JPS6052758B2 - Heterotricyclic compounds - Google Patents
Heterotricyclic compoundsInfo
- Publication number
- JPS6052758B2 JPS6052758B2 JP13135080A JP13135080A JPS6052758B2 JP S6052758 B2 JPS6052758 B2 JP S6052758B2 JP 13135080 A JP13135080 A JP 13135080A JP 13135080 A JP13135080 A JP 13135080A JP S6052758 B2 JPS6052758 B2 JP S6052758B2
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- Japan
- Prior art keywords
- group
- substituted
- lower alkyl
- formula
- atom
- 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.)
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は一般式〔Ｉ〕で表わされる二分子間チオラクト
ンに関するものであり、本発明化合物は血圧降下剤とし
て有用なものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to bimolecular thiolactones represented by general formula [I], and the compounds of the present invention are useful as antihypertensive agents.
゜゜？コ」 ｋｌ〔Ｉ〕 〔式中、Ｑはメチレン基またはイオウ原子を示す。 ゜゜? Ko" kl [I] [In the formula, Q represents a methylene group or a sulfur atom.
Ｒ゛は水素原子、低級または高級アルキル基、シクロア
ルキル基、アラルキル基、フェニル基、フリル基、チエ
ニル基、ピリジル基若しくはナフチル基を示す。夫々の
基は低級アルキル基、ヒドロキシ基、メルカプト基、低
級アルコキシ基、低級アルキレンジオキシ基、アシルオ
キシ基、アシルメルカプト基、ハロゲン原子、ニトロ基
、アミノ基、低級アルキル置換アミノ基、アシルアミノ
基、カルボキシ基で置換されていてもよい。Ａは１〜３
個の炭素原子を有する直鎖または分校のアルキレンを示
す。尚式〔Ｉ〕に示される・化合物のＲ゛における低級
アルキル基、高級アルキル基、シクロアルキル基、アラ
ルキル基、フェニル基、フリル基、チエニル基、ピリジ
ル基およびナフチル基の夫々の基はヒドロキシ低級アル
キル基で置換されていてもよい。また、Ｒ１はベンゾフ
リル基、ベンゾチエニル基、イミダゾリル基およびイン
ドリル基のいずれかであつてもよく、夫々の基は低級ア
ルキル基、ヒドロキシ基、ヒドロキシ低級アルキル基、
メルカプト基、低級アルコキシ基、低級アルキレンジオ
キシ基、アシルオキシ基、アシルメルカプト基、ハロゲ
ン原子、ニトロ基、アミノ基、アルキル置換アミノ基、
アシルアミノ基、カルボキシ基で置換されていてもよい
。低級アルキル基またはアルキレン基とは炭素原子１〜
６個を有する飽和または不飽和の直鎖若しくは分枝のも
のをいい、高級アルキル基とは？素原子７〜加個を有す
る飽和または不飽和の直鎖若しくは分枝のものをいい、
またアシル基としては例えばアセチル基、ピバロイル基
、非置換または置換ベンゾイル基、ベンジルオキシカル
ボニル基が挙げられ、アラルキル基としては例えばベン
ジル基が挙げられ、イミド基としてはフタルイミド基、
グルタルイミド基、サクシニルイミド基が挙げられる。
以下の説明においてはこれらの全ての基を含むものとす
る。以下同じ。〕本発明化合物〔１〕は、人または動物
に投与された時に、酵素的およびまたは化学的に加水分
解され、高血圧症状に有効なアンジオテンシン変換酵素
阻害剤であるチオール化合物を遊離する化合物である。R' represents a hydrogen atom, a lower or higher alkyl group, a cycloalkyl group, an aralkyl group, a phenyl group, a furyl group, a thienyl group, a pyridyl group, or a naphthyl group. Each group is a lower alkyl group, hydroxy group, mercapto group, lower alkoxy group, lower alkylene dioxy group, acyloxy group, acylmercapto group, halogen atom, nitro group, amino group, lower alkyl-substituted amino group, acylamino group, carboxy It may be substituted with a group. A is 1-3
represents a straight-chain or branched alkylene having 5 carbon atoms. Each of the lower alkyl group, higher alkyl group, cycloalkyl group, aralkyl group, phenyl group, furyl group, thienyl group, pyridyl group, and naphthyl group in R of the compound represented by formula [I] is a hydroxy lower It may be substituted with an alkyl group. Further, R1 may be any one of a benzofuryl group, a benzothienyl group, an imidazolyl group, and an indolyl group, and each group is a lower alkyl group, a hydroxy group, a hydroxy lower alkyl group,
Mercapto group, lower alkoxy group, lower alkylenedioxy group, acyloxy group, acylmercapto group, halogen atom, nitro group, amino group, alkyl-substituted amino group,
It may be substituted with an acylamino group or a carboxy group. A lower alkyl group or an alkylene group has 1 to 1 carbon atom.
What is a saturated or unsaturated straight chain or branched alkyl group having 6 alkyl groups? Refers to a saturated or unsaturated straight chain or branched chain having 7 to 7 elementary atoms,
Examples of the acyl group include an acetyl group, a pivaloyl group, an unsubstituted or substituted benzoyl group, and a benzyloxycarbonyl group, examples of the aralkyl group include a benzyl group, and examples of the imide group include a phthalimide group,
Examples include glutarimide group and succinylimide group.
In the following description, all of these groups are included. same as below. [Compound [1] of the present invention is a compound that is enzymatically and/or chemically hydrolyzed when administered to humans or animals, liberating a thiol compound that is an angiotensin-converting enzyme inhibitor effective for treating hypertension symptoms.
この化合物は遊離酸であるチオール化合物に比べて親油
性が増加することにより吸収特性を改善することができ
、また持続時間の延長も図ることができた。本発明化合
物は、例えば次のような方法で合成．される。This compound was able to improve the absorption properties and extend the duration due to increased lipophilicity compared to thiol compounds, which are free acids. The compounds of the present invention can be synthesized, for example, by the following method. be done.
一般式〔旧〔式中、Ｑ，Ｒｌ，Ａは前記と同義である。General formula [old] In the formula, Q, Rl, and A have the same meanings as above.
〕で表わされる化合物を、脱水剤、例えば、カルボジイ
ミド類（シンクロヘキシルカルボジイミド、１一〔３−
（Ｎ，Ｎ−ジメチルアミノ）プロピル〕−３−エチルカ
ルボジイミド・塩酸塩など）、オキ・シ塩化リン、三塩
化リンなどと、窒素あるいはアルゴンなどの不活性ガス
気流下、ジクロロメタン、クロロホルム、テトラヒドロ
フラン、エーテルなどの有機溶媒中で反応させる事によ
つて得られる。以下に代表的な化合物について実施例を
示すが、本発明はこれらの実施例に限定されるものでは
ない。実施例１
（３Ｓ，７Ｓ，１３Ｓ，１７Ｓ）−３，１３−ジメチル
ー５，１５−ジチアー１，１１ージアザー２，６，１２
，１６−テトラオキソトリシクロ〔１５．３．０．０７
，１１〕エイコサンの製造窒素気流下、１−〔３−Ｎ，
Ｎ−ジメチルアミノ）プロピル〕−３−エチルカルボジ
イミド●塩酸塩３．９ｙのジクロロメタン２ｅ溶液に、
（２Ｓ）−１−〔（２Ｓ）−３−メルカプトー２−メチ
ルプロパノール〕プロリン４．４ｆのジクロロメタン２
００ｍ１溶液を、室温で攪拌しながら滴下する。] The compound represented by [3-
(N,N-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, etc.), phosphorus oxychloride, phosphorus trichloride, etc. under a stream of inert gas such as nitrogen or argon, dichloromethane, chloroform, tetrahydrofuran, etc. Obtained by reaction in an organic solvent such as ether. Examples of typical compounds are shown below, but the present invention is not limited to these examples. Example 1 (3S,7S,13S,17S)-3,13-dimethyl-5,15-dithia 1,11-diaza 2,6,12
, 16-tetraoxotricyclo[15.3.0.07
, 11] Production of eicosane Under nitrogen flow, 1-[3-N,
N-dimethylamino)propyl]-3-ethylcarbodiimide Hydrochloride In a dichloromethane 2e solution of 3.9y,
(2S)-1-[(2S)-3-mercapto-2-methylpropanol]proline 4.4f dichloromethane 2
00ml solution is added dropwise with stirring at room temperature.
更に同温で２日間静置した後、減圧下、ジクロロメタン
を留去する。油状の残渣に酢酸エチルを加え、不溶物を
デカントで除いた後、酢酸エチル溶液を、水、飽和食塩
水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧
下に、濃縮乾固する。油状の残渣３．５ｑをシリカゲル
カラムクロマトにより精製して、標記化合物２．０ｙを
得た。融点１６０〜１６３℃（テトラヒドロフランー水
）ＣＩＭＳ（１−Ｃ４ＨｌＯ）ｍ／ｚ；３９９（ＭＨつ
〔α〕？−１５０．８１（ｃ＝０．２４、ジメチルスル
ホキシド）ＩＲ（ＫＢｒ，ｃｒｆｌ−１；１７４５，１
６８５，１６３０，１４６０，１４２０，１１７０，１
１２０Ｒｆ値※０．４９
※シリカゲル、ベンゼンニ酢酸エチルリエタノールニ酢
酸＝１４：１４：２：１（以下同じ）実施例２
（３Ｓ，７Ｓ，１３Ｓ，１７Ｓ）−３，１３−ジメチル
ー５，９，１５，１９−テトラチアー１，１１ージアザ
ー２，６，１６−テトラオキソトリシクロ〔１５．３．
０．０７，１１〕エイコサンの製造１−〔３−（Ｎ，Ｎ
−ジメチルアミノ）プロピル〕−３−エチルカルボジイ
ミド・塩酸塩３．９ｙと、（．４Ｒ）−３−〔（２Ｓ）
−３−メルカプトー２−メチルプロパノール〕−４−チ
アゾリジンカルボン酸４．７ｙを用い、実施例１と同様
に反応させ、得られた油状物５．９ｙをシリカゲルカラ
ムクカマトにより精製し、標記化合物１．５ｙを得た。After further standing at the same temperature for 2 days, dichloromethane was distilled off under reduced pressure. After adding ethyl acetate to the oily residue and removing insoluble matter by decantation, the ethyl acetate solution is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. 3.5q of oily residue was purified by silica gel column chromatography to obtain 2.0y of the title compound. Melting point 160-163°C (tetrahydrofuran-water) CIMS (1-C4HlO) m/z; 399 (MH [α]?-150.81 (c = 0.24, dimethyl sulfoxide) IR (KBr, crfl-1; 1745,1
685, 1630, 1460, 1420, 1170, 1
120Rf value *0.49 *Silica gel, benzene diacetate ethylliethanol diacetate = 14:14:2:1 (same below) Example 2 (3S,7S,13S,17S)-3,13-dimethyl-5,9, 15,19-tetrathia 1,11-diaza 2,6,16-tetraoxotricyclo [15.3.
0.07,11] Production of eicosane 1-[3-(N,N
-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride 3.9y and (.4R)-3-[(2S)
Using 4.7y of -3-mercapto-2-methylpropanol]-4-thiazolidinecarboxylic acid, the reaction was carried out in the same manner as in Example 1, and the resulting oily product, 5.9y, was purified using a silica gel column. I got .5y.
融点 非晶性粉末ＣＩＭＳ（１−Ｃ４ＨｌＯ）ｍ／ｚ；
４３５（ＭＨ＋）〔α〕ｆ−２１４．３１（ｃ＝０．５
１、ジメチルスルホキシド）Ｒ（ＫＢｒ，ｃ７７！−１
）；１７５０，１６９０，１６３０，１４５０，１４２
０，１１８０，１０９５Ｒｆ値０．８３
実施例３
（７Ｓ，１０Ｒ，１７Ｓ，２０Ｒ）−１０，２０−ビス
（２ーヒドロキシシフニル）−５，９，１５，１９−テ
トラチアー１，１１ージアザー２，６，１２，１６−テ
トラオキソトリシクロ〔１５．３．０．０７，１１〕エ
イコサンの製造窒素気流下、１−〔３−（Ｎ，Ｎ−ジメ
チルアミノ）プロピル〕−３−エチルカルボジイミド●
塩酸塩３．９ｆのテトラヒドロフラン１１−ジクロロメ
タン１′の混合溶液に、（２Ｒ，４Ｒ）−２一（２−ヒ
ドロキシフェニル）−３−（３−メルカプトプロピオニ
ル）−４−チアゾリジンカルボン酸６．３ｙのテトラヒ
ドロフラン２００ｍ１溶液を、室温で攪拌しながら滴下
する。Melting point amorphous powder CIMS (1-C4HlO) m/z;
435 (MH+) [α] f-214.31 (c=0.5
1, dimethyl sulfoxide) R (KBr, c77!-1
); 1750, 1690, 1630, 1450, 142
0,1180,1095Rf value 0.83 Example 3 (7S,10R,17S,20R)-10,20-bis(2-hydroxysifnyl)-5,9,15,19-tetrathia 1,11-diaza 2, Production of 6,12,16-tetraoxotricyclo[15.3.0.07,11]eicosane 1-[3-(N,N-dimethylamino)propyl]-3-ethylcarbodiimide ●
To a mixed solution of 3.9f of hydrochloride and 11-dichloromethane 1' of tetrahydrofuran was added 6.3y of (2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid. A solution of 200 ml of tetrahydrofuran is added dropwise with stirring at room temperature.
更に同温で２日間静置した後、減圧下、溶媒を留去する
。油状の残渣にテトラヒドロフランおよび酢酸エチルを
加え、不溶物を戸別し、沖液を濃縮乾固し、標記化合物
３．５ｙを得た。融点１８９℃（分解）（エタノ−ルー
テトラヒドロフランー酢酸エチル）ＣＩＭＳ（１−Ｃ４
ＨｌＯ）ｍ／ｚ；５９１（ＭＨ＋）〔α〕？＋１６３．
１１（ｃ＝０．５２、ジメチルスルホキシドー）ＩＲ（
ＫＢｒ，ｃｆｎ−１）；３２００，１６９０，１６８０
，１６２０，１６００，１４６０，１１２５Ｒｆ値０．
５１。After further standing at the same temperature for 2 days, the solvent was distilled off under reduced pressure. Tetrahydrofuran and ethyl acetate were added to the oily residue, insoluble matter was filtered out, and the Oki liquid was concentrated to dryness to obtain the title compound 3.5y. Melting point 189°C (decomposition) (ethanol-tetrahydrofuran-ethyl acetate) CIMS (1-C4
HlO) m/z; 591 (MH+) [α]? +163.
11 (c=0.52, dimethyl sulfoxide) IR (
KBr, cfn-1); 3200, 1690, 1680
, 1620, 1600, 1460, 1125 Rf value 0.
51.
Claims (1)
はメチレン基またはイオウ原子を示す。 Ｒ＾１は水素原子、低級または高級アルキル基、シクロ
アルキル基、アラルキル基、フェニル基、フリル基、チ
ェニル基、ピリジル基若しくはナフチル基を示す。夫々
の基は低級アルキル基、ヒドロキシ基、メルカプト基、
低級アルコキシ基、低級アルキレンジオキシ基、アシル
オキシ基、アシルメルカプト基、ハロゲン原子、ニトロ
基、アミノ基、低級アルキル置換アミノ基、アシルアミ
ノ基、カルボキシ基で置換されていてもよい。Ａは１〜
３個の炭素原子を有する直鎖または分枝のアルキレンを
示す。〕[Claims] 1. A compound represented by the following general formula [I]. ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕〔In the formula, Q
represents a methylene group or a sulfur atom. R^1 represents a hydrogen atom, a lower or higher alkyl group, a cycloalkyl group, an aralkyl group, a phenyl group, a furyl group, a chenyl group, a pyridyl group, or a naphthyl group. Each group is a lower alkyl group, a hydroxy group, a mercapto group,
It may be substituted with a lower alkoxy group, lower alkylenedioxy group, acyloxy group, acylmercapto group, halogen atom, nitro group, amino group, lower alkyl-substituted amino group, acylamino group, or carboxy group. A is 1~
Indicates a straight-chain or branched alkylene having 3 carbon atoms. ]
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13135080A JPS6052758B2 (en) | 1980-09-20 | 1980-09-20 | Heterotricyclic compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13135080A JPS6052758B2 (en) | 1980-09-20 | 1980-09-20 | Heterotricyclic compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5756488A JPS5756488A (en) | 1982-04-05 |
| JPS6052758B2 true JPS6052758B2 (en) | 1985-11-21 |
Family
ID=15055872
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13135080A Expired JPS6052758B2 (en) | 1980-09-20 | 1980-09-20 | Heterotricyclic compounds |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6052758B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62142447A (en) * | 1985-10-09 | 1987-06-25 | エヌ・ベ−・フイリツプス・フル−イランペンフアブリケン | Telephone |
| JPH0226853U (en) * | 1988-08-08 | 1990-02-21 |
-
1980
- 1980-09-20 JP JP13135080A patent/JPS6052758B2/en not_active Expired
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62142447A (en) * | 1985-10-09 | 1987-06-25 | エヌ・ベ−・フイリツプス・フル−イランペンフアブリケン | Telephone |
| JPS62161239A (en) * | 1985-10-09 | 1987-07-17 | エヌ・ベ−・フイリツプス・フル−イランペンフアブリケン | Telephone |
| JPH0226853U (en) * | 1988-08-08 | 1990-02-21 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5756488A (en) | 1982-04-05 |
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