JPS5944353A

JPS5944353A - Benzenesulfonic acid ester derivative and its preparation

Info

Publication number: JPS5944353A
Application number: JP15567582A
Authority: JP
Inventors: Setsuo Fujii; 藤井　節郎; Kazuo Ogawa; 和男小川; Toshiusu Hamakawa; 浜川　寿薄; Yoshiyuki Muranaka; 村中　義幸
Original assignee: Taiho Pharmaceutical Co Ltd
Current assignee: Taiho Pharmaceutical Co Ltd
Priority date: 1982-09-06
Filing date: 1982-09-06
Publication date: 1984-03-12
Also published as: JPH0113706B2

Abstract

NEW MATERIAL:The compound of formula I (R1 is lower alkyl or lower alkoxy; l is 0 or 1-3; R2 and R3 are lower alkyl). EXAMPLE:1-( p-Methylbenzenesulfonyloxy )-2-( trans-1, 4-diethylcyclohexyl )-2-ethanone. USE:An immunoregulator and antilipemia. It has esterase-inhibiting and antilipemic activities. PROCESS:The compound of formula I can be prepared by reacting the compound of formula II with the compound of formula III (m is 0, 1 or 2) in a solvent such as THF at 10-60 deg.C.

Description

【発明の詳細な説明】水ざを明は新規なｌ＼ンＬンスルｉｊ〜ン酸Ｉ−スプル
誘導体及び・（の製造方法に関づ−る。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel I-spur derivatives and methods for producing them.

本発明のペンげンスルホン酸土スプル誘導体は、文献未
記載の新規な化合物であり、下記一般式％式％〔式中）く１は低級アルキル基又は低級アル−ｊキシ基
、１は０又は１〜３３の整数並びに１＜２及びＲ３はイ
れぞれ低級アルキル基を示り。〕上記一般式（ＩＩ　）
中１’（＋　、Ｒ２及びＲ３′ｃ示される低級））ルキ
ル基どしては、炭素数１〜６の直鎖状もしくは分校状の
アルキル基、例えばスプル、エチル、プロピル、イソプ
ロピル、エチル、ペンデル、ヘキシル阜等を、１＜１（
・表わされる低級ｊ７ルニ］キシ阜どしＣは、炭素数１
−４のり７ルニー】−Ｖシ基、例え（、Ｌメトキシ、土
［−二１シ、）１１ビルΔ１シ、イソプロピルＡキシ、
ノ１−ルＡ−１シ基等を人々例示づることかぐきる。、
　Ｊ：　／こ一１記１＜＋ｃ表わされる装置８基は、ベ
ンゼン環上の１］后、の位置に存在し１５ノるもの（゛
・あり、１個である必戟は４＋　＜、２・〜・３３個存
在しくいＣもよい。The pengensulfonic acid earth sprue derivative of the present invention is a novel compound that has not been described in any literature, and has the following general formula % [wherein 1 is a lower alkyl group or a lower alkoxy group, 1 is 0 or An integer of 1 to 33, 1<2 and R3 each represent a lower alkyl group. ]The above general formula (II)
The alkyl group (lower indicated by +, R2 and R3'c) is a linear or branched alkyl group having 1 to 6 carbon atoms, such as sprue, ethyl, propyl, isopropyl, ethyl, Pendel, hexyl, etc., 1 < 1 (
・Represented lower j7 luni] kishifudoshi C has 1 carbon number
-4 glue 7 luny] -V cy group, e.g.
People can exemplify ``Nol'', ``A-'', and the like. ,
J: /Koichi 1 1<+c The 8 devices represented exist at the position after 1 on the benzene ring, and there are 15 (゛), and there must be one device at 4+ <, 2・～・33 pieces C is also good.

また本発明化合物は、一般式［，１，）ぐ表わされる構
造式Ｊ、り明らかなＪ、・うに、シクロへキリン環に基
づく幾何異性体をし包含する６のＧ、ある。Further, the compound of the present invention has a structural formula J represented by the general formula [,1,), a clear J, and a G of 6, which includes geometric isomers based on the cyclohexyl ring.

本発明の」−８記一般式（］）（表４）８れる化合物は
、例えば１・記に示８れるよ゛う／、τ／’Ｊ　’ｄ、
により製造りることが（゛さる。即ち一般式〔式中（く２及び１（３はぞれぞれ低級ノフル：（ル埜
を示づ５．〕で表わされる化合物と、一般式（式中［く１は低級アルキル基又は低級ノフル」キシ基
、１はＯ又（よ１〜３の整数及び０１はＯ１゛１又は２
を小づ。）で表わされる化合物とを反応させることにより製造゛す
ることがＣぎる。Compounds represented by the general formula (]) (Table 4) of the present invention include /, τ/'J 'd,
In other words, a compound represented by the general formula [wherein 2 and 1 (3 each represents a lower nofur] and a compound represented by the general formula 1 is a lower alkyl group or a lower nofuloxy group, 1 is an integer from 1 to 3, and 01 is O1, 1 or 2
Small. ) can be produced by reacting with a compound represented by:

上記す法にａ５りる反応は、通富帛媒中（−行なわれる
。溶媒としては、反応に関与しないしのである限り特に
限定されイ＝いが、一般にジメブール上−デル、ジエヂ
ル工−デル、テトラヒト１」フラン、ジーキリン等のエ
ーテル類、ン７Ｌ！１・ニトリルロロホルム、ジクロロ
メタン等の非ブＵＪ　ｌ〜ン性溶媒、６油ニーデル、リ
グロイン等が好適に用いられる。化合物（１１〕と化合
物（Ｉ［Ｉ）との使用割合は、適宜選択りればよいが、
　＃に（よ化合物（　ＩＩ　）に対しＣ化合物（■１）
を等モル以ー１ーｌＩｔ！用りるのが右利Ｃ゛゛ある。The reaction a5 in the above method is carried out in a tungsten solvent (-).The solvent is not particularly limited as long as it does not participate in the reaction, but it is generally a dimebool-based solvent, a diezyl-based solvent, etc. Ethers such as , tetrahydrofuran, diquiline, non-butylene solvents such as nitrile loloform, dichloromethane, 6-oil needle, ligroin, etc. are preferably used.Compound (11) and compound The ratio of use with (I[I) can be selected appropriately, but
# (compound (II) vs. compound C (■1)
Equal moles of it! There is a right hand C゛゛ that is used.

また反応は一般に約　１０・〜６　０　’Ｃ：、好まし
くは約Ｏ℃〜・γ濡稈度に＋Ｉｊい（イｊ刊に進ｔＪり
る１。The reaction is generally carried out at a temperature of about 10°C to 60°C, preferably at about 0°C to γ culm wetness.

！−記（こｄ３い（１京第３１どじ（用いられる化合物
（］ｌ）は、通常上記のようにしＣ製造される。即らシ
ス−１−シンス混含物Ｃ゛ある化合物（ＩＶＩＩこ、塩
化ＪＡニル（３０２ＣＩ　＞を作用さｌｉＣシス−トラ
ンス混合物−（パある化合物１）をＯｆ、これにジノ′
ツメタン（Ｃｔ１２Ｎ２）を作用させ（シス−１−ノン
ス混含物Ｃ゛ある化合物（　Ｖ＋　３を４４４、これを
富法に従い例えばり１」７１〜グラフイにか（］Ｃ、シ
ス休（ＩＩ−ａ）及び１〜ランス１木（　ＩＩ　−　１
＋　、１　４分ＭｌりることにＪ、り収得される。! - The compound () used is usually prepared as described above. That is, a certain compound (IVII) containing cis-1-synthe Of the cis-trans mixture (compound 1) treated with JANyl chloride (302CI), dino'
A compound containing cis-1-nonce (Ct12N2) is added to a certain compound (V+3) at 444, and this is prepared according to the Fu method, e.g. ) and 1 to lance 1 tree (II-1
+, J, was obtained in 14 minutes.

（ｙ）　　　　　　　　　　　　　（ｖ）上記化合物（
ＩＶ　）と塩化チＡニルとの反応、化合物（Ｖ）とジア
ゾメタンとの反応及び得られる化合物（Ｖｌ　）からの
カラｌ＼クロマトグラノイにＪ、るシス休とトランス体
との分前は、夫々通常のｈ法に従い実施（・きる。例え
ば化合物（Ｖ）とジアゾメタンとの反応は、前記本発明
化合物の製造法に例示したと同様の溶媒中、化合物（Ｖ
）に対しＵ−−一般に２倍Ｅル以上のジノ７ゾメタンを
用い（、約−１０℃−・室濡稈度の温度条１′１１・に
イ１刊に１１イ１われる。−１−記各反１．６のｉ、￥
Ｓｔ＋＋は、（稔ｎｌｊ参考例（Ｊ小り通りＣ′ある。(y) (v) The above compound (
The reaction of the compound (V) with thianyl chloride, the reaction of the compound (V) with diazomethane, and the reaction of the resulting compound (Vl) with the chromatogranoyl J, the cis and trans isomers are as follows: For example, the reaction between compound (V) and diazomethane can be carried out in accordance with the usual method H.
), generally using dino-7zomethane of 2 times more or more (approximately -10°C - room wet culm temperature range 1'11) -1- Each anti-1.6 i, ¥
St++ is (Mori nlj reference example (J small street C').

上記ブＪ　’ｔＡにより得られる木光明の化合物（，１
）は、通１ｉの分前手段、例えはカッムク１１＼ノ１−
グーノノイ、再結晶、減ＬＥ蒸留等にＪ、り甲１！ＩＩ
Ｉ　ＮＪることがＣきる。Kikomei's compound (,1
) is the means of distribution of 1i, for example, kamuku 11\no1-
J, Riko 1 for Goononoi, recrystallization, reduced LE distillation, etc.! II
I NJ can do C.

木光明化合物（，１，）は、ｊスＩノーｃ　ｌ！１１害
作用、抗脂血症作用をイｊし、免疫調Ｎｊ剤、抗脂血症
剤としくイノ用（゛ある。Mokkomyo compound (,1,) is j snow I no c l! 11 It has harmful effects and antilipidemic effects, and is used as an immunostimulatory agent and an antilipidemic agent.

以１・、ホ光明化合物（］）を製造りるために用いる一
般式（＋１　）で表わされる化合物の製造例を参考例と
しく挙げ、次いで木光明化合物（１）の製造例を実施例
どし−Ｃ挙Ｕる。尚各側にＪ３い（ｉ−１られた化合物
及びイれらのイ］りる物＋’＋を人々表１及び表２に承
り。各表中ＩＶＩ　Ｓはンススベクトル分析結果（Ｍ’
）を小し、またＩＩ　−Ｎ　Ｍ　ｌ＜は核磁気共鳴スベ
ク１〜ル分Ｍ１結果〈（）伯、ＣＩ）Ｃ１ｔ中）を承り
。まｌご、表中のシス及びトランスの扉外・は、［り、
及び１＜３の関係に基づ゛くものＣある。Hereinafter, the production example of the compound represented by the general formula (+1) used to produce the Hokomyo compound (]) will be listed as a reference example, and then the production example of the Mokkomyo compound (1) will be described as an example.し-C enumerate. In addition, each side received J3 (i-1 compound and their own) +'+ in Tables 1 and 2. In each table, IVIS is the result of the vector analysis (M'
) is smaller, and II -N M l< accepts the nuclear magnetic resonance spectrum 1-1 M1 result ((), CI). Sorry, outside the door of cis and trans in the table is [ri,
And there is a species C based on the relationship 1<3.

参考例　１４−イソプロピル−１−メチルシクロｌ＼キシルカルボ
ン酸（シス：ｌ−ランス−１：　ｌ、ｈｐ、　＝１２２
°’Ｃ／　２ｍｍ１Ｎ］　）　１０（Ｊに、過剰の塩化
チオニルを加えて３時間撹拌りる。反応後、過剰の塩化
ヂＡニルを減圧ト留去し、得られた油状物を減圧蒸留し
−Ｃ１沸点１５０〜１５２°Ｃ／（３０ｍｍｌ１ｇの４
−イソブ″ロビル−１−メチルシク目ｌ＼二１−シルカ
ルボニルり１」ライｌ”　９　、５　’Ｊ　’！！−得
る。Reference example 1 4-isopropyl-1-methylcyclol\xylcarboxylic acid (cis:l-lance-1: l, hp, = 122
°'C/2mm1N]) Add excess thionyl chloride to 10 (J) and stir for 3 hours. After the reaction, excess dianyl chloride was distilled off under reduced pressure, and the resulting oil was distilled under reduced pressure. -C1 boiling point 150-152 °C/(30 mml 1g 4
-Isobutrovyl-1-methyl-2-1-methylcarbonyl-1"9,5'J'!!-obtained.

収率ａ６．４％次に、ニトロソウレア　１５　ＩＩから調製したジノ７
ゾメタン］ニーｊル溶液’１５０ｍ１中に、室渇十−ｅ
　Ａ−イソプ［。１ビル−１−メチルシクロｌ＼キシル
７Ｊルボニルクロライド５．０ｇを瀾下りる。約２時間
空温で（鎚打りる。反応後、７ｄ姪を減紅上で留去し、
淡黄色曲状の１−ジアゾ−２−（４−イソゾロピル−１
−メチルシクロヘキシル）−２−、］。、タメタンシス
：トランス−１：１）を足鉛的に得る。Yield a6.4% Next, dino 7 prepared from nitrosourea 15 II
] In 150 ml of needle solution,
A-isoprop[. 5.0 g of 1-biru-1-methylcyclol\xyl 7J rubonyl chloride was poured down. Leave at air temperature for about 2 hours.
Pale yellow curved 1-diazo-2-(4-isozolopyl-1
-methylcyclohexyl)-2-, ]. , tamethansis:trans-1:1) was obtained in a direct manner.

上記で得られｌこシス−トランス混合体のジアゾメタン
イ本を、シリカグルカノムクＬ、ｌ　ｖ’　ｌ〜グシノ
イ（展開溶媒；り■［」ホルｌ＼）に（分離精製しく、
先の分画Ｊ、り淡黄色油状の１−シｊ′ゾ　２−（１〜
ランス−４−イソブＵビルー１−メチルシク［、ｆ＋　
／＼−１シル）−２−１−メタン（化合物に）２．Ｆ）
りを得る。まノこ、後の分画Ｊ、り淡黄色曲状の１　ジ
ノ′シー２−（シス−４−イソブ真−１ピル−′１　メ
′ｆ−ルシクロｌ＼キシル）−２−土タノンく化合物１
）　）２．４ｑを得る。。The diazomethane of the cis-trans mixture obtained above was separated and purified in silica glucanoyl, lv'l~gusinoyelate (developing solvent;
The above fraction J is a pale yellow oily 1-cyj′zo2-(1~
lance-4-isobu-Ubi-1-methylsic [, f+
/\-1sil)-2-1-methane (to the compound)2. F)
get the benefits. Manoko, later fraction J, pale yellow curved 1-di-2-(cis-4-isobutylene-1-pyl-'1 m-f-lcyclol\xyl)-2-earth tanone Compound 1
)) Obtain 2.4q. .

参も例　２１．４　ジ［ｆ）レーシク１ｍｌ　／＼−（ンルカル小
ン酸（シス：１ヘランス＝３：１．１月）、　−＝　１
２　り〜′）２８℃７４１１１１１１１１　！＋　＞及
び４−イソノブルー　１メヂル−シフＵ　／＼キリンカ
ルボン酸〈シス：１−［ノンスー・１：１１月＋、−１
２６−・１２８°Ｃ／２．ｅ）ｍｌｌｔｌ−ＮＪ）を原
註としく参考例′Ｉと同様（、ニしく化合物へ、］３、
Ｉ−及０１丁を含成りる、。Example 2 1.4 Di[f) LASIK 1ml /\-(Nrucaronic acid (cis:1 herans = 3:1.1 month), -= 1
2 ri~') 28℃7411111111! + > and 4-isonoblue 1 medyl-Schiff U /\ Kirin carboxylic acid <cis: 1-[Nonsu・1: November +, -1
26-・128°C/2. e) mlltl-NJ) and the same as Reference Example 'I (to the compound,] 3,
Comprising I- and 01-cho.

実施例　１１−ジアゾ−２−（トランス−１，４−ジ土デルシクロ
ヘキシル）−２−エタノン０．２ｇを１−チル５Ｑｍｌ
に溶解しく、室温下、ρ−１〜ル上ンスルホン酸を過剰
に加えて窒素ノＪスの発生がなくなるま−Ｃ′撹拌覆る
。反応後、ニーデル層を水洗して無水硫酸す１−リウケ
で乾燥する。乾燥後、減圧下に溶媒を留去し−（、残漬
をシリ／Ｊグルカラムクロマ１〜グラフィ（展開溶媒；
クロロホルムンにで分離精製して、融貞４５）〜４６℃
の無色結晶の１−（ｐ−メチルヘンＵンスルホニルＡキ
シ）−２−（トランス−１，４−ジ土アルシク１−１１
＼１シル）−２−エタノン（化合物２　）　Ｏ、ｖ３　
！Ｊ　（！：ｉＨる。Example 1 0.2 g of 1-diazo-2-(trans-1,4-di-earthylcyclohexyl)-2-ethanone was dissolved in 5 Qml of 1-thyl
Add an excess of sulfonic acid to ρ-1 to 1 at room temperature and stir until no nitrogen gas is generated. After the reaction, the needle layer was washed with water and dried over anhydrous sulfuric acid. After drying, the solvent was distilled off under reduced pressure.
Separate and purify with chloroform and melt at 45-46℃.
Colorless crystals of 1-(p-methylhenunsulfonylAxy)-2-(trans-1,4-di-earthyl 1-11
\1sil)-2-ethanone (compound 2) O, v3
! J (!:iHru.

収率ε３８．７％実施例　２実施例′１と同様にし−Ｃ１化合物′１及び３３・〜１
３を得る。Yield ε38.7% Example 2 Same as Example '1 - C1 compounds '1 and 33.~1
Get 3.

次に、本発明スル小ネート誘導体につき？ｊなわれた桑
即試験を説明づる。Next, what about the sulnate derivatives of the present invention? I will explain the kuwa soku exam.

１１−スｊラー１２１（１１害作用０．１［ルのＩ−リス塙酸緩別液（＋＋ＩＩε３．Ｏ）
の一定１−１に、基質としＣスプルノＪレートｌ　Ｏ１
１モルの５０％」タノール溶液を加え、史にこれに本発
明化合物の５５０％−１タノール溶液を加えた後、直ら
に精製したラツｌ−１１’ｌ臓ンイク１−１ン一ム画分
」−スｊラー１溶液（３７’Ｃ１１肋間（ご（９μヒル
のメチルゾヂレー１〜を水解づるＪ、′）に調整りる）
を加え、３７℃にＵ６０分間反１芯を（ｌ　’、’ｉ　
”’）。11-Solar 121 (11 Adverse Effects 0.1)
1-1, the substrate is C spruno J rate l O1
After adding 1 mol of 50% ethanol solution and adding 550% ethanol solution of the compound of the present invention thereto, the purified rat viscera 1-1 mol fraction was immediately purified. ''-Solar 1 solution (adjust to 37'C11 intercostal (g) (9μ Hill's methylzodire 1~ is dissolved in water J,'))
was added and heated to 37°C for 60 minutes (l','i
”').

反応終了後、メチルゾチレー１−のアルカリ１４じド１
−１４シルノ７ミン（ごＪ、るヒト１」１−リム酸誘導
体に第二鉄塩を加え−Ｃ１生ずる赤色を比色（波長：〕
４０　ｎｍ）　Ｌ、、残存量るメチルノブレ−１・含量
を定ｈ４覆る。本発明化合物の各種濃度（３点以上）に
お（）る土ス１ラーＵ阻害率を縦軸にゾ１１ツ１〜し、
その濃度の対数を横軸にプロワ１−シ（得られた直線よ
り５０％叶１害１ｌｆｉｌｆｉ（ＩＧ！、０）を求める
。After the reaction is completed, the alkali 14d 1 of methylzotyre 1-
-14Cilno7mine (Go J, Ruhito 1) Add ferric salt to 1-rimic acid derivative -C1 Colorimetrically measure the resulting red color (wavelength:)
40 nm) L, covering the remaining amount of methyl noble-1 content at a constant h4. The soil slurry U inhibition rate at various concentrations (3 points or more) of the compound of the present invention is plotted on the vertical axis,
Using the logarithm of the concentration as the horizontal axis, calculate 50% filtration (IG!, 0) from the obtained straight line.

２　キモトリプシン阻害作用０．１モルの１へリス塩酸緩衝液（１）Ｌ１８．０＞の
一定量に、酵素液（キモトリプシンの０．１１−ツ１へ
）を加え、史に本発明化合物の５０％］−タノール溶液
を加えた後、３７°Ｃにで２０分間反応を（ｊなう。2 Chymotrypsin inhibitory effect To a certain amount of 0.1 mol of 1 Helis hydrochloric acid buffer (1) L18.0, add enzyme solution (0.11 to 1 of chymotrypsin), and add 50% of the compound of the present invention to 0.1 mol of chymotrypsin. %] - After adding the tanol solution, the reaction was continued at 37°C for 20 minutes.

反応終了後直らに、基質としＵＮ−アレチル−Ｌ−チロ
シンエチルエステル μモルを加え一Ｃ、３７°Ｃにて３０分間反応をｔＪ　
’Ｊう。反応終了後Ａ１”［ニドの残存量を」−スノー
ラーゼＮ１害活性測定法と同様のヒドロキリム酸法に−
（定量づ−る。キモ１−リプシン阻害率（％）は下式に
Ｊ、り算出される。Immediately after the completion of the reaction, μmol of UN-aretyl-L-tyrosine ethyl ester was added as a substrate and the reaction was continued at 1C for 30 minutes at 37°C.
'J. After the completion of the reaction, A1" [remaining amount of Nido] - Hydrochilic acid method similar to the snorase N1 harmful activity measurement method -
(Quantification) Kimo-1-lipsin inhibition rate (%) is calculated using the following formula.

阻害率（％）−（△−１３）／ΔＸ　１　０　（、）Ａ
：本発明化合物を添加しない反応系のＪ−スフル水解桁に３：本発明化合物を添加した反応系の１スｊ−ル水Ｍ
量３　抗脂血症効果試験７週齢、体重２００−２２０ＣＩのウィスター系雄性ラ
ツ１〜を〜ＡＹ５匹どして試験に用いる。Inhibition rate (%)-(△-13)/ΔX10 (,)A
: J-suffle water in the reaction system to which the compound of the present invention is not added 3: 1-sful water M in the reaction system to which the compound of the present invention is added
Amount 3 Antilipidemic Effect Test One to five male Wistar rats, 7 weeks old and weighing 200-220 CI, are used for the test.

本発明化合物ｉｏｏ＋ｚを：）ｎ＋１のＡリーノ浦に）
Ｈ解し゛（試験に用いる。本発明化合物を含むＡリーノ
浦を：）＋ｎ　ｌ　／　ｋ！＋相当に（ノツ１−にソン
ｊを用いて経口投勺し、２時間後」−ノル麻酔］・に１
１・ｉＪ人静脈Ｊ、リヘバリンを含む（１身・Ｉ　ｉｉ
：ｌ　ＩＪ．　（　、’ｔゝ而Ｏ面１を採取りる。１Ｓ
〕られた血液を′り−に　、　３　０　０　０　ｒｐｍ
Ｃ”＋’Ｈ心分饋し、血漿をＣＩる，。Compound of the present invention ioo+z:) n+1 A Rinoura)
H solution (Used for testing.Arinoura containing the compound of the present invention:)+n l/k! + equivalently (oral administration using Sonj for Notu 1-, 2 hours later - Nor anesthesia), to 1
1・iJ human vein J, containing rehevarin (1・I ii
:l IJ. ( , 't, then take O side 1. 1S
] 3000 rpm
C"+'H heart and blood plasma CI.

百られ／ｊ血漿のトリクリレライトａｍを、和光紳桑礼
装の１−リグリレシイ１〜測〉ｒ〜ツ１−（Ｉ−リクリ
セライド−１３）ス１〜ＩノＷ−）を用い（測定りる。Hyakure/J Plasma tricrylic acid am was measured using Wako Shinso's 1-Liglyceride 1 ~ Measurement> .

対象８Ｙにはオリ−１油のみを同＋Ａｉにしく投りりる
。For target 8Y, properly throw only Ori-1 oil to the target 8Y.

ＩＩ−富１１Ｙには伺らの処置も行なわない、、これら
両Ｉ）Ｙとｂ本発明化合物処置ＪｊＹと同様、＋ｌｉ　
’４ｎ中の１−リクリセライド含晴を測定りる。II-Tofu 11Y is not treated with the above treatment, both I) Y and b are treated with the compound of the present invention as well as +li
Measure the 1-lyclyceride content in '4n.

本発明化合物の，Ｉ’％脂面＃１１．　Ｊ＋’＋＋　Ａ
’ｌｌ＋十を次式（ごよりＣ９出りる。I'% fat side of the compound of the present invention #11. J+'++ A
'll+10 is converted to the following formula (from C9.

抑制率（％）＝（Ａ−Ｃｌ’（Ａ１３）Ｘ１００／＼：
対照群１ーリグリレ″ノイド含量Ｉ３：往−常８Ｙ．　
１〜リクリしシイト含ｉ７１Ｃ：木発明化合物処置群１
〜リクリ［）で１・倉ら１−１記試ｉｆ、！ｉｉの結ｊ
１４をト記表３）に示り。該Ｉ４；日、ニ（１５いη１
ヘリグリ（、テライト抑制率（Ｊ、１０抑利率と表示り
る、１表　　　　３代理人　弁即十　二　枝　英　Ｅ　　　゛手続補正書（
酊）昭和５８年ｔ３．，１−り゛月５　日持１；′「庁長盾　　　（、’１’　！’、’　ト］り
に　　　殿１、事件の表示昭和５７年　特　許　願第１５５６７５　　号事件との
関係　特許出願人４代理人大阪市東区平野町２の１（１７尺の鶴ヒル７［（話０［
１−２０３−０９４１（代）７°　有Ｄ　ｒＥ　Ｏ）　
対ＫＬ　　明細−）中「発明のＭ’（細な説明」の項８
、補正の内容別紙添附の通りｈｌｉ　　　正　　の　　内　　容Ｉ　明細ｔ１ｔ　ｐｉ’ｓ　＋　２頁に記載の表１中「
化合物Ｆ」の項の後に下記「化合物Ｇ」及び［化合物Ｉ
Ｉ　Ｊの各項を追加する。Suppression rate (%) = (A-Cl'(A13)X100/\:
Control group 1 - Liglinoid content I3: normal 8Y.
1 to i71C containing Rikuri Shiite: Wood invention compound treatment group 1
~ Rikuri [) 1, Kura et al. 1-1 test if,! conclusion of ii
14 is shown in Table 3). Said I4; day, d (15 η1
Heriguri (, terite suppression rate (J, expressed as 10 suppression rate), 1 Table 3 Agent Ben Soku 12 Ed E
Drunkenness) 1981 t3. , 1 - 5 days 1; ' Chief Shield (,'1'!',' To) 1, Indication of the case 1981 Patent Application No. 155675 Relationship with the case Patent application Person 4 Agent 2-1 Hirano-cho, Higashi-ku, Osaka (17-shaku Tsuru Hill 7 [(story 0 [
1-203-0941 (main) 7° Yes DrE O)
Section 8 of "M' (Detailed Description of the Invention)" in V.KL Specification-)
, Contents of Amendment As attached to the attached sheet, hli Correct Contents I Specifications t1t pi's + "
After the “Compound F” section, the following “Compound G” and “Compound I
Add each term of IJ.

「」２　明細ｆ４ｆ第１３頁第７行に「−ナトリウケ」とあ
るを「ナトリウム」と訂正する。`` '' 2 In the 7th line of page 13 of the specification f4f, the phrase ``-natriuke'' is corrected to ``sodium''.

３　明細書第１８員に記載の表２　「１１ｒ化合物＋３
Ｊの項の後に、下記［化合物＋４Ｊ及び［化合物１５Ｊ
の各項を追加する。3 Table 2 described in the 18th member of the specification “11r compound +3
After the J section, the following [Compound +4J and [Compound 15J]
Add each term.

」４　明細書第１９貝に記載の表２中Ｉ化自物１３」のＪ
目の後に、下記［化合物１４Ｊ及び［−ｆヒ合物１５」
の各Ｊ１″１を追加する。" 4 J of "I-made natural product 13" in Table 2 described in Specification No. 19
After the eyes, apply the following [Compound 14J and [-f Compound 15]
Add each J1″1 of .

［」（以　上）[ ” (that's all)

Claims

[Claims] ■ General formula [in the formula [<1 is a lower alkyl group or a lower alkyl group], 1 is ○ or an integer from 1 to 3, and 1<. and 1<3 each represents a lower alkyl group. ] A benzenesulfonic acid Nisder derivative represented by ■ A compound represented by the general formula (in the formula, 1 and 1 represent lower nonol, respectively) and a compound represented by the general formula (in the formula, 1 and 1 represent lower nonol: 1- ru group or lower)'ru'
xy group, 1 is 0 or an integer of 1...3'S and n) is 0
．． Shows 1 or 2. ) to avoid the compound represented by C', c, and 'B'.
i if'i. [In the formula, t<+, Rp, R3 and 1 have the same meanings as above. ] A method for producing a pembin sulfo>M-I7.7yl derivative represented by: