JPS6313993B2 - - Google Patents
Info
- Publication number
- JPS6313993B2 JPS6313993B2 JP54081043A JP8104379A JPS6313993B2 JP S6313993 B2 JPS6313993 B2 JP S6313993B2 JP 54081043 A JP54081043 A JP 54081043A JP 8104379 A JP8104379 A JP 8104379A JP S6313993 B2 JPS6313993 B2 JP S6313993B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- hydroxyphenyl
- general formula
- dithiobis
- propanoyl
- 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
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- -1 disulfide compound Chemical class 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- APAUAYLVDHNFBF-UHFFFAOYSA-N 2-(2-hydroxyphenyl)-1,3-thiazolidine-4-carboxylic acid Chemical compound N1C(C(=O)O)CSC1C1=CC=CC=C1O APAUAYLVDHNFBF-UHFFFAOYSA-N 0.000 description 10
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 10
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 10
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VURCJRMYKFUQSW-UHFFFAOYSA-N 3-[(3-chloro-3-oxopropyl)disulfanyl]propanoyl chloride Chemical compound ClC(=O)CCSSCCC(Cl)=O VURCJRMYKFUQSW-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- YVKSGVDJQXLXDV-BYPYZUCNSA-N ethyl (2r)-2-amino-3-sulfanylpropanoate Chemical compound CCOC(=O)[C@@H](N)CS YVKSGVDJQXLXDV-BYPYZUCNSA-N 0.000 description 2
- VFUHEWBBJAYHNQ-FTNKSUMCSA-N ethyl (4r)-2-(2-hydroxyphenyl)-1,3-thiazolidine-4-carboxylate Chemical compound N1[C@H](C(=O)OCC)CSC1C1=CC=CC=C1O VFUHEWBBJAYHNQ-FTNKSUMCSA-N 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- APAUAYLVDHNFBF-JAVCKPHESA-N (4r)-2-(2-hydroxyphenyl)-1,3-thiazolidine-4-carboxylic acid Chemical compound N1[C@H](C(=O)O)CSC1C1=CC=CC=C1O APAUAYLVDHNFBF-JAVCKPHESA-N 0.000 description 1
- UUSLLECLCKTJQF-UHFFFAOYSA-N 2-(bromomethyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CBr)C(=O)C2=C1 UUSLLECLCKTJQF-UHFFFAOYSA-N 0.000 description 1
- RYIVRLWJRCHUCL-UHFFFAOYSA-N 2-phenyl-1,3-thiazolidin-2-ol Chemical group C=1C=CC=CC=1C1(O)NCCS1 RYIVRLWJRCHUCL-UHFFFAOYSA-N 0.000 description 1
- HOCPDSKONPQIQM-UHFFFAOYSA-N 4-(2-bromoethyl)isoindole-1,3-dione Chemical compound BrCCC1=CC=CC2=C1C(=O)NC2=O HOCPDSKONPQIQM-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- CYJYHSYAYORDLU-LURJTMIESA-N butyl (2r)-2-amino-3-sulfanylpropanoate Chemical compound CCCCOC(=O)[C@@H](N)CS CYJYHSYAYORDLU-LURJTMIESA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 1
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- WDCDAAMJNUHOIY-UHFFFAOYSA-N ethyl acetate;2-propan-2-yloxypropane Chemical compound CCOC(C)=O.CC(C)OC(C)C WDCDAAMJNUHOIY-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- SRRKNRDXURUMPP-UHFFFAOYSA-N sodium disulfide Chemical compound [Na+].[Na+].[S-][S-] SRRKNRDXURUMPP-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は下記一般式〔〕で表わされるチアゾ
リジン誘導体のエステル型ジスルフイド化合物に
関するものである。
〔式中、R1はヒドロキシ基を示す。
R2は低級アルキル基、アシロキシ低級アルキ
ル基またはフタルイミド低級アルキル基を示す。
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。以下同じ。〕
本発明化合物〔〕は、人または動物に投与さ
れたときに、酵素的およびまたは化的に加水分解
され、高血圧症状に有効なアンジオテンシン変換
酵素阻害剤であるメルカプトアシルアミノ酸を遊
離するエステルである。このエステルは遊離酸で
あるメルカプトアシルアミノ酸に比べて親油性が
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を画ることもできる。
本発明化合物〔〕は、例えば次のＡ〜Ｄのよ
うな方法で合成される。
(A) 一般式〔〕
で表わされる化合物と一般式〔〕
R2−Ｘ 〔〕
〔式中、Ｘはハロゲン原子を示す。以下同じ。〕
で表わされる化合物を反応させるか、塩化水
素、パラトルエンスルホン酸または、三フツ化
ホウ素エチルエーテルなどの酸触媒の存在下、
低級アルコールと反応させることにより本発明
化合物を得ることができる。
(B) 一般式〔〕
で表わされる化合物を例えば空気、ヨウ素、第
二鉄塩、過硫酸塩、過酸化水素で酸化すること
により本発明化合物を得ることができる。
(C) 一般式〔〕
−〔Ｓ−Ａ−CO−Ｙ〕2 〔〕
〔式中、Ｙは水酸基またはハロゲン原子を示
す。以下同じ。〕で表わされる化合物と一般式
〔〕
で表わされる化合物から、シヨツテンパウマン
反応、混合酸無水物法等の一般的方法により本
発明化合物を得ることができる。
(D) 一般式〔〕
Ｘ−Ａ−CO−Ｙ 〔〕
で表わされる化合物と一般式〔〕で表わされ
る化合物から、シヨツテンパウマン反応、混合
酸無水物法等の一般的方法により一般式〔〕
で表わされる化合物を得、次いで二硫化ナトリ
ウム等を反応させることにより本発明化合物を
得ることができる。
(D) 一般式〔〕の化合物を一般式〔〕
式〔中、Ｚは−Ｘ、−NO、−CN、−SCN、−
SO3M、−SR、−SO−Ｒ、−SO2−Ｒ、−Ｓ−
CO2−Ｒ、
The present invention relates to an ester type disulfide compound of a thiazolidine derivative represented by the following general formula []. [In the formula, R 1 represents a hydroxy group. R 2 represents a lower alkyl group, an acyloxy lower alkyl group or a phthalimide lower alkyl group. A represents straight-chain or branched alkylene having 1 to 3 carbon atoms. same as below. ] The compound of the present invention [ ] is an ester that, when administered to humans or animals, is enzymatically and/or chemically hydrolyzed to liberate mercaptoacyl amino acids, which are angiotensin-converting enzyme inhibitors effective in treating hypertension symptoms. . This ester can improve the absorption properties due to increased lipophilicity compared to the free acid mercaptoacylamino acid, and can also provide a longer duration. The compound of the present invention [] is synthesized, for example, by the following methods A to D. (A) General formula [] A compound represented by the general formula [] R 2 -X [] [wherein, X represents a halogen atom]. same as below. ]
or in the presence of an acid catalyst such as hydrogen chloride, para-toluenesulfonic acid or boron trifluoride ethyl ether,
The compound of the present invention can be obtained by reacting with a lower alcohol. (B) General formula [] The compound of the present invention can be obtained by oxidizing the compound represented by, for example, with air, iodine, ferric salt, persulfate, or hydrogen peroxide. (C) General formula [] -[S-A-CO-Y] 2 [] [In the formula, Y represents a hydroxyl group or a halogen atom. same as below. ] and the general formula [] The compound of the present invention can be obtained from the compound represented by the formula by a general method such as the Schotten-Paumann reaction or the mixed acid anhydride method. (D) From the compound represented by the general formula [] X-A-CO-Y [] and the compound represented by the general formula [], the general formula [] The compound of the present invention can be obtained by obtaining a compound represented by and then reacting with sodium disulfide or the like. (D) Compound of general formula [] Formula [wherein Z is -X, -NO, -CN, -SCN, -
SO 3 M, -SR, -SO-R, -SO 2 -R, -S-
CO2 -R,
【式】
またはフタルイミド基を示す。Ｍはアルカリ金
属を示す。以下同じ。〕に導き、これを一般式
〔〕で表わされる化合物と反応させることに
より本発明化合物を得ることができる。
尚本発明化合物〔〕は１個ないし複数の不整
炭素原子を有するので立体異性体が存在する。こ
れらはいずれも本発明化合物の範囲に包含され
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のでは
なく血圧降下作用を有し、ヒドロキシフエニルチ
アゾリジン環を有するすべてのメルカプトアシル
アミノ酸に適用されるものである。
実施例 １
（4R，4′R）−３，3′−〔３，3′−ジチオビス
（プロパノイル）〕ビス〔２−（２−ヒドロキシ
フエニル）−４−チアゾリジンカルボン酸（１，
３−ジヒドロ−１，３−ジオキソ−2H−イソ
インドール−２−イル）メチルエステル〕の製
造
（4R，4′R）−３，3′−〔３，3′−ジチオビス
（プロパノイル）〕ビス〔２−（２−ヒドロキシフ
エニル）−４−チアゾリジンカルボン酸〕3.12ｇ
の無水Ｎ，Ｎ−ジメチルホルムアミド15ml溶液
に、トリエチルアミン1.4ml、Ｎ−ブロモメチル
フタルイミド2.4ｇを加え、90℃で６時間攪拌す
る。反応混合物を30mlの氷水の中に移し、エーテ
ル抽出する。有機層を飽和食塩水で洗浄後、硫酸
マグネシウムで脱水するエーテルを減圧留去後、
得られた抽状物をシリカゲルカラムクロマトで精
製し標記化合物3.9ｇ（収率81％）を得る。
融点 105〜111℃（クロロホルム−エーテル）
〔α〕25 D＋102.1゜（Ｃ＝1.0、アセトン）
IR（nujol、cm-1.以下特記なき限り同じ）
3300、1783、1755、1727、1651、1157、729
実施例 ２
（4R，4′R）−３，3′−〔３，3′−ジチオビス
（プロパノイル）〕ビス〔２−（２−ヒドロキシ
フエニル）−４−チアゾリジンカルボン酸２−
（１，３−ジヒドロ−１，３−ジオキソ−2H−
イソインドール−２−イル）メチルエステル〕
の製造
窒素雰囲気下、（4R，4′R）−３，3′−〔３，3′−
ジチオビス（プロパノイル）〕ビス〔２−（２−ヒ
ドロキシフエニル）−４−チアゾリジンカルボン
酸〕3.12ｇの無水Ｎ，Ｎ−ジメチルホルムアミド
15ml溶液に、トリエチルアミン1.4ml、Ｎ−（２−
ブロモエチル）フタルイミド2.54ｇを加え、90℃
で６時間攪拌する。以下実施例１と同様に操作し
標記化合物2.1ｇ（収率43％）を得る。
融点 70〜76℃
〔α〕25 D＋73.6゜（Ｃ＝0.9、アセトン）
IR3300、1771、1739、1707、1645、1597、1168、
720
実施例 ３
（4R，4′R）−３，3′−〔３，3′−ジチオビス
（プロパノイル）〕ビス〔２−（２−ヒドロキシ
フエニル）−４−チアゾリジンカルボン酸（２，
２−ジメチル−１−オキソプロポキシ）メチル
エステル〕の製造
（4R，4′R）−３，3′−〔３，3′−ジチオビス
（プロパノイル）〕ビス〔２−（２−ヒドロキシフ
エニル）−４−チアゾリジンカルボン酸〕3.12ｇ
の無水Ｎ，Ｎ−ジメチルホルムアミド15ml溶液に
トリエチルアミン1.4ml、クロロメチルピバレー
ト1.5ｇを加え、室温にて一夜攪拌する。以下実
施例１と同様に操作し標記化合物2.1ｇ（収率49
％）を得る。
融点 84〜86℃（ベンゼン）
〔α〕27 D＋115.0゜（ｃ＝1.1、メタノール）
IR3350、1756、1626、1601、1112、993、764
実施例 ４
（4R，4′R）−３，3′−〔３，3′−ジチオビス
（プロパノイル）〕ビス〔２−（２−ヒドロキシ
フエニル）−４−チアゾリジンカルボン酸１−
（２，２−ジメチル−１−オキソプロポキシ）
エチルエステル〕の製造
窒素雰囲気下、（4R，4′R）−３，3′−〔３，3′−
ジチオビス（プロパノイル）〕ビス〔２−（２−ヒ
ドロキシフエニル）−４−チアゾリジンカルボン
酸〕3.12ｇの無水Ｎ，Ｎ−ジメチルホルムアミド
15ml溶液にトリエチルアミン1.4ml、１−Ｎ−ク
ロロエチルピバレート1.7ｇを加え、90℃で６時
間撹拌する。以下実施例１と同様に操作し標記化
合物2.0ｇ（収率45％）を得る。
融点 61〜65℃
〔α〕25 D＋139.8゜（ｃ＝0.9、メタノール）
IR3200、1755、1627、1600、1065、762
実施例 ５
（4R，4′R）−３，3′−〔３，3′−ジチオビス
（プロパノイル）〕ビス〔２−（２−ヒドロキシ
フエニル）−４−チアゾリジンカルボン酸エチ
ルエステル〕の製造
(i) （4R）−２−（２−ヒドロキシフエニル）−４
−チアゾリジンカルボン酸エチルエステル（Ｌ
−システインエチルエステルとサリチルアルデ
ヒドより合成。融点75〜77℃、〔α〕25 D−105.1゜
（ｃ＝0.9、メタノール））2.35ｇを水30mlとテ
トラヒドロフラン40mlの混液に溶解し、炭酸ナ
トリウム1.1ｇを加える。氷冷下攪拌しながら
３，3′−ジチオジプロパノイルクロリド1.36ｇ
を滴下する。滴下終了後室温でさらに30分間攪
拌後水100mlを加えエーテルで抽出する。有機
層を飽和食塩水で洗浄後、硫酸マグネシウムで
脱水する。溶媒を減圧留去し標記化合物2.3ｇ
（収率68％）を得る。
融点 195〜201℃（Ｎ，Ｎ−ジメチルホルムア
ミド−水）。
〔α〕24 D＋162.7゜（ｃ＝0.5、Ｎ，Ｎ−ジメチル
ホルムアミド）
IR3340、1745、1625、1600、1255、1230、766
(ii) （4R）−２−（２−ヒドロキシフエニル）−４
−チアゾリジンカルボン酸エチルエステル（Ｌ
−システインエチルエステルとサリチルアルデ
ヒドより常法により合成）2.5ｇおよびトリエ
チルミン1.0ｇのクロロホルム溶液に、氷冷下
攪拌しながら３，3′−ジチオジプロパノイルク
ロリド1.2ｇを滴下する。滴下終了後室温でさ
らに２時間攪拌後、水次いで飽和食塩水で洗浄
後、硫酸マグネシウムで脱水する。クロロホル
ムを減圧留去し標記化合物1.9ｇ（収率61％）
を得る。
実施例 ６
（4R，4′R）−３，3′−〔３，3′−ジチオビス
（プロパノイル）〕ビス〔２−（２−ヒドロキシ
フエニル）−４−チアゾリジンカルボン酸ブチ
ルエステル〕の製造
（4R）−２−（２−ヒドロキシフエニル）−４−
チアゾリジンカルボン酸ブチルエステル（Ｌ−シ
ステインブチルエステルとサリチルアルデヒドよ
り常法により合成。融点74〜76℃、〔α〕25 D−96.5°
（ｃ＝1.0、メタノール）を用い実施例５と同様に
操作し標記化合物を得る。
融点 182〜184℃（酢酸エチル−イソプロピルエ
ーテル）
〔α〕24 D＋143.7゜（ｃ＝0.5、Ｎ，Ｎ−ジメチルホ
ルムアミド）
IR3340、1743、1626、1600、1190、1172、763[Formula] or represents a phthalimide group. M represents an alkali metal. same as below. The compound of the present invention can be obtained by reacting this with a compound represented by the general formula []. Since the compound of the present invention [ ] has one or more asymmetric carbon atoms, stereoisomers exist. All of these are included within the scope of the compounds of the present invention. Examples of typical compounds are shown below, but the present invention is not limited to these examples, but is applicable to all mercaptoacylamino acids that have a blood pressure lowering effect and have a hydroxyphenylthiazolidine ring. It is something. Example 1 (4R,4′R)-3,3′-[3,3′-dithiobis(propanoyl)]bis[2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid (1,
Production of (4R,4′R)-3,3′-[3,3′-dithiobis(propanoyl)]bis[3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl ester] 2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid 3.12g
To 15 ml of anhydrous N,N-dimethylformamide solution were added 1.4 ml of triethylamine and 2.4 g of N-bromomethylphthalimide, and the mixture was stirred at 90°C for 6 hours. The reaction mixture is transferred into 30 ml of ice water and extracted with ether. After washing the organic layer with saturated brine and dehydrating it with magnesium sulfate, the ether was distilled off under reduced pressure.
The obtained extract was purified by silica gel column chromatography to obtain 3.9 g (yield: 81%) of the title compound. Melting point 105-111℃ (chloroform-ether) [α] 25 D +102.1゜ (C = 1.0, acetone) IR (nujol, cm -1 . The same below unless otherwise specified) 3300, 1783, 1755, 1727, 1651, 1157, 729 Example 2 (4R,4′R)-3,3′-[3,3′-dithiobis(propanoyl)]bis[2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid 2-
(1,3-dihydro-1,3-dioxo-2H-
isoindol-2-yl)methyl ester]
Production of (4R,4′R)−3,3′−[3,3′−
Dithiobis(propanoyl)]bis[2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid] 3.12 g of anhydrous N,N-dimethylformamide
Add 1.4 ml of triethylamine, N-(2-
Add 2.54g of (bromoethyl)phthalimide and heat to 90℃.
Stir for 6 hours. Thereafter, the same procedure as in Example 1 was carried out to obtain 2.1 g (yield: 43%) of the title compound. Melting point 70-76℃ [α] 25 D +73.6゜ (C=0.9, acetone) IR3300, 1771, 1739, 1707, 1645, 1597, 1168,
720 Example 3 (4R,4'R)-3,3'-[3,3'-dithiobis(propanoyl)]bis[2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid (2,
(4R,4′R)-3,3′-[3,3′-dithiobis(propanoyl)]bis[2-(2-hydroxyphenyl)- 4-thiazolidinecarboxylic acid〕3.12g
To a 15 ml solution of anhydrous N,N-dimethylformamide were added 1.4 ml of triethylamine and 1.5 g of chloromethyl pivalate, and the mixture was stirred overnight at room temperature. The following procedure was carried out in the same manner as in Example 1 to obtain 2.1 g of the title compound (yield: 49
%). Melting point 84-86℃ (benzene) [α] 27 D +115.0゜ (c=1.1, methanol) IR3350, 1756, 1626, 1601, 1112, 993, 764 Example 4 (4R, 4′R)-3, 3′-[3,3′-dithiobis(propanoyl)]bis[2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid 1-
(2,2-dimethyl-1-oxopropoxy)
Production of ethyl ester] Under nitrogen atmosphere, (4R,4′R)-3,3′-[3,3′-
Dithiobis(propanoyl)]bis[2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid] 3.12 g of anhydrous N,N-dimethylformamide
Add 1.4 ml of triethylamine and 1.7 g of 1-N-chloroethyl pivalate to the 15 ml solution, and stir at 90°C for 6 hours. Thereafter, the same procedure as in Example 1 was carried out to obtain 2.0 g (yield: 45%) of the title compound. Melting point 61-65℃ [α] 25 D +139.8゜ (c=0.9, methanol) IR3200, 1755, 1627, 1600, 1065, 762 Example 5 (4R, 4'R) -3, 3' - [3 , 3'-dithiobis(propanoyl)]bis[2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid ethyl ester] (i) (4R)-2-(2-hydroxyphenyl)-4
-thiazolidinecarboxylic acid ethyl ester (L
-Synthesized from cysteine ethyl ester and salicylaldehyde. Melting point: 75-77°C, [α] 25 D -105.1° (c = 0.9, methanol)) 2.35g is dissolved in a mixture of 30ml of water and 40ml of tetrahydrofuran, and 1.1g of sodium carbonate is added. 1.36 g of 3,3'-dithiodipropanoyl chloride while stirring under ice cooling.
drip. After the addition was completed, the mixture was stirred at room temperature for another 30 minutes, then 100 ml of water was added and extracted with ether. The organic layer is washed with saturated brine and then dehydrated with magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.3 g of the title compound.
(yield 68%). Melting point 195-201°C (N,N-dimethylformamide-water). [α] 24 D +162.7° (c=0.5, N,N-dimethylformamide) IR3340, 1745, 1625, 1600, 1255, 1230, 766 (ii) (4R)-2-(2-hydroxyphenyl) -4
-thiazolidinecarboxylic acid ethyl ester (L
1.2 g of 3,3'-dithiodipropanoyl chloride is added dropwise to a chloroform solution of 2.5 g (synthesized from cysteine ethyl ester and salicylaldehyde) and 1.0 g of triethylmine with stirring under ice cooling. After the dropwise addition was completed, the mixture was stirred at room temperature for another 2 hours, washed with water and then with saturated saline, and then dehydrated with magnesium sulfate. Chloroform was distilled off under reduced pressure to obtain 1.9 g of the title compound (yield 61%).
get. Example 6 Production of (4R,4′R)-3,3′-[3,3′-dithiobis(propanoyl)]bis[2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid butyl ester] ( 4R)-2-(2-hydroxyphenyl)-4-
Thiazolidine carboxylic acid butyl ester (synthesized from L-cysteine butyl ester and salicylaldehyde by a conventional method. Melting point 74-76℃, [α] 25 D -96.5°
(c=1.0, methanol) in the same manner as in Example 5 to obtain the title compound. Melting point 182-184℃ (ethyl acetate-isopropyl ether) [α] 24 D +143.7゜ (c=0.5, N,N-dimethylformamide) IR3340, 1743, 1626, 1600, 1190, 1172, 763
Claims (1)
スルフイド化合物。 〔式中、R1はヒドロキシ基を示す。 R2は低級アルキル基、アシロキシ低級アルキ
ル基またはフタルイミド低級アルキル基を示す。 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。〕[Scope of Claims] 1. An ester type disulfide compound represented by the following general formula []. [In the formula, R 1 represents a hydroxy group. R 2 represents a lower alkyl group, an acyloxy lower alkyl group or a phthalimide lower alkyl group. A represents straight-chain or branched alkylene having 1 to 3 carbon atoms. ]
Priority Applications (18)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8104379A JPS565415A (en) | 1979-06-26 | 1979-06-26 | Ester-type hypotensor |
| US06/104,970 US4347371A (en) | 1978-12-30 | 1979-12-18 | Disulfide compounds |
| AU54024/79A AU536307B2 (en) | 1978-12-30 | 1979-12-19 | Disulphide derivatives of pyrrolidine and thiazolidine |
| SE7910554A SE446864B (en) | 1978-12-30 | 1979-12-20 | Disulfide compounds, procedure for producing the same and pharmaceutical composition containing said disulfide compounds |
| CA342,420A CA1128517A (en) | 1978-12-30 | 1979-12-20 | Disulfide compounds |
| DE19792952594 DE2952594A1 (en) | 1978-12-30 | 1979-12-28 | DISULFID COMPOUNDS |
| NL7909334A NL7909334A (en) | 1978-12-30 | 1979-12-28 | METHOD FOR PREPARING A BLOOD PRESSURE REDUCING AGENT BASED ON DISULFIDE COMPOUNDS, THE MEDICINE PREPARED AND A METHOD FOR PREPARING THE ACTIVE COMPONENT. |
| GB7944544A GB2042517B (en) | 1978-12-30 | 1979-12-28 | Disulphide compounds |
| AT0820179A AT377516B (en) | 1978-12-30 | 1979-12-28 | METHOD FOR PRODUCING DISULFIDE COMPOUNDS AND THEIR SALTS |
| IT28440/79A IT1127323B (en) | 1978-12-30 | 1979-12-28 | COMPOUNDS CONSTITUTED FROM DISULFURI |
| CH11528/79A CH647769A5 (en) | 1978-12-30 | 1979-12-28 | DISULFID COMPOUNDS. |
| ES487373A ES8101549A1 (en) | 1978-12-30 | 1979-12-28 | Process for the preparation of disulpho derivatives |
| FR7932060A FR2445324A1 (en) | 1978-12-30 | 1979-12-28 | NOVEL DISULFIDE DERIVATIVES CONTAINING A PYRROLIDINE OR THIAZOLIDINE CYCLE USEFUL AS ANTIHYPERTENSORS AND FOR PREVENTING AND TREATING DIABETES COMPLICATIONS AND METHODS FOR THEIR PREPARATION |
| ES494655A ES8106495A1 (en) | 1978-12-30 | 1980-08-29 | Process for the preparation of disulpho derivatives |
| ES494656A ES494656A0 (en) | 1978-12-30 | 1980-08-29 | A PROCEDURE FOR THE PREPARATION OF DIFFERENCES |
| ES494654A ES494654A0 (en) | 1978-12-30 | 1980-08-29 | A PROCEDURE FOR THE PREPARATION OF DIFFERENCES |
| ES494657A ES8106497A1 (en) | 1978-12-30 | 1980-08-29 | Process for the preparation of disulpho derivatives |
| US06/186,271 US4410542A (en) | 1978-12-30 | 1980-09-11 | Disulfide compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8104379A JPS565415A (en) | 1979-06-26 | 1979-06-26 | Ester-type hypotensor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS565415A JPS565415A (en) | 1981-01-20 |
| JPS6313993B2 true JPS6313993B2 (en) | 1988-03-29 |
Family
ID=13735401
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8104379A Granted JPS565415A (en) | 1978-12-30 | 1979-06-26 | Ester-type hypotensor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS565415A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5382778A (en) * | 1976-12-03 | 1978-07-21 | Squibb & Sons Inc | Thiazolidinecarboxylate derivative and related compounds thereof process for preparing same and application thereof |
| JPS5432466A (en) * | 1977-08-15 | 1979-03-09 | Yoshitomi Pharmaceut Ind Ltd | Thiazolidine derivatives and their preparation |
| JPS5466675A (en) * | 1977-09-28 | 1979-05-29 | Science Union & Cie | Omegaamercaptopropionamido*its manufacture and medical composition |
-
1979
- 1979-06-26 JP JP8104379A patent/JPS565415A/en active Granted
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5382778A (en) * | 1976-12-03 | 1978-07-21 | Squibb & Sons Inc | Thiazolidinecarboxylate derivative and related compounds thereof process for preparing same and application thereof |
| JPS5432466A (en) * | 1977-08-15 | 1979-03-09 | Yoshitomi Pharmaceut Ind Ltd | Thiazolidine derivatives and their preparation |
| JPS5466675A (en) * | 1977-09-28 | 1979-05-29 | Science Union & Cie | Omegaamercaptopropionamido*its manufacture and medical composition |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS565415A (en) | 1981-01-20 |
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