JPH0321030B2 - - Google Patents
Info
- Publication number
- JPH0321030B2 JPH0321030B2 JP13745982A JP13745982A JPH0321030B2 JP H0321030 B2 JPH0321030 B2 JP H0321030B2 JP 13745982 A JP13745982 A JP 13745982A JP 13745982 A JP13745982 A JP 13745982A JP H0321030 B2 JPH0321030 B2 JP H0321030B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- hydrogen atom
- ergoline
- general 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.)
- Expired
Links
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 6
- AWFDCTXCTHGORH-HGHGUNKESA-N 6-[4-[(6ar,9r,10ar)-5-bromo-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carbonyl]piperazin-1-yl]-1-methylpyridin-2-one Chemical class O=C([C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC(Br)=C(C=34)C2)C1)C)N(CC1)CCN1C1=CC=CC(=O)N1C AWFDCTXCTHGORH-HGHGUNKESA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- -1 R 6 isocyanate Chemical class 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000012948 isocyanate Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid 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 in position 8
- C07D457/06—Lysergic acid amides
Description
本発明は一般式：
〔式中R1は水素原子又はメチル基を表わし、
R2は水素原子、ハロゲン原子又はメチル基を表
わし、R3は水素原子又はメトキシ基を表わし、
R4は炭素原子数１〜４を有する炭化水素基を表
わし、R6は炭素原子数１〜４を有するアルキル
基、シクロヘキシル基又は置換又は非置換のフエ
ニル基又は式：（CH2）oＮ（CH3）2（ここでｎは整
数である）のジメチルアミノアルキル基を表わ
し、R5はR6が表わすものの任意の基又は水素原
子又はピリジル、ピリミジル、ピラジニル、ピリ
ダジニル、チアゾリル又はチアジアゾリル基を表
わす〕のエルゴリン誘導体のレジオ特異的な製法
に関し、その方法は、次の一般式のエルゴリン
アミドと一般式のイソシアネートとを反応させ
ることによりなる。：
The present invention has the general formula: [In the formula, R 1 represents a hydrogen atom or a methyl group,
R 2 represents a hydrogen atom, a halogen atom or a methyl group, R 3 represents a hydrogen atom or a methoxy group,
R 4 represents a hydrocarbon group having 1 to 4 carbon atoms, R 6 represents an alkyl group having 1 to 4 carbon atoms, a cyclohexyl group, a substituted or unsubstituted phenyl group, or a formula: (CH 2 ) o N (CH 3 ) 2 (where n is an integer) represents a dimethylaminoalkyl group, and R 5 is any group represented by R 6 or a hydrogen atom or a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl group. Regarding the regiospecific preparation of the ergoline derivatives shown below, the method consists of reacting an ergolinamide of the following general formula with an isocyanate of the general formula. :
【式】R6−Ｎ＝Ｃ＝Ｏ
（）
〔式中R1，R2，R3，R4，R5及びR6は前記のも
のを表わす〕。この反応は、70〜120℃の温度で、
ジオキサン、ベンゼン、トルエン、シクロヘキサ
ン等の適当な溶剤中で、24〜72時間にわたり実施
するのが有利である。反応の終りに、生成物は慣
用の方法例えばクロマトグラフイ及び／又は結晶
化及び造塩により単離しかつ精製することができ
る。
本発明によるこの方法で使用される出発物質は
公知化合物であるか又は公知化合物から出発して
慣用方法で製造でき、更に式のいくつかの化合
物は、特開昭58−24584号明細書及びベルギー特
許第888243号明細書に記載されている。
一般式のいくつかの化合物及びその製法は、
特開昭56−156279号明細書及び相応するベルギー
特許第888243号及び西ドイツ特許出願第3112861
号中に記載されている。ここに記載の方法では、
一般式の対称的誘導体を良好な収率で製造する
ことができるが、その実際的な重要性は、基R5
及びR6は異なるものを表わす一般式の化合物
の製造に使用される際に低下している。この場合
に、相互のレジオ異性体が得られ、単離の困難性
の結果として、屡々、単離された生成物の収率は
低い。本発明の方法は、それがレジオ特異性であ
り、前記の困難を除きかつ所望のカルボジイミド
の不安定性に基づき、従来の特開昭56−156279号
明細書に記載の方法で得ることはできなかつたあ
る種の生物学的に活性の化合物の製造を可能とす
るので、最も実際的であることが立証された。
次の例は本発明を説明するものであつて、本発
明はこれらのみに限定されるものではない。
例 １
６−アリル−8β−〔１−エチル−３−（３−ジ
メチルアミノプロピル）−ウレイドカルボニル〕
エルゴリン
： R1＝R2＝Ｒ＝Ｈ、 R4＝アリル
R5＝（CH3）2N−CH2CH2CH2、R6＝C2H5
トルエン1000ml中の６−アリル−8β−（３−ジ
メチルアミノプロピル−カルバモイル）−エルゴ
リン（融点198〜200℃）20ｇ及びエチルイソシア
ネート150mlの混合物を72時間還流させる。生じ
る溶液を70〜80℃及び300mmの圧力で蒸溜させ、
残分をシリカゲル（0.05〜0.2mm）60ｇの充填さ
れたクロマトグラフイカラムに施こし、アセトン
で溶離させる。生成物を含有していることを示し
ている溶離液フラクシヨンを集め減圧下に溶剤を
これから除去すると、フオームとしての表題化合
物20ｇが得られ、２燐酸塩としてのその融点は
152〜154℃であつた。
例 ２
６−アリル−8β−（１−エチルウレイドカルボ
ニル）−エルゴリン
：R1＝R2＝R3＝R5＝Ｈ、R4＝アリル、R6＝
C2H5
６−アリル−8β−（３−ジメチルアミノプロピ
ル−カルバモイル）−エルゴリンの代りに６−ア
リル−8β−カルバモイル−エルゴリン（融点190
〜193℃）を用いて、例１に記載と同様に操作す
ると、表題化合物（融点210〜212℃）が90％の収
率で得られた。
例 ３
６−アリル−8β−（１，３−ジメチルウレイド
カルボニル）−エルゴリン
：R1＝R2＝R3＝Ｈ、R4＝アリル、R5＝R6＝
CH3
６−アリル−8β−（３−ジメチルアミノプロピル
−カルバモイル）−エルゴリンの代りに６−アリ
ル−8β−メチルカルバモイル−エルゴリンを用
い、エチルイソシアネートの代りにメチルイソシ
アネートを用いて、例１に記載と同様に操作する
と、表題化合物（融点106〜108℃）が87％の収率
で得られた。[Formula] R 6 -N=C=O () [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 represent the above]. This reaction takes place at temperatures between 70 and 120°C.
Advantageously, it is carried out in a suitable solvent such as dioxane, benzene, toluene, cyclohexane, etc. over a period of 24 to 72 hours. At the end of the reaction, the products can be isolated and purified by customary methods such as chromatography and/or crystallization and salt formation. The starting materials used in this process according to the invention are known compounds or can be prepared in conventional manner starting from known compounds; furthermore, some compounds of the formula are described in JP-A-58-24584 and Belgium It is described in Patent No. 888243. Some compounds with the general formula and their production methods are:
JP-A-56-156279 and the corresponding Belgian Patent No. 888243 and West German Patent Application No. 3112861
It is listed in the issue. In the method described here,
Although symmetrical derivatives of the general formula can be prepared in good yields, their practical importance lies in the radical R 5
and R 6 are lowered when used to prepare compounds of different general formulas. In this case, mutual regioisomers are obtained and, as a result of isolation difficulties, the yield of isolated product is often low. The method of the present invention is regiospecific, eliminates the above-mentioned difficulties, and is based on the instability of the desired carbodiimide, which cannot be obtained by the conventional method described in JP-A-56-156279. It has proven to be the most practical as it allows the production of certain biologically active compounds. The following examples are illustrative of the invention, but are not intended to limit it thereto. Example 1 6-allyl-8β-[1-ethyl-3-(3-dimethylaminopropyl)-ureidocarbonyl]
Ergoline: R 1 = R 2 = R = H, R 4 = Allyl R 5 = (CH 3 ) 2 N-CH 2 CH 2 CH 2 , R 6 = C 2 H 5 6-allyl-8β- in 1000 ml of toluene A mixture of 20 g (3-dimethylaminopropyl-carbamoyl)-ergoline (melting point 198-200 DEG C.) and 150 ml ethyl isocyanate is refluxed for 72 hours. The resulting solution was distilled at 70-80 °C and a pressure of 300 mm,
The residue is applied to a chromatography column packed with 60 g of silica gel (0.05-0.2 mm) and eluted with acetone. The eluent fractions shown to contain the product were collected and the solvent removed from them under reduced pressure to give 20 g of the title compound as a form whose melting point as the diphosphate was
The temperature was 152-154℃. Example 2 6-allyl-8β-(1-ethylureidocarbonyl)-ergoline: R 1 = R 2 = R 3 = R 5 = H, R 4 = allyl, R 6 =
C 2 H 5 6-allyl-8β-carbamoyl-ergoline (melting point 190
Working as described in Example 1 using 210-212 DEG C.), the title compound (mp 210-212 DEG C.) was obtained in 90% yield. Example 3 6-allyl-8β-(1,3-dimethylureidocarbonyl)-ergoline: R 1 = R 2 = R 3 = H, R 4 = allyl, R 5 = R 6 =
CH 3 As described in Example 1, using 6-allyl-8β-methylcarbamoyl-ergoline instead of 6-allyl-8β-(3-dimethylaminopropyl-carbamoyl)-ergoline and using methyl isocyanate instead of ethyl isocyanate. The title compound (melting point 106-108°C) was obtained in a yield of 87%.
Claims (1)
R2は水素原子、ハロゲン原子又はメチル基を表
わし、R3は水素原子又はメトキシ基を表わし、
R4は炭素原子数１〜４を有する炭化水素基を表
わし、R6は炭素原子数１〜４を有するアルキル
基、シクロヘキシル基、置換又は非置換のフエニ
ル基又は式：（CH2）oＮ（CH3）2（ここでｎは整数
である）のジメチルアミノアルキル基を表わし、
R5はR6が表わすものの任意の基又は水素原子、
ピリジル基、ピリミジル基、ピラジニル基、ピリ
ダジニル、チアゾリル基又はチアジアゾリル基を
表わす〕のエルゴリン誘導体を製造するために、
適当な溶剤中に溶かした一般式： 〔式中R1，R2，R3，R4，R5及びR6は前記のも
のを表わす〕のエルゴリンアミドと、式： R6−Ｎ＝Ｃ＝Ｏ （） 〔式中R6は前記のものを表わす〕のイソシア
ネートとを、70〜120℃の温度で24〜72時間反応
させて所望の式のエルゴリン誘導体を形成さ
せ、場合によつては、これを精製しかつ公知方法
で単離することを特徴とするエルゴリン誘導体の
製法。[Claims] 1. General formula: [In the formula, R 1 represents a hydrogen atom or a methyl group,
R 2 represents a hydrogen atom, a halogen atom or a methyl group, R 3 represents a hydrogen atom or a methoxy group,
R 4 represents a hydrocarbon group having 1 to 4 carbon atoms, and R 6 represents an alkyl group having 1 to 4 carbon atoms, a cyclohexyl group, a substituted or unsubstituted phenyl group, or a formula: (CH 2 ) o N represents a dimethylaminoalkyl group of (CH 3 ) 2 (where n is an integer),
R 5 is any group or hydrogen atom represented by R 6 ,
pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl, thiazolyl group or thiadiazolyl group].
General formula dissolved in a suitable solvent: [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 represent the above] ergolinamide and the formula: R 6 −N=C=O () [In the formula R 6 isocyanate as defined above] at a temperature of 70 to 120° C. for 24 to 72 hours to form an ergoline derivative of the desired formula, which may optionally be purified and purified by known methods. A method for producing an ergoline derivative, which comprises isolating it.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8124549 | 1981-08-11 | ||
| GB8124549 | 1981-08-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5838282A JPS5838282A (en) | 1983-03-05 |
| JPH0321030B2 true JPH0321030B2 (en) | 1991-03-20 |
Family
ID=10523868
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13745982A Granted JPS5838282A (en) | 1981-08-11 | 1982-08-09 | Manufacture of ergoline derivative |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPS5838282A (en) |
| BE (1) | BE894060A (en) |
| DE (1) | DE3229665A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20060028761A (en) * | 2003-05-08 | 2006-04-03 | 아이박스 파마슈티컬스 에스.알.오. | Polymorphs of cabergoline |
-
1982
- 1982-08-09 BE BE0/208772A patent/BE894060A/en not_active IP Right Cessation
- 1982-08-09 DE DE19823229665 patent/DE3229665A1/en not_active Ceased
- 1982-08-09 JP JP13745982A patent/JPS5838282A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| BE894060A (en) | 1982-12-01 |
| DE3229665A1 (en) | 1983-02-24 |
| JPS5838282A (en) | 1983-03-05 |
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