JPH035425A - Anti-ulcer agent - Google Patents
Anti-ulcer agentInfo
- Publication number
- JPH035425A JPH035425A JP13809889A JP13809889A JPH035425A JP H035425 A JPH035425 A JP H035425A JP 13809889 A JP13809889 A JP 13809889A JP 13809889 A JP13809889 A JP 13809889A JP H035425 A JPH035425 A JP H035425A
- Authority
- JP
- Japan
- Prior art keywords
- ulcer
- group
- cooh
- tetrazoyl
- thiazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003699 antiulcer agent Substances 0.000 title claims abstract description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 10
- MESFXNGUDNODTJ-UHFFFAOYSA-N 2h-thiazine 1,1-dioxide Chemical class O=S1(=O)NC=CC=C1 MESFXNGUDNODTJ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 13
- 230000000767 anti-ulcer Effects 0.000 abstract description 11
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 230000001681 protective effect Effects 0.000 abstract description 8
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- NGHIOTWSWSQQNT-UHFFFAOYSA-N methyl 4-hydroxy-2-methyl-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound C1=CC=C2S(=O)(=O)N(C)C(C(=O)OC)=C(O)C2=C1 NGHIOTWSWSQQNT-UHFFFAOYSA-N 0.000 abstract description 2
- 230000001737 promoting effect Effects 0.000 abstract 1
- 208000025865 Ulcer Diseases 0.000 description 19
- 231100000397 ulcer Toxicity 0.000 description 18
- 230000005764 inhibitory process Effects 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 208000008469 Peptic Ulcer Diseases 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
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- 238000002360 preparation method Methods 0.000 description 7
- 229960001380 cimetidine Drugs 0.000 description 6
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- 210000002784 stomach Anatomy 0.000 description 6
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- 239000003795 chemical substances by application Substances 0.000 description 4
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- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
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- 229930182816 L-glutamine Natural products 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
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- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
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- 208000007107 Stomach Ulcer Diseases 0.000 description 1
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- HOBWAPHTEJGALG-JKCMADFCSA-N [(1r,5s)-8-methyl-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate;sulfate Chemical compound [O-]S([O-])(=O)=O.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1 HOBWAPHTEJGALG-JKCMADFCSA-N 0.000 description 1
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Abstract
Description
【発明の詳細な説明】
［産業上の利用分野コ
本発明は、消化性潰瘍の治療薬として好適な抗潰瘍剤に
関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to an anti-ulcer agent suitable as a therapeutic agent for peptic ulcers.
［従来の技術］
胃潰瘍や十二指腸潰瘍等の消化性潰瘍の成因については
未だ明らかではないが、攻撃因子（胃酸、ペプシン、ガ
ストリン等）と防御因子（胃粘液、粘膜血流、肉芽増殖
など胃粘膜保護修復に関与すると考えられる諸因子）の
バランスが破綻するために発生するという説が一般的で
ある。したがって消化性潰瘍の内科的治療は、攻撃因子
を抑制する攻撃因子抑制剤または防御因子を増強する防
御因子増強剤を投与することにより行われている。[Prior art] Although the etiology of peptic ulcers such as gastric ulcers and duodenal ulcers is still unclear, there are aggressive factors (gastric acid, pepsin, gastrin, etc.) and protective factors (gastric mucus, mucosal blood flow, granulation growth, etc.). The general theory is that it occurs due to a disruption in the balance of various factors thought to be involved in protection and repair. Therefore, medical treatment of peptic ulcers is carried out by administering an aggressive factor suppressor that suppresses the aggressive factor or a defensive factor enhancer that enhances the defensive factor.
攻撃因子抑制剤としては、炭酸水素ナトリウムや炭酸マ
グネシウム等の制酸剤、硫酸アトロピンや臭化ブチルス
コポラミン等の抗コリン剤、シメチジン等のヒスタミン
Ｈ２受容体拮抗剤等が使用されており、防御因子増強剤
としては、ビタミンＵ製剤やＬ−グルタミン製剤などの
抗潰瘍性因子剤、塩酸セトラキサート、ゲファルナート
製剤、グリチルリチン誘導体等の粘膜機能亢進剤等が使
用されている。As aggressive factor inhibitors, antacids such as sodium bicarbonate and magnesium carbonate, anticholinergic agents such as atropine sulfate and butylscopolamine bromide, and histamine H2 receptor antagonists such as cimetidine are used, and defensive factors are used. As the enhancer, anti-ulcer factor agents such as vitamin U preparations and L-glutamine preparations, mucosal function enhancing agents such as cetraxate hydrochloride, gefarnate preparations, and glycyrrhizin derivatives are used.
これらの攻撃因子抑制剤や防御因子増強剤は、単独ある
いは併用して投与されるが、特にシメチジン等のヒスタ
ミンＨ２受容体拮抗剤は他の抗潰瘍剤に比べて優れた抗
潰瘍性を示す半面、潰瘍が完全に治癒する前に服用を止
めると潰瘍が再発し悪化しやすいために、防御因子増強
剤と併用して投与されることが多い。These aggressive factor inhibitors and defensive factor enhancers are administered alone or in combination, but histamine H2 receptor antagonists such as cimetidine in particular exhibit superior anti-ulcer properties compared to other anti-ulcer agents. If the drug is stopped before the ulcer is completely healed, the ulcer is likely to recur and worsen, so it is often administered in combination with a protective factor enhancer.
なお、ストレス潰瘍の内科的治療には、攻撃因子抑制剤
や防御因子増強剤の他、鎮静・精神安定剤等の中枢性抗
潰瘍剤も使用されている。In the medical treatment of stress ulcers, in addition to aggressive factor inhibitors and defensive factor enhancers, central anti-ulcer agents such as sedatives and tranquilizers are also used.
［発明が解決しようとする課題］
本発明は、このような消化性潰瘍の内科的治療の現状に
鑑み、消化性潰瘍の内科的治療の多様化を図るべくなさ
れたものであり、本発明の目的は、防御因子増強剤とし
て有用な新規な抗潰瘍剤を提供することにある。[Problems to be Solved by the Invention] The present invention has been made in view of the current state of medical treatment of peptic ulcers, and aims to diversify the medical treatment of peptic ulcers. The objective is to provide novel anti-ulcer agents useful as protective factor enhancers.
［課題を解決するための手段］
本発明者らは、式
で示される、抗炎症剤、ピロキシカムの基本骨格構造と
、式
で示される、抗アレルギー剤、トラニラストの基本骨格
構造とを併有する多種のハイブリッド化合物を合成し、
その生理活性について検討を加えた。[Means for Solving the Problems] The present inventors have proposed a variety of products that have both the basic skeletal structure of an anti-inflammatory agent, piroxicam, represented by the formula, and the basic skeletal structure of tranilast, an anti-allergic agent, represented by the formula. synthesize a hybrid compound of
We investigated its physiological activity.
その結果、一般式（１）
％式％
４−Ｃ０ＯＨおよび２− （５’ −テトラゾイル）基
からなる群より選択される１種の置換基であり、Ｒ１が
２−Ｃ０ＯＨのときＲ１はＨまたは４−Ｎ０ｇ、Ｒ１が
３−Ｃ０ＯＨ，４−Ｃ０ＯＨまたは２− （５’ −テ
トラゾイル）基のときＲ２はＨである）
で表される、特定のチアジン−１，１−ジオキシド誘導
体が、優れた防御因子増強作用を有し抗潰瘍剤として有
用であることを見出し、本発明を完成した。As a result, the general formula (1) is one type of substituent selected from the group consisting of 4-C0OH and 2-(5'-tetrazoyl) group, and when R1 is 2-C0OH, R1 is H or 4-N0g, R2 is H when R1 is 3-C0OH, 4-C0OH or 2-(5'-tetrazoyl) group). It was discovered that it has a protective factor enhancing effect and is useful as an anti-ulcer agent, and the present invention was completed.
一般式（１）のハイブリッド化合物のベースとなったピ
ロキシカムおよびトラニラストが抗潰瘍作用を有しない
ことから、この一般式（１）の化合物の抗潰瘍作用は、
ハイブリッド化によって新たに出現した生理活性である
。Since piroxicam and tranilast, which are the bases of the hybrid compound of general formula (1), do not have anti-ulcer activity, the anti-ulcer effect of the compound of general formula (1) is
This is a new physiological activity that has emerged due to hybridization.
上記の如く、一般式（Ｉ）において、Ｒ１は２−Ｃ０Ｏ
Ｈ，３−Ｃ０ＯＨ，４−Ｃ０ＯＨおよび２− （５’
−テトラゾイル）基からなる群より選択される１種の置
換基に限定され、Ｒ１が２−Ｃ００ＨのときＲ２はＨま
たは４− Ｎ Ｏ２に、Ｒ１が３−Ｃ０ＯＨ，４−Ｃ０
ＯＨまたは２− （５’−テトラゾイル）基のときＲ２
はＨに限定される。As mentioned above, in general formula (I), R1 is 2-C0O
H, 3-C0OH, 4-C0OH and 2-(5'
-Tetrazoyl) group, and when R1 is 2-C00H, R2 is H or 4-N O2, and R1 is 3-C0OH, 4-C0
R2 when OH or 2- (5'-tetrazoyl) group
is limited to H.
その理由は、Ｒ１とＲ２が上記の如き関係にあると、後
述の実施例より明らかなように、優れた抗潰瘍作用が得
られるのに対し、例えば、Ｒ１を２−Ｃ０ＯＨとしＲε
を４−ＣＩとした場合や、Ｒ１およびＲ２を共にＨとし
た場合等、Ｒ１とＲ２が上記の如き関係を満たさないと
、抗潰瘍作用が得られないことが確認されているからで
ある。The reason for this is that when R1 and R2 have the above relationship, an excellent anti-ulcer effect can be obtained, as will be clear from the examples described later, whereas, for example, when R1 is 2-COOH, Rε
This is because it has been confirmed that if R1 and R2 do not satisfy the above relationship, such as when 4-CI is used or when R1 and R2 are both H, an anti-ulcer effect cannot be obtained.
一般式（Ｉ）で表されるチアジン−１，１−ジオキシド
誘導体において、Ｒ１が２− （５’ −テトラゾイル
）基で、Ｒ２がＨである化合物が特に抗潰瘍作用に優れ
ている。Among the thiazine-1,1-dioxide derivatives represented by the general formula (I), compounds in which R1 is a 2-(5'-tetrazoyl) group and R2 is H have particularly excellent antiulcer effects.
本発明において、一般式（Ｉ）のチアジン−１゜１−ジ
オキシド誘導体は、防御因子増強作用を有するため、単
独で用いてもよいが、他の防御因子増強剤や、シメチジ
ン等の攻撃因子抑制剤と併用することもできる。In the present invention, the thiazine-1゜1-dioxide derivative of general formula (I) has a protective factor-enhancing effect, so it may be used alone, but it can also be used with other protective factor-enhancing agents or attacking factor inhibitors such as cimetidine. It can also be used in combination with agents.
本発明の抗潰瘍剤の投与剤型としては、散剤、細粒剤、
顆粒剤、錠剤、被覆錠剤、カプセル剤等の経口用固形剤
やシロップ剤等の経口用液体剤を挙げることができ、製
剤化の際には通常の製剤坦体を用いて常法により製造す
ることができる。The dosage forms of the anti-ulcer agent of the present invention include powders, fine granules,
Examples include oral solid preparations such as granules, tablets, coated tablets, and capsules, and oral liquid preparations such as syrups, and are manufactured by conventional methods using ordinary pharmaceutical carriers. be able to.
すなわち、経口用固形剤を調製する場合は、上記有効成
分に賦形剤を添加し、さらに必要に応じて結合剤、崩壊
剤、滑沢剤、着色剤、矯味矯臭剤を加えた後、常法によ
り散剤、細粒剤、顆粒剤、錠剤、被覆錠剤、カプセル剤
等とする。That is, when preparing a solid dosage form for oral use, excipients are added to the above-mentioned active ingredient, and binders, disintegrants, lubricants, colorants, and flavorings are added as necessary, and then the usual According to the law, it is made into powders, fine granules, granules, tablets, coated tablets, capsules, etc.
賦形剤としては、乳糖、コーンスターチ、白糖、ブドウ
糖、ソルビット、結晶セルロース、二酸化ケイ素等を用
いることができ、結合剤としては、ポリビニルアルコー
ル、ポリビニルエーテル、エチルセルロース、メチルセ
ルロース、アラビヤゴム、トラガント、ゼラチン、シュ
ラツク、ヒドロキシプロピルセルロース、ヒドロキシプ
ロピルスターチ、ポリビニルピロリドン等を用いること
ができる。また崩壊剤としては、デンプン、寒天、ゼラ
チン末、結晶セルロース、炭酸カルシウム、炭酸水素ナ
トリウム、クエン酸カルシウム、デキストリン、ペクチ
ン等を用いることができ、滑沢剤としては、ステアリン
酸マグネシウム、タルク、ポリエチレングリコール、シ
リカ、硬化植物油等を用いることができる。着色剤とし
ては医薬品に添加することが許容されてい物質を用い、
矯味矯臭剤としては、ココア末、ハツカ脳、芳香酸、ハ
ツカ油、電脳、桂皮末等を用いることができる。As excipients, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, etc. can be used, and as binders, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, schlag, etc. can be used. , hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc. can be used. In addition, as a disintegrant, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, etc. can be used, and as a lubricant, magnesium stearate, talc, polyethylene, etc. can be used. Glycol, silica, hydrogenated vegetable oil, etc. can be used. We use substances that are allowed to be added to pharmaceuticals as colorants,
As the flavoring agent, cocoa powder, peppermint, aromatic acid, peppermint oil, cypress, cinnamon powder, etc. can be used.
なお、経口用固形剤とするにあたっては、糖衣、ゼラチ
ン衣等によりコーティングしてもさしつかえないことは
もちろんである。In addition, in preparing a solid preparation for oral use, it is of course possible to coat it with sugar coating, gelatin coating, etc.
経口用液体剤とする場合には、例えば通常のシロップ剤
（溶液）では、甘味剤として白糖、ソルビトール等を添
加し、溶解補助剤としてソルビタン脂肪酸エステル、ポ
リソルベート、ポリビニルピロリドン、エチレンジアミ
ン、グリセリン等を添加し、必要に応じてパラオキシ安
息香酸エステル類、安息香酸ナトリウム、ベンジルアル
コール、デヒドロ酢酸ナトリウム等の防腐剤を添加する
。When making an oral liquid preparation, for example, in a normal syrup (solution), white sugar, sorbitol, etc. are added as a sweetening agent, and sorbitan fatty acid ester, polysorbate, polyvinylpyrrolidone, ethylenediamine, glycerin, etc. are added as a solubilizing agent. If necessary, preservatives such as paraoxybenzoic acid esters, sodium benzoate, benzyl alcohol, and sodium dehydroacetate are added.
また、懸濁シロップ剤とする場合には、上記製剤原料の
他に、懸濁剤としてアラビヤゴム、トラガント、ナトリ
ウムカルボキシメチルセルロース、メチルセルロース等
を添加する。When preparing a suspension syrup, in addition to the above-mentioned pharmaceutical raw materials, gum arabic, tragacanth, sodium carboxymethylcellulose, methylcellulose, etc. are added as suspending agents.
本発明の抗潰瘍剤を消化性潰瘍罹患者に投与する場合、
その投与曾は潰瘍の発生部位、病状の程度、罹患者の年
齢、健康状態、併用する薬剤の有無等により異なるため
特定することはできないが、有効成分であるチアジン−
１，１−ジオキシド誘導体を概ね１〜１０００ ｍｇ／
ｋｇ／日の割合で投与することにより、所望の効果を
得ることができる。When administering the anti-ulcer agent of the present invention to a patient suffering from peptic ulcer,
The dosage cannot be determined because it varies depending on the site of the ulcer, the severity of the disease, the age and health condition of the patient, the presence or absence of concomitant drugs, etc., but the active ingredient thiazine
Approximately 1 to 1000 mg/1,1-dioxide derivative
The desired effect can be obtained by administering at a rate of kg/day.
［実施例］ 以下、本発明の実施例について説明する。[Example] Examples of the present invention will be described below.
実施例１
体重が２００〜２５０ｇのＳＤ系雌雄性ラット５個体ら
なるグループを９グループ用い、各個体とも２４時間絶
食させた後に、１５０ｍＭ塩酸−６０％エタノールを１
．０ｍｌ／２００ｇの割合で経口投与して、塩酸−エタ
ノール潰瘍を惹起させた。Example 1 Using 9 groups of 5 male and female SD rats weighing 200 to 250 g, each animal was fasted for 24 hours and then treated with 150 mM hydrochloric acid-60% ethanol.
．． Hydrochloric acid-ethanol ulcers were induced by oral administration at a rate of 0 ml/200 g.
この後、１グループを対照群として、塩酸−エタノール
投与の１時間後にエーテル致死せしめて胃を摘出し、胃
内に生理食塩水１０ｍ１を注入した後、１％ホルマリン
液中に１０分間浸漬して固定し、胃を大溝に沿って切開
し７て、解剖顕微鏡下（ｘｌｏ）にて腺胃部に発生した
粘膜潰瘍の長さ（ｍｍ）を測定し、５個体の長さの平均
値を潰瘍係数とした。After this, one group was used as a control group, and 1 hour after the administration of hydrochloric acid and ethanol, the stomach was killed with ether, the stomach was removed, 10 ml of physiological saline was injected into the stomach, and the stomach was immersed in 1% formalin solution for 10 minutes. After fixation, the stomach was incised along the major groove 7 and the length (mm) of the mucosal ulcer that occurred in the glandular stomach was measured under a dissecting microscope (XLO), and the average length of the 5 specimens was calculated as the ulcer. It was taken as a coefficient.
一方、他の８グループは、塩酸−エタノール投与の３０
分前に、
■ 前述の一般式（Ｉ）でＲ１が２−（５’テトラゾイ
ル）基でＲ２がＨであるチアジン−１，１−ジオキシド
誘導体（以下、５Ｃ−２００と称す）を３ｍｇ／ｋｇ経
口投与するグル−ブ、
■ ５Ｃ−２００を１０ｍｇ／ｋｇ経口投与するグルー
プ、
■ ５Ｃ−２００を３０ｍｇ／ｋｇ経口投与するグルー
プ、
■ ５Ｃ−２００を１００ｍｇ／ｋｇ経口投与するグル
ープ、
■ 前述の一般式（Ｉ）でＲ１が２−Ｃ０ＯＨでＲ２が
Ｈであるチアジン−１，１−ジオキシド誘導体（以下、
５Ｃ−１００と称す）を１０ｍｇ／ｋｇ経口投与するグ
ループ、■ 前述の一般式（Ｉ）でＲ１が２−Ｃ０ＯＨ
でＲ２が４−ＮＯ２であるチアジン−１，１−ジオキシ
ド誘導体（以下、５Ｃ−１１３と称す）を１０ｍｇ／ｋ
ｇ経口投与するグループ、■ 前述の一般式（Ｉ）でＲ
１が４−Ｃ０ＯＨでＲ２がＨであるチアジン−１，１−
ジオキシド誘導体（以下、５Ｃ−１７０と称す）を１０
ｍｇ／ｋｇ経口投与するグループ、とに分け、対照群と
同様にして粘膜潰瘍の長さ（ｍｍ）を測定して各グルー
プの潰瘍係数を算出し、さらに各チアジン−１，１−ジ
オキシド誘導体の塩酸−エタノール潰瘍に対する抑制率
を、次式に基づいてグループ毎に算出した。On the other hand, the other 8 groups received 30% hydrochloric acid-ethanol administration.
3 mg/kg of the thiazine-1,1-dioxide derivative (hereinafter referred to as 5C-200) in which R1 is a 2-(5'tetrazoyl) group and R2 is H in the general formula (I) described above. Group for oral administration, ■ Group for oral administration of 5C-200 at 10 mg/kg, ■ Group for oral administration of 5C-200 at 30 mg/kg, ■ Group for oral administration of 5C-200 at 100 mg/kg, ■ General group as described above. Thiazine-1,1-dioxide derivatives of formula (I) in which R1 is 2-COOH and R2 is H (hereinafter,
5C-100) at a dose of 10 mg/kg;
thiazine-1,1-dioxide derivative (hereinafter referred to as 5C-113) in which R2 is 4-NO2 at 10 mg/k
g Orally administered group, ■ R in the above general formula (I)
Thiazine-1,1- where 1 is 4-C0OH and R2 is H
Dioxide derivative (hereinafter referred to as 5C-170) at 10
The length (mm) of mucosal ulcers was calculated in the same manner as the control group, and the ulcer coefficient of each group was calculated. The inhibition rate against hydrochloric acid-ethanol ulcer was calculated for each group based on the following formula.
抑制御１ （％）＝ Ｘｃ ” ｘｌＯＯｃ
Ｘｃ：対照群の潰瘍係数
Ｘ ：各チアジン−１，１−ジオキシド誘導体の投与群
の潰瘍係数
これらの結果を表−１に示す。Inhibition control 1 (%) = Xc''
表−１から明らかなように、５Ｃ−２００，５Ｃ−１０
０，５Ｃ−１１３および５Ｃ−１７０のいずれも塩酸−
エタノール潰瘍に対する抗潰瘍作用を有しており、特に
５Ｃ−２００を１０〜１００ｍｇ／ｋｇ経口投与した場
合、５Ｃ−１００を１０ｍｇ／ ｋｇ経口投与した場合
および５Ｃ−１１３を１α■／ｋｇ経口投与した場合の
抑制率は、７６．９〜９５．７％と極めて高いものであ
った。As is clear from Table 1, 5C-200, 5C-10
Both 0,5C-113 and 5C-170 are hydrochloric acid-
It has an anti-ulcer effect on ethanol ulcers, especially when 5C-200 is orally administered at 10 to 100 mg/kg, 5C-100 is orally administered at 10 mg/kg, and 5C-113 is orally administered at 1α/kg. In this case, the inhibition rate was extremely high, ranging from 76.9 to 95.7%.
比較例１
実施例１の比較例として、塩酸−エタノール投与の３０
分前に、防御因子増強剤の１つである塩酸セトラキサー
トを３０ｍｇ／ｋｇ経口投与した場合および１００ ｍ
ｇ／ｋｇ経口投与した場合の潰瘍係数と抑制率を、実施
例１と同様にして測定した。この結果も表−１に示す。Comparative Example 1 As a comparative example of Example 1, 30% of hydrochloric acid-ethanol administration
When cetraxate hydrochloride, one of the protective factor enhancers, was orally administered at 30 mg/kg before
The ulcer index and inhibition rate when administered orally at a dose of g/kg were measured in the same manner as in Example 1. The results are also shown in Table-1.
表−１から明らかなように、塩酸セトラキサートを３０
ｍｇ／ｋｇ経口投与した場合の抑制率は４４゜５％、１
００ｍｇ／ｋｇ経口投与した場合の抑制率は７３．０％
であり、同一投与量の５Ｃ−２００に比べ、はるかに抑
制率が低かった。As is clear from Table 1, cetraxate hydrochloride
The inhibition rate when administered mg/kg orally was 44.5%, 1
The inhibition rate when administered orally at 00 mg/kg was 73.0%.
The inhibition rate was much lower than that of 5C-200 at the same dose.
比較例２〜３
塩酸−エタノール投与の３０分前に、前述の一般式（Ｉ
）でＲ１とＲ２がともにＨである、本発明の限定範囲外
のチアジン−１，１−ジオキシド誘導体（以下、５Ｃ−
００１と称す）を１０ｍｇ／ｋｇ経口投与した場合（比
較例２）、および前述の一般式（Ｉ）でＲ１が２−Ｃ０
ＯＨでＲ２が４−ＣＩである、本発明の限定範囲外のチ
アジン−１゜１−ジオキシド誘導体（以下、５Ｃ−１０
３と称す）を１０ｍｇ／ｋｇ経口投与した場合（比較例
３）の潰瘍係数と抑制率を、実施例１と同様にして測定
した。この結果も表−１に示す。Comparative Examples 2-3 Thirty minutes before hydrochloric acid-ethanol administration, the general formula (I
), in which both R1 and R2 are H, thiazine-1,1-dioxide derivatives outside the limited scope of the present invention (hereinafter referred to as 5C-
001) is orally administered at 10 mg/kg (Comparative Example 2), and when R1 is 2-C0 in the general formula (I) described above,
Thiazine-1°1-dioxide derivatives (hereinafter referred to as 5C-10
The ulcer index and inhibition rate were measured in the same manner as in Example 1 when 10 mg/kg of 10 mg/kg (referred to as Comparative Example 3) was orally administered. The results are also shown in Table-1.
表−１から明らかなように、５Ｃ−００１を投与した場
合の抑制率は−５０，５％、５Ｃ−１０３を投与した場
合の抑制率は−４５，７％であり、いずれの場合も抗潰
瘍作用は認められなかった。As is clear from Table 1, the inhibition rate when 5C-001 was administered was -50.5%, and the inhibition rate when 5C-103 was administered was -45.7%. No ulcerative effects were observed.
（以下、余白） ＊１：いずれも経口投与。(Hereafter, margin) *1: All administered orally.
＊２：抗潰瘍剤は使用せず。*2: No anti-ulcer drugs were used.
表−１
実施例２
体重が２００〜２５０ｇのＳＤ系雌雄性ラット５個体ら
なるグループを３グループ用い、各個体とも１６時間水
浸拘束して、水浸拘束ストレス潰瘍を惹起させた。Table 1 Example 2 Three groups of five male and female SD rats weighing 200 to 250 g were used, and each rat was immersed in water for 16 hours to induce water immersion stress ulcers.
この後、１グループを対照群として、水浸拘束直後にエ
ーテル致死せしめて、実施例１の対照群と同様に腺背部
に発生した粘膜潰瘍の長さ（ｍｍ）を測定し、５個体の
長さの平均値を潰瘍係数とした。After this, one group was used as a control group, and the length (mm) of the mucosal ulcer that had developed on the back of the gland was measured in the same manner as the control group in Example 1 by killing them with ether immediately after water immersion restraint. The average value of the values was taken as the ulcer coefficient.
一方、他の２グループは、水浸拘束の６０分前に５Ｃ−
２００を３０ｍｇ／ｋｇ経口投与するグループと１００
ｍｇ／ｋｇ経口投与するグループとに分け、対照群と同
様にして各個体の粘膜潰瘍の長さ（ｍｍ）を測定して各
グループの潰瘍係数を算出し、さらに５Ｃ−２００の水
浸拘束ストレス潰瘍に対する抑制率を、実施例１と同様
にして算出した。この結果を表−２に示す。On the other hand, the other two groups received 5C-
A group receiving 30 mg/kg of 200 orally and a group of 100
The length (mm) of the mucosal ulcer of each individual was measured in the same way as the control group, and the ulcer coefficient of each group was calculated. The inhibition rate against ulcers was calculated in the same manner as in Example 1. The results are shown in Table-2.
表−２から明らかなように、本発明の抗潰瘍剤の１つで
ある５Ｃ−２００は、水浸拘束ストレス潰瘍に対する抗
潰瘍作用をも有しており、特に１００ｍｇ／ｋｇ投与し
た場合の抑制率は、８６．５％と極めて高いものであっ
た。As is clear from Table 2, 5C-200, one of the antiulcer agents of the present invention, also has an antiulcer effect on water immersion restraint stress ulcers, especially when administered at 100 mg/kg. The rate was extremely high at 86.5%.
比較例４
実施例２の比較例として、水浸拘束の６０分前に、攻撃
因子抑制剤の１つであるシメチジンを３０ｍｇ／ｋｇ経
口投与した場合の潰瘍係数と抑制率を、実施例２と同様
にして測定した。この結果を表−２に示す。Comparative Example 4 As a comparative example of Example 2, the ulcer coefficient and inhibition rate when cimetidine, one of the aggressive factor inhibitors, was orally administered at 30 mg/kg 60 minutes before water immersion restraint were compared with Example 2. Measurements were made in the same manner. The results are shown in Table-2.
表−２から明らかなように、シメチジンを３０ｍｇ／ｋ
ｇ経口投与した場合の抑制率は６４．８％であった。As is clear from Table 2, cimetidine was administered at 30 mg/k.
gThe inhibition rate when administered orally was 64.8%.
（以下、余白） 表−２ ＊１：いずれも経口投与。単位はｍｇ／ ｋｇ。(Hereafter, margin) Table-2 *1: All administered orally. The unit is mg/kg.
＊２：抗潰瘍剤は使用せず。*2: No anti-ulcer drugs were used.
＊３：抗潰瘍剤としてシメチジン３０ｍｇ／ｋｇを経口
投与。*3: Cimetidine 30mg/kg was orally administered as an anti-ulcer agent.
［チアジン−１，１−ジオキシド誘導体の製造例コ（１
）ＳＣ−２００
６重量部の４−ヒドロキシ−２−メチル−３−メトキシ
カルボニル−２Ｈ−１，２−ベンゾチアジン−１，１−
ジオキシドと３．６重量部の２− （５’ −テトラゾ
イル）−アニリンとを混合し、得られた混合物を１００
重量部のＯ−キシレン中で２４時間還流下に加熱して縮
合させた後、不溶物を熱時濾取し、Ｏ−キシレンで洗浄
した後の残渣をジオキサン−水から再結晶させて、５Ｃ
−２００（前述の一般式（Ｉ）で、Ｒ１が２− （５’
−テトラゾイル）基でＲ２がＨである）を得た。融点
２５６〜２５８℃
（２）ＳＣ−１００，５Ｃ−１１３およびＳＣ−７０
出発物質および反応条件を適宜変えた以外は５Ｃ−２０
０の製造の場合と同様にして、上記４種の化合物を得た
。[Production example of thiazine-1,1-dioxide derivative (1)
) SC-200 6 parts by weight of 4-hydroxy-2-methyl-3-methoxycarbonyl-2H-1,2-benzothiazine-1,1-
Dioxide and 3.6 parts by weight of 2-(5'-tetrazoyl)-aniline were mixed, and the resulting mixture was
After condensation by heating under reflux for 24 hours in part by weight of O-xylene, insoluble matter was filtered off while hot, and the residue after washing with O-xylene was recrystallized from dioxane-water to obtain 5C
-200 (in the above general formula (I), R1 is 2- (5'
-tetrazoyl) group in which R2 is H) was obtained. Melting point 256-258°C (2) SC-100, 5C-113 and SC-70 5C-20 except that the starting materials and reaction conditions were changed as appropriate
The above four types of compounds were obtained in the same manner as in the production of No. 0.
これらの化合物の融点は以下のとうりである。The melting points of these compounds are as follows.
５Ｃ−１００２５９〜２６２℃
５Ｃ−１１３２８４〜２８８℃
５Ｃ−１７０２９０℃以上
［急性毒性試験］
ｄｄｙ系雄性マウスを用いて静脈投与による急性毒性試
験を行ったところ、５Ｃ−２００は１０ｍｇ／ ｋｇ〜
５００ ｍｇ／ ｋｇの投与範囲において死亡例を認め
なかった（各群５個体）。5C-100259~262℃ 5C-113284~288℃ 5C-170290℃ or higher [Acute toxicity test] When an acute toxicity test was conducted by intravenous administration using ddy male mice, 5C-200 was found to be 10mg/kg~
No deaths were observed within the dosage range of 500 mg/kg (5 animals in each group).
［発明の効果］
以上説明したように、本発明の抗潰瘍剤は、消化性潰瘍
に対する優れた抗潰瘍作用を有し、かつ極めて低毒性で
ある。[Effects of the Invention] As explained above, the anti-ulcer agent of the present invention has an excellent anti-ulcer effect on peptic ulcers and has extremely low toxicity.
したがって、本発明の抗潰瘍剤を使用することにより、
消化性潰瘍の内科的治療法を更に多様化することが可能
となる。Therefore, by using the anti-ulcer agent of the present invention,
It becomes possible to further diversify medical treatments for peptic ulcers.
Claims (1)
ＯＯＨおよび２−（５’−テトラゾイル）基からなる群
より選択される１種の置換基であり、Ｒ＿１が２−ＣＯ
ＯＨのときＲ＿２はＨまたは４−ＮＯ＿２、Ｒ＿１が３
−ＣＯＯＨ、４−ＣＯＯＨまたは２−（５’−テトラゾ
イル）基のときＲ＿２はＨである） で表されるチアジン−１，１−ジオキシド誘導体を有効
成分として含有することを特徴とする抗潰瘍剤。(1) The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(I) (However, R_1 is 2-COOH, 3-COOH, 4-C
One type of substituent selected from the group consisting of OOH and 2-(5'-tetrazoyl) group, and R_1 is 2-CO
When OH, R_2 is H or 4-NO_2, R_1 is 3
-COOH, 4-COOH or 2-(5'-tetrazoyl) group, R_2 is H) An anti-ulcer agent characterized by containing as an active ingredient a thiazine-1,1-dioxide derivative represented by .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13809889A JPH035425A (en) | 1989-05-31 | 1989-05-31 | Anti-ulcer agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13809889A JPH035425A (en) | 1989-05-31 | 1989-05-31 | Anti-ulcer agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH035425A true JPH035425A (en) | 1991-01-11 |
Family
ID=15213905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13809889A Pending JPH035425A (en) | 1989-05-31 | 1989-05-31 | Anti-ulcer agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH035425A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0455830A1 (en) * | 1989-11-30 | 1991-11-13 | Nippon Hypox Laboratories Incorporated | Medicine containing thiazine dioxide derivative |
| JPH04117470A (en) * | 1982-06-24 | 1992-04-17 | Rohm & Haas Co | Coating agent composition |
| JP2009072634A (en) * | 2009-01-14 | 2009-04-09 | Yaskawa Electric Corp | Lower limb rehabilitation apparatus |
-
1989
- 1989-05-31 JP JP13809889A patent/JPH035425A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04117470A (en) * | 1982-06-24 | 1992-04-17 | Rohm & Haas Co | Coating agent composition |
| EP0455830A1 (en) * | 1989-11-30 | 1991-11-13 | Nippon Hypox Laboratories Incorporated | Medicine containing thiazine dioxide derivative |
| JP2009072634A (en) * | 2009-01-14 | 2009-04-09 | Yaskawa Electric Corp | Lower limb rehabilitation apparatus |
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