR activity.

Experimental Example 2 The acute toxicity of the hydantoin derivatives of the present invention was investigated. Example 1, 2゜5.6, 7, 8, 2 of the present invention for each group of 5 ICR male mice or ddY male mice
Compounds 3, 35, 65, 67.68, and 69.70 were orally administered at Ig/kg, respectively, and observations were made up to 7 days later, and no deaths were observed.

As is clear from the above experimental results, the hydantoin derivatives of the present invention have a strong ability to inhibit AR activity.

It also has low toxicity and is suitable for animal experimental models.

Since it exhibits stronger diabetic cataract suppressing effect, diabetic neuropathy suppressing effect, and blood sugar lowering effect compared to known compounds,9 the drug containing the hydantoin derivative of the present invention as an active ingredient is useful for the treatment and prevention of the above-mentioned diabetic complications. Useful.

The hydantoin derivatives of the present invention may be prepared using commonly used suitable carriers or vehicles, such as sterile water, vegetable oil, and non-toxic organic solvents or non-toxic solubilizers (e.g. glycerin, propylene glycol), etc., as necessary. The following dosage forms can be obtained by appropriately selecting and combining excipients, binders, lubricants, coloring agents, flavoring agents, emulsifiers or suspending agents (for example, Tween 80, gum arabic, etc.). tablet.

Capsules, granules, fine granules, powders, suppositories, syrups, inhalants, ointments9 ophthalmic solutions, aqueous or non-aqueous injections, emulsion or suspension injections, or dissolve before use; Orally or parenterally (e.g., intravenous, intramuscular, subcutaneous, rectal, transdermal or transmucosal absorption, etc.) in the form of solid injections used as emulsions or suspensions.
It is administered to patients regardless of their condition. The daily dosage is tablets, capsules, powders, injections, suppositories, syrups, and inhalers.

In the case of an ointment, the amount is 1 in terms of the hydantoin derivative.
mg ~ 3000 mg + preferably 10 mg ~ 50
0 mg + 1 μg to 10 mg for eye drops + preferably 10 μg to 1 mg + 1 for ointment
It is preferable to apply an appropriate amount of ~10% ointment to the affected area, but the amount can be increased or decreased as appropriate depending on the patient's condition, and the entire amount may be administered once or in 2 to 6 doses, or administered intravenously. Both are possible.

Next, the method for producing the compound of the present invention will be specifically illustrated by Examples, but the present invention is not limited to the following Examples.

[Example] (Example 1) Production process of 1-(benzo[b]chen-2-ylsulfonyl)hydantoin 1 Production of benzo[b]chen-2-ylsulfonyl chloride 38.3 g of benzo[b]thiophene was dissolved in anhydrous ether 18
Dissolve in 0 ml and cool with water under nitrogen atmosphere.

1.6M n-butyllithium-hexane solution 220ml
was dripped. After heating under reflux for 40 minutes, sulfur dioxide gas was blown into the mixture for 2.75 hours while stirring at an internal temperature of -30°C. After stirring at room temperature for 1 hour, the precipitate precipitated was collected by filtration and benzo[b]
Lithium chen-2-ylsulfinate was obtained. This was suspended in a mixed solution of 400 ml of concentrated hydrochloric acid and 100 ml of water, the internal temperature was kept at -5°C, and chlorine gas was blown into the suspension for 1.5 hours while stirring. The reaction solution was poured into 500ml of ice water and extracted twice with 1.51ml of methylene chloride. After washing the extract with saturated saline, it was dried over anhydrous magnesium sulfate.

The solvent, methylene chloride, was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 40.4 g of the above title compound.

IR spectrum (KB r : cm-') 1495.
1384.1189,1168°NMR spectrum (C
DCl3: I) pm) 7.49-7.68
(2H, m) 7.86-8.03 (2H, m) 8.14 (IH, s) Step 2 Production of N-(benzo[b]chen-2-ylsulfonyl)glycine 15.7 g of glycine and anhydrous carbonic acid 28.9 g of potassium was dissolved in 450 ml of water, and 40.4 g of pen'r[b]chen-2-ylsulfonyl chloride was added thereto at room temperature.
The mixture was heated under reflux for 30 minutes. After cooling the reaction solution, 2M hydrochloric acid was added to adjust the pH to 1 to 2, and the resulting precipitate was collected by filtration to obtain 36.3 g of the title compound.

Melting point: 171.3-172.4°C IR spectrum (KBr: cm-1) 3267.1
735, 1352, 1258° NMR spectrum (D
M S Oda ; ppm ) 3.73 (2H, d
, J=6.0Hz)7.39~7.61 (2H, m
) 7.77~8.13 (3H, m) 8.51 (IH, d, J=6.0Hz) 12.68
(IH, bs) Step 3 1-(benzo[b]chen-2-ylsulfonyl)-2
-Production of thiohydantoin 16.3 g of N-(benzo[b]chen-2-ylsulfonyl)glycine and 10.1 g of ammonium thiocyanate
After adding s anhydride, 12.6 ml of lysine and 40 ml of acetic anhydride, the reaction solution was heated at 80°C for 15 minutes. After cooling, it was poured into 300 ml of ice water, the resulting precipitate was collected by filtration, and thoroughly washed with water. 8.6 g of the above title compound was obtained.

Melting point: 218.6°C (decomposed) IR spectrum (KBr; am”) 1759.1374, 1255, 1171° NMR spectrum (DMS Ode; pI) m)4
．． 74 (2H, s) 7.35-7.69 (2H, m) 8.04-8.21 (2H, m) 8.45 (IH, 5) 12.72 (IH, bs) Step 4 1- Preparation of (benzo[b]thien-2-ylsulfonyl)hydantoin 1-(benzo[b]thien-2-ylsulfonyl)-2-thiohydantoin was added to a solution of 7.12 ml of iodine monochloride mixed in 200 ml of IM hydrochloric acid. After adding 8.5 g of 8.5 g and 200 ml of dichloromethane and stirring at room temperature for 20 minutes, 6.85 g of sodium hydrogen carbonate was added and the mixture was further stirred for 15 minutes, followed by extraction with 11 and 300 ml of ethyl acetate. The extract was washed successively with saturated aqueous sodium sulfite solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent ethyl acetate was distilled off under reduced pressure, and the residue was thoroughly washed with methylene chloride to obtain 4.83 g of the above title compound.

Melting point 251.8-254.2°C R spectrum (KBr; cm-1) 3245.1803.1740', 1376°1352
．． 1167 NMR spectrum (DMS Oda; pp
m ) 4.48 (2H, s) 7.51”?, 63 (2H, m ) 8.05-8.20 (2H, m) 8.33 (IH, 5) 11.71 (IH, bs) (Example 2) Production process of 1-(benzo[b]furan-2-ylsulfonyl)hydantoin 1 Production of benzo[bfuran-2-ylsulfonyl chloride using benzo[b]furan-Example 1 Step 1 The above title compound was obtained in the same manner as above.

IR spectrum (KBr; am-”) 1533.1
389, 1244, 1193° NMR spectrum (CD
CIs; l) I) m) 7.32-7.82 (5H, m
) Step 2 Production of N-(benzo[bfuran-2-ylsulfonyl)chrysin The above title compound was obtained in the same manner as in Example 1 Step 2 using benzo[b]furan-2-ylsulfonyl chloride. .

Melting point 17? , O ~ 178.2°C IR spectrum (KBr; am”) 3289., 1724.1347, 1162 NMR spectrum (DMSO-do; T)
, d, J=6.3Hz)? , 35-7.81 (5H
, m) 8.72 (IH,, t, J=e, 3Hz) 12.6
9(IH, bs) Step 3 1-(benzo[b]furan-2-ylsulfonyl)-2
- To 37 g of the compound obtained in thiohydantoin production step 2, 24.3 g of ammonium thiocyanate*100 ml of acetic anhydride was added, and 30.5 ml of anhydrous pyridine was added dropwise.

After cooling the reaction solution heated at 70 to 80°C for 1.5 hours,
Pour into 800 g of ice to obtain a precipitate. After thorough washing with water and drying, 18.5 g of the above title compound was obtained.

Melting point 213.0°C (decomposition) IR spectrum (KBr; cm”) 3080.1759.1386, 1255°1167.
1010 86N spectrum (DM S Ode; 1) p
m ) 4.76 (28, s) 7.34-8.04 (5H, m ) 12.81 (IH, bs) Step 4 Manufacturing process of 1-(benzo[b]furan-2-ylsulfonyl)hytantoin Using the compound obtained in Step 8, the above title compound was obtained in the same manner as in Step 4 of Example 1.

Melting point 255.9-256.4°C IR spectrum (KBr; am”) 1803.1735, 1398, 1360° NMR spectrum (DMS Oda; pI) m)4
．． 49 (2H, s) 7.33-8.08 C5H, m) 11.79 (IH, bs) Examples 3 to 41 were carried out in the same manner as Example 1, and the IR and NMR spectra of the obtained compounds were The data and melting points are shown in Table 2.

2nd base (Example 42) Production process of 1-(4,5-diphenylthiethyl-2-ylsulfonyl)hydantoin 1 Production of 4.5-diphenylthiethyl-2-ylsulfonyl chloride 2. Using 3-diphenylthiophene The above title compound was obtained in the same manner as in Example 1 Step 1.

IR spectrum (KBr; cm-1) 138
2.1172,1038,698°NMR spectrum (
C'DCla; I) pm) 7.27-7.33
(IOH, m) 7.89 (IH, s) Step 2 Production of N-(4,5-diphenylthiec-2-ylsulfonyl)glycine ethyl ester 4.5-diphenylthiec-2-ylsulfonyl chloride 36.5 g+ Glycine ethyl ester hydrochloride 30.4gt Methylene chloride 32
Add 30.3ml of triethylamine to 0ml of suspension under water cooling.
After that, 200 ml of water was added to the reaction mixture, which was then stirred at room temperature for 160 minutes, and extracted with methylene chloride. The extract was washed successively with 1M hydrochloric acid, water, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent, methylene chloride, was distilled off under reduced pressure, and the residue was reprecipitated with ethyl acetate-hexane to obtain 41.1 g of the title compound.

Melting point 151.2-152.7°C IR spectrum (KBr; cm-1) 3266.1734,1354,1231°1215.
1164.1127 NMR spectrum (DMSO-da; pl
) m)1-12 (3H=t* J=7.1H
z ) 3.88 (2H, d, J = 6.3Hz) 4.04
(2H=q, J=7.1Hz) 6.84-7.44
(IOH, m) 7.67 (IH, s) 8.57 (IH, t, J = 6.3 Hz) Step 3 Production of N-(4,5-diphenylthiethyl-2-ylsulfonyl) glycine Sodium hydroxide 12.4 g was dissolved in 73 ml of water, 41.4 g of the compound obtained in step 2 dissolved in 730 ml of tetrahydrofuran was added thereto, and the mixture was heated at 60°C for 25 ml.
Heated for minutes. The solvent was distilled off under reduced pressure, and 300ml of water was added to the residue.
After adding concentrated hydrochloric acid under water cooling to adjust the pH to 1, the mixture was extracted with 800 ml of ethyl acetate. The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent ethyl acetate was distilled off under reduced pressure, and the residue was reprecipitated with ethyl acetate-hexane to obtain 37.6 g of the title compound.

Melting point 172.2-174.4°C IR spectrum (KBr; cm-1) 3268.1736, 1353, 1159 NMR spectrum (DMS Oda; 1) pm)3.
78 (2H, d, J=5.9Hz) 7.12-7.4
2 (IOH, m) 7.67 (IH, s) 8.39 (IH, t, J=5.9Hz) 12.78 (I
H, bs) Step 4 The above title was prepared in the same manner as in Step 3 of Example 1 using the compound obtained in Step 3 of producing l-(4,5-diphenylthiethyl-2-ylsulfonyl)-2-thiohydantoin. The compound was obtained.

Melting point 213.2-215.4°C IR spectrum (KBr: cm-”) 1752.1446, 1376.1168° NMR spectrum (DMS Oda; 1)I) m)
4.77 (2H, s) 7.32-7.46 (IOH, m) 8.12 (IH, 5) 12.73 (IH, bs) Step 5 l-(4,5-diphenylthiocyst 2- The above-mentioned title compound was obtained in the same manner as in Step 4 of Example 1 using the compound obtained in Step 4 of producing (ylsulfonyl)hydantoin.

Melting point 242.5-243.9°C IR spectrum (KBr; cm-”) 173'l,
1386. 1165 NMR spectrum (DMSO-da; ppm) 4.53
(2H, s) 7.32-7.45 (IOH, m) 8.00 (IH, 5) 11.72 (IH, bs) Examples 43 to 48 were carried out in the same manner as Example 42,
The IR and NMR spectral data and melting point of the obtained compound are shown in Table 3.

The following margin (Example 49) Production process of 1-(5-nitrobenzo[b]thien-2-ylsulfonyl)hydantoin 1 Production of 5-nitrobenzo[b]thien-2-ylsulfonyl chloride 60 g of 5-nitrobenzo[b]thiophene Dissolved in anhydrous tetrahydrofuran 21 and cooled to an internal temperature of -70°C *1
．． A lithium diisopropylamide solution prepared from 240 ml of 6M n-butyllithium-hexane solution, 57.8 ml of diisopropylamine and 170 ml of anhydrous ether was added dropwise under nitrogen atmosphere with stirring. After stirring for 30 minutes, sulfur dioxide gas was blown in for 90 minutes while stirring at the same temperature. After stirring at room temperature for 1 hour, the precipitate was collected by filtration.
-Nitrobenzo[b]thien-2-yl lithium sulfinate was obtained. Add this to 500ml of concentrated hydrochloric acid and 125ml of water.
The mixture was suspended in a mixed solution of 1, kept the internal temperature below 0° C., and chlorine gas was blown into it for 8 hours while stirring thoroughly. After stirring at room temperature for 1 hour, it was extracted twice with 400 ml of methylene chloride. The extract was washed successively with water and saturated brine, then dried over anhydrous sodium sulfate, and the solvent, methylene chloride, was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography to obtain 21 g of the above title compound.

IR spectrum (KBr; cm") 1602.1519.137B, 1340° NMR spectrum (CDCI3; ppm) 8.10 (IH, d, J
=8.9Hz) 8.31 (IH, s) 8.46 (IH, dd.

J=8.9, 2.0Hz) 8.90 (IH, d, J=2.0Hz) Step 2 Production of N-(5-nitrobenzo[b]chen-2-ylsulfonyl)chrysine 5-nitrobenzo[b] The above title compound was obtained in the same manner as in Example 1 Step 2 using thien-2-ylsulfonyl chloride.

Melting point 187.2-194.8°C IR spectrum (KBricm-') 3325, 1734. 1530. 1377135
1, 1159 NMR spectrum (DMSO-dsippm) 3.76
(2H, d, J=5.9Hz)8.22(IH,
s) 8.32-8.91 (4H, m) 12.72 (IH, bs) Step 3 Obtained in production step 2 of l-(5-nitrobenzo[b]chen-2-ylsulfonyl)-2-thiohydantoin The above-mentioned title compound was obtained in the same manner as in Example 1, Step 3 using the obtained compound.

Melting point 217.4°C (decomposed) IR spectrum (KBr; cm-1) 1762.1521, 1470, 1389°1347.
1248,1173.101087N spectrum (D
M S Oda ; ppm ) 4.73 (2H, s
) 8-25 to 9-09 (4H*m) 12.7
8 (IH, bs) Step 4 50% (w/v) to 1.66 g of the compound obtained in manufacturing step 3 of l-(5-nitrobenzo[b]chen-2-ylsulfonyl)hydantoin
The reaction solution, which was heated at t60''c for 6 hours after adding 35 ml of nitric acid, was poured into 150 ml of ice water, and the resulting precipitate was collected by filtration and washed with acetone to obtain 0.47 g of the title compound.

Melting point 282.4°C (decomposition) IR spectrum (KBr; cm”) 3100.173?, 1522.1385°1349.
1176 NMR spectrum (D M S Ode; pI)
m) 4.47 (2H, s) 8.22-9.05 (4H, m) 11.70 (IH, bs) (Example 50) 1-(5-cyanobenzo[b] chain-2-i, le Production process of sulfonyl)hydantoin 1 Production of 5-cyanobenzo[b]chen-2-ylsulfonyl chloride The above title compound was obtained in the same manner as in Example 49 Step 1 using benzo[b]chen-5-yl carbonitrile. .

IR spectrum (KB r : cm-') 2236.
1500, 1376.1171° NMR spectrum (D
MSO-d6; ppm) 7.56 (IH, s) 7.70 (IH, dd.

J = 8.9, 2.0Hz) 8.15 (IH, d, J-8, 9Hz) 8.37 (I
H, d, J = 2.0Hz) Step 2 Production of N-(5-cyanobenzo[b]chen-2-ylsulfonyl)glycine Using 5-cyanobenzo[b]chen-2-ylsulfonyl chloride Example 1 Step 2 The above title compound was obtained in the same manner as above.

IR spectrum (KBr; cm-1) 3289.2
235.1?14,1350°NMR spectrum (D
M S Ode ; pI) m ) 3.75 (2H
, d, J=5.6Hz) 7.87 (IH, dd.

J = 8.6, 1.3Hz) 8.06 (IH, s) 8.34 (IH, d, J = 8.6Hz) 8.56 (IH
, d, J=1.3Hz)8.70(IH,t,,y=
5.6 Hz) 12.69 (IH, bs ) Step 3 Example 1 Step using the compound obtained in Production Step 2 of l-(5-cyanobenzo[b]chen-2-ylsulfonyl)-2-thiohydantoin The above title compound was obtained in the same manner as in Example 3.

IR spectrum (KB r ; cm-1) 2231.
1762, 1451, 1243゜1173, 10'l
'I NMR spectrum (DMS Ode; 1)l
) m ) 4.73 (2H, s) 7.95 (IH, dd.

J=8. a, 1.7Hz) 8.41 (IH, d, J = 8.6Hz) 8.53 (IH
, s) 8.63 (IH, d, J = 1.7Hz) 12.72 (I
H, bs) Step 4 50% (w/v) to 0.39 g of the compound obtained in step 3 of producing l-(5-cyanobenzo[b]thien-2-ylsulfonyl)hydantoin.
After adding 8.2 ml of nitric acid and heating at 80°C for 5 minutes, the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into 35 ml of ice water, and the resulting precipitate was collected by filtration and washed with 100 ml of acetone to obtain 0.11 g of the above title compound. I got it.

Melting point 276.3°C (decomposition) IR spectrum (KBr; cm-”) 3100.2231, 1740, 1386° NMR spectrum (DMSOda; I) pm) 4.47 (2H
,s) 7.95 (IH, dd.

J = 8.6, 1.7Hz) 8.41 (IH, s) 8.42 (IH, d, J = 8.6Hz) 8.85 (I
H, d, J = 1.7 Hz) 11.75 (IH, bs) (Example 51) Production of 1-(5-carboxybenzo[b]chen-2-ylsulfonyl)hydantoin Example 50 Obtained in Step 4 0.1 g of the compound added to 1.0 g of water.
Add 5 ml, add 1.5 ml of water-cooled sulfuric acid and 1.5 ml of acetic acid.
1 was added slowly, and the reaction solution was heated under reflux for 2 hours.
After cooling the reaction solution, the resulting precipitate was collected by filtration and added with 20ml of acetone.
Washed with 1. The washing liquid was concentrated under reduced pressure, and the residue was dissolved in ether 2.
ml to obtain 0.02 g of the above title compound.

Melting point: 300°C or higher IR spectrum (KB r ; cm-') 174
3.1690,138.0,1163NMR spectrum (D M S Oda ; 1) l) m ) 4.4
6 (2H, s) 8.07 (IH, dd.

J=8.611.78Z) 8.28(IH, d, J=8.6Hz) 8.48(IH
,s) 8.69 (IH, d, J=1.7Hz) (Example 5
2) Production process of 1-(indol-2-ylsulfonyl)hydantoin 1 Production of 1-benzenesulfonylindol-2-ylsulfonyl chloride 1.6M n-butyllithium-hexane solution 422ml
A solution of 150 g of 1-benzenesulfonylindole dissolved in 2060 ml of anhydrous ether was added dropwise at an internal temperature of 0° C. to a lithium diisopropylamide solution prepared from 101 ml of diisopropylamine and 260 ml of anhydrous ether. After stirring at the same temperature for 15 minutes, the reaction solution was
In addition to 125 ml of sulfuryl chloride cooled to -50°C,
The 8 reaction mixture was stirred at room temperature for 2 hours and poured into 2.5 mL of ice water.
After thorough stirring, the mixture was separated into two liquids. The aqueous layer was extracted with 21 ml of ethyl acetate, combined with the ether layer, and extracted with water.

After washing successively with saturated brine, it was dried over anhydrous sodium sulfate, and the solvents ether and ethyl acetate were distilled off under reduced pressure. The residue was triturated in ether to give 146 g of the above title compound.
I got it.

IR spectrum (KB r , 'am-') 1513
．． 1387, 1378, 1245° NMR spectrum (
CD Cl 3s ppm ) 7.29-8.36 (
IOH, m) Step 2 Production of N-(1-benzenesulfonylindol-2-ylsulfonyl)glycine ethyl ester The above procedure was carried out in the same manner as in Example 42 Step 2 using 1-benzenesulfonylindol-2-ylsulfonyl chloride. The title compound was obtained.

IR spectrum (KBr; am-1) 3335.1746, 1346.1338°NMR spectrum (DMSOda; I) pm) 1
．． 11 (3H, t, J=7.3Hz) 3.94 (2H,
d, J=5.6Hz)4.06(2H,q,J='1
．． 3Hz) 6.38 (IH, t, J=5.6Hz)7.
14-=8.32 (IOH, m) Step 3 Production of N-(indol-2-ylsulfonyl)glycine 1.6 g of sodium hydroxide was dissolved in 7 ml of water.

To this was added a solution of 4.22 g of the compound obtained in step 2 in 70 ml of tetrahydrofuran at room temperature, and
Heated at 75°C for 5 minutes. After distilling off tetrahydrofuran under reduced pressure, 0.4 g of sodium hydroxide was added to the residue and 2 ml of water was added.
The reaction solution was heated at 65 to 75°C for 5 hours, then cooled, washed with ether, and cooled with water for 6 hours.
The pH was adjusted to 1 by adding M hydrochloric acid, and the mixture was extracted three times with 15 ml of ethyl acetate. After sequentially washing the extract with water and saturated saline,
It was dried with anhydrous sodium sulfate. The solvent ethyl acetate was distilled off under reduced pressure, and the residue was pulverized in ethyl acetate-hexane to obtain 1.66 g of the title compound.

Melting point 170.2-171.9°C IR spectrum (KBr; cm-') 332B, 1707, 1340, 1155°NMR spectrum
(Cut) Lt (DM S Ode; I) I)
m) 3.73 (2H, d, J=6.3Hz)6.
94-7.70 (5H, m) 8.05 (IH, t,, r=a, 3Hz) 11.90 (
IH, bs) 12.67 (IH, bs) Step 4 The same method as in Example 1 Step 3 using the compound obtained in Production Step 3 of 1-(indol-2-ylsulfonyl)-2-thiohydantoin. The above title compound was obtained.

Melting point 209.2-210.4℃! R spectrum (KB r ; cm-1) 3131.
3103,1755,1473゜1367.1249,
1197,1165°1147.1010 79N spectrum (DMSOdo; ppm) 4.81 (
2H,s) 7.08-7.78 (5H,m) 12.33(IH,bs) 12.66(11(,bs) Step 5 Production step 4 of 1-(indol-2-ylsulfonyl)hydantoin The above title compound was obtained in the same manner as in Example 1 Step 4 using the compound obtained in .

Melting point 287.1°C (decomposed) IR spectrum (KBr; cm-') 3290.1'18'l, 1725, 1389°136
5.1156 NMR spectrum (DMS Oda; ppm
)4.67 (2H,s) 7.29-7.58 (5H,m) 11.67(IH,bs) 12.63(IH,bs) (Example 53) 1-(2-carboxychromone- 6-ylsulfonyl)
Production process of hydantoin 1 Production of 2-methoxycarbonylchromon-6-ylsulfonyl chloride 132 ml of water was added to 20 g of 6-aminochromone-2-carboxylic methyl, and 26° 4 ml of concentrated sulfuric acid was added under water cooling. Add 9.0 g of sodium nitrite to this at 0°C, and
After stirring for a minute, 19.7 ml of sulfur dioxide and 11 ml of acetic acid were added.
2m1. A mixture of 26 ml of hydrochloric acid and 11.2 g of cupric chloride dihydrate were added and stirred for 15 minutes. The precipitate precipitated was collected by filtration, dissolved in 60 Oml of methylene chloride, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent methylene chloride was distilled off under reduced pressure to obtain 22 g of the title compound. Ta.

IR spectrum (KB r ; am-') 1744.
1661,1381,1287°11?4,60O NMR spectrum (DMS Oda; pI)
m ) 6.96 (IH, s) 7.70 (IH, d, J = 8.6Hz) 8.04 (IH
, dd.

J=8.6,2.0Hz) 8-25 (IH=d*J=2-OHz
) Step 2 Production of N-(2-methoxycarbonylchromon-〇-ylsulfonyl)glycine 20 g of 2-methoxycarbonylchromon-6-ylsulfonyl chloride, 6.1 g of chrysine in 600 ml of acetone
5g * 3.28g of sodium hydroxide and 6.11g of sodium hydrogen carbonate dissolved in 300ml of water were slowly added, and the mixture was stirred at room temperature for 85 minutes. 6M hydrochloric acid was added to the reaction solution to adjust the pH to about 6. Acetone was distilled off under reduced pressure, and insoluble matter was filtered off. Add 2M hydrochloric acid to the filtrate under water cooling,
H1 and extracted three times with 350 ml of ethyl acetate.

The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 5.45 g of the title compound.

Melting point 210.6-212.8°C IR spectrum (KB r ; cm-1) 3327
．． 1746, 1716, 1659゜1288.1266
．． 1165 NMR spectrum) Lt (D M S Oda;
l) pm ) 3.67 (2H, d, J = 5.982)
3.96 (38,s) 7.04(IH,s) 7.89-8.42 (4H,m) Step 3 l-(2-methoxycarbonylchromon-6-ylsulfonyl)-2-thiohydantoin Using the compound obtained in Production Step 2, the above title compound was obtained in the same manner as in Step 8 of Example 1.

Melting point 217.4°C (decomposed) IR spectrum (KBr; cm”) 1748.1660, 1443.1374°1282.
1260,1174 NMR spectrum (DMS Ode; 1)
pm ) 3.96 (3H, s) 4.84 (2H, s) 7.07 (IH, S) 7.97-8.71 (38, m) 12.68 (IH, bs) Step 4 1- The title compound was obtained in the same manner as in Step 4 of Example 1 using the compound obtained in Step 3 of producing (2-methoxycarbonylchromon-6-ylsulfonyl)hydantoin.

Melting point 300℃ or higher IR spectrum (KBr", cm-") 1751.17
41,1664,1617°1375.11'17 NMR spectrum (DMS Oda; pI)
m) 3.96 (3H, s) 4.52 (2H, s) 7.07 (IH, s) 7.98-8.64 (3H, m) Step 5 l-(2-carboxychromone-6- ylsulfonyl)
2.27 g of the compound obtained in hydantoin production step 4 was dissolved in 22.7 ml of a saturated aqueous sodium bicarbonate solution and heated at 40°C for 2 hours. The reaction solution was washed with ethyl acetate, and then cooled with water for 2 hours.
Add M hydrochloric acid to adjust pH to 1.

The resulting precipitate was collected by filtration to obtain 0.2 g of the above title compound. I got it.

Melting point: 279.3°C (decomposed) IR spectrum (KBr; cm-') 32
20.1751,1663,1376°NMR spectrum (DMS Ods; ppm) 4.54 (
2H,s) 7.02(IH,s) 7.95-8.61 (3H,m) 11.63(IH,bs) (Example 54) 1-(benzothiazol-2-ylsulfonyl)hydantoin Production process 1 Production of 2-benzylthiobenzothiazole 250 g of 2-benzothiazolethiol was added to N.

It was dissolved in 11 ml of N-dimethylformamide, and 208 ml of triethylamine was added under water cooling. Add 178 ml of benzyl bromide to the reaction solution and 300 ml of N,N-dimethylformamide.
was added dropwise and stirred for 40 minutes. The reaction solution was poured into 10 liters of water, and the precipitate was collected by filtration, dissolved in 31 liters of methylene chloride, and dried over anhydrous magnesium sulfate.The solvent, methylene chloride, was distilled off under reduced pressure to obtain 378 g of the title compound.

Step 2 Production of benzothiazol-2-ylsulfonyl chloride Add 50 g of acetic acid to 100 g of 2-benzylthiobenzothiazole.
Add a mixture of 0ml and 500ml of water.

The reaction solution into which chlorine gas was blown for 1.5 hours with stirring at an internal temperature of -15°C was poured into 1.5 liters of ice water, and the precipitate deposited was collected by filtration to obtain 90.9 g of the title compound.

Step 3 Preparation of N2-(benzothiazol-2-ylsulfonyl) chrysinamide 43 g of chrysinamide hydrochloride, 90 g of benzothiazol-2-ylsulfonyl chloride under water cooling in dioxane 11.
After adding 9 g, the pH was adjusted to 8 using a saturated aqueous sodium hydrogen carbonate solution, and the mixture was stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, 1.51 g of water was added to the residue, and the pH was adjusted to 2 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration and the title compound 59.
8g was obtained.

Melting point 179.7-181.8°C IR spectrum (KBr; Cm”) 3426.1682, 1346, 1165 NMR spectrum (D M S Oda ; I) pm ) 3.7
3 (2H, s) 7.08 (IH, bs) 7.36 (IH, bs) 7.52-8.29 (4H, m) 8.80 (IH, bs) Step 4 N2-(benzothiazole- 2-ylsulfonyl)-N
102.3 g of the compound obtained in 2-methoxycarbonylglycinamide production step 3 was dissolved in 1.21 g of N,N-dimethylformamide, and 16.7 g of 60% sodium hydride was slowly added under water cooling, and then the mixture was stirred at room temperature. Stirred for 1 hour. 35.8 g of methyl chloroformate was added, and the mixture was further stirred at room temperature for 1 hour. After distilling off the solvent, add 3 parts of water to the residue.
．． Add 51.

The resulting precipitate was collected by filtration to obtain 60.5 g of the above title compound.

Melting point 153.1℃ (decomposition)! R spectrum (KBr", Cm-1) 3459.33
46.1'137.1689゜13B6,1343,1
250,1171 NMR spectrum (DMSO-
da; ppm) 3.70 (3H, s) 4.51 (2H, s) 7.30 (IH, bs) 7.60-7.76 (3H, m) 8.20-8.39 (2H , m) Step 5 Production of 1-(benzothiazol-2-ylsulfonyl)hydantoin 20 g of the compound obtained in Step 4 was dissolved in 200 ml of N,N-dimethylformamide, and 2.67 g of 60% sodium hydride was slowly added. rear.

Heated at 70°C for 13.5 hours. After distilling off the solvent, 11 parts of water was added to the residue, and the mixture was extracted with 1,51 parts of ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent ethyl acetate was distilled off under reduced pressure, and the residue was washed with acetone-chloroform (100ml+200ml) to obtain 2.12g of the above title compound.

Melting point 260.4-261.9°C ■R spectrum (KB r ; cm-1) 3200.
3105,1739.1393°1355.1173 NMR spectrum (DMSO-da; ppm) 4.55
(2H, s) 7.61=7.81 (2H, m) 8.18 to 8.40 (2H, m) 11.88 (IH, bs) Below, Examples 55 and 56 were carried out in the same manner as Example 54. carried out,
Table 4 shows the IR and NMR spectral data and melting point of the obtained compound.

Margin below (Example 57) Production process of 1-(benzo[C]chen-1-ylsulfonyl)hydantoin l Production of N2-(benzo[C]chen-1-ylsulfonyl)chrysinamide 5.5 g of benzo[c]thiophene anhydrous ether 50m
1.6Mn dissolved in
-Butyllithium-hexane solution 52.2ml/! :
dripped. After stirring for 1 hour, sulfur dioxide gas was blown into the mixture for 1 hour while stirring at the same temperature. The solvent was distilled off under reduced pressure, and the remaining liquid was cooled to an internal temperature of 0°C, followed by 200ml of isopropyl alcohol.
and 200 ml of water, 6.5 g of N-chlorosuccinimide was added thereto, and the mixture was stirred at 0° C. for 30 minutes.

1.63 g of N-chlorosuccinimide was added to the reaction solution, and the mixture was further stirred for 1 hour. Extraction was carried out twice with 11 portions of methylene chloride, and the extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent, methylene chloride, was distilled off under reduced pressure while cooling. Using the obtained residue and chrysinamide hydrochloride, the above title compound was obtained in the same manner as in Example 54, Step 3.

NMR spectrum (D M S Oda ; I) p
m) 3.40 (2H, d, J=6.9Hz) 7.0
6-8.22 (5H, m) 8.49 (IH, s) Step 2 N2-(benzo[c]chen-1-ylsulfonyl')
0.45 g of the compound obtained in Step 1 of producing -N1-methoxycarbonylglycinamide was dissolved in 5 ml of N,N-dimethylformamide, 75 mg of 60% sodium hydride was slowly added, and the mixture was stirred at room temperature for 30 minutes.

0.14 ml of methyl chloroformate was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. 75 mg of 60% sodium hydride was added, and the mixture was stirred at room temperature for 1.5 hours and then heated at 70°C for 15 minutes. After cooling the reaction solution, 20 ml of water was added to the residue, and the mixture was extracted three times with 20 ml of ethyl acetate. The extract was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the above title compound (0.1%).
8g was obtained.

NM, R spectrum (CDCl a ; pl) m
)3.74(3H,s) 4.24(2H,d,J=5.3Hz)5.92(I
H,tt J=5.3Hz)7.17~8.31 (6
H, m) Step 3 1-(benzo[c]chen-1-ylsulfonyl)hydantoin production 0.18 g of the compound obtained in step 2 was dissolved in 3 ml of N,N-dimethylformamide, and 48 mg of 60% sodium hydride was added. was added slowly and heated at 70°C for 2.5 hours. After distilling off the solvent, add 20ml of ice water to the residue to make 1M
The pH of the reaction solution was adjusted to 4 with hydrochloric acid. ethyl acetate 20ml
The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent ethyl acetate was distilled off under reduced pressure, and the residue was triturated in methylene chloride to obtain 0.03 g of the title compound.

Melting point: 223.6-226.9°C IR spectrum (KB r ; cm-') 1736.
1378.11B5, 1162°NMR spectrum (D
M S Oda ; p p m )4.51 (2
H,s) 7.20-8.16 (4H,m) 8.82(IH,5) 11.54(IH,bs) (Example 58) 1-(3-Carboxymethylbenzo[b]thiene- 2-
Production Example 32 of hydantoin (ylsulfonyl) 9 ml of 60% (w/v) nitric acid was added to 0.85 g of the compound obtained in step 4, heated at 70°C for 140 minutes, and then cooled.
The resulting precipitate was collected by filtration and washed with ether to obtain 0.21 g of the above title compound.

Melting point 224.4°C (decomposed) IR spectrum (KBr; cm-1) 3220.1800, 1736.1718°1374.
117O NMR spectrum (DMSO-da; ppm) 4.32
(2H, s) 4.47 (2H, s) 7.55 to 7.65 (2H, m) 7.99 to 8.19 (2H, m) 11.71 (IH, bs) (Example 59) 1-(3-methylsulfinylbenzo[b]thiene-2
-ylsulfonyl)hydantoin 0.65 g of the compound obtained in Example 55 was suspended in 26 ml of dichloromethane, 0.41 g of metachloroperbenzoic acid was added, and the mixture was stirred at room temperature for 1.5 hours.The reaction solution was vacuumed at room temperature. Concentrate below;
The residue was washed with 30 ml of ether. The title compound 0 was purified by silica gel column chromatography.
゜48 gtl-obtained.

Melting point: 215.0-221.0°C IR spectrum (KB r ; cm-') 1792.
1743.1379.118ONMR spectrum (D
M S Ode ; ppm ) 3.10 (3H, s
) 4.57 (2H, s) 7.51 = 8.89 (4H, m) 11.81 (IH, bs) (Example 60) 1-(3-methylsulfonylbenzo[b]thiene-2-
Production of hydantoin (ylsulfonyl) 0.65 g of the compound obtained in Example 55 was suspended in 26 ml of ethyl acetate,
After adding 0.82 g of metachloroperbenzoic acid and heating under reflux for 1.5 hours, 0.16 g of metachloroperbenzoic acid was added and the mixture was further heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure.
The residue was washed with methanol and ether to obtain 0.40 g of the above title compound.

Melting point 224.0-245.0°C JR spectrum (KBr; cm-') 1771.1372, 1324.1179 NMR spectrum (DMS Ode; l) pm)3.
47 (3H, s) 4.63 (2H, s) 7.66-8.59 (4H, m) 11.90 (IH, bs) (Example 61) 1-(3-cyanohenzo[b]chain-2 -ylsulfonyl)hydantoin 11.3 g of the compound obtained in Example 31 and cyanide -
After adding 42 ml of pyridine to 4.1 g of copper and stirring at 70°C for 17 hours, 15°7 g of ferric chloride dihydrochloride + 3.0 g of concentrated hydrochloric acid were added.
A mixture of 9 ml and 23.6 ml of water was added dropwise and heated at 50° C. for 5 minutes. The precipitate was separated by filtration and the filtrate was diluted with 300 ml of ethyl acetate.
Extracted with ml.

The extract was washed successively with water and saturated brine, then dried over anhydrous sodium sulfate, and the solvent ethyl acetate was distilled off under reduced pressure. The residue was combined with the residue obtained by extracting and concentrating the above-mentioned precipitate with ethanol, and was purified by silica gel column chromatography to obtain 1.21 g of the above-titled compound.

Melting point 238.9-242.5°C IR spectrum (KB r ; am-1) 2233.
180? , 1746, 17361388.1167 NMR spectrum (DMS Oda; ppm
) 4.51 (2H,s) 7.70-8.47 (4H,m) 11.83 (IH, bs) (Example 62) 1-(8-Hydroxybenzo[blthiec-2-ylsulfonyl)hydantoin To 2.5 g of the compound obtained in Production Example 56 was added 7 ml of acetic acid, 4
Add 8.9 ml of 7% hydrobromic acid and incubate at room temperature for 1 hour.
After heating at ℃ for 1 hour and 50℃ for 1 hour, add 7 ml of acetic acid, 47
Add 8.9 ml of % hydrobromic acid and incubate at 60°C for 1 hour at 80°C.
Heated at ℃ for 2 hours.

The reaction solution was poured into 300ml of water, extracted with 1.21ml of ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent ethyl acetate was distilled off under reduced pressure, and the residue was dissolved in acetone 800 ml.
After decolorizing using activated carbon, the acetone was distilled off, and the residue was dissolved in ethyl acetate.

After successive washing with ether, 1.13 g of the above title compound was obtained.

Melting point: 171.8℃ (decomposition) IR spectrum (KBr; am”) 3260.1800.1735, 135B.

1185.1164 NMR spectrum (DMS Od e sp p
m) 4.60 (2H, s) 7.46-8.19 (48, m) 11.70 (IH, bs) (Example 63) 1-(3-carbamoylbenzo[b]thien-2-yl Production of sulfonyl)hydantoin 0.84 g of the compound obtained in Example 61 was added to 16.3 ml of 80% (v/v) sulfuric acid.
The reaction mixture was stirred at 70°C for 8 hours and then poured into ice water at 200°C.
Pour into m1.

The precipitate was collected by filtration. The mixture was washed successively with water, ethanol, and acetone to obtain 0.16 g of the title compound.

Melting point 241.9-244.6°C IR spectrum (KBr; cm-') 3412.3197, 1795.1?41°1376.
1162 NMR spectrum (DMS Od a i ppm
) 4.51 (2H, s) 7.56-8.44 (6H, m) 11.73 (IH, bs) (Example 64) 1-(3-carboxybenzo[b]chen-2-ylsulfonyl) Production of hydantoin 0.60 g of the compound obtained in Example 63 was added to 18 m of concentrated sulfuric acid.
1 and cooled to -15°C with sodium nitrite 2.4
g was added. 15 minutes at -15°C.

After stirring at 0° C. for 30 minutes and at room temperature for 50 minutes, 1.2 g of sodium nitrite was added and stirred at room temperature for 30 minutes.

Add 0.1M sodium bicarbonate aqueous solution to adjust the pH to approximately 9.
After washing with ethyl acetate, add concentrated hydrochloric acid to adjust the pH to approximately 2.
The mixture was extracted with 200ml of ethyl acetate. Add the extract to water,
After sequential washing with saturated saline.

It was dried over anhydrous sodium sulfate, and the solvent ethyl acetate was distilled off under reduced pressure. The residual liquid was purified by silica gel column chromatography to obtain 0.18 g of the above title compound.

Melting point 228.8-235.1°C IR spectrum (KBr; cm-1) 3450.1739, 1735, 1380° NMRX vector (D M S Oda * ppm) 4.7
3(2H,s) 7.45-8.17 (4H,m) 11.76(IH,bs) (Example 65) Production of 1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin Step 1 Production of 3-chlorobenzo[bfuran--2-ylsulfonyl chloride 11.4 g of 3-chlorobenzo[b]furan was dissolved in 62 ml of anhydrous ether and cooled to -70°C.

62 ml of a hexane solution of 1.5 M lithium diisopropylamide monotetrahydrofuran was added dropwise under nitrogen atmosphere. After stirring for 30 minutes, sulfur dioxide gas was blown into the mixture for 1 hour while stirring at an internal temperature of -60°C.

After stirring at room temperature for 1 hour, the precipitate precipitated was collected by filtration to obtain lithium 3-chlorobenzo[bfuran-2-sulfinate. This was suspended in 250 ml of methylene chloride, and the internal temperature was -5.
At 0''C, 11.0 g of N-chlorosuccinimide was added and stirred at the same temperature for 3 hours and under water cooling for 2 hours. Purification by chromatography yielded the above title compound 8.
8g was obtained.

Melting point 60.6-68.2°C IR spectrum (KBr; cm-') 1538.1402,1232,1183°1151.
1010 39N spectrum (CDC13+i)l)m)7.40
~7.98 (4H, m) Step 2 Production of N-(3-chlorobenzo[bfuran-2-ylsulfonyl)glycine ethyl ester 3-chlorobenzo[bfuran-2-ylsulfonyl chloride 8.6 gt
To a suspension of 9.6 g of glycine ethyl ester hydrochloride and 83 ml of methylene chloride, 10.0 g of triethylamine was added under water cooling.
4 ml was added slowly and then stirred at room temperature for 30 minutes.

Add 150ml of water to the reaction solution, adjust the pH to 2 with 1M hydrochloric acid,
Extraction was performed with 300 ml of ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent ethyl acetate was distilled off under reduced pressure to obtain 10.2 g of the above title compound.

Melting point 104.5-110.8°C IR spectrum (KBr; am-1) 3203.1736, 1365, 1230° NMR spectrum (DMS Ode; ppm) 1.0
1 (3H, t, J=7.1Hz) 3.89 (2H,
q, J='1. IHz) 3.94 (2H, s) 7.50-7.73 (4H, m) 9.12 (IH* b s ) Step 3 N-(8-chlorobenzo[b]furan-2-ylsulfonyl) Production of glycine 10.2 g of N-(3-chlorobenzo[bfuran--2-ylsulfonyl)glycine ethyl ester was dissolved in 160 ml of tetrahydrofuran, and an aqueous solution of 449 g of sodium hydroxide dissolved in 16 ml of water was added under water cooling. dripped. The mixture was stirred for 1 hour under water cooling and for 30 minutes at room temperature. The solvent was distilled off under reduced pressure, 200 ml of water was added to the residue, and then hydrochloric acid was added under water cooling to adjust the pH to 1, and 500 ml of ethyl acetate was added.
Extracted with l. After washing the extract with saturated saline.

It was dried with anhydrous magnesium sulfate. The solvent ethyl acetate was distilled off under reduced pressure to obtain 9.2 g of the above title compound.

Melting point 163.8-167.9°C IR spectrum (KBr; cm-') 3236.1709, 1369, 1232° NMR spectrum 7L/(DMSO-d6; ppm) 3.84 (
2H, d, J=5.9Hz)7.38~7.81 (
4H, m ) 9.03 (IH, t, J = 5.9Hz) 12.67 (I
H, bs) Step 4 Preparation of l-(3-chlorobenzo[b furan--2-ylsulfonyl)-2-thiohydantoin N-(8-chlorobenzo[b furan--2-ylsulfonyl)glycine 9
．． To 2 g, 5.32 g of ammonium thiocyanate*18 ml of acetic anhydride was added, and 6.68 ml of pyridine was added dropwise under water cooling, followed by stirring at room temperature for 30 minutes and at 40° C. for 30 minutes.

After cooling the reaction solution heated at 70-80°C for 2 hours.

The mixture was poured into 300 ml of ice water to obtain a precipitate. This was thoroughly washed with a mixture of ethanol and water, and 6.73 g of the above title compound was obtained.
I got it.

Melting point 195.4-204.7°C IR spectrum (KBr; am-1) 3158.1758, 1393, 1234° NMR spectrum (DMS Od a * l) pm) 4
．． 83 (2H, s) 7.56-7.90 (4H, m) Step 5 Production of l-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin - 5.3 ml of iochloride "ig" was added to 160 ml of IM hydrochloric acid The mixed solution was cooled on ice, and 1-(3-chlorobenzo[bfuran-2-ylsulfonyl)-2-thiohydantoin 6
．． 7 g was added thereto, and 200 ml of methylene chloride was gradually added dropwise. 1.5 hours under water cooling.

After stirring at room temperature for 1.5 hours, a saturated aqueous solution of sodium sulfite was added to the reaction solution 9, and the mixture was poured into 600 ml of ethyl acetate. Add the extract to saturated aqueous sodium sulfite solution.

After sequentially washing with saturated saline, the anhydrous sulfuric acid magnesilano was dried. The solvent ethyl acetate was distilled off under reduced pressure.

The residue was thoroughly washed with ether and a mixed solution of ether and ethyl acetate to obtain 3.15 g of the title compound.

Melting point 246.6-256.8°C IR spectrum (KBr; am”) 3226.1744, 1397, 1363°1174.
1156 NMR spectrum (DMS Oda; ppm
) 4.51 (2H, s) 7.54-7.89 (4H, m) 11.81 (IH, bs) (Example 66) 1-(4-bromobenzo[bfuran--2-ylsulfonyl) Production of hydantoin 1 Culm 1 Production of dimethyl acetal (3-bromophenyloxy)acetaldehyde 60 g of 60% sodium hydride was suspended in 1.4 l of N,N-dimethylformamide, and 260 g of 3-bromophenol was added dropwise under water cooling. Stir for 10 minutes after completion of dropping,
318 g of bromoacetaldehyde dimethyl acetal was added dropwise and heated at 90"C for 3 hours. Water was added to the cooled reaction mixture, made weakly acidic with 1M hydrochloric acid, and extracted with ether 31. The extract was mixed with water and saturated sodium bicarbonate. Washed sequentially with an aqueous solution and saturated brine, and dried over anhydrous sodium sulfate.Ether was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound 363.
．． 3g was obtained.

IR spectrum (thin film; Cm-1) 2941.2835, 1615, 1506° NMR spectrum (CDCI3; ppm) 3.44 (6H, s) 3.96 (2H, d, J = 5.0Hz) 4.69 ( I
H, t, J=5.0Hz) 6.17-7.26. (4H
, m) Step 2 4-bromobenzo[bfuran- and 6-bromobenzo[
b. Preparation of furan mixture 413.5 ml of phosphoric acid was cooled on ice to obtain 344.5 ml of phosphorous pentaoxide.
Add 2g and further add 870ml of chlorobenzene,
It was heated to 125°C using an oil bath.

A solution prepared by dissolving 181.7 g of the compound obtained in Step 1 in 150 ml of chlorobenzene was added dropwise to this, and after the completion of 9 dropwise additions, the mixture was heated and stirred at the same temperature for 1 hour. The reaction solution was cooled, poured into ice water 21, and extracted with ether 21. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. ether under reduced pressure,
Chlorobenzene was distilled off, and the residue was purified by silica gel column chromatography to obtain 116 g of the above-titled mixture.
I got it.

Step 3 100 g of the mixture obtained in step 2 of producing 4-bromobenzo[bfuran-2-ylsulfonyl chloride was dissolved in 430 g of anhydrous ether.
ml, cooled to -70°C, and heated under nitrogen atmosphere.
430 ml of a cyclohexane solution of 5M lithium diisopropylamide monotetrahydrofuran was added dropwise. 30
After stirring for 1 minute, sulfur dioxide gas was blown in for 1 hour while stirring at an internal temperature of -60°C. After stirring at room temperature for 3 hours, the deposited precipitate was collected by filtration. and 6-bromobenzo[b]furan-2
- A mixture of lithium sulfinates was obtained.

This was suspended in 21 g of methylene chloride, and 96 g of N-chlorosuccinimide was added at an internal temperature of -50'C.

The mixture was stirred for 3 hours while cooling with water. The insoluble matter was filtered off, and the :a liquid was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 14.1 g of the above-mentioned title compound.

Melting point 87.2°C IR spectrum (KBr; am-”) 1603.1578.13B9, 1175° NMR spectrum (CD Cl 3 ; )) pm ) 7.43~
7.67 (4H, m) Step 4 Using 14.1 g of the compound obtained in the production step 3 of N-(4-bromobenzo[b]furan-2-1lsulfonyl)glycine ethyl ester] Example 65 Step 16.8 g of the above title compound 41 was obtained by the same method as in 2.

Melting point 115.6-117.3°C IR spectrum (KBr; am”) 3199.1361, 1221, 1158 NMR spectrum (CDCl2; I) I) m) 1.18 (3H, t
, J=7.1Hz ) 3.97 (2H, d, J=5.
3Hz) 4.09 (2H, Qt J=7.1Hz)
5.45 (IH, t, J=5.3Hz) 7.26-7.
58 (4H, m) Step 5 N-(4-bromobenzo[b]furan-2-ylsulfonyl)glycine Production Example 65 using 16.8 g of the compound obtained in Step 4
14.4 g of the above title compound was obtained by the same method as in Step 3.
I got it.

Melting point 180.0-182.1°C IR spectrum (KB r ; cm”) 3253.1
738, 1361, 1262° NMR spectrum (DM
SO-da; ppm) 3.81 (2H, s) 7.38-7.81 (4H, m) 8.85 (IH, bs) Step 6 l-(4-bromobenzo[b]furan-2-yl 14.4 g of the compound obtained in step 5 of producing sulfonyl)-2-thiohydantoin was added to 7.2 g of ammonium thiocyanate.
The suspension was suspended in 28 ml of acetic anhydride together with g, and 9.1 ml of pyridine was added dropwise while cooling with water, followed by heating at 60 to 70°C for 2 hours. After cooling, the 9 reaction solutions were poured into 500 ml of ice water to obtain a precipitate.

This was washed with a small amount of ethanol, and the above title compound 10 was obtained.
．． 7gt-obtained.

Melting point 253.3°C ■R spectrum (KBr; am-1) 3140.1756, 1391, 1248° NMRX vector (DMSOda; ppm) 4.77 (2H, s) 7.45 = 7.88 (3H, m) 7.95 (IH, 5) 12.86 (IH, bs ) Step 7 10.7 g of the compound obtained in production step 6 of l-(4-bromobenzo[bfuran-2-ylsulfonyl)hydantoin] Example 65 using
4.8 g of the above title compound was obtained in the same manner as in Step 5.

Melting point 291.7-293.5°C IR spectrum (KBr; am-') 3240.1741, 1390, 1355°NMRX”
7) Li (D M S Ode ; 'Q pm
) 4.48 (2H, s) 7.45-7.90 (4H, m ) 11.78 (IH, bs) (Example 67) 1-(7-fluorobenzo[b]furan-2-ylsulfonyl ) Production process of hydantoin 1 Production of 7-fluorobenzo[b]furan-2-ylsulfonyl chloride Using 10.4 g of 7-fluorobenzo[bfuran, Example 65 By the same method as Step 1, the above 5.7 g of the title compound was obtained.

Melting point 114°C IR spectrum (KBr; cm-1) 1596.1546, 1372, 1267° NMR spectrum (CD CI 3 : pI) m) 7.24
~7.69 (4H, m) Step 2 Example 65 Step 2 using 5.7 g of the compound obtained in Production Step 1 of N-(7-fluorobenzo[b-cotlan-2-ylsulfonyl)glycine ethyl ester 6.45 g of the above title compound was obtained in the same manner as above.

Melting point 84.5°C IR spectrum (KBr; cm-1) 3238.1734, 1376.1232° NMR spectrum (DMSO-da; ppm) 1.03 (3H,
t, J=T, IHz) 3.89 (2H, d, J=6.
3Hz) 3.92 (2H, q, J=T, IHz)7.
32-7.66 (4H, m) 9.05 (IH, t, J = 6.8Hz) Step 3 Obtained in production step 2 of N-(7-fluorobenzo[b]furan-2-ylsulfonyl)glycine Example 65 using 6.4 g of the compound obtained
In the same manner as in Step 3, 5.42 g of the above title compound was obtained.

Melting point 140.1℃ (decomposition) IR spectrum (KBr; cm") 3303.1734, 1349.1262゜16O NMR spectrum (D M S Oda ; pl)
m)3.80 (2H, d, J=5.0Hz)7
．． 28-7.66 (4H, m) 8.90 (IH, t, J = 5.0Hz) Step 4 Production of N-(7-fluorobenzo[b]furan-2-ylsulfonyl)-2-thiohydantoin 5.4 g of the compound obtained in step 3 and 3.32 g of ammonium thiocyanate
g was suspended in 12.7 ml of acetic anhydride, and 4.16 ml of pyridine was slowly added dropwise under nitrogen atmosphere and cooling with water. 70
Raise the temperature to ℃.

Heated for 2 hours. The reaction solution was cooled, poured into 200 ml of ice water, and a small amount of ethanol was added to obtain a precipitate. This was dissolved in 200ml of ethyl acetate.

It was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was washed with ethanol to obtain 2.83 g of the above title compound.

Melting point 229.9-232.0°C IR spectrum (KBr; cm-') 325B, 1765, 1744, 1448° NMR spectrum (DMS Ode; pprn)4.
73 (2H, s) 7.39~7.7”I (3H, m) 8.13 (IH, d, J=2.6Hz) 12.83 (I
H, bs) Step 5 Example 65 using 2.8 g of the compound obtained in production step 4 of l-(7-fluorobenzo[bfuran-2-ylsulfonyl)hydantoin
In the same manner as in Step 5, 1.1 g of the above title compound was obtained.

Melting point: 300°C or higher IR spectrum (KBr:Cm-') 3381.1735.1610, 1383° NMR spectrum (D M S Od a i p p m ) 3
．． 98 (2H, s) 7.34-7.71 (3H, m) 7.78 (IH, d, J yo 3.0Hz) (Example 68
) Production process of 1-(4,5-dichlorobenzo[b]furan-2-ylsulfonyl)hydantoin 1 Production of (3,4-dichlorophenyloxy)acetaldehyde dimethyl acetal 3. Example using 200 g of 4-dichlorophenol 6
6 The above title compound 218.
8g was obtained.

IR spectrum (thin film; cm-1) 2940.2830,1595,1475°1297.
1235 NMR spectrum (CD Cl 3+ pI m )
3.45 (6H, s) 3.96 (2H, d, J=5.3Hz) 4.89 (I
H, t, J = 5.3 Hz) 6.78 (IH, dd.

J = 8.9, 3.0Hz ) 7.02 (IH, d, J = 3.0Hz ) 7.31 (I
H, d, J = 8.9 Hz) Step 2 4.5-dichlorobenzo[b]furan- and 5゜6-dichlorobenzo[b]furan - Performed using 218.8 g of the compound obtained in mixture production step 1 Example 66 The above titled mixture 102. Igt-obtained.

Step 3 4.5-dichlorobenzo[b]furan-2-ylsulfonyl chloride and 5.6-dichlorobenzo[bfuran-
-2-ylsulfonyl chloride production process 2 100g of the mixture obtained in anhydrous ether/lz4
Dissolve in 40 ml, cool to -70°C, and incubate for 1 hour under nitrogen atmosphere.
．． 440 ml of a cyclohexane solution of 5M lithium diisopropylamide monotetrahydrofuran was added dropwise over 1 hour. After the completion of the dropwise addition, sulfur dioxide gas was blown in at the same temperature for 1.5 hours. After stirring at room temperature for 1 hour, ether was distilled off from the reaction solution. Ether was added to the residual liquid, the precipitate was collected by filtration, and 4
．． Lithium 5-dichlorobenzo[b]furan-2-sulfinate and 5,6-dichlorobenzo[bfuran--2-
A mixture of lithium sulfinates was obtained. This was suspended in 1.81 g of methylene chloride, and 92.1 g of N-chlorosuccinimide was added at an internal temperature of -50°C, followed by stirring at the same temperature for 1.5 hours. Insoluble matter was filtered off at room temperature, and the filtrate was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography to give 17.4 g of 4.5-dichlorobenzo[b]furan-2-ylsulfonyl chloride and 7.4 g of 5.6-dichlorobenzo[b]furan-2-ylsulfonyl chloride.
g was obtained.

4.5-Dichlorobenzo[bfuran-2-ylsulfonyl chloride Melting point 114.6°C IR spectrum (KB r ; cm-1) 1529.
1444, 1401, 1191 NMR spectrum (DM
SO-do; ppm) 6.87 (IH, d, J=1.
0Hz)7.55 (IH, d, J=8.9Hz)7.
69 (IH, dd.

J=8.9, 1.0Hz) 5.6-dichlorobenzo[b]furan-2-ylsulfonyl chloride Melting point 159.8°C IR spectrum (KBr; cm'''1) 1537.13
90,1163,101081N spectrum CD M
S Oda; 1) l) m) 6.87 (IH,
d, J = 1.0) lz) 7.92 (IH, s) 8.02 (IH, d, J = 1.0 Hz) Step 4 N-(4,5-dichlorobenzo[b]furan-2- Example 6 Using 17 g of 4,5-dichlorobenzo[b]furan-2-ylsulfonyl chloride obtained in Step 3 of producing glycine ethyl ester
5 The above title compound 18.2 was prepared in the same manner as in Step 2.
I got g.

Melting point 155.2-155.5℃ IR spectrum (KBr; cm") 3199.1?37,1225.116ONMR spectrum (DMSOda; pI)"m) 1.05 (3H, t
, J='1. IHz) 3.92 (2H, s) 3.95 (2H, q, J = 7.1Hz) 7.56 (IH
,s) 7.78(2H,s) 9.09(IH,bs) Step 5 Compound obtained in N-(4,5-dichlorobenzo[b]furan-2-ylsulfonyl)glycine production step 4 Using 18 g, 16.2 g of the above title compound was obtained in the same manner as in Example 65 Step 3.

Melting point 189.8-194.7°C IR spectrum (KBr; cm”) 3320.1719, 1366.1256° NMR spectrum (DMS Oda; ppm) 3.8
3 (2H, d, J = 6.3Hz) 7.56 (IH, s
) 7.76 (2H,s) 8.97 (IH,t, J=e, 3Hz) Step 6 l-(4,5-dichlorobenzo[b]furan-2-ylsulfonyl)-2-thiohydantoin Using 16 g of the compound obtained in Production Step 5, 7.4 g of the above title compound was obtained in the same manner as in Example 65 Step 4.

Melting point 214.6-217.5℃! R spectrum (KBr; cm-') 1793, 1762. 1445. 1167NMR
Spectrum (D M S Oda ; ppm) 4.
77(2H,s) 7.85(2H,s) 8.11(IH,5) 12.95(IH,bs) Step 7 l-(4,5-dichlorobenzo[b]furan-2-ylsulfonyl ) Production of hydantoin - iodine chloride 6.3m
A solution of 150 ml of 1M hydrochloric acid was cooled on ice, 7.3 g of the compound obtained in step 6 was added, and 15 ml of methylene chloride was added.
0ml was added dropwise over 10 minutes. After stirring for 2.5 hours at room temperature9
The reaction solution was ice-cooled, a saturated aqueous sodium sulfite solution was added, and after stirring for a while, the precipitate that had precipitated was collected by filtration.

Further washing was performed with water, followed by washing with ethanol and ether to obtain 4.8 g of the above-mentioned title compound.

Melting point 290.7-292.0°C (decomposed) IR spectrum (KB r ; cm-1) 3256.1742,1
391,1356°NMR spectrum (DMSO
d a i pI) m ) 4.47 (2H, s) 7.85 (2H, s) 7.98 (IH, 5) 11.80 (IH, bs) (Example 69) 1-(5,6 Production process of -dichlorobenzo[b]furan-2-ylsulfonyl)hydantoin Production Example 68 of I N-(5,6-dichlorobenzo[b]furan-2-ylsulfonyl)glycine ethyl ester Obtained in step 3 7.4 g of 5,6-dichlorobenzo[b]furan-2-ylsulfonyl chloride was dissolved in 60 ml of methylene chloride.

Suspend 7.95 g of glycine ethyl ester hydrochloride,
Triethylamine 7.89ml under nitrogen atmosphere and water cooling
was added little by little. After stirring for 20 minutes, the reaction solution was diluted with 10% water.
The mixture was poured into a 0ml volume, acidified with 1M hydrochloric acid, extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was washed with hexane.

8.7 g of the above title compound was obtained.

Melting point 132.7-133.5°C IR spectrum (KBr; cm-1) 322
7.1735, 1360, 1225°NMR spectrum (DMS Oda; ppm) 1.06 (3
H, t, J=6.9Hz ) 3.90 (2H, s) 3.95 (2H, q, J=6.9Hz ) 7.52 (
IH,s) 8.08(IH,s) 8.20(IH,s) 9.05(IH,bs) Step 2 N-(5,6-dichlorobenzo[b]furan-2-ylsulfonyl)glycine Example 65 using 8.6 g of the compound obtained in Production Step 1 of
In the same manner as in Step 3, 7.8 g of the above title compound was obtained.

Melting point 192.6-201.8°C IR spectrum (KBr; am-') 3367.1719, 1359, 1248° NMR spectrum (DMS Ode; pI) m)3
．． 80 (2H, d, J=5.9Hz)7.51 (
IH, d, J = 1.0Hz) 8, '08 (IH, s) 8.19 (IH, d, J = 1.0Hz) 8.92 (IH
, t, J = 5.9 Hz) Step 3 Using 7.7 g of the compound obtained in production step 2 of l-(5,6-dichlorobenzo[bfuran--2-ylsulfonyl)-2-thiohydantoin] Example 65
3.7 gfe of the above title compound was obtained in the same manner as in step 4.
:Obtained.

Melting point 246℃ (decomposition)! R spectrum (KBr; cm”) 3100.1743, 1449, 1246° NMR spectrum (D M S Oda ; 1) I) m )
4.73 (2H, s) 8.02 (IH, d, J=1.0Hz) 8.20 (IH
, s) 8.26 (IH, d, J = 1.0Hz) 12.82 (I
H, bs) Step 4 The same method as in Example 65 Step 5 using 3.7 g of the compound obtained in Step 3 of producing l-(5,6-dichlorobenzo[b]furan-2-ylsulfonyl)hydantoin. 2.7 g of the above title compound was obtained.

Melting point: 300°C or higher (decomposed) IR spectrum (KBr; am-1) 1732.1389, 1188, 1167 NMR spectrum (DMS Oda; ppm) 4.31
(2H, s ) 7.82 (IH, d, J = 0.7Hz) 8.16 (IH
,s) 8.27 (IH, d, J=0.7Hz) (Example 7
0) 1-(3-bromo-7-fluorobenzo[bfuran--
Production process of 2-ylsulfonyl)hydantoin 1 Production of 2.3-dibromo-2,3-dihydro-7-fluorobenzo[bfuran]
A solution of 22 g of bromine in 40 ml of carbon disulfide was added dropwise thereto at an internal temperature of -30°C.

After stirring at the same temperature for 1 hour, the reaction solution was brought to room temperature, and the precipitate that had precipitated was collected by filtration to obtain 34.4 g of the above-mentioned title compound.

IR spectrum (KBr; cm-”) 1834.1801.1489.1459°1279,
1179 NMR spectrum (CD Cl 3 s pI) m
) 5.74 (IH, d, J = 1.3Hz) 8.93 (I
H,s) 7.11-7.35 (3H,m) Step 2 3-Bromo-7-fluorobenzo[b]furan - Production Dissolve 12.7 g of potassium hydroxide in 180 ml of ethanol, and process under water cooling in Step 1. 34 g of the compound obtained in step 1 was gradually added. After stirring for 3 hours, one reaction solution was neutralized with acetic acid, water was added, and the mixture was extracted with ether.

The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Ether was distilled off under reduced pressure to obtain 24.1 g of the above title compound.

IR spectrum (neat; cm-”) 3150.16
36,1595,1494°1434.1322 NMR spectrum (CD Cl 3 : p l) m
) 6.98 to 7.36 (3H, m) 7.68 (IH, s) Step 3 Compound obtained in production step 2 of 3-bromo-7-fluorobenzo[b]furan-2-ylsulfonyl chloride Example 65 using 24.1 g
12.2 g of the above title compound was obtained by the same method as in Step 1.
I got it.

IR spectrum (KBr; cm-1) 1602.1533, 1385, 1168 NMR spectrum (DMSOda; p'pm)7.
33-7.39 (3H, m) Step 4 N-(3-bromo-7-fluorobenzo[bfuran--
Using 12.2 g of the compound obtained in Step 3 of producing 2-ylsulfonyl)glycine ethyl ester.

Example 65 10.2 g of the above title compound was obtained in the same manner as in Step 2.

Melting point: 126.2-126.4°C IR spectrum (KB r : Cm-1) 3200.
1731,1366.1237°NMR spectrum (D
MS Ods: ppm) 1.01 (3H
,t, J=7.1Hz )3.89 (2H,q,J=
7. 1Hz ) 3.96 (2H, d, J = 5.6Hz
) 7.47 to 7.66 (3H, m) 9.32 (IH, t, J = 5.6Hz) Step 5 N-(3-bromo-7-fluorobenzo[b]furan-
Production of 2-ylsulfonyl)glycine Using 10.2 g of the compound obtained in Step 4, 7.25 g of the title compound was obtained in the same manner as in Step 3 of Example 65.

Melting point 148.5-159.6°C IR spectrum (KBr; cm”) 3223.1716, 1373.1246° NMR spectrum (D M S Od 6; pI) m) 3.8
6(2H,s) 7.46-7.58 (3H,m) 9.18(IH,bs) Step 6 l-(3-bromo-7-fluorobenzo[bfuran--
Example 65 using 7.2 g of the compound obtained in manufacturing step 5 of 2-ylsulfonyl)-2-thiohydantoin
5.07 g of the above title compound was obtained in the same manner as in Step 4.

Melting point 224.3-224.7°C (decomposed) IR spectrum (KB r ; cm-1) 3290.1793
, 1765, 1235° NMR spectrum (DMS
Oda: ppm ) 4.83 (2H, s) 7.57-7.72 (3H, m) 12.93 (IH, bs) Step 7 l-(3-bromo-7-fluorobenzo[b]furan −
Production of 2-ylsulfonyl)hydantoin A solution of 3.3 ml of iodine monochloride mixed in 110 ml of IM hydrochloric acid was cooled with ice, and 5 g of the compound obtained in step 6 was added.
140 ml of methylene chloride was added dropwise. After stirring at room temperature for 6 hours, 1.7 ml of -iodine chloride was added, and the mixture was further stirred for 1 hour. Add saturated aqueous sodium sulfite solution to the reaction solution,
The deposited precipitate was collected by filtration. Wash the filtrate with saturated saline,
It was dried with anhydrous magnesium sulfate. Precipitate with IM hydrochloric acid 1
00ml, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate.

The solvent was distilled off from both sleeves under reduced pressure, and the residue was washed successively with ethanol and ether to obtain 1.66 g of the title compound.

Melting point 266.6-270.6°C IR spectrum (KBr; cm-”) 3160.1725, 1393.1184° NMR spectrum (DMSOdapppm) 4.50 (2H, s
) 7.53~7.7'l (3H9m) 11.85(
IH, bs) Examples 71 to 76 were carried out in the same manner as Example 65, and the IR and NMR spectrum data and melting points of the obtained compounds are shown in Table 5.

The IR and NMR spectrum data and melting points of the intermediate compounds of Example 3 to 41.43 to 48.55 to 56 and 71 to 76 are shown in Tables 6 to 10 below.

Table Q-3-C with blank space below NMR spectrum data marked with * were measured in CDCl3.

NMR spectrum data marked with *81I in LtCDC13.

NMR spectral data marked * were measured in CDCl3.

NMR spectral data marked with * were measured in CDC11.

NMR spectral data marked * were measured in CDCl3.

NMR spectral data marked * were measured in CDCl3.

NMR spectral data marked * were measured in CDCl3.

*The NMR spectral data presented were measured in CDCh.

Table 1 Q-3O,NHCH2C00Et First entrance Q-5O2NHCH2CO2H first day table Q-SO2N'HCH2CON'H.

Examples of preparations containing the compounds of the present invention are shown below.9
The present invention is not limited to the following examples.

Example A Capsule Compound of Example 1 300g Lactose 685g Magnesium stearate 15g The above components are weighed and mixed uniformly. 200 mg each of the mixed powder is filled into No. 1 hard capsules to prepare capsules.

Example B Capsule Compound of Example 35 250g Lactose 730g Magnesium stearate 20g The above components are weighed and mixed uniformly. 200 mg of the mixed powder is filled into No. 1 hard capsules to prepare capsules.

Example C tablet Compound of Example 37 300g Lactose 550g Potato starch 120g Polyvinyl alcohol 15g Magnesium stearate 15g After weighing the above ingredients, the compound of Example 37.

Mix lactose and potato starch evenly. An aqueous solution of polyvinyl alcohol is added to this mixture, and granules are prepared by wet granulation. The granules were dried, mixed with magnesium stearate, and compressed into tablets weighing 200 mg.
tablets.

Example D Powder Compound of Example 75 200g Lactose 790g Magnesium stearate 10g The above components were each weighed and mixed uniformly to give 20g of the compound of Example 75.
% powder.

Example E Suppository Compound of Example 68 100 g Polyethylene glycol 1500 180 g Polyethylene glycol 4000 720 g The compound of Example 68 was thoroughly ground in a mortar to form a fine powder, and then 1
Use it as a rectal suppository.

[Effects of the Invention] The substance of the present invention has a strong ability to inhibit AR activity, and at the same time exhibits cataract-preventing action, neuropathy-preventing action, and blood sugar-lowering action in experimental animal models.

It is expected to have therapeutic and preventive effects on various complications of diabetes.

In addition, the substance of the present invention is a novel substance that has not been previously reported, and has a stronger ability to inhibit AR activity than the sulfonylhydantoin derivatives reported in the past.
It shows the ability to inhibit the AR activity of bovine lens, and therefore, when applied to medicine as a therapeutic agent for various complications of diabetes,
It is expected to have a more powerful therapeutic effect than conventional substances, and it will also be possible to treat diseases that are currently difficult to treat.

Completely new effects are also expected.

In addition, the substance of the present invention has a stronger ability to inhibit AR activity than conventional sulfonylhydantoin derivatives.

A smaller amount of the substance is required to expect the same level of effect, there is less risk of side effects, and it can be used more economically.

Patent applicant: Mochida Pharmaceutical Co., Ltd.

Claims (14)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, Q is a straight or branched alkyl group having 1 to 8 carbon atoms, or a straight or branched alkyl group having 3 to 8 carbon atoms. Up to 6 cyclic alkyl groups, biphenylyl groups, or halogen atoms, lower alkyl groups, nitro groups, cyano groups, optionally protected carboxyl groups, optionally protected carboxymethyl groups, halogenated lower alkyl groups, lower Alkylthio group, lower alkylcarbonyl group, lower alkoxy group, lower alkylsulfinyl group, lower alkylsulfonyl group,
A monocyclic heterocyclic group or a fused heterocyclic group that may be substituted with one or more of the same or different groups selected from the group consisting of an optionally protected hydroxyl group, an optionally protected amino group, a carbamoyl group, or a phenyl group. hydantoin derivatives represented by (representing a ring group), salts and solvates thereof, and solvates of salts. (2) The fused heterocyclic group may be substituted with benzo [b
] The compound according to claim 1, which is a thien-2-yl group, a salt, a solvate thereof, and a solvate of a salt. (3) The compound, salt, solvate, and solvate of a salt thereof according to claim 1, wherein the fused heterocyclic group is a benzo[b]furan-2-yl group which may be substituted with a substituent. (4) The compound, salt, solvate, and solvate of a salt thereof according to claim 3, wherein the substituent is 1 to 3 halogen atoms. (5) General formula (II) Q-SO_2NHCH_2CONH_2(II) (in the formula,
Q is a linear or branched alkyl group having 1 to 8 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, a biphenylyl group, or a halogen atom, a lower alkyl group, a nitro group, a cyano group, or a protected optionally protected carboxyl group, optionally protected carboxymethyl group, halogenated lower alkyl group, lower alkylthio group, lower alkylcarbonyl group, lower alkoxy group, lower alkylsulfinyl group, lower alkylsulfonyl group, unprotected a hydroxyl group that may be protected, an amino group that may be protected,
A sulfonylglycine derivative represented by a monocyclic heterocyclic group or a fused heterocyclic group optionally substituted with one or more of the same or different groups selected from the group consisting of a carbamoyl group or a phenyl group is used as a halogenated formate ester. General formula (I) consisting of a step of cyclization in the presence of
▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) A method for producing a hydantoin derivative represented by (in the formula, Q has the same meaning as above), its salt, solvate, and solvate of the salt. (6) General formula (III) Q-SO_1NHCH_2CO-R^1(III) (wherein, Q is a linear or branched alkyl group having 1 to 8 carbon atoms, cyclic alkyl group,
biphenylyl group, or halogen atom, lower alkyl group, nitro group, cyano group, optionally protected carboxyl group, optionally protected carboxymethyl group,
Halogenated lower alkyl group, lower alkylthio group, lower alkylcarbonyl group, lower alkoxy group, lower alkylsulfinyl group, lower alkylsulfonyl group, optionally protected hydroxyl group, optionally protected amino group, carbamoyl group or phenyl represents a monocyclic heterocyclic group or a fused heterocyclic group which may be substituted with one or more of the same or different groups selected from the group consisting of R^
1 represents a hydroxyl group or an alkoxy group) and a thiocyanate, the general formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (wherein, Q is as above). The general formula (I) consists of a step of forming a thiohydantoin derivative represented by (having the same meaning) and a step of oxidizing or hydrolyzing the derivative. , Q has the same meaning as above), a salt thereof, a solvate thereof, and a method for producing a solvate of the salt. (7) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, Q is a straight or branched alkyl group having 1 to 8 carbon atoms, or a straight or branched alkyl group having 3 to 8 carbon atoms. Up to 6 cyclic alkyl groups, biphenylyl groups, or halogen atoms, lower alkyl groups, nitro groups, cyano groups, optionally protected carboxyl groups, optionally protected carboxymethyl groups, halogenated lower alkyl groups, lower Alkylthio group, lower alkylcarbonyl group, lower alkoxy group, lower alkylsulfinyl group, lower alkylsulfonyl group,
A monocyclic heterocyclic group or a fused heterocyclic group that may be substituted with one or more of the same or different groups selected from the group consisting of an optionally protected hydroxyl group, an optionally protected amino group, a carbamoyl group, or a phenyl group. A pharmaceutical composition containing as an active ingredient at least one of a hydantoin derivative represented by (representing a ring group), a salt, a solvate thereof, or a solvate of a salt thereof. (8) The fused heterocyclic group may be substituted with benzo [b
] The pharmaceutical composition according to claim 7, which is a thien-2-yl group. (9) The pharmaceutical composition according to claim 7, wherein the fused heterocyclic group is a benzo[b]furan-2-yl group which may be substituted with a substituent. (10) The pharmaceutical composition according to claim 9, wherein the substituent is 1 to 3 halogen atoms. (11) General formula (V) Ω-SO_1NHCH_2CO-R(V) (wherein, Q is a straight or branched alkyl group having 1 to 8 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms) group, biphenylyl group, halogen atom, lower alkyl group, nitro group, cyano group, optionally protected carboxyl group, optionally protected carboxymethyl group, halogenated lower alkyl group, lower alkylthio group, lower alkyl group carbonyl group, lower alkoxy group, lower alkylsulfinyl group, lower alkylsulfonyl group,
A monocyclic heterocyclic group or a fused heterocyclic group that may be substituted with one or more of the same or different groups selected from the group consisting of an optionally protected hydroxyl group, an optionally protected amino group, a carbamoyl group, or a phenyl group. A sulfonylglycine derivative which is an intermediate compound in the synthesis of a hydantoin derivative represented by a ring group (R represents an amino group optionally substituted with a hydroxyl group, an alkoxy group or an alkoxycarbonyl group). (12) The fused heterocyclic group may be substituted with benzo[
b] The sulfonylglycine derivative according to claim 11, which is a thien-2-yl group. (13) The fused heterocyclic group may be substituted with benzo[
b] The sulfonylglycine derivative according to claim 11, which is a furan-2-yl group. (14) The sulfonylglycine derivative according to claim 13, wherein the substituent is 1 to 3 halogen atoms.