JPS58180484A - 1-substituted n-/8 alpha-ergolinyl/-n',n'- diethylurea and manufacture - Google Patents
1-substituted n-/8 alpha-ergolinyl/-n',n'- diethylurea and manufactureInfo
- Publication number
- JPS58180484A JPS58180484A JP58039349A JP3934983A JPS58180484A JP S58180484 A JPS58180484 A JP S58180484A JP 58039349 A JP58039349 A JP 58039349A JP 3934983 A JP3934983 A JP 3934983A JP S58180484 A JPS58180484 A JP S58180484A
- Authority
- JP
- Japan
- Prior art keywords
- ergolinyl
- general formula
- diethylurea
- methyl
- formula
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/10—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hetero atoms directly attached in position 8
- C07D457/12—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
Abstract
(57)【要約】本公報は電子出願前の出願データであるた
め要約のデータは記録されません。(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】
本発明は一般式■
／
２
（式中Ｒ″は１〜４個の炭素原子を有する低級アルキル
基金表わし、Ｒ″は１〜４個の炭素原子を有すル低級ア
ルキル基、ベンジル基、アリル基又はＲ１が水素原子も
しくは１〜２個の炭素原子を有するアルキル基金衣わし
、ｎが整数１〜４である一般式−／Ｃ山／ｎＣ０ＯＲ”
の基金衣わす。）？有する１−１を換Ｎ−／８α−
エルゴリニル／−Ｎ’、 Ｎ’−ジエチルウレア及びそ
の製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula ■/2 (wherein R'' represents a lower alkyl group having 1 to 4 carbon atoms; R'' represents a lower alkyl group having 1 to 4 carbon atoms; An alkyl group, a benzyl group, an allyl group, or an alkyl group in which R1 is a hydrogen atom or has 1 to 2 carbon atoms, and n is an integer of 1 to 4, the general formula is -/C/nC0OR"
The fund is worth it. )? Replace 1-1 with N-/8α-
The present invention relates to ergolinyl/-N', N'-diethylurea and its production method.
以下に与えられた一般式Ｈの化合物である、１の位置に
置換された８α−エルゴリニル−Ｎ’Ｉ Ｎ’ −ジエ
チルウレア、例えばＮ−／Ｄ−６−メチル−（４）
８α−エルゴリニル／ −Ｎ’、 Ｎ’−ジエチルウレ
ア（チェコスロバキア発明証番号第１５２１５３−Ｕ及
びその６−プロピル類似体（チェコスロバキア発明田＃
ＡＰＶ７１１３−７９及びＰＶ４１６８−８０ン、が動
的にひいてプロラクチン及び成長ホルモンの分泌に対し
て強い抑制効果並びにゴナドトロピンの分泌に別して刺
激的な効果を示すということは知られている。さて本発
明の発明者は一般式Ｉ金石するこれらの尿素の１＝置換
誘導体がまた実験動物に２いてプロラクチン分泌の強い
抑制斉りであることがわかった。8α-ergolinyl-N'IN'-diethylurea substituted in position 1, for example N-/D-6-methyl-(4) 8α-ergolinyl/, which is a compound of general formula H given below. -N', N'-diethylurea (Czechoslovak Invention No. 152153-U and its 6-propyl analogue (Czechoslovak Invention No. 152153-U)
It is known that APV7113-79 and PV4168-80 dynamically exhibit a strong inhibitory effect on the secretion of prolactin and growth hormone, and a separately stimulating effect on the secretion of gonadotropins. The inventors of the present invention have now found that these 1=substituted derivatives of ureas of the general formula I also exhibit strong inhibition of prolactin secretion in experimental animals.
一般式Ｉの８α−エルゴリニルウレアは分子中に５，８
及び１０の位置に３個の不斉炭素を含み、その空間釣部
ｔｉＩｔはＤ −９，１０−ジヒドロイソリゼルグ版−
Ｉ：
（Ｃ１５／に２ける水素はβ−位位置万有くこの炭素に
２ける配ｔは５Ｒである）、Ｃ／８．７に２ける尿素の
残基はα−位置にあり（この炭素に２ける配置は８８で
ある）そしてＣ７□０／にυける水素はα−位置にある
（この炭素に２ける配置はＩＯＲである）。）
に３ける場合と同じである。8α-ergolinyl urea of general formula I has 5,8
and contains three asymmetric carbons at position 10, and its spatial part tiIt is D-9,10-dihydroisolyserg version-
I: (Hydrogen at C15/2 is at the β-position, and the t position at this carbon is 5R), the urea residue at C/8.7 is at the α-position (this The configuration at carbon 2 is 88) and the hydrogen at C7□0/ is in the α-position (the configuration at carbon 2 is IOR). ) is the same as adding 3 to .
本発明によれば一般式Ｉの１−置換８α−エルゴリニル
ウレアは一般式■（式中Ｒ１は前記意味のものである）
の１の位置にｔ侯された８α−エルゴリニル−Ｎ’、
Ｎ’−ジエチルウレア７＞Ｅ 一般式１１１％式％
（式中Ｒ２は一般式ＩＫ２いて与えられた意味のもので
あり、Ｘはハロゲン原子又はエステル結合された脂肪族
もしくは芳香族スルホン酸の残基あるいはエステル結合
された硫酸の残基全衣わす。）′ｆｒ、！するアルキル
化剤と反応するという方法で製造され得る。According to the invention, the 1-substituted 8α-ergolinyl urea of the general formula I is of the general formula ■ (wherein R1 has the above meaning)
8α-ergolinyl-N′ in position 1 of
N'-Diethylurea 7>E General formula 111% Formula % (In the formula, R2 has the meaning given in general formula IK2, and X is a halogen atom or the residue of an ester-bonded aliphatic or aromatic sulfonic acid. All residues of sulfuric acid bonded to groups or esters are covered.)'fr,! It can be produced by reacting with an alkylating agent.
一般式Ｈの出発原料は既知の方法（％粁文献の参考資＃
＋に前記診照）によって製造することができる。The starting materials for general formula H can be obtained by known methods (%
+ can be manufactured by the above-mentioned examination).
一般式Ｈの化合物のアルキル化は遊Ｗｉ＆’［−−４０
°Ｃ〜＋５０°Ｃの範囲の温度で結合する塩基の存在で
不活性浴痢中に２ける１〜５モル当量の一般式■のアル
キル化剤と一般式Ｈの化合物の溶液との作用によって本
発明に従って成し遂げられる。Alkylation of compounds of general formula H is
By the action of a solution of a compound of general formula H with 1 to 5 molar equivalents of an alkylating agent of general formula H in the presence of a combined base at a temperature in the range from °C to +50 °C. Accomplished according to the present invention.
一般式■のアルキル化剤としてアルキルハロゲン化物を
使用することができ、好葦しくに沃化物もしくはアルキ
ルプロミド、アリルプロミド、ベンジルプロミド又はω
−ブロムアルカン酸及びそのエステル全使用することが
でき、あるいはジメチルスルフェート４しく’Ｕジエチ
ルスルフェートのよ′）ｌ硫酸のアルキルエステル又は
脂肪族もしくに芳香族スルホン酸のエステル、例えばア
ルキル−メタンスルホネートもしくはアルキル−ｐ−ト
ルエンスルホネート全１更用することができる０不活性
溶剤としてジメナルホルムアミド、ジメチルスルホキシ
ド、燐酸もしくはアセトンのヘキ（７）
サメチルトリアミド、又に液体アンモニアのような極性
のある中性溶媒全使用することができる。Alkyl halides can be used as alkylating agents of general formula (2), preferably iodides or alkyl bromides, allyl bromides, benzyl bromides or
- All bromoalkanoic acids and their esters can be used, or alkyl esters of sulfuric acid or esters of aliphatic or aromatic sulfonic acids, such as dimethyl sulfate or diethyl sulfate. methanesulfonate or alkyl-p-toluenesulfonate all 1 can be used as inert solvents such as dimenalformamide, dimethylsulfoxide, phosphoric acid or acetone hex(7) samethyltriamide, or polar solvents such as liquid ammonia Any neutral solvent can be used.
遊啼蹟全結合する塩基として強塩基、例えばナトリウム
もしくはカリウムアミド、リチウムジイソプロピルアミ
ド、ナトリウムメチラート又は水酸化ナトリウムもしく
はカリウム、全イ史用することができる。特に一般式■
の化合物の有利な表遣方伝は与えられた媒体にひいて同
一反応系で製造されるナトリウムアミドもしくはカリウ
ムアミドの存在で、一般式１１の化合物全液体アンモニ
ア媒体中でアルキルハロゲン化物でアルキル化すること
にある。もとになる一般式Ｉの化合物は通常の分離及び
単陥方法金用いて、例えば浴剤全蒸発させることによっ
て並びにクロマトグラフィー及び／又は得られた粗生成
物の結晶化によって、反応混合物から分離することがで
きる。Strong bases, such as sodium or potassium amide, lithium diisopropylamide, sodium methylate or sodium or potassium hydroxide, can be used as the base for binding the radical. Especially general formula■
An advantageous way of representing compounds of general formula 11 is alkylation with alkyl halides in an all-liquid ammonia medium in the presence of a sodium amide or potassium amide prepared in the same reaction system in a given medium. It's about doing. The starting compound of general formula I is separated from the reaction mixture using conventional separation and single-layer methods, for example by total evaporation of the bath and by chromatography and/or crystallization of the crude product obtained. can do.
−ｆｆ式Ｉの１−置１Ｎ−（８α−エルゴリニル）−Ｎ
’、 Ｎ’−ジエチルウレアは強力な無機及び育磯版と
の付加基金もたらす塩基性を有する無色精品の化合物で
ある。治療学的な目的のために塩酸、硫（８）
酸、メタンスルホン酸、エタンスルホン酸、マレイン飲
、リンゴ酸、酒石酸、くえん酸等のよつな製業学的に満
足な無毒性の酸との水溶性塩が適当である。前記堪は適
当な不活性浴剤、好１しくにメタノール、エタノール、
アセトン、水もしくハその混合物にひける少なくとも１
モル当量のｒ″Ｒと１モル当量の一般式■の化合物との
反応によって製造することができる。-ff 1-position 1N-(8α-ergolinyl)-N of formula I
',N'-Diethylurea is a colorless, refined compound with strong inorganic and basic properties that provide additional support with mineral deposits. For therapeutic purposes, commercially acceptable non-toxic acids such as hydrochloric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, malic acid, tartaric acid, citric acid, etc. A water-soluble salt of is suitable. Said agent is a suitable inert bath agent, preferably methanol, ethanol,
At least 1% in acetone, water or a mixture thereof
It can be produced by reacting a molar equivalent of r''R with 1 molar equivalent of the compound of general formula (2).
一般式Ｉの化合物は動物に２いてプロラクチン及び成長
ホルモンの分泌の１要な抑制朔並びにゴナドトロピンの
分泌の刺激Ｍ１１であり、前記ホルモンによって調節さ
れた生理学的及び病理学的方法に影＊を与え、さらに機
能を制御された生理学的及び病理学的ドーパミン受容体
に対してドーパミン作用企及ぼす。従ってそれらはプロ
ラクチン及び成長ホルモンの童の抑制のための人及び獣
医学の治療、例えば過プロラクチン症、巨端症及びパー
キンソン症候群の医学治療に使用てれ得るか、又はそれ
らはカナドトロビンの童のＪ曽カロ、汐りえば哺乳動物
に２いて発す＃現象全誘発せしめる場合、及び鳥に２い
て卵の産卵全誘発せしめるのに使用され得る。Compounds of the general formula I are shown in animals to be an important inhibitor of the secretion of prolactin and growth hormone and a stimulus of the secretion of gonadotropins, influencing the physiological and pathological processes regulated by said hormones. , further exerts dopaminergic effects on physiological and pathological dopamine receptors whose functions are regulated. They can therefore be used in human and veterinary treatments for the inhibition of prolactin and growth hormone, for example in the medical treatment of hyperprolactinosis, macrocrotia and parkinsonism, or they can be used for the inhibition of prolactin and growth hormone in children. It can be used to fully induce the #phenomenon in mammals and to induce egg production in birds.
−Ｈ式Ｉの１−ｉｌ［８α−エルゴリニルウレア金製造
する方法はそれにもかかわらず発明の範囲全眠足しない
次の実施態様のレロによってさらに説明されている。そ
の化合物の融点にコッフレル（ｋｏｆｌｅｒ ）段階を
用いて測足し、他の温度データと同様に’Ｃで与える。-H The method of preparing 1-il[8α-ergolinyl urea gold of formula I is further illustrated by Lero in the following embodiments which nevertheless do not extend the scope of the invention. The melting point of the compound is measured using a kofler step and is given in 'C as with other temperature data.
比旋元度のイばは透明な溶削のない化合物に関するもの
である。The degree of specific rotation is related to transparent, uncut compounds.
例Ｉ
Ｎ −／Ｄ −１，６−シメチルー８α−エルゴリニル
／ −Ｎ’、 Ｎ’−ジエチルウレア
０．２２５ ｒ／４ ミ！Ｊモル／の粉末化された水酸
化カリウム全２０−の無水アセトン中０．３４ｒ／１ミ
リモル／のＮ−／Ｄ−６−メチル−８α−エルゴリニル
／ −Ｎ’ 、 Ｎ’−ジエチルウレアの＃液に添加し
、その混合物を２３〜２６°Ｃで１０分撹拌し、さらに
０．２８４ ｒ／２ ミｌ）モル／のメチルヨーシト金
次いで同じ温度で藺加する。反応混合物全室温で２時間
撹拌し、さらに０．２８４ ｒ／２ ミリモル／のメチ
ルヨーシト金次いで冷加し、その混合物上さらに３時間
撹拌する。無機部分音Ｐ遇し、溶剤全減圧下で涙液から
蒸留し、蒸発残留物全クロロホルムと水の混合物の中へ
取り去り、有機部分全無水硫酸ナトリウムで乾燥し、そ
して溶剤全減圧下で蒸留する。粗生成物１０．４Ｆ／會
化合物の溶離のためにクロロホルムとエタノール／９５
：５／の混合物音用い、シリカゲルに２けるカラムクロ
マトグラフィーを用いてｆｌｓし、−緒にした均質留分
全溶剤の蒸発後アセトンから再結晶化させる。題目にあ
る化合物はｍ、ｐ、 １３６〜１３８°Ｃ１比旋元度〔
α）、 ＝ ＋２４．４’／Ｃ＝ ０．２、ピリジン／
金石する無色結晶の形で／Ｉ、Ｒ’＝Ｒ”−メチル／全
得る。Example I N-/D-1,6-dimethyl-8α-ergolinyl/-N', N'-diethylurea 0.225 r/4 mi! J mol/of powdered potassium hydroxide total 20- 0.34 r/1 mmol/ of N-/D-6-methyl-8α-ergolinyl/-N', N'-diethylurea in anhydrous acetone The mixture was stirred for 10 minutes at 23-26°C and a further 0.284 r/2 ml/mol/gold of methyliositomate was added at the same temperature. The reaction mixture is stirred for 2 hours at room temperature, then added with a further 0.284 r/2 mmol/gold of methyl iositoside, cooled and the mixture is stirred for a further 3 hours. The inorganic partial P is removed, the solvent is distilled from the lachrymal fluid under full vacuum, the evaporation residue is all removed into a mixture of chloroform and water, the organic part is completely dried over anhydrous sodium sulfate, and the solvent is distilled under full vacuum. . Crude product 10.4F/chloroform and ethanol/95 for elution of compounds
A mixture of: 5/2 fls was purified using 2 column chromatography on silica gel, and the combined homogeneous distillates were recrystallized from acetone after evaporation of all the solvent. The compound in the title has m, p, 136-138°C1 specific degree of rotation [
α), = +24.4'/C= 0.2, pyridine/
/I, R'=R''-methyl/total is obtained in the form of colorless crystals.
ＩＪ２
Ｎ−／Ｄ−１−メチル−６−ｎ−プロピル−８α−エル
ゴリニル／ −Ｎ’、 Ｎ’−ジエチルウレアはぼ１０
＃ｖの硝酸鉄／ｍ７には＃’ｆ １００ ｒｎｔの液体
アンモニア中６２．４〜／２．７１５ミリモル／のナト
リウムの浴液に撹拌下で添加し、ＩＩ液を脱色後５００
キ／１．３５７はリモル／のＮ−／Ｄ−６−フロピルー
８α−エルコリニル／ −Ｎ’、 Ｎ’−ジエチルウレ
ア全ナトリウムアミドのもとになるサスペンションに添
加する。ウレアの浴屏俊／２よそ３０分俊／３８５ ｆ
／２．７１５ミリモル／のメチルヨーシト全滴加し、そ
の反応混合物全アンモニアの沸点に２いて１時間撹拌す
る。次いでアンモニア全蒸発させ、蒸発残留物全クロロ
ホルムと水の混合物の中へ取り去り、クロロホルム留分
を水で洗浄し、無水硫酸ナトリウムで乾燥し、さらにそ
の溶剤を減圧下で蒸留する。粗生成物１０．５５Ｖ／は
ｍ、ｐ、 １１７〜１１９°Ｃ；〔α］；’＝＋ ２６
．３゜／Ｃ＝０．２、ピリジン／七有する無色結晶の形
で題目に与えられた化合物／Ｉ、Ｒ′−メチル、Ｒ１＝
プロピル／をアセトンからの再結晶俊与える。IJ2 N-/D-1-methyl-6-n-propyl-8α-ergolinyl/ -N', N'-diethylurea is 10
For #v iron nitrate/m7, add #'f 100 rnt to a bath solution of 62.4 to 2.715 mmol/m of sodium in liquid ammonia under stirring, and after decolorizing solution II, 500
Ki/1.357 is added to the suspension that becomes the source of the rimole/N-/D-6-furopyru-8α-ercorinyl/-N', N'-diethylurea total sodium amide. Urea's bath screen / 2 30 minutes / 385 f
A total of 2.715 mmol of methyl iosite was added dropwise and the reaction mixture was brought to the boiling point of all the ammonia and stirred for 1 hour. The ammonia is then completely evaporated, the entire evaporation residue is taken up in a mixture of chloroform and water, the chloroform fraction is washed with water and dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. Crude product 10.55V/m, p, 117-119°C; [α];' = + 26
．． The compound given in the title in the form of colorless crystals with 3°/C=0.2, pyridine/7/I, R'-methyl, R1=
Propyl/propyl is recrystallized from acetone.
ｔ１３
Ｎ−／Ｄ−１−メチル−６−エチル−８α−エルゴリ＝
ル／ −Ｎ’、 Ｎ’−ジエチルウレア、ｍ、ｐ、
１０３〜１０５°Ｃ，Ｃα、１．＝＋２６．３°／Ｃ＝
０．２、ピリジン／、及びＮ−／Ｄ−１−メチル−６−
プチルー８α−エルゴリニル／ −Ｎ／、 Ｎ／ −ジ
エチルウレア、ｍ、ｐ、 ７５〜７７°Ｃ，Ｃα］：’
＝ ＋３２．９°／Ｃ＝ ０．２、ピリジン／全、等モ
ル置のＮ−／Ｄ−６−エチル−８α−エルゴリニル／−
もしくはＮ−／Ｄ−６−７ｆルー８α−エルコリニル／
−Ｎ’、Ｎ’−ジエチルウレアがＮ−／Ｄ−６−７’ロ
ピルー８α−エルゴリニル／ −Ｎ’、 Ｎ’−ジエチ
ルウレアの代りに使用される虞全除いて、し１ｊ２と同
じ方法によって製造する。t13 N-/D-1-methyl-6-ethyl-8α-ergoly=
-N', N'-diethylurea, m, p,
103-105°C, Cα, 1. =+26.3°/C=
0.2, pyridine/, and N-/D-1-methyl-6-
Petit-8α-ergolinyl/-N/, N/-diethylurea, m, p, 75-77°C, Cα]:'
= +32.9°/C=0.2, pyridine/total, equimolar N-/D-6-ethyl-8α-ergolinyl/-
or N-/D-6-7f-8α-ercholinyl/
-N',N'-diethylurea is used in place of N-/D-6-7'ropyru-8α-ergolinyl/-N',N'-diethylurea by the same method as in 1j2. Manufacture.
例４
Ｎ−／Ｄ−１−エチル−６−ブロビルー８α−エルゴリ
ニル／ −Ｎ’、 Ｎ’−ジエチルウレア、ｍ、ｐ。Example 4 N-/D-1-ethyl-6-broby-8α-ergolinyl/ -N', N'-diethylurea, m, p.
８５〜８６°Ｃ，Ｃα〕も０＝＋ａｏ、４°／ｃ＝ｏ、
２、ピリジン／、及びＮ−／Ｄ−１，６−シグロビルー
８α−エルゴリニル／ ＋ Ｎ’＋ Ｎ／ −ジエチル
ウレア全１等モル量のエチルヨーシトもしくはプロピル
プロミドがメチルヨーシトの代ジに使用されるのｔ除い
て、例２と同じ方法によって製造する。85-86°C, Cα] is also 0=+ao, 4°/c=o,
2. Pyridine/, and N-/D-1,6-siglovir-8α-ergolinyl/+N'+ N/-diethylurea A total of 1 equimolar amount of ethyl iosito or propyl bromide is used as a substitute for methyl iosite. Produced by the same method as Example 2 except for t.
ｔ１５
次の化合’ｔｌｌＪ：
Ｎ−／Ｄ−１−エチル−６−メチル−８α−エルゴリニ
／ｌ／ ／ −Ｎ’、 Ｎ’−ジエチルウレア、ｍ、ｐ
、 １２４〜１２６°Ｃ，Ｃα）、 ＝＋２０．５°／
Ｃ＝０．２、ピリジン／；
Ｎ−／Ｄ −１−プロビル−６−メチル−８α−エルゴ
リニル／ −Ｎ’、 Ｎ’−ジエチルウレア、ｍ、ｐ、
６３〜６６°Ｃ１〔α〕も””＋２１．９’／Ｃ＝０
．２、ピリジン／；
Ｎ−／Ｄ−１−ブチル−６−メチル−８α−エルゴリニ
ル／−Ｎ／、Ｎｌ−ジエチルウレア；Ｎ−／Ｄ−１−ア
リル−６−メチル−８α−エルゴリニル／ ＋ Ｎ／、
Ｎ／−ジエチルウレア、ｍ、ｐ、 ８２〜８４°Ｃ１
〔α霜−−１−１８．０°／Ｃ＝０．２、ピリジン／；
Ｎ−／Ｄ−１−ベンジル−６−メチル−８α−エルゴリ
ニ／Ｉ／ ／ −Ｎ’、 Ｎ’−ジエチルウレア、ｍ、
ｐ、 １６７〜１６９°Ｃ，（α〕。＝＋１５．０°／
Ｃ＝２、ピリジン／；
及びＮ−／Ｄ−１−エトキシカルボニルメチル−６−メ
チル−８α−エルゴリニル／ −Ｎ’、 Ｎ’−ジエチ
ルウレア、ｍ、ｐ、 ５７〜５９°Ｃ％ ［α］”＝
十Ｄ
１７．０°／Ｃ＝０．２、ピリジン／全、等モル量のＮ
−／Ｄ−６−メチル−８α−エルゴリニル／ −Ｎ’。t15 The following compound 'tllJ: N-/D-1-ethyl-6-methyl-8α-ergolini/l/ / -N', N'-diethylurea, m, p
, 124-126°C, Cα), =+20.5°/
C=0.2, pyridine/; N-/D -1-propyl-6-methyl-8α-ergolinyl/ -N', N'-diethylurea, m, p,
63~66°C1 [α] is also “”+21.9'/C=0
．． 2, Pyridine/; N-/D-1-butyl-6-methyl-8α-ergolinyl/-N/, Nl-diethylurea; N-/D-1-allyl-6-methyl-8α-ergolinyl/ + N /,
N/-diethylurea, m, p, 82-84°C1
[α frost--1-18.0°/C=0.2, pyridine/; N-/D-1-benzyl-6-methyl-8α-ergolini/I/ / -N', N'-diethylurea ,m,
p, 167-169°C, (α].=+15.0°/
C=2, pyridine/; and N-/D-1-ethoxycarbonylmethyl-6-methyl-8α-ergolinyl/ -N', N'-diethylurea, m, p, 57-59°C% [α] ”＝
10D 17.0°/C=0.2, pyridine/total, equimolar amount of N
-/D-6-methyl-8α-ergolinyl/ -N'.
Ｎ′−ジエチルウレアがＮ−／Ｄ−６−ブロビル＝８α
−エルゴリニル／ −Ｎ’、 Ｎ’−ジエチルウレアの
代りに便用され、等モル量のアルキルプロミド、アリル
プロミド、ベンジルプロミド又はエチルブロモアセテー
トが使用されるの上瞼いて、例２と同じ方法によって製
造する。N'-diethylurea is N-/D-6-brobyl=8α
-Ergolinyl/-N', N'-The same method as in Example 2 for the upper eyelid, conveniently replacing the N'-diethyl urea and using equimolar amounts of alkyl bromide, allyl bromide, benzyl bromide or ethyl bromoacetate. Manufactured by.
特許出願人
スボファ、スポジェネ ボドニキイ プロズドラボトニ
コウ ブイログ
特許出願代理人
弁理士 青水 朗
弁理士 西舘和之
弁理士 内 １）幸 男
弁理士 山 口 昭 之
（１５）
６３５−Patent applicant Subofa, Spogen Bodniky Prozdrabotnikou Vlog Patent application agent Patent attorney Akira Aomizu Patent attorney Kazuyuki Nishidate Patent attorney 1) Yukio Patent attorney Akiyuki Yamaguchi (15) 635-
Claims (1)
表わし、Ｒ”は１〜４個の炭素原子′？！：有する低級
アルキル基、ベンジル基、アリル基又はＲ４が水素原子
もしくは１〜２ｉｌｉＩの炭素原子を有するアルキル基
金表わし、ｎが整数１〜４である一般式％式％［） ｋ有−ｊる１ −を挨Ｎ−／８α−エルゴリニル／−Ｎ
’、 Ｎ’−ジエチルウレア。 ２、Ｎ−／Ｄ−１，６−シメチルー８α−エルゴリニル
／ −Ｎ’、 Ｎ’−ジエチルウレアである％許梢求の
範囲第１項記載の化合物。 ３、Ｎ−／Ｄ−１−メチル−６−エチル−８α−エルゴ
リニル／ −Ｎ’、 Ｎ’−ジェチルウレアテメルＷｇ
ｔＦ請求の範囲第１項記載の化合物。 ４、Ｎ−／Ｄ−１−メチル−６−ブロビルー８α−エル
ゴリニル／−Ｎ’、Ｎ’−シェチルウレアテする特許請
求の範囲第１項記載の化合物。 ５、Ｎ−／Ｄ−１−メチル−６−プチルー８α−エルゴ
リニル／−Ｎ’、Ｎ’−シェチルウレアテあル特許請求
の範囲第１項記載の化合物。 ６、一般式■（式中Ｒ１及びＲ２は前記意味を有する）
を有するｌ−置侯８α−エルゴリニルウレア全製造する
方法であって、一般式■ （式中Ｒ１は前記意味を有する） 金石する１の位置に置換された８α−エルゴリニ／ｌ／
−Ｎ’、 Ｎ’−ジエチルウレアが一般式■Ｒｔ
Ｘ ／ｌＩＩ／。 （式中Ｒ２は前記意味金石し、Ｘはハロゲン原子又はエ
ステル結合された脂肪族もしくは芳香族スルホン酸の残
基あるいはエステル結合された硫酸の残基金衣わす。） 金石するアルキル化剤と反応すること’に０ｍとする方
法。 ７、反応が１〜５モル当重のアルカリ金属アミド、好１
しくぼナトリウムアミドもしくはカリウムアミドの存在
で液体アンモニア中に２いて行なわれること全特徴とす
る特許請求の範囲第６項＾己載の方法。 ８、反応が１〜５モル当量のアルカリ金属水酸化物、好
１しくに水酸化ナトリウムもしくは水酸化カリウム、の
存在でアセトン中に２いて行なわれること金％欧とする
特許請求の範囲第６項記載の方法。 （３）[Claims] 1. General formula I (in the formula, R1 represents an alkyl group having 1 to 4 carbon atoms, and R'' represents a lower alkyl group having 1 to 4 carbon atoms, a benzyl group) , allyl group or R4 represents a hydrogen atom or an alkyl group having 1 to 2 carbon atoms, and n is an integer 1 to 4. Ergolinyl/-N
', N'-diethylurea. 2, N-/D-1,6-dimethyl-8α-ergolinyl/ -N', N'-diethyl urea. 3, N-/D-1-methyl-6-ethyl-8α-ergolinyl/ -N', N'-jethylureatemel Wg
tF The compound according to claim 1. 4,N-/D-1-methyl-6-broby-8α-ergolinyl/-N',N'-chetyl ureate compound according to claim 1. 5,N-/D-1-methyl-6-butyl-8α-ergolinyl/-N',N'-shetylureateal The compound according to claim 1. 6. General formula ■ (in the formula, R1 and R2 have the above meanings)
8α-ergolinyl urea having the general formula (wherein R1 has the above meaning) 8α-ergolinyl/l/
-N', N'-diethylurea has the general formula ■Rt
X /lII/. (In the formula, R2 represents the above-mentioned meaning, and X represents a halogen atom, a residue of an ester-bonded aliphatic or aromatic sulfonic acid, or a residue of ester-bonded sulfuric acid.) Reacts with an alkylating agent that reacts with gold. How to set it to 0m. 7. Alkali metal amide having a reaction weight of 1 to 5 molar equivalents, preferred 1
6. The process as claimed in claim 6, characterized in that it is carried out in liquid ammonia in the presence of sodium amide or potassium amide. 8. Claim 6 provides that the reaction is carried out in acetone in the presence of 1 to 5 molar equivalents of an alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide. The method described in section. (3)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS821734A CS231214B1 (en) | 1982-03-12 | 1982-03-12 | Processing method of 1-substituted n+l8alpha-ergoline+p-n,diethyl urea |
| CS173482 | 1982-03-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS58180484A true JPS58180484A (en) | 1983-10-21 |
Family
ID=5352449
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58039349A Pending JPS58180484A (en) | 1982-03-12 | 1983-03-11 | 1-substituted n-/8 alpha-ergolinyl/-n',n'- diethylurea and manufacture |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS58180484A (en) |
| AT (1) | AT383349B (en) |
| AU (1) | AU555961B2 (en) |
| BE (1) | BE896122A (en) |
| CA (1) | CA1203531A (en) |
| CH (1) | CH652125A5 (en) |
| CS (1) | CS231214B1 (en) |
| DE (1) | DE3308719A1 (en) |
| DK (1) | DK84683A (en) |
| FI (1) | FI830754L (en) |
| FR (1) | FR2523131B1 (en) |
| GB (1) | GB2116548B (en) |
| IT (1) | IT1161209B (en) |
| NL (1) | NL8300829A (en) |
| SE (1) | SE452321B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59176285A (en) * | 1983-03-14 | 1984-10-05 | シエ−リング・アクチエンゲゼルシヤフト | Novel substituted ergoline, manufacture and medicine active to central nervous system |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0208417A3 (en) * | 1985-06-12 | 1989-09-06 | SPOFA Spojené Podniky Pro Zdravotnickou Vyrobu | Use of 1-(8-alpha-ergolinyl)-3,3-diethyl urea derivatives in the treatment of endometritis |
| DE3522894A1 (en) * | 1985-06-24 | 1987-01-02 | Schering Ag | USE OF TERGURID AS GERIATRIC |
| FR2584720B1 (en) * | 1985-07-11 | 1987-10-02 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF N-METHYL DERIVATIVES OF ERGOLINE |
| DE3620293A1 (en) * | 1986-06-16 | 1987-12-17 | Schering Ag | 1 AND / OR 2 SUBSTITUTED ERGOL DERIVATIVES |
| DE3623503A1 (en) * | 1986-07-09 | 1988-01-21 | Schering Ag | 1-ARYL-ERGOLINYL-UREA DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THE USE OF THESE COMPOUNDS AS A MEDICINAL PRODUCT |
| DE10212564B4 (en) * | 2002-03-12 | 2007-04-19 | Neurobiotec Gmbh | 1-Allyl ergot alkaloid derivatives and their use for the prophylaxis and treatment of migraine |
| US20140058108A1 (en) * | 2010-11-11 | 2014-02-27 | Sinoxa Pharma Ug | Lisuride, Terguride and Derivatives Thereof for Use in the Prophylaxis and/or Treatment of Fibrotic Changes |
| BR112017015487A2 (en) | 2015-01-20 | 2018-01-30 | Xoc Pharmaceuticals Inc | COMPOUND; COMPOSITION; METHOD OF TREATMENT AND / OR PREVENTION OF MIGRAINE, ALS, ALZHEIMER'S DISEASE, PARKINSON'S DISEASE, EXTRAPYRIMIDAL DISORDERS, DEPRESSION, NAUSEA, AEMESIS, SYNDROME OF THE WASTE LEGS, INSOMENESS, HYGERNESS, AGING , ANXIETY, DRUG DEPENDENCIES, DYSTONIA, PARASSONIA OR HYPERLACTINEMIA IN AN INDIVIDUAL; AGONIZATION METHODS OF D2, 5-HT1D, 5-HT1A AND 5-HT2C RECEPTORS, IN AN INDIVIDUAL; ANTAGONIZATION METHOD OF THE D3 RECEPTOR IN AN INDIVIDUAL; METHODS OF SELECTIVE AGONIZATION OF RECEPTORS 5 -HT1D, AND 5-HT2C, METHOD OF PROVIDING FUNCTIONAL ANTAGONIST ACTIVITY IN RECEPTOR 5 -HT2B OR IN RECEIVER 5-HT7, OR IN BOTH, IN AN INDIVIDUAL; METHOD OF PROVIDING FUNCTIONAL ANTAGONIST ACTIVITY IN ADRENERGIC RECEPTORS IN AN INDIVIDUAL |
| MX2017009406A (en) | 2015-01-20 | 2018-01-18 | Xoc Pharmaceuticals Inc | Isoergoline compounds and uses thereof. |
| BR112019025420A2 (en) | 2017-06-01 | 2020-06-16 | Xoc Pharmaceuticals, Inc. | POLYCYCLICAL COMPOUNDS AND USES OF THESE |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH344731A (en) * | 1956-05-18 | 1960-02-29 | Sandoz Ag | Process for the production of new derivatives of the lysergic acid series alkylated on the indole nitrogen |
| AT231082B (en) * | 1960-10-12 | 1964-01-10 | Sandoz Ag | Process for the production of new urea derivatives |
| DE3063869D1 (en) * | 1979-06-13 | 1983-07-28 | Schering Ag | (ergolin-yl)-n', n'-diethyl urea derivatives, their preparation and pharmaceutical compositions containing them |
-
1982
- 1982-03-12 CS CS821734A patent/CS231214B1/en unknown
-
1983
- 1983-02-24 DK DK84683A patent/DK84683A/en not_active Application Discontinuation
- 1983-03-02 GB GB08305735A patent/GB2116548B/en not_active Expired
- 1983-03-02 AT AT0072783A patent/AT383349B/en not_active IP Right Cessation
- 1983-03-07 NL NL8300829A patent/NL8300829A/en not_active Application Discontinuation
- 1983-03-07 IT IT19935/83A patent/IT1161209B/en active
- 1983-03-07 FI FI830754A patent/FI830754L/en not_active Application Discontinuation
- 1983-03-08 SE SE8301257A patent/SE452321B/en not_active IP Right Cessation
- 1983-03-08 AU AU12167/83A patent/AU555961B2/en not_active Ceased
- 1983-03-10 BE BE0/210287A patent/BE896122A/en not_active IP Right Cessation
- 1983-03-10 CA CA000423264A patent/CA1203531A/en not_active Expired
- 1983-03-11 JP JP58039349A patent/JPS58180484A/en active Pending
- 1983-03-11 FR FR8304005A patent/FR2523131B1/en not_active Expired
- 1983-03-11 DE DE3308719A patent/DE3308719A1/en not_active Withdrawn
- 1983-03-11 CH CH1351/83A patent/CH652125A5/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59176285A (en) * | 1983-03-14 | 1984-10-05 | シエ−リング・アクチエンゲゼルシヤフト | Novel substituted ergoline, manufacture and medicine active to central nervous system |
Also Published As
| Publication number | Publication date |
|---|---|
| AU555961B2 (en) | 1986-10-16 |
| AT383349B (en) | 1987-06-25 |
| SE8301257L (en) | 1983-09-13 |
| FI830754L (en) | 1983-09-13 |
| DE3308719A1 (en) | 1983-09-22 |
| SE452321B (en) | 1987-11-23 |
| IT8319935A0 (en) | 1983-03-07 |
| CS231214B1 (en) | 1984-10-15 |
| DK84683D0 (en) | 1983-02-24 |
| CH652125A5 (en) | 1985-10-31 |
| NL8300829A (en) | 1983-10-03 |
| FR2523131A1 (en) | 1983-09-16 |
| ATA72783A (en) | 1986-11-15 |
| BE896122A (en) | 1983-07-01 |
| GB2116548A (en) | 1983-09-28 |
| GB2116548B (en) | 1985-03-20 |
| DK84683A (en) | 1983-09-13 |
| AU1216783A (en) | 1983-09-15 |
| FI830754A0 (en) | 1983-03-07 |
| SE8301257D0 (en) | 1983-03-08 |
| CA1203531A (en) | 1986-04-22 |
| IT1161209B (en) | 1987-03-18 |
| GB8305735D0 (en) | 1983-04-07 |
| FR2523131B1 (en) | 1987-08-28 |
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