JPS591709B2 - 1,2-dithiol - Google Patents
1,2-dithiolInfo
- Publication number
- JPS591709B2 JPS591709B2 JP56146022A JP14602281A JPS591709B2 JP S591709 B2 JPS591709 B2 JP S591709B2 JP 56146022 A JP56146022 A JP 56146022A JP 14602281 A JP14602281 A JP 14602281A JP S591709 B2 JPS591709 B2 JP S591709B2
- Authority
- JP
- Japan
- Prior art keywords
- dithiol
- pyridazin
- thione
- methyl
- carbon atoms
- 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.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/14—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/20—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/38—One sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/16—Halogen atoms; Nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は治療的に有用な、新規な１・２−ジチオール誘
導体、それらの製造方法、およびこれらを含有する医薬
組成物に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel therapeutically useful 1,2-dithiol derivatives, processes for their preparation, and pharmaceutical compositions containing them.
本発明の新規な１・２−ジチオール誘導体は一般式〔式
中Ｈｅｔはピリダジン一３−イルまたはピリダジン一４
−イル基（これらの各基は場合によりメルカプト基また
は各アルキル基が１ないし４個の炭素原子を有するジア
ルキルアミノ基で置換されていてもよい）を表わし、そ
してＲは１ないし４個の炭素原子を有するアルキル基を
表わす〕で示される化合物である。The novel 1,2-dithiol derivative of the present invention has the general formula [wherein Het is pyridazine-3-yl or pyridazine-4].
-yl group (each of these groups may optionally be substituted with a mercapto group or a dialkylamino group having 1 to 4 carbon atoms in each alkyl group), and R represents a group having 1 to 4 carbon atoms. represents an alkyl group having an atom.
本発明に従い、一般式１（式中ＨｅｔおよびＲは前記定
義のとおりである）の化合物は、一般式（式中Ｈｅｔ゛
は前記したＨｅｔと同じ意味を有するか、または窒素原
子に対しα位置が炭素原子１〜４個を有するアルコキシ
基で置換されたピリダジン一３−イルまたは−４−イル
基を表わし、Ｒは前記定義のとおりであり、そしてＲ１
は炭素原子１〜４個を有するアルキル基である）の複素
環化合物を五硫化リンと反応させることにより製造でき
る。According to the present invention, compounds of the general formula 1, in which Het and R are as defined above, are prepared by compounds of the general formula 1, in which Het' has the same meaning as Het as defined above, or represents a pyridazin-3-yl or -4-yl group substituted with an alkoxy group having 1 to 4 carbon atoms, R is as defined above, and R1
is an alkyl group having 1 to 4 carbon atoms) by reacting a heterocyclic compound with phosphorus pentasulfide.
この反応は一般に、五硫化リンにたいして不活性な有機
溶媒、たとえばピリジン、ベンゼン、トルエン、キシレ
ンまたはクロロベンゼン中、５００ないし２００℃の温
度で実施する。The reaction is generally carried out in an organic solvent inert towards phosphorus pentasulfide, such as pyridine, benzene, toluene, xylene or chlorobenzene, at a temperature of 500 to 200°C.
一般式において、ピリダジニル基Ｈｅｔ′が窒素原子に
対してα一位置の炭素原子に、１゛ないし４個の炭素原
子を有するアルコキシ基を有する化合物を五硫化リンと
反応させると、一般式１においてＨｅｔが窒素原子に対
してα一位置がメルカプト基で置換されたピリダジン一
３−イルまたは一４−イル基である化合物が得られる。In the general formula, when a compound in which the pyridazinyl group Het' has an alkoxy group having 1 to 4 carbon atoms at the carbon atom at the α-position relative to the nitrogen atom is reacted with phosphorus pentasulfide, in the general formula 1, A compound is obtained in which Het is a pyridazin-13-yl or -4-yl group substituted with a mercapto group at the α-position relative to the nitrogen atom.
一般式の複素環化合物は以下の方法のいずれか１つに従
い得ることができる：（ａ） 一般式
（式中ＲおよびＲ１は前記定義のとおりである）で示さ
れるエステルを一般式（式中Ｈｅｔ′は前記定義のとお
りであり、Ｒ２は炭素原子１ないし４個を有するアルキ
ル基である）で示される複素環誘導体と反応させる。Heterocyclic compounds of the general formula can be obtained according to any one of the following methods: (a) An ester of the general formula, in which R and R1 are as defined above, is converted into an ester of the general formula, in which Het' is as defined above and R2 is an alkyl group having 1 to 4 carbon atoms).
この反応は、一般に、β−ケトエステルの製法であるク
ライゼン反応の通常の条件によつて行われる。さらに詳
しくは、縮合は、アルコキシド、たとえばナトリウムエ
トキサイドまたはナトリウムｔ−ブトキサイドの存在下
に、１００ないし１００゜Ｃの温度で実施できる。無水
有機溶媒たとえば芳香族炭化水素（たとえばベンゼン、
トルエンまたはキシレン）中で操作し、反応中に生成し
たアルコールＲ２−０Ｈ（Ｒ２は前記定義のとおりであ
る）を蒸留により除去しながら行つてもよい。この縮合
はまた、ジエチルエーテル中、水素化ナトリウムの存在
下に実施することもできる。This reaction is generally carried out under the usual conditions of the Claisen reaction, which is a method for producing β-ketoesters. More particularly, the condensation can be carried out in the presence of an alkoxide, such as sodium ethoxide or sodium t-butoxide, at a temperature of 100 to 100°C. Anhydrous organic solvents such as aromatic hydrocarbons (e.g. benzene,
The reaction may be carried out by operating in toluene or xylene) and removing the alcohol R2-0H (R2 is as defined above) produced during the reaction by distillation. This condensation can also be carried out in diethyl ether in the presence of sodium hydride.
（ｂ） 一般式（式中Ｒは前記定義のとおりであり、Ｚ
は反応性エステルの酸残基、たとえばハロゲン原子また
は硫酸もしくはスルホン酸エステル残基である）で示さ
れる反応性エステルを一般式（式中Ｈｅｔ′およびＲ１
は前記定義のとおりである）のβ−ケトエステルと反応
させる。(b) General formula (wherein R is as defined above, Z
is an acid residue of the reactive ester, such as a halogen atom or a sulfuric acid or sulfonic acid ester residue.
is as defined above).
この反応は一般に、有機溶媒たとえばアセトン中、縮合
剤、たとえばアルカリ金属炭酸塩、たとえば炭酸ナトリ
ウムまたはカリウムの存在下に行われる。This reaction is generally carried out in an organic solvent such as acetone in the presence of a condensing agent such as an alkali metal carbonate such as sodium or potassium carbonate.
また、アルカリ金属ヨウ化物たとえばヨウ化ナトリウム
またはカリウムをさらに存在させてもよい。有機溶媒、
たとえばエーテルまたは芳香族炭化水素中ナトリウムエ
トキサイドまた｝ま水素化ナトリウムの存在下に実施す
ることもできる。一般式のβ−ケトエステルは、一般式
（Ｒ１は前記定義のとおりである）で示される酢酸エス
テルを一般式の複素環化合物と、一般式のエステルと一
般式の複素環化合物との反応について上述したと同じ条
件下に反応さぜＣ得ることができる。Additionally, alkali metal iodides such as sodium or potassium iodide may also be present. organic solvent,
For example, it can be carried out with sodium ethoxide in ether or an aromatic hydrocarbon or in the presence of sodium hydride. The β-keto ester of the general formula is as described above for the reaction of the acetate ester represented by the general formula (R1 is as defined above) with the heterocyclic compound of the general formula, and the reaction of the ester of the general formula with the heterocyclic compound of the general formula. Under the same conditions as above, reaction C can be obtained.
上述の方法によつて得られた一般式１の新規化合物は、
所望により、結晶化またはクロマトグラフイ一等のよう
な物理的方法によつて精製することができる。The novel compound of general formula 1 obtained by the above method is:
If desired, it can be purified by physical methods such as crystallization or chromatography.
一般式１の１・２−ジチオール誘導体は顕著な化学療法
活性を有する。The 1,2-dithiol derivatives of general formula 1 have significant chemotherapeutic activity.
本発明の化合物は、とくに、抗ビルハルツ住血吸虫剤と
して有用である。しかも、この化合物の毒性は低く、大
部分の化合物の５０％致死用量（ＬＤ５Ｏ）は、マウス
に経口投与した場合、１０００Ｗ１９／Ｋ９体重以上で
ある。抗ビルハルツ住血吸虫活性は、ＳｃｈｉｓｔＯｓ
ＯｍａｍａｎｓＯｎｉに感染したマウスに用量１日１０
ないし１０００η／Ｋｇ体重を５日間、経口または皮下
投与すると現われる。１回投与では、この活性は経口ま
たは皮下投与の場合、１００ないし５００Ｔ！１９／Ｋ
ｇ体重で発現する。The compounds of the invention are particularly useful as anti-Bilharzian agents. Moreover, the toxicity of this compound is low, and the 50% lethal dose (LD5O) of most compounds is greater than 1000 W19/K9 body weight when administered orally to mice. The anti-Bilharzian Schistosoma activity was determined by SchistOs
Mice infected with OmamansOni were given a dose of 10 per day.
Appears after oral or subcutaneous administration of 1000 η/Kg body weight for 5 days. For a single dose, this activity is 100 to 500 T! for oral or subcutaneous administration! 19/K
Expressed in g body weight.
サル〔Ｍａｃｅａｃａｍｕｌａｔｔａ（Ｖａｒ．ｒｈｅ
ｓｕｓ）〕では、抗ビルハイツ活性は、１日５ないし１
００ｍ９／Ｋｇ体重を５日間経口投与すると現われる。Monkey [Maceacamulatta (Var.rhe
sus)], the antiviral height activity is 5 to 1 per day.
Appears after oral administration of 00m9/Kg body weight for 5 days.
一般式の１・２−ジチオール誘導体の抗ビルハイツ住血
吸虫活性を下記の試験に従い下記例１〜８の１・２−ジ
チオール生成物について得られた結果により説明する。
試験：ＳｃｈｉｓｔＯｓＯｍａｍａｎｓＯｒｌｉに実験
的に感染させたマウスに対する抗ビルハルツ住血吸虫活
性被験生成物は、２ケ月前にＳｃｈｉｓｔＯｓＯｍａｍ
ａｒｌｓＯｎｉに感染させたマウスに、５日連続で１日
１回、経口または皮下投与した。The anti-Schistosomiasis activity of the 1,2-dithiol derivatives of the general formula is illustrated by the results obtained for the 1,2-dithiol products of Examples 1 to 8 below according to the following tests.
Testing: Anti-Bilharzian Schistosoma activity against mice experimentally infected with SchistOsOmansOrli The test product was
Mice infected with arlsOni were administered orally or subcutaneously once a day for 5 consecutive days.
１投与量当り８〜１０匹のマウスを使用した。8-10 mice were used per dose.
処置した後の１０〜１５日目にマウスを死体解剖した。Mice were necropsied 10-15 days after treatment.
門脈、腸間膜静脈、肝臓および肺臓内の（生きているお
よび死んだ）寄生虫の数をかぞえた。The number of parasites (live and dead) in the portal vein, mesenteric vein, liver and lungs were counted.
ＥＤ５Ｏ値は５日間毎日投与した場合に、対照実験に比
較して、ＳｅｈｉｓｔＯｓＯｍｅｓの５０％を殺す生成
物の投与量である。表にはまた各生成物の毒性をマウス
に経口投与した場合の５０％致死量（ＬＤ５Ｏ）として
η／Ｋ９動物体重で示す。The ED5O value is the dose of product that kills 50% of SehistOsOmes when administered daily for 5 days compared to the control experiment. The table also shows the toxicity of each product as the 50% lethal dose (LD5O) when administered orally to mice in η/K9 animal weight.
とくに興昧のある化合物は、一般式１の以下の化合物で
ある：４−メチル−５−（ピリダジン一３−イル）−１
・２−ジチオール−３−チオン、４−エチル−５−（ピ
リダジン一３−イル）−１・２−ジチオール−３−チオ
ン、４−メチル−５（ピリダジン一４−イル）−１・２
−ジチオール−３−チオン、４−ブチル−５−（ピリダ
ジン３−イル）−１・２−ジチオール−３−チオンおよ
び５−（６−ジメチルアミノピリタジン一３−イル）−
４−メチル−１・２−ジチオール−３チオン。A compound of particular interest is the following compound of general formula 1: 4-methyl-5-(pyridazin-3-yl)-1
・2-dithiol-3-thione, 4-ethyl-5-(pyridazin-3-yl)-1,2-dithiol-3-thione, 4-methyl-5(pyridazin-4-yl)-1,2
-dithiol-3-thione, 4-butyl-5-(pyridazin-3-yl)-1,2-dithiol-3-thione and 5-(6-dimethylaminopyritazin-3-yl)-
4-Methyl-1,2-dithiol-3thione.
次に、本発明の１・２−ジチオール誘導体の製法を以下
の実施例により詳細に説明するが、これは本発明を限定
するものではない。Next, the method for producing the 1,2-dithiol derivative of the present invention will be explained in detail with reference to the following examples, but the present invention is not limited thereto.
例１
２−メチル−３−（ピリダジン一３−イル）３−オキソ
プロピオン酸エチルエステル（１１３．８ｆ）のトルエ
ン（５００ＣＣ）溶液を、２５分を要して、還流下に加
熱した五硫化リン（１８２７）のトルエン（１３００Ｃ
Ｃ）懸濁液に加える。Example 1 A solution of 2-methyl-3-(pyridazin-3-yl)3-oxopropionic acid ethyl ester (113.8f) in toluene (500 CC) was heated under reflux for 25 minutes. (1827) toluene (1300C
C) Add to suspension.
加え終つたのちもさらに還流加熱を１時間続ける。約２
０℃に冷却したのち、得られた不溶性生成物をろ取し、
ついで４５分間、約２０℃で、クロロホルム（１５００
ＣＣ）、蒸留水（５００ｃＣ）および１１Ｎアンモニア
（１０００ｃｃ）の混合物とともに攪拌する。不溶性の
残渣をろ去したのち、有機相を傾潟し、硫酸マグネシウ
ム上で乾燥させ、ろ過し、減圧下に蒸発乾固する。得ら
れた残留物をジエチルエーテル（５００ｃｃ）で、つい
でメチレンクロライド（２５０ＣＣ）で洗浄する。残留
物を１・２−ジクロロエタン（３８０ＣＣ）から再結晶
すると、４−メチル−５−（ピリダジン一３−イル）−
１・２−ジチオール−３−チオン（４．８６７）、融点
１９３℃、が得られる。２−メチル−３−（ピリダジン
一３−イル）３−オキソプロピオン酸エチルエステルは
以下の方法により製造できる。After the addition is complete, continue heating under reflux for another hour. Approximately 2
After cooling to 0°C, the obtained insoluble product was collected by filtration,
Then, for 45 minutes at about 20°C, chloroform (1500
CC), distilled water (500 cC) and 11N ammonia (1000 cc). After filtering off the insoluble residue, the organic phase is decanted, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. The resulting residue is washed with diethyl ether (500 cc) and then with methylene chloride (250 cc). The residue was recrystallized from 1,2-dichloroethane (380 CC) to give 4-methyl-5-(pyridazin-3-yl)-
1,2-dithiol-3-thione (4.867), melting point 193°C, is obtained. 2-Methyl-3-(pyridazin-3-yl)3-oxopropionic acid ethyl ester can be produced by the following method.
ナトリウム−ｔ−ブトキサイド（１９２７）の無水トル
エン（３０００ＣＣ）懸濁液に約３５℃で１３分を要し
、（ピリダジン３−イル）カルボン酸エチルエステル（
３０４７）およびプロピオン酸エチルエステル（２０４
ｙ）の無水トルエン（１０００ｃｃ）溶液を加える。反
応混合物を約２５℃で１２時間攪拌したのち、蒸留水（
３０００ｃｃ）を加える．水相を傾潟し、１２Ｎ塩酸（
１５０ＣＣ）で酸性にしたのち、メチレンクロライド（
１５００ＣＣ）、ついでメチレンクロライド（３×５０
０ＣＣ）で傾潟して洗浄する。有機相を合せ、硫酸マグ
ネシウム上で乾燥させ、ろ過し、減圧下に蒸発乾固する
。２−メチル−３一（ピリダジン一３−イル）−３−オ
キソプロピオン酸エチルエステル（２２７．７ｙ）が赤
色油状物として得られる。A suspension of sodium-t-butoxide (1927) in anhydrous toluene (3000 CC) at about 35°C takes 13 minutes to form (pyridazin-3-yl)carboxylic acid ethyl ester (
3047) and propionic acid ethyl ester (204
Add a solution of y) in anhydrous toluene (1000 cc). After stirring the reaction mixture at about 25°C for 12 hours, distilled water (
Add 3000cc). Decant the aqueous phase and 12N hydrochloric acid (
After acidifying with 150 CC), methylene chloride (
1500 CC), then methylene chloride (3 x 50
Wash by inclining at 0cc). The organic phases are combined, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. 2-Methyl-3-(pyridazin-3-yl)-3-oxopropionic acid ethyl ester (227.7y) is obtained as a red oil.
（ピリダジン一３−イル）カルボン酸エチルエステルは
、Ｗ．Ｊ．Ｌａｅｎｚａ等の：Ｊ．Ａｍｅｒ．Ｃｈｅｍ
．ＳＯｃ．７５、４０８６（１９５３）記載の方法にし
たがい製造できる。(Pyridazin-3-yl)carboxylic acid ethyl ester was prepared by W. J. Laenza et al.: J. Amer. Chem
．． SOc. 75, 4086 (1953).
例２
２−（ピリダジン一３−イル）カルボニルヘキサン酸エ
チルエステル（８０７）およびトルエン（１２００ＣＣ
）に懸濁した五硫化リン（１０６．５ｙ）を原料とする
以外は例１と同様に処理し、残留物を酢酸エチル（１０
ｃｃ）から再結晶して、４ブチル−５−（ピリダジン一
３−イル）−１・２−ジチオール−３−チオン（４ｙ）
が得られる。Example 2 2-(pyridazin-3-yl)carbonylhexanoic acid ethyl ester (807) and toluene (1200CC)
) was treated in the same manner as in Example 1 except that phosphorus pentasulfide (106.5y) suspended in
cc) to give 4-butyl-5-(pyridazin-3-yl)-1,2-dithiol-3-thione (4y)
is obtained.
融点９４℃２−（ピリダジン一３−イル）カルボニルヘ
キサン酸エチルエステルは、（ピリダジン一３−イル）
カルボン酸エチルエステル（１１４ｙ）、ヘキサン酸エ
チルエステル（１０８７）およびナトリウム−ｔ−ブト
キサイド（７２７）を無水トルエン（］５００ＣＣ）に
懸濁して製造できる。Melting point 94℃ 2-(pyridazin-3-yl)carbonylhexanoic acid ethyl ester is (pyridazin-3-yl)
It can be prepared by suspending carboxylic acid ethyl ester (114y), hexanoic acid ethyl ester (1087) and sodium-t-butoxide (727) in anhydrous toluene (]500CC).
２（ピリダジン一３−イル）カルボニルヘキサン酸エチ
ルエステル（】６０ｙ）が褐色油状物として得られる。2(pyridazin-3-yl)carbonylhexanoic acid ethyl ester (]60y) is obtained as a brown oil.
例３
２−メチル−３−（ピリダジン一４−イル）−３−オキ
ソプロピオン酸エチルエステル（２０６７）とトルエン
（２０６０ＣＣ）懸濁五硫化リン（２２０ｙ）から出発
する以外は例１と同様に処理し、残留物をアセトニトリ
ル（１２０ＣＣ）から再結晶すると、１４６℃で、次い
で１５０℃で溶融する４−メチル−５−（ピリダジン一
４−イル）１・２−ジチオール−３−チオン（５．１５
７）が得られる。Example 3 Processed as in Example 1 except starting from 2-methyl-3-(pyridazin-4-yl)-3-oxopropionic acid ethyl ester (2067) and phosphorus pentasulfide (220y) suspended in toluene (2060CC). and recrystallization of the residue from acetonitrile (120 CC) gives 4-methyl-5-(pyridazin-4-yl)1,2-dithiol-3-thione (5.15
7) is obtained.
２−メチル−３−（ピリダジン一４−イル）３−オキソ
プロピオン酸エチルエステルは、（ピリダジン一４−イ
ル）カルボン酸エチルエステル（１９４７）、プロピオ
ン酸エチルエステル（１３０．５ｙ）および無水トルエ
ン（３２４０ＣＣ）に懸濁したナトリウム−ｔ−ブトキ
サイド（１２３７）から製造できる。2-Methyl-3-(pyridazin-4-yl)3-oxopropionic acid ethyl ester is produced by (pyridazin-4-yl)carboxylic acid ethyl ester (1947), propionic acid ethyl ester (130.5y) and anhydrous toluene ( 3240CC) suspended in sodium t-butoxide (1237).
２−メチル−３（ピリダジン一４−イル）−３−オキソ
プロピオン酸エチルエステル（２０６７）が褐色油状物
として得られる。2-Methyl-3(pyridazin-4-yl)-3-oxopropionic acid ethyl ester (2067) is obtained as a brown oil.
（ピリダジン一４−イル）カルボン酸エチルエステルは
、Ｇ．Ｈｅｉｎｉｓｈ：ＭＯｎａｔｓｃｈ．Ｃｈｅｍ．
ｌ９７３、Ｕ広Ａｌ９５３に記載された方法にしたがつ
て製造できる。(Pyridazin-4-yl)carboxylic acid ethyl ester is produced by G. Heinish: MOnatsch. Chem.
It can be produced according to the method described in 1973 and Uhiro Al953.
例４
２−エチル−３−（ピリダジン一３−イル）３−オキソ
プロピオン酸エチルエステル（１９３７）と五硫化リン
（２３１ｙ）をトルエン（３０００ＣＣ）に懸濁し、約
２０℃で１５分間攪拌する。Example 4 2-Ethyl-3-(pyridazin-3-yl)3-oxopropionic acid ethyl ester (1937) and phosphorus pentasulfide (231y) are suspended in toluene (3000 CC) and stirred at about 20°C for 15 minutes.
ついで反応混合物を還流下に１時間加熱する。約２０℃
に冷却したのち、不溶性の生成物をろ取し、クロロホル
ム（３０００ＣＣ）、蒸留水（１０００ｃｃ）および１
１Ｎアンモニア（１０００ｃＣ）の混合物とともに１．
５時間攪拌する。ついで水相を傾潟し、クロロホルム（
５００ｃｃ）で洗浄する。有機分画を集め、硫酸マグネ
シウム上で乾燥し、ろ過し、減圧下に蒸発乾固する。得
られた残留物をメチレンクロライド（２５０ｅｃ）に溶
解し、径６．８ＣＴＬのカラムに充填したシリカゲル（
１６００ｙ）を通してろ過する。ついで、カラムを純粋
なメチレンクロライド（７０００ｃｃ）、次にメチレン
クロライドとメタノールとの９９．５：０．５（容量比
）混合物（７０００ｃｃ）で溶出する。これらの溶出液
は捨てる。最後に、カラムをメチレンクロライドとメタ
ノールの９９：１（容量比）混合物で溶出する。相当す
る溶出液を減圧下に蒸発乾固し、得られた残渣を、ジエ
チルエーテル（２００ｃｃ）、ジイソプロピルエーテル
（３×３０ＣＣ）で順次洗浄する。メタノール（５００
ＣＣ）から再結晶すると、４−エチル−５−（ピリダジ
ン一３−イル）−］・２−ジチオール−３−チオン（７
７）が得られる。融点１３『Ｃ２−エチル−３−（ピリ
ダジン一３−イル）３−オキソプロピオン酸エチルエス
テルは、（ピリダジン一３−イル）カルボン酸エチルエ
ステル（２０１．７７）、酪酸エチルエステル（１５３
，９７）無水トルエン（２７００ＣＣ）に懸濁したナト
リウム−ｔ−ブトキサイド（１２７．２７）から製造で
きる。The reaction mixture is then heated under reflux for 1 hour. Approximately 20℃
After cooling to a
1. with a mixture of 1N ammonia (1000 cC).
Stir for 5 hours. The aqueous phase was then decanted and chloroform (
500cc). The organic fractions are collected, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The obtained residue was dissolved in methylene chloride (250 ec) and packed in a column with a diameter of 6.8 CTL (silica gel).
1600y). The column is then eluted with pure methylene chloride (7000 cc) and then with a 99.5:0.5 (by volume) mixture of methylene chloride and methanol (7000 cc). Discard these eluates. Finally, the column is eluted with a 99:1 (by volume) mixture of methylene chloride and methanol. The corresponding eluate is evaporated to dryness under reduced pressure and the resulting residue is washed successively with diethyl ether (200 cc) and diisopropyl ether (3 x 30 cc). Methanol (500
Recrystallization from CC) gives 4-ethyl-5-(pyridazin-3-yl)-].2-dithiol-3-thione (7
7) is obtained. Melting point 13 'C2-Ethyl-3-(pyridazin-3-yl)3-oxopropionic acid ethyl ester is (pyridazin-3-yl)carboxylic acid ethyl ester (201.77), butyric acid ethyl ester (153
, 97) can be prepared from sodium t-butoxide (127.27) suspended in anhydrous toluene (2700 CC).
２−エチル−３−（ピリダジン一３イル）−３−オキソ
プロピオン酸エチルエステル（２１５７）が緑色油状物
として得られる。2-Ethyl-3-(pyridazin-3-yl)-3-oxopropionic acid ethyl ester (2157) is obtained as a green oil.
例５２−プロピル−３−（ピリダジン一３−イル）一３
−オキソプロピオン酸エチルエステル（１０９．８ｙ）
およびトルエン（１４００ＣＣ）懸濁五硫化リン（１２
４７）から出発する以外は例４と同様に処理する。Example 52-Propyl-3-(pyridazin-3-yl)-3
-Oxopropionic acid ethyl ester (109.8y)
and toluene (1400 CC) suspended phosphorus pentasulfide (12
Process as in Example 4 except starting from 47).
メタノール（５０ｃｃ）から再結晶後、７７℃で、次い
で１０３℃で融解する４−プロピル−５−（ピリダジン
一３−イル）一１噛２−ジチオーノレ一３−チオン（４
．０５７）が得られる。２−フ冶ピル一３−（ピリダジ
ン一３−イル）一３−オキソプロピオン酸エチルエステ
ルは、（ピリダジン一３−イル）カルボン酸エチルエス
テル（１０１７）、吉草酸エチルエステル（８６．５７
）、および乾燥トルエン（１４００ＣＣ懸濁ナトリウム
−ｔ−ブトキサイド（６３．７ｙ）から製造できる。After recrystallization from methanol (50 cc), 4-propyl-5-(pyridazin-3-yl)-2-dithionole-3-thione (4
．． 057) is obtained. 2-Fjipyr-3-(pyridazin-3-yl)-13-oxopropionic acid ethyl ester is (pyridazin-13-yl)carboxylic acid ethyl ester (1017), valeric acid ethyl ester (86.57)
), and dry toluene (1400 cc suspended sodium-t-butoxide (63.7y)).
２−プロピル−３−（ピリダジン一３−イル）−３−オ
キソプロピオン酸エチルエステル（１３３．４７）が褐
色油状物として得られる。2-Propyl-3-(pyridazin-3-yl)-3-oxopropionic acid ethyl ester (133.47) is obtained as a brown oil.
例６
３−（６−ジメチルアミノピリダジン一３−イル）−２
−エチル−３−オキソプロピオン酸エチルエステル（５
８ｙ）、およびトルエン（１１６０ｃＣ）懸濁五硫化リ
ン（７３７）から出発する以外は例４と同様に処理する
。Example 6 3-(6-dimethylaminopyridazin-3-yl)-2
-Ethyl-3-oxopropionic acid ethyl ester (5
8y) and phosphorus pentasulfide (737) suspended in toluene (1160 cC).
］・２−ジクロロエタン（３８ＣＣ）から再結晶後、１
６０℃、次いで１６４℃で融解する５−（６−ジメチル
アミノピリダジン一３−イル）−４−エチル−１・２−
ジチオール−３−チオン（５．７７）が得られる。３−
（６−ジメチルアミノピリダジン一３−イル）−２−エ
チル−３−オキソプロピオン酸エチルエステルは、（６
−ジメチルアミノピリダジンー３−イル）カルボン酸エ
チルエステル（５７ｙ）酪酸エチルエステル（６７．７
７）、および乾燥トルエン（１２６０ＣＣ）懸濁ナトリ
ウム−ｔ−ブトキサイド（５６ｙ）から製造できる。]・After recrystallization from 2-dichloroethane (38CC), 1
5-(6-dimethylaminopyridazin-3-yl)-4-ethyl-1.2- melting at 60°C and then at 164°C.
Dithiol-3-thione (5.77) is obtained. 3-
(6-dimethylaminopyridazin-3-yl)-2-ethyl-3-oxopropionic acid ethyl ester is (6-dimethylaminopyridazin-3-yl)-2-ethyl-3-oxopropionic acid ethyl ester
-dimethylaminopyridazin-3-yl)carboxylic acid ethyl ester (57y)butyric acid ethyl ester (67.7
7), and sodium-t-butoxide (56y) suspended in dry toluene (1260CC).
３−（６ジメチルアミノピリダジン一３−イル）−２−
エチル−３−オキサプロピオン酸エチルエステル（５８
ｙ）が褐色油状物として得られる。3-(6dimethylaminopyridazin-3-yl)-2-
Ethyl-3-oxapropionic acid ethyl ester (58
y) is obtained as a brown oil.
例７
３−（６−ジメチルアミノピリダジン一３−イル）−２
−メチル−３−オキソプロピオン酸エチルエステル（９
．８ｙ）のトルエン（１１５ＣＣ）溶液を、約１１０℃
に加熱した五硫化リン（１２．９９ｔ）のトルエン（１
１５ＣＣ）懸濁液に、１５分を要して加える。Example 7 3-(6-dimethylaminopyridazin-3-yl)-2
-Methyl-3-oxopropionic acid ethyl ester (9
．． 8y) in toluene (115CC) at about 110°C.
Phosphorus pentasulfide (12.99 t) heated to toluene (1
15CC) into the suspension over a period of 15 minutes.
還流下に加熱を４５分続ける。約２０℃に冷却したのち
、反応混合物に、蒸留水（２３０ＣＣ）、酢酸（２３０
ＣＣ）およびクロロホルム（２３０ｅｃ）を順次加える
。この混合物を約２０℃で２０時間攪拌したのち、ジメ
チルホルムアミド（５０ＣＣ）および炭酸カリウム（３
００７）を加える。水相を傾潟し、クロロホルム（３×
１００ＣＣ）で洗浄する。有機相を集め、硫酸ナトリウ
ム上で乾燥し、ろ過し、減圧下に蒸発乾固する。得られ
た残渣をクロロホルム（６００ｃｃ）に溶解し、得られ
た溶液を径３．５（１７７Ｚのカラムに充填したシリカ
ゲル上でろ過する。このカラムを純粋なクロロホルム（
８００ＣＣ）で溶出する。この溶出液は捨てる。ついで
カラムを純粋なクロロホルム（７００ＣＣ）で溶出し、
相当する溶出液を減圧下に蒸発乾固する。５−（６−ジ
メチルアミノピリダジン一３−イル）−４−メチル−１
・２−ジチオール−３−チオン（１．８５ｙ）が得られ
る。Continue heating under reflux for 45 minutes. After cooling to about 20°C, distilled water (230cc) and acetic acid (230cc) were added to the reaction mixture.
CC) and chloroform (230ec) are added sequentially. After stirring this mixture at about 20°C for 20 hours, dimethylformamide (50CC) and potassium carbonate (3CC) were added.
007) is added. The aqueous phase was decanted and chloroform (3x
Wash with 100cc). The organic phases are combined, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The resulting residue was dissolved in chloroform (600 cc) and the resulting solution was filtered over silica gel packed in a column of diameter 3.5 (177Z).
Elute at 800 CC). Discard this eluate. The column was then eluted with pure chloroform (700 CC) and
The corresponding eluate is evaporated to dryness under reduced pressure. 5-(6-dimethylaminopyridazin-3-yl)-4-methyl-1
-2-dithiol-3-thione (1.85y) is obtained.
融点２１６℃３−（６−ジメチルアミノピリダジン一３
−イル）−２−メチル−３−オキサプロピオン酸エチル
エステルは、（６−ジメチルアミノピリダジンー３−イ
ル）カルボン酸エチルエステル（２２．８ｙ）、プロピ
オン酸エチルエステル（１１．９３７）、および無水ト
ルエン（４００ｃｃ）懸濁ナトリウムｔ−ブトキサイド
（１１．２３７）から製造できる。Melting point 216℃ 3-(6-dimethylaminopyridazine-3
-yl)-2-methyl-3-oxapropionic acid ethyl ester is (6-dimethylaminopyridazin-3-yl)carboxylic acid ethyl ester (22.8y), propionic acid ethyl ester (11.937), and anhydrous It can be prepared from sodium t-butoxide (11.237) suspended in toluene (400 cc).
３−（６−ジメチルアミノピリダジン一３ーイル）−２
−メチル−３！オキソプロピオン酸エチルエステル（９
．８ｙ）が褐色油状物として得られる。3-(6-dimethylaminopyridazine-3-yl)-2
-Methyl-3! Oxopropionic acid ethyl ester (9
．． 8y) is obtained as a brown oil.
（６−ジメチルアミノピリダジン一３−イル）カルボン
酸エチルエステルは、３−シアノ−６−ジメチルアミノ
ピリダジン（５２．７ｙ）を、蒸留水（６００ｃｃ）、
１０Ｎ水酸化ナトリウム溶液（２００ｃｃ）およびエタ
ノール（４００ＣＣ）の混合物中に懸濁し、約７０℃に
４．５時間加熱すると得られる。(6-dimethylaminopyridazine-3-yl)carboxylic acid ethyl ester was obtained by mixing 3-cyano-6-dimethylaminopyridazine (52.7y) with distilled water (600cc),
Obtained by suspending in a mixture of 10 N sodium hydroxide solution (200 cc) and ethanol (400 cc) and heating to about 70° C. for 4.5 hours.
約２０℃に冷却したのち、反応混合物にメチレンクロラ
イド（２００ＣＣ）を加え、これを約２０℃に約１２時
間放置する。水相を傾潟し、１２Ｎ塩酸（１５０ＣＣ）
で酸性にし、減圧下に蒸発乾固する。かくして得られた
残渣に、エタノール（３６０ＣＣ）、１・２−ジクロロ
エタン（３６０ＣＣ）および純粋なメタンスルホン酸（
７６ｙ）を加える。得られた混合物を還流下に２０時間
加熱する。約２０℃に冷却したのち、生成した不溶性の
物質をろ過し、メチレンクロライド（３×２０ＣＣ）で
洗浄する。ろ液に飽和炭酸ナトリウム水溶液（７２０Ｃ
Ｃ）を加える。得られた不溶性生成物をろ過し、メチレ
ンクロライド（２×２００ＣＣ）で洗浄する。水相を傾
潟し、メチレンクロライド（２×１００ＣＣ）で洗浄す
る。有機分画を集め、硫酸マグネシウム上で乾燥し、ろ
過し、減圧下に蒸発乾固する。かくして、（６−ジメチ
ルアミノピリダジン一３−イル）カルボン酸エチルエス
テル（５０．８］ｔ）が得られる。融点１１２℃３−シ
アノ−６−ジメチルアミノピリダジンは、３−ヨード−
６−ジメチルアミノピリダジン（６３．７ｆ）とシアン
化第一銅（３４．３ｒ）をジメチルホルムアミド（３８
０ＣＣ）に懸濁して、約１５０℃に１０分間加熱するこ
とにより製造できる。After cooling to about 20° C., methylene chloride (200 CC) is added to the reaction mixture and it is left at about 20° C. for about 12 hours. Decant the aqueous phase and add 12N hydrochloric acid (150CC).
and evaporate to dryness under reduced pressure. The residue thus obtained was treated with ethanol (360 CC), 1,2-dichloroethane (360 CC) and pure methanesulfonic acid (
76y) is added. The resulting mixture is heated under reflux for 20 hours. After cooling to about 20° C., the insoluble material formed is filtered and washed with methylene chloride (3×20 CC). Add saturated aqueous sodium carbonate solution (720C
Add C). The resulting insoluble product is filtered and washed with methylene chloride (2 x 200 CC). The aqueous phase is decanted and washed with methylene chloride (2 x 100 CC). The organic fractions are collected, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. Thus, (6-dimethylaminopyridazin-3-yl)carboxylic acid ethyl ester (50.8]t) is obtained. Melting point 112℃ 3-cyano-6-dimethylaminopyridazine is 3-iodo-
6-dimethylaminopyridazine (63.7f) and cuprous cyanide (34.3r) were dissolved in dimethylformamide (38
It can be produced by suspending the mixture at 0 CC) and heating it at about 150°C for 10 minutes.
約２０℃に冷却したのち、反応混合物を、蒸留水（３０
００ｃｃ）、メチレンクロライド（７００ｃｃ）、重炭
酸アンモニウム（１１０ｙ）および１１Ｎアンモニア（
１１５ＣＣ）の混合物中に注ぐ。この混合物を１０分間
、約２０℃で攪拌したのち、水相を傾潟し、メチレンク
ロライド（３×３００ｃｃ）で洗浄する。有機相を集め
、硫酸マグネシウム上で乾燥し、減圧下に蒸発乾固する
。３−シアノ−６−ジメチルアミノピリダジン（３０．
５ｙ）が得られる。After cooling to about 20°C, the reaction mixture was diluted with distilled water (30°C
00cc), methylene chloride (700cc), ammonium bicarbonate (110y) and 11N ammonia (
115cc) mixture. After stirring the mixture for 10 minutes at about 20° C., the aqueous phase is decanted and washed with methylene chloride (3×300 cc). The organic phases are collected, dried over magnesium sulphate and evaporated to dryness under reduced pressure. 3-cyano-6-dimethylaminopyridazine (30.
5y) is obtained.
融点１５０℃３−ヨード−６−ジメチルアミノピリダジ
ンは以下の方法で製造できる。3-Iodo-6-dimethylaminopyridazine having a melting point of 150°C can be produced by the following method.
３・６−ジヨードピリダジン（２０３，７ｙ）およびジ
メチルアミン（２７６７）をメタノール（ト）５００Ｃ
Ｃ）に溶解し、約２０℃において４８時間攪拌する。3,6-diiodopyridazine (203,7y) and dimethylamine (2767) in methanol (t) 500C
C) and stirred at about 20° C. for 48 hours.
減圧下に蒸発乾固したのち、得られた残渣を１５分間、
蒸留水（１５００ＣＣ）と攪拌する。不溶性の生成物を
ろ取し、蒸留水（２×２００ＣＣ）で洗浄する。６−ジ
メチルアミノ−３−ヨードピリダジン（１］３．７ｆ７
）が得られる。After evaporating to dryness under reduced pressure, the resulting residue was evaporated for 15 minutes.
Stir with distilled water (1500 CC). The insoluble product is filtered off and washed with distilled water (2 x 200 CC). 6-dimethylamino-3-iodopyridazine (1) 3.7f7
) is obtained.
融点１３５℃例８五硫化リン（１５５ｆ／）をトルエン
（１０００ｃｃ）に懸濁して還流下に加熱し、３−（６
−メトキシピリダジン一３−イル）−２−メチル−３オ
キソプロピオン酸エチルエステル（１８４．５ｙ）のト
ルエン（１０００ｃｃ）溶液を１０分間で加える。Melting point 135°C Example 8 Phosphorus pentasulfide (155 f/) was suspended in toluene (1000 cc) and heated under reflux to form 3-(6
-Methoxypyridazin-3-yl)-2-methyl-3oxopropionic acid ethyl ester (184.5y) in toluene (1000 cc) is added over 10 minutes.
反応混合物を３０分間還流させる。反応混合物を約８０
℃に冷却したのち、上澄液を除去する。沈殿を約８０℃
でトルエン（２５０ＣＣ）にとる。トルエン溶液を沈殿
から分離する。トルエン相を合して、約２０℃に冷却し
、蒸留水（４×５００ｃｃ）、１０％（Ｗ／Ｖ）重炭酸
カリウム水溶液（２×５００ＣＣ）および蒸留水（５×
５００ＣＣ）で洗浄し、硫酸マグネシウム上で乾燥し、
ろ過し、減圧（３０ｍｍＨｇ）下に蒸発乾固する。残渣
を約２０℃でトルエン（２００ｃｃ）にとる。The reaction mixture is refluxed for 30 minutes. The reaction mixture was heated to approx.
After cooling to °C, remove the supernatant. Precipitate at about 80℃
Add toluene (250CC). Separate the toluene solution from the precipitate. The toluene phases were combined, cooled to about 20° C., distilled water (4×500 cc), 10% (W/V) potassium bicarbonate aqueous solution (2×500 cc) and distilled water (5×
500 CC), dried over magnesium sulfate,
Filter and evaporate to dryness under reduced pressure (30 mmHg). The residue is taken up in toluene (200 cc) at about 20°C.
生成物の沈殿をろ取し、トルエン（３×２０ＣＣ）、蒸
留水（３×１５ＣＣ）およびジイソプロピルエーテル（
４Ｘ１０ＣＣ）で洗浄する。かくして、５−（６−メル
カプトピリダジン一３−イル）−４−メチル−１・２−
ジチオール−３−チオン（１，４ｙ）が得られる。融点
２４５℃ｏ先に沈殿をろ過して得られたトルエン溶液に
トルエン（１３００ＣＣ）を加え、この溶液を還流下に
加熱する。The product precipitate was collected by filtration and mixed with toluene (3 x 20 CC), distilled water (3 x 15 CC) and diisopropyl ether (
Wash with 4×10 CC). Thus, 5-(6-mercaptopyridazin-3-yl)-4-methyl-1,2-
Dithiol-3-thione (1,4y) is obtained. Toluene (1300 CC) is added to the toluene solution obtained by filtering the precipitate at a melting point of 245°C, and the solution is heated under reflux.
ついで、五硫化リン（１７３７）を少量ずつ４５分で加
える。還流を１０分間続ける。トルエン溶液を前述した
と同様に８０℃で処理すると、５−（６−メルカプトピ
リダジン一３−イル）−４−メチル−１・２−ジチオー
ル−３−チオン（６．１７）、融点２４５℃が得られる
。３−（６−メトキシピリダジン一３−イル）２−メチ
ル−３−オキソプロピオン酸エチルエステルは以下の方
法により製造できる。Then, phosphorus pentasulfide (1737) is added little by little over 45 minutes. Continue refluxing for 10 minutes. When the toluene solution was treated at 80°C in the same manner as described above, 5-(6-mercaptopyridazin-3-yl)-4-methyl-1,2-dithiol-3-thione (6.17) with a melting point of 245°C was obtained. can get. 3-(6-methoxypyridazin-3-yl)2-methyl-3-oxopropionic acid ethyl ester can be produced by the following method.
６−メトキシピリダジン一３−カルボン酸メチルエステ
ル（５０ｙ）をプロピオン酸エチルエステル（２２０ｙ
）にとり、この溶液に、約９８℃で、水素化ナトリウム
（１９．２７）（鉱油中５０％）を、２０分間を要して
少量ずつ加える。6-Methoxypyridazine-3-carboxylic acid methyl ester (50y) was converted into propionic acid ethyl ester (220y).
) and to this solution at about 98° C., sodium hydride (19.27) (50% in mineral oil) is added in portions over a period of 20 minutes.
反応混合物をさらに３０分間還流させる。ついで約２０
℃に冷却し、エタノール（１０ｃｃ）を注意深く加え、
さらに蒸留水（８００ｃｃ）を加える。水相を除去し、
ジイソプロピルエーテル（３×２５０ＣＣ）で傾潟して
洗浄し、純粋な酢酸（２５０ＣＣ）を加え（ＰＨ５−６
）、水相を再び酢酸エチル（３×１５０ＣＣ）で洗浄す
る。有機相を集め、硫酸マグネシウム上で乾燥し、ろ過
し、減圧（３０ｍｍＨｇ）下に蒸発乾固すると、３−（
６−メトキシピリダジン一３−イル）−２−メチル−３
−オキソプロピオン酸エチルエステル（３７．２ｙ）が
黄色油状物として得られる。６−メトキシピリダジン一
３−カルボン酸メチルエステルは、Ｔ．ＮａｋａｇＯｍ
ｅ等によるＪ．Ｈｅｔ．Ｃｈｅｍ．、３７９頁（１９６
８）に従い製造できる。The reaction mixture is refluxed for an additional 30 minutes. Then about 20
Cool to ℃, carefully add ethanol (10 cc),
Furthermore, add distilled water (800 cc). removing the aqueous phase;
Wash by decanting with diisopropyl ether (3 x 250 CC) and add pure acetic acid (250 CC) (PH 5-6).
), and the aqueous phase is washed again with ethyl acetate (3×150 CC). The organic phases were collected, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (30 mmHg) to give 3-(
6-methoxypyridazin-3-yl)-2-methyl-3
-Oxopropionic acid ethyl ester (37.2y) is obtained as a yellow oil. 6-Methoxypyridazine-3-carboxylic acid methyl ester is manufactured by T. NakagOm
J.E. et al. Het. Chem. , 379 pages (196
8).
本発明は、一般式１の１・２−ジチオール誘導体の少な
くとも１種を活性成分とし、これを適合性ある医薬的に
許容されうる希釈剤または補助剤と配合してなる医薬組
成物も包含する。本発明はとくに、経口、非経口または
直腸投与用のこの種の組成物を包含する。経口投与用の
固体組成物としては、たとえば錠剤、丸剤、粉末剤、ゼ
ラチン被覆丸剤または顆粒剤を挙げることができる。The present invention also encompasses pharmaceutical compositions comprising at least one 1,2-dithiol derivative of general formula 1 as an active ingredient in combination with compatible pharmaceutically acceptable diluents or adjuvants. . The invention particularly encompasses compositions of this type for oral, parenteral or rectal administration. Solid compositions for oral administration can include, for example, tablets, pills, powders, gelatin-coated pills or granules.
この種の固体組成物は、活性化合物に少なくとも１種の
不活性希釈剤、たとえば蔗糖、乳糖またはデンプンを配
合してなるものである。この種の組成物には、常法によ
り、不活性希釈剤以外の添加剤、たとえば、滑沢剤にと
えばステアリン酸マグネシウムまたは湿潤剤を加えるこ
ともできる。経口投与用の液体組成物としては、本技術
分野で慣用される不活性希釈剤、たとえば、水、流動パ
ラフイン等を含有する、医薬的に許容される乳濁液、溶
液、懸濁液、シロツプ、エリキシール等を挙げることが
できる。不活性希釈剤のほかに、補助剤、たとえば湿潤
剤、乳化剤、懸濁剤、甘昧剤、矯昧剤、賦香剤等を加え
ることもできる。本発明の経口投与用組成物には、活性
物質を単独に、または希釈剤もしくは賦形剤とともに、
吸収性物質たとえばゼラチン中に包有させたカプセル剤
も包含される。本発明の非経口投与用組成物としては、
滅菌水性または非水性溶液、懸濁液または乳濁液を挙げ
ることができる。Solid compositions of this type consist of an active compound combined with at least one inert diluent, such as sucrose, lactose or starch. In addition to inert diluents, additives other than inert diluents can also be added to compositions of this type, for example lubricants such as magnesium stearate or wetting agents. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups containing inert diluents conventionally used in the art, such as water, liquid paraffin, etc. , elixir, etc. Besides inert diluents, auxiliary agents such as wetting agents, emulsifying agents, suspending agents, sweetening agents, corrigents, flavoring agents, etc. can also be added. Compositions for oral administration according to the invention contain the active substance alone or together with diluents or excipients.
Capsules enclosed in absorbent materials such as gelatin are also included. The composition for parenteral administration of the present invention includes:
Mention may be made of sterile aqueous or non-aqueous solutions, suspensions or emulsions.
非水性溶媒またはベヒクルの例としては、プロピレング
リコール、ポリエチレングリコール、植物油、たとえば
オリーブ油、注射可能な有機エステル、たとえばオレイ
ン酸エチルエステルがある。この種の組成物には、補助
剤、たとえば防腐剤、湿潤剤、乳化剤、分散剤を加える
こともできる。この種の組成物は、たとえば、滅菌ろ過
、滅菌剤の添加、照射または加熱によつて滅菌すること
ができる。また滅菌固体組成物の形にしてもよく、これ
は使用の直前に滅菌水または他の滅菌注射用媒体に溶解
することができる。直腸投与用組成物としては、活性成
分のほかに、賦形剤、たとえばカカオ脂または適当なロ
ウ基剤を含有する坐剤がある。本発明の組成物はヒトの
治療において、とくにビルハイツ住血吸虫症の治療に有
用である。Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as oleic acid ethyl ester. Compositions of this type can also contain auxiliary agents, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Compositions of this type can be sterilized, for example, by sterile filtration, addition of sterilizing agents, irradiation or heating. They may also be in the form of sterile solid compositions, which can be dissolved in sterile water or other sterile injectable medium immediately before use. Compositions for rectal administration include suppositories containing, in addition to the active ingredient, excipients such as cocoa butter or a suitable wax base. The compositions of the invention are useful in the treatment of humans, particularly for the treatment of Billheits schistosomiasis.
本発明組成物中の活性成分の含量は任意に変化させるこ
とができるが、適当な投与量が達成できるような割合で
あることが必要である．投与量は、所望の治療効果、投
与経路、処置期間等によつて決まる。ヒトの治療におい
て、本組成物を成人に投与する場合は、一般的に、経口
では、活性物質１日１０Ｔｆ１９ないし１００ｍ９／Ｋ
ｇ体重が、非経口投与では１日１ないし５０Ｔｆ１９／
Ｋｇ体重が投与されるようにしなければならない。一般
には、処置すべき患者の年令、体重、その他の固有の因
子を考慮して、医師が適宜、用量を決定すべきである。
以下に、本発明の医薬組成物の例を示す。例９
活性成分１００ηを含有し、以下の組成を有する錠剤を
常法により製造する。The content of the active ingredient in the composition of the present invention can be varied as desired, but it is necessary that the proportion be such that an appropriate dosage can be achieved. The amount administered depends on the desired therapeutic effect, route of administration, duration of treatment, etc. In human therapy, when the composition is administered to adults, the active substance is generally administered orally at between 10 Tf19 and 100 m9/K per day.
g body weight is 1 to 50 Tf19/day for parenteral administration.
Kg body weight must be administered. In general, the physician should determine the appropriate dosage, taking into consideration the age, weight, and other specific factors of the patient being treated.
Examples of the pharmaceutical composition of the present invention are shown below. Example 9 Tablets containing 100 η of active ingredient and having the following composition are prepared in a conventional manner.
一般式１の１・２−ジチオールのその他の誘導体、たと
えば前記例２〜８の生成物として得られた化合物も４−
メチル−５−（ピリダジン一３イル）−１・２−ジチオ
ール−３−チオンの代りに同様の医薬組成物に使用でき
る。Other derivatives of 1,2-dithiol of general formula 1, such as the compounds obtained as products of Examples 2 to 8 above, are also 4-
It can be used in place of methyl-5-(pyridazin-3-yl)-1,2-dithiol-3-thione in similar pharmaceutical compositions.
Claims (1)
−４−イル基（これらの各基は場合によりメルカプト基
、または各アルキル基が１ないし４個の炭素原子を有す
るジアルキルアミノ基で置換されていてもよい）を表わ
し、そしてＲは１ないし４個の炭素原子を有するアルキ
ル基を表わす〕で示される１・２−ジチオール誘導体。 ２ ４−メチル−５−（ピリダジン−３−イル）−１・
２−ジチオール−３−チオンである特許請求の範囲第１
項に記載の１・２−ジチオール誘導体。 ３ ４−ブチル−５−（ピリダジン−３−イル）−１・
２−ジチオール−３−チオンである特許請求の範囲第１
項に記載の１・２−ジチオール誘導体。 ４ ４−メチル−５−（ピリダジン−４−イル）−１・
２−ジチオール−３−チオンである特許請求の範囲第１
項に記載の１・２−ジチオール誘導体。 ５ ４−エチル−５−（ピリダジン−３−イル）−１・
２−ジチオール−３−チオンである特許請求の範囲第１
項に記載の１・２−ジチオール誘導体。 ６ ４−プロピル−５−（ピリダジン−３−イル）−１
・２−ジチオール−３−チオンである特許請求の範囲第
１項に記載の１・２−ジチオール誘導体。 ７ ５−（６−ジメチルアミノピリダジン−３−イル）
−４−エチル−１・２−ジチオール−３−チオンである
特許請求の範囲第１項に記載の１・２−ジチオール誘導
体。 ８ ５−（６−ジメチルアミノピリダジン−３−イル）
−４−メチル−１・２−ジチオール−３−チオンである
特許請求の範囲第１項に記載の１・２−ジチオール誘導
体。 ９ ５−（６−メルカプトピリダジン−３−イル）−４
−メチル−１・２−ジチオール−３−チオンである特許
請求の範囲第１項に記載の１・２−ジチオール誘導体。 １０ 一般式 ▲数式、化学式、表等があります▼ 〔式中Ｈｅｔはピリダジン−３−イルまたはピリダジン
−４−イル基（これらの各基は場合によりメルカプト基
、または各アルキル基が１ないし４個の炭素原子を有す
るジアルキルアミノ基で置換されていてもよい）を表わ
し、そしてＲは１ないし４個の炭素原子を有するアルキ
ル基を表わす〕で示される１・２−ジチオール誘導体の
製造方法であつて、一般式▲数式、化学式、表等があり
ます▼ （式中Ｈｅｔ′はＨｅｔについて上記した意味を有する
か、または窒素原子に対しα−位置が１ないし４個の炭
素原子を有するアルコキシ基で置換されたピリダジン−
３−イルまたは−４−イル基を表わし、Ｒは上記定義の
とおりであり、そしてＲ＿１は１ないし４個の炭素原子
を有するアルキル基を表わす）で示される複素環化合物
を五硫化リンと反応させることよりなる方法。 １１ 活性成分として、一般式 ▲数式、化学式、表等があります▼ 〔式中Ｈｅｔはピリダジン−３−イルまたはピリダジン
−４−イル基（これらの各基は場合によりメルカプト基
、または各アルキル基が１ないし４個の炭素原子を有す
るジアルキルアミノ基で置換されていてもよい）を表わ
し、そしてＲは１ないし４個の炭素原子を有するアルキ
ル基を表わす〕で示される１・２−ジチオール誘導体の
少なくとも１種を、これと適合性の医薬として許容され
うる稀釈剤または助剤の１種またはそれ以上と組合せて
含有する抗ビルハルツ住血吸虫剤。[Claims] 1 General formula ▲ Numerical formulas, chemical formulas, tables, etc. 1,2-dithiol of the formula (optionally substituted by a dialkylamino group having 1 to 4 carbon atoms) and R represents an alkyl group having 1 to 4 carbon atoms derivative. 2 4-methyl-5-(pyridazin-3-yl)-1.
Claim 1 which is 2-dithiol-3-thione
1,2-dithiol derivatives described in . 3 4-Butyl-5-(pyridazin-3-yl)-1.
Claim 1 which is 2-dithiol-3-thione
1,2-dithiol derivatives described in . 4 4-Methyl-5-(pyridazin-4-yl)-1.
Claim 1 which is 2-dithiol-3-thione
1,2-dithiol derivatives described in . 5 4-ethyl-5-(pyridazin-3-yl)-1.
Claim 1 which is 2-dithiol-3-thione
1,2-dithiol derivatives described in . 6 4-propyl-5-(pyridazin-3-yl)-1
- The 1,2-dithiol derivative according to claim 1, which is 2-dithiol-3-thione. 7 5-(6-dimethylaminopyridazin-3-yl)
1.2-dithiol derivative according to claim 1, which is -4-ethyl-1.2-dithiol-3-thione. 8 5-(6-dimethylaminopyridazin-3-yl)
1.2-dithiol derivative according to claim 1, which is -4-methyl-1.2-dithiol-3-thione. 9 5-(6-mercaptopyridazin-3-yl)-4
The 1,2-dithiol derivative according to claim 1, which is -methyl-1,2-dithiol-3-thione. 10 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, Het is a pyridazin-3-yl or pyridazin-4-yl group (each of these groups may be a mercapto group, or 1 to 4 alkyl groups) optionally substituted with a dialkylamino group having 1 to 4 carbon atoms, and R represents an alkyl group having 1 to 4 carbon atoms. Therefore, there are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. substituted pyridazine-
3-yl or -4-yl group, R is as defined above and R_1 is an alkyl group having 1 to 4 carbon atoms) is reacted with phosphorus pentasulfide. How to be more than let. 11 As active ingredients, there are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. optionally substituted with a dialkylamino group having 1 to 4 carbon atoms, and R represents an alkyl group having 1 to 4 carbon atoms. An anti-bilharzian hematobium agent containing at least one in combination with one or more pharmaceutically acceptable diluents or auxiliaries compatible therewith.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7603604A FR2340730A1 (en) | 1976-02-10 | 1976-02-10 | Heterocyclic (1,2)-dithiole-(3)-thione derivs. - for treatment of bilharziasis (BE 9.8.77) |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5781484A JPS5781484A (en) | 1982-05-21 |
| JPS591709B2 true JPS591709B2 (en) | 1984-01-13 |
Family
ID=9168948
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP56146023A Expired JPS591710B2 (en) | 1976-02-10 | 1981-09-16 | 1,2-dithiol compound |
| JP56146022A Expired JPS591709B2 (en) | 1976-02-10 | 1981-09-16 | 1,2-dithiol |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP56146023A Expired JPS591710B2 (en) | 1976-02-10 | 1981-09-16 | 1,2-dithiol compound |
Country Status (5)
| Country | Link |
|---|---|
| JP (2) | JPS591710B2 (en) |
| BE (1) | BE851262A (en) |
| FR (1) | FR2340730A1 (en) |
| MW (1) | MW477A1 (en) |
| ZA (1) | ZA77743B (en) |
-
1976
- 1976-02-10 FR FR7603604A patent/FR2340730A1/en active Granted
-
1977
- 1977-02-09 BE BE174799A patent/BE851262A/xx not_active IP Right Cessation
- 1977-02-09 MW MW4/77A patent/MW477A1/en unknown
- 1977-02-09 ZA ZA770743A patent/ZA77743B/en unknown
-
1981
- 1981-09-16 JP JP56146023A patent/JPS591710B2/en not_active Expired
- 1981-09-16 JP JP56146022A patent/JPS591709B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2340730B1 (en) | 1980-05-09 |
| BE851262A (en) | 1977-08-09 |
| FR2340730A1 (en) | 1977-09-09 |
| ZA77743B (en) | 1977-12-28 |
| MW477A1 (en) | 1978-05-10 |
| JPS57112391A (en) | 1982-07-13 |
| JPS591710B2 (en) | 1984-01-13 |
| JPS5781484A (en) | 1982-05-21 |
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