JPS6257619B2 - - Google Patents
Info
- Publication number
- JPS6257619B2 JPS6257619B2 JP54041319A JP4131979A JPS6257619B2 JP S6257619 B2 JPS6257619 B2 JP S6257619B2 JP 54041319 A JP54041319 A JP 54041319A JP 4131979 A JP4131979 A JP 4131979A JP S6257619 B2 JPS6257619 B2 JP S6257619B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- tiopronin
- compound
- title compound
- groups
- 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
- 150000001875 compounds Chemical class 0.000 claims description 31
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 5
- 108010024636 Glutathione Proteins 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229960003180 glutathione Drugs 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- YTGJWQPHMWSCST-UHFFFAOYSA-N Tiopronin Chemical compound CC(S)C(=O)NCC(O)=O YTGJWQPHMWSCST-UHFFFAOYSA-N 0.000 description 18
- 229960004402 tiopronin Drugs 0.000 description 17
- 108010058907 Tiopronin Proteins 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- 238000004519 manufacturing process Methods 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- -1 sulfide compound Chemical class 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 150000003946 cyclohexylamines Chemical class 0.000 description 2
- 229960003067 cystine Drugs 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- VHJLVAABSRFDPM-ZXZARUISSA-N dithioerythritol Chemical compound SC[C@H](O)[C@H](O)CS VHJLVAABSRFDPM-ZXZARUISSA-N 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 description 1
- MXBCRXQYFIPNMH-UHFFFAOYSA-N 2-[2-[[1-(carboxymethylamino)-1-oxopropan-2-yl]disulfanyl]propanoylamino]acetic acid Chemical compound OC(=O)CNC(=O)C(C)SSC(C)C(=O)NCC(O)=O MXBCRXQYFIPNMH-UHFFFAOYSA-N 0.000 description 1
- MONMFXREYOKQTI-UHFFFAOYSA-N 2-bromopropanoic acid Chemical compound CC(Br)C(O)=O MONMFXREYOKQTI-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 108010053070 Glutathione Disulfide Proteins 0.000 description 1
- 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 1
- 235000019393 L-cystine Nutrition 0.000 description 1
- 239000004158 L-cystine Substances 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ABRJVLRUVDJIJJ-UHFFFAOYSA-N OC(=O)CNC(=O)C(C)SSCC(N)C(O)=O Chemical compound OC(=O)CNC(=O)C(C)SSCC(N)C(O)=O ABRJVLRUVDJIJJ-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- MBRZVWSXTLBVNY-UHFFFAOYSA-N acetic acid;chloroform;ethanol Chemical compound CCO.CC(O)=O.ClC(Cl)Cl MBRZVWSXTLBVNY-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- ZYZWOSIRFVIBRH-UHFFFAOYSA-N chloroform;cyclohexane Chemical compound ClC(Cl)Cl.C1CCCCC1 ZYZWOSIRFVIBRH-UHFFFAOYSA-N 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- WACQKHWOTAEEFS-UHFFFAOYSA-N cyclohexane;ethyl acetate Chemical compound CCOC(C)=O.C1CCCCC1 WACQKHWOTAEEFS-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- PLVPMKWGXOOSKL-RGVONZFCSA-L disodium;(2r)-2-amino-3-[[(2r)-2-amino-2-carboxylatoethyl]disulfanyl]propanoate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CSSC[C@H](N)C([O-])=O PLVPMKWGXOOSKL-RGVONZFCSA-L 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- YPZRWBKMTBYPTK-BJDJZHNGSA-N glutathione disulfide Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@H](C(=O)NCC(O)=O)CSSC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O YPZRWBKMTBYPTK-BJDJZHNGSA-N 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- YPZRWBKMTBYPTK-UHFFFAOYSA-N oxidized gamma-L-glutamyl-L-cysteinylglycine Natural products OC(=O)C(N)CCC(=O)NC(C(=O)NCC(O)=O)CSSCC(C(=O)NCC(O)=O)NC(=O)CCC(N)C(O)=O YPZRWBKMTBYPTK-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229960001639 penicillamine Drugs 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- HLLMICMHTKJPJM-UHFFFAOYSA-M sodium;ethoxy-oxido-oxo-sulfanylidene-$l^{6}-sulfane Chemical compound [Na+].CCOS([O-])(=O)=S HLLMICMHTKJPJM-UHFFFAOYSA-M 0.000 description 1
- HLZPPBJQBJXVNG-UHFFFAOYSA-M sodium;methoxy-oxido-oxo-sulfanylidene-$l^{6}-sulfane Chemical compound [Na+].COS([O-])(=O)=S HLZPPBJQBJXVNG-UHFFFAOYSA-M 0.000 description 1
- WAEFQZYNSITAQT-UHFFFAOYSA-M sodium;octoxy-oxido-oxo-sulfanylidene-$l^{6}-sulfane Chemical compound [Na+].CCCCCCCCOS([O-])(=O)=S WAEFQZYNSITAQT-UHFFFAOYSA-M 0.000 description 1
- NRCOBPBOOMYKGU-UHFFFAOYSA-M sodium;oxido-oxo-(oxolan-2-ylmethoxy)-sulfanylidene-$l^{6}-sulfane Chemical compound [Na+].[O-]S(=O)(=S)OCC1CCCO1 NRCOBPBOOMYKGU-UHFFFAOYSA-M 0.000 description 1
- GJNRIGCZVXQSHN-UHFFFAOYSA-M sodium;oxido-oxo-propoxy-sulfanylidene-$l^{6}-sulfane Chemical compound [Na+].CCCOS([O-])(=O)=S GJNRIGCZVXQSHN-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
- Furan Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本発明は下記一般式〔〕で表わされる化合物
およびその塩類に関する。
式中、R1は１〜８個の炭素原子を有する直鎖
または分枝の飽和アルキル基又はアリル基又はグ
ルタチオンよりメルカプト基を除いた基を示し、
前記アルキル基はカルボキシ基、アミノ基および
テトラヒドロフリル基から選択される同一かまた
は異なる１〜２個の基で置換されていてもよい。
ｎは１または２の整数を示す。以下同じ。
本発明化合物〔〕はチオプロニンの非対称型
（ジ）スルフイド化合物であつて、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学的
に（ジ）スルフイドの開裂が起こり、医薬として
広く使用されているチオプロニンを遊離するもの
である。チオプロニンはフリーラジカルを除去す
ることから肝障害抑制剤として有用であり、Ｄ−
ペニシラミンに類似した作用機序により抗リウマ
チ作用が期待され、また白内障治療剤としても利
用されるという医薬として極めて高い価値をもつ
物質である。
本発明においては効果を長く持続させるだけで
なく、安定性が増大し、より簡便な合成法が可能
であるという特徴を有する。
本発明化合物〔〕は、例えば次のＡ〜Ｃのよ
うな方法で合成される。
(A) 式〔〕
で表わされるチオプロニンと、式〔〕におい
てｎが１のときは式〔〕
R1−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と反応させ、ｎが２のとき
は式〔〕の化合物を式〔〕
R1−Ｓ−Ｙ 〔〕
〔式中、ＹはＸ、NO、CN、SCN、SO3A、
SR、SO−Ｒ、SO2−Ｒ、Ｓ−CO2−Ｒ、
The present invention relates to compounds represented by the following general formula [] and salts thereof. In the formula, R 1 represents a linear or branched saturated alkyl group or allyl group having 1 to 8 carbon atoms, or a group obtained by removing a mercapto group from glutathione,
The alkyl group may be substituted with 1 to 2 groups, which may be the same or different, selected from carboxy groups, amino groups, and tetrahydrofuryl groups.
n represents an integer of 1 or 2. same as below. The compound of the present invention [ ] is an asymmetric (di)sulfide compound of tiopronin, and when administered to humans or animals, the (di)sulfide is enzymatically and/or chemically cleaved, and it is widely used as a medicine. It liberates the tiopronin that is present in the body. Tiopronin is useful as a liver damage inhibitor because it scavenges free radicals, and D-
It is a substance with extremely high value as a medicine, as it is expected to have anti-rheumatic effects due to its mechanism of action similar to that of penicillamine, and is also used as a cataract treatment. The present invention is characterized by not only a long-lasting effect but also increased stability and a simpler synthesis method. The compound of the present invention [] can be synthesized, for example, by the following methods A to C. (A) Formula〔〕 Tiopronin represented by the formula [] and when n is 1 in the formula [], the formula [] R 1 -X [] [wherein, X represents a halogen atom]. same as below. ] When n is 2, the compound of the formula [] is reacted with the compound of the formula [] R 1 -S-Y [] [where Y is X, NO, CN, SCN, SO 3 A,
SR, SO-R, SO2 -R, S- CO2 -R,
【式】
またはフタルイミド基を示す。Ａはアルカリ金
属原子を示す。以下同じ。〕で表わされる化合
物に導き、これと式〔〕のチオプロニンを反
応させることにより本発明化合物〔〕を得る
ことができる。
(B) 式〔〕
R1−SH 〔〕
で表わされる化合物と、式〔〕においてｎが
１のときは式〔〕
で表わされる化合物と反応させ、ｎが２のとき
は式〔〕
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。
(C) 式〔〕
〔式中、Ｚは水酸基またはハロゲン原子を示
す。〕
で表わされる化合物とグリシンからシヨツテン
バウマン反応、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。
上記Ａ〜Ｃの方法により合成した一般式〔〕
で表わされる本発明化合物は必要に応じてナトリ
ウム、カリウム、カルシウム、アルミニウム、ア
ンモニウム、ジエチルアミンやトリエタノールア
ミン等の医薬として慣用される塩とすることがで
きる。尚本発明化合物〔〕は１個または複数の
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に包含され
る。以下に実施例を示すが、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
Ｎ−（Ｓ−カルボキシメチル−２−メルカプト
プロピオニル）グリシンの製造
チオプロニン〔Ｎ−（２−メルカプトプロピオ
ニル）グリシン〕16.3ｇの1M炭酸カリウム溶液
300mlにモノクロロ酢酸9.4ｇを加え、室温下、一
夜撹拌する。濃塩酸にて酸性化後、食塩を飽和溶
解し、酢酸エチルで抽出する。有機層を飽和食塩
水で洗浄し、硫酸マグネシウムで脱水後、酢酸エ
チルを留去すると油状物を得る。この油状物をエ
タノールに溶かし、シクロヘキシルアミン16.8ｇ
を加え、析出した針状結晶を濾取、乾燥すると標
記化合物のシクロヘキシルアミン塩28.0ｇ（収率
67％）を得る。
融点113−115℃（水−アセトン）
IR（nujol、cm-1、以下特記なき限り同じ）
1630、1415、1310、1140、930
この塩を常法により脱塩すると標記化合物を得
る。
実施例 ２
Ｎ−〔Ｓ−（１−カルボキシエチル）−２−メル
カプトプロピオニル〕グリシンの製造
チオプロニン16.3ｇと２−ブロモプロピオン酸
15.3ｇを用い実施例１と同様に操作して標記化合
物16.9ｇ（収率72％）を得る。
融点103−108℃（分解）
シクロヘキシルアミン塩
融点175−177℃（分解）（水−アセトン）
IR1660、1625、1405、1305、1235、1040、885
実施例 ３
Ｎ−（２−メチルジスルフアニルプロピオニ
ル）グリシンの製造
チオプロニン1.6ｇのＮ水酸化ナトリウム溶液
20mlとメチルチオ硫酸ナトリウム3.0ｇの水溶液
10mlを混合し、１分間振とうする。塩酸で酸性化
後、酢酸エチルで抽出する。有機層を水洗し、硫
酸マグネシウムで脱水後、酢酸エチルを留去する
と油状物を得る。この油状物をシリカゲルカラム
クロマトで精製して標記化合物0.18ｇ（収率９
％）を得る。
融点96−98℃（クロロホルム）
IR3230、1726、1636、1552、1411、1234、
1210、1080、1022、922、862
TLC（Rf値(a)）0.40
(a)シリカゲル、クロロホルム−エタノール−酢
酸（10：１：１）、以下同じ。
実施例 ４
Ｎ−〔２−〔（テトラヒドロフルフリル）ジスル
フアニル〕プロピオニル〕グリシンの製造
チオプロニン1.6ｇとテトラヒドロフルフリル
チオ硫酸ナトリウム4.4ｇを用い実施例３と同様
に操作して標記化合物0.7ｇ（収率25％）を得
る。
IR（neat、cm-1）3255、1740、1640、1415、
1200、1045、875
TLC（Rf値(a)）0.43
実施例 ５
Ｎ−（２−エチルジスルフアニルプロピオニ
ル）グリシンの製造
チオプロニン1.6ｇとエチルチオ硫酸ナトリウ
ム3.3ｇを用い実施例３と同様に操作して標記化
合物0.5ｇ（収率22％）を得る。
融点67−68℃（酢酸エチル）
IR3340、1748、1607、1418、1212、1075、
1025、840
TLC（Rf値(a)）0.46
実施例 ６
Ｎ−〔２−〔（２−アミノ−２−カルボキシエチ
ル）ジチオ〕プロピオニル〕グリシンの製造
Ｌ−シスチン2.4ｇをＮ塩酸30mlに溶解した
後、Ｎ水酸化ナトリウム50mlを加えＬ−シスチン
ナトリウム塩溶液とする。チオプロニン1.6ｇの
Ｎ水酸化ナトリウム溶液10mlを先に調製したＬ−
シスチンナトリウム塩溶液に加え１分間撹拌す
る。Ｎ塩酸でPH3.0とした後、カラムクロマトで
精製して標記化合物を得る。
日立034型液体クロマトグラフ（アミノ酸分析
計）で日立イオン交換樹脂782−2612を52cm充填
したカラムを用い、PH3.25の0.2Nクエン酸緩衝液
で標記化合物を１ml／分、55℃にて溶出させ、ニ
ンヒドリンで検出すると溶出時間は47分である。
また、標記化合物をジチオエリスリトールで還
元処理後、上記の方法で溶出するとチオプロニン
（溶出時間25分）とシステイン（溶出時間77分）
が当量検出できる。
実施例 ７
Ｎ−（２−プロピルジスルフアニルプロピオニ
ル）グリシンの製造
チオプロニン1.6ｇとプロピルチオ硫酸ナトリ
ウム3.6ｇを用い実施例３と同様に操作して標記
化合物0.9ｇ（収率38％）を得る。
融点90−91.5℃（クロロホルム）
IR3320、1760、1735、1610、1200、850、
TLC（Rf値(a)）0.52
実施例 ８
Ｎ−（２−アリルジスルフアニルプロピオニ
ル）グリシンの製造
チオプロニン1.6ｇとアリルチオ硫酸ナトリウ
ム3.5ｇを用い実施例３と同様に操作して標記化
合物1.0ｇ（収率43％）を得る。
融点60−61℃（酢酸エチル−シクロヘキサン）
IR3320、1765、1745、1614、1404、1198、
1079、1025、920、858
TLC（Rf値(a)）0.43
実施例 ９
Ｎ−（２−オクチルジスルフアニルプロピオニ
ル）グリシンの製造
チオプロニン1.6ｇとオクチルチオ硫酸ナトリ
ウム5.0ｇを用い実施例３と同様に操作して標記
化合物0.35ｇ（収率12％）を得る。
融点74−75℃（クロロホルム−シクロヘキサン）
IR3385、1762、1736、1626、1410、1195、
1080、1025、860
TLC（Rf値(a)）0.54
実施例 10
グルタチオン チオプロニン ジスルフイドの
製造
酸化型グルタチオン6.1ｇのＮ水酸化ナトリウ
ム溶液40mlとチオプロニン1.6ｇのＮ水酸化ナト
リウム溶液10mlを用い実施例６と同様に操作して
標記化合物を得る。
日立034型液体クロマトグラフ（アミノ酸分析
計）で日立イオン交換樹脂782−2612を52cm充填
したカラムを用い、PH3.25の0.2Nクエン酸緩衝液
で標記化合物を１ml／分、45℃にて溶出させ、ニ
ンヒドリンで検出すると溶出時間は39分である。
また、標記化合物をジチオエリスリトールで還
元処理後、上記の方法で溶出するとチオプロニン
（溶出時間27分）とグルタチオン（溶出時間48
分）が当量検出できる。[Formula] or represents a phthalimide group. A represents an alkali metal atom. same as below. ] The compound of the present invention [ ] can be obtained by reacting this with tiopronin of the formula [ ]. (B) A compound represented by the formula [] R 1 −SH [] and when n is 1 in the formula [], a compound represented by the formula [] When n is 2, the formula [] The compound of the present invention [] can be obtained by reacting with the compound represented by (C) Formula〔〕 [In the formula, Z represents a hydroxyl group or a halogen atom. ] The compound of the present invention [ ] can be obtained from the compound represented by the formula and glycine by a general method such as Schotten-Baumann reaction or mixed acid anhydride method. General formula synthesized by methods A to C above []
The compound of the present invention represented by can be converted into a salt commonly used as a medicine such as sodium, potassium, calcium, aluminum, ammonium, diethylamine or triethanolamine, if necessary. Since the compound of the present invention [ ] has one or more asymmetric carbon atoms, stereoisomers exist. All of these are included in the compounds of the present invention. Examples are shown below, but the present invention is not limited to these examples. Example 1 Production of N-(S-carboxymethyl-2-mercaptopropionyl)glycine 16.3 g of 1M potassium carbonate solution of tiopronin [N-(2-mercaptopropionyl)glycine]
Add 9.4 g of monochloroacetic acid to 300 ml and stir at room temperature overnight. After acidifying with concentrated hydrochloric acid, the salt was dissolved to saturation, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, and ethyl acetate is distilled off to obtain an oil. Dissolve this oil in ethanol and add 16.8g of cyclohexylamine.
was added, the precipitated needle crystals were collected by filtration, and dried to give 28.0 g of the cyclohexylamine salt of the title compound (yield:
67%). Melting point 113-115℃ (water-acetone) IR (nujol, cm -1 , same below unless otherwise specified)
1630, 1415, 1310, 1140, 930 This salt is desalted by a conventional method to obtain the title compound. Example 2 Production of N-[S-(1-carboxyethyl)-2-mercaptopropionyl]glycine 16.3 g of thiopronin and 2-bromopropionic acid
Using 15.3 g, the same procedure as in Example 1 was carried out to obtain 16.9 g (yield: 72%) of the title compound. Melting point 103-108℃ (decomposition) Cyclohexylamine salt Melting point 175-177℃ (decomposition) (water-acetone) IR1660, 1625, 1405, 1305, 1235, 1040, 885 Example 3 N-(2-methyldisulfanylpropionyl ) Manufacture of glycine 1.6 g of tiopronin in N sodium hydroxide solution
Aqueous solution of 20ml and 3.0g of sodium methylthiosulfate
Mix 10ml and shake for 1 minute. After acidification with hydrochloric acid, extract with ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate, and ethyl acetate is distilled off to obtain an oil. This oil was purified by silica gel column chromatography to obtain 0.18 g of the title compound (yield: 9.
%). Melting point 96-98℃ (chloroform) IR3230, 1726, 1636, 1552, 1411, 1234,
1210, 1080, 1022, 922, 862 TLC (Rf value (a) ) 0.40 (a) Silica gel, chloroform-ethanol-acetic acid (10:1:1), the same hereinafter. Example 4 Production of N-[2-[(tetrahydrofurfuryl)disulfanyl]propionyl]glycine The title compound was produced in the same manner as in Example 3 using 1.6 g of tiopronine and 4.4 g of sodium tetrahydrofurfurylthiosulfate (yield: 0.7 g). 25%). IR (neat, cm -1 ) 3255, 1740, 1640, 1415,
1200, 1045, 875 TLC (Rf value (a) ) 0.43 Example 5 Production of N-(2-ethyldisulfanylpropionyl)glycine The same procedure as in Example 3 was carried out using 1.6 g of tiopronin and 3.3 g of sodium ethylthiosulfate. 0.5 g (yield 22%) of the title compound is obtained. Melting point 67-68℃ (ethyl acetate) IR3340, 1748, 1607, 1418, 1212, 1075,
1025, 840 TLC (Rf value (a) ) 0.46 Example 6 Production of N-[2-[(2-amino-2-carboxyethyl)dithio]propionyl]glycine 2.4 g of L-cystine was dissolved in 30 ml of N hydrochloric acid. After that, add 50 ml of N-sodium hydroxide to prepare an L-cystine sodium salt solution. Add 10 ml of N sodium hydroxide solution containing 1.6 g of tiopronin to the previously prepared L-
Add to cystine sodium salt solution and stir for 1 minute. After adjusting the pH to 3.0 with N-hydrochloric acid, the mixture is purified by column chromatography to obtain the title compound. Using a column packed with 52 cm of Hitachi ion exchange resin 782-2612 using a Hitachi Model 034 liquid chromatograph (amino acid analyzer), the title compound was eluted with 0.2N citric acid buffer of pH 3.25 at 1 ml/min at 55°C. When detected with ninhydrin, the elution time is 47 minutes. In addition, when the title compound was reduced with dithioerythritol and eluted using the above method, tiopronin (elution time 25 minutes) and cysteine (elution time 77 minutes) were obtained.
can detect the equivalent amount. Example 7 Production of N-(2-propyldisulfanylpropionyl)glycine 0.9 g (yield: 38%) of the title compound is obtained in the same manner as in Example 3 using 1.6 g of tiopronin and 3.6 g of sodium propylthiosulfate. Melting point 90-91.5℃ (chloroform) IR3320, 1760, 1735, 1610, 1200, 850, TLC (Rf value (a) ) 0.52 Example 8 Production of N-(2-allyldisulfanylpropionyl)glycine 1.6 g of tiopronin and Using 3.5 g of sodium allylthiosulfate, the same procedure as in Example 3 was carried out to obtain 1.0 g (yield: 43%) of the title compound. Melting point 60-61℃ (ethyl acetate-cyclohexane) IR3320, 1765, 1745, 1614, 1404, 1198,
1079, 1025, 920, 858 TLC (Rf value (a) ) 0.43 Example 9 Production of N-(2-octyldisulfanylpropionyl)glycine Same as Example 3 using 1.6 g of tiopronin and 5.0 g of sodium octylthiosulfate. Operation gives 0.35 g (12% yield) of the title compound. Melting point 74-75℃ (chloroform-cyclohexane) IR3385, 1762, 1736, 1626, 1410, 1195,
1080, 1025, 860 TLC (Rf value (a) ) 0.54 Example 10 Production of glutathione tiopronin disulfide Example 6 using 40 ml of N sodium hydroxide solution containing 6.1 g of oxidized glutathione and 10 ml of N sodium hydroxide solution containing 1.6 g of tiopronin. The title compound is obtained by the same procedure as above. Using a column packed with 52 cm of Hitachi ion exchange resin 782-2612 using a Hitachi Model 034 liquid chromatograph (amino acid analyzer), the title compound was eluted with 0.2N citrate buffer of pH 3.25 at 1 ml/min at 45°C. When detected with ninhydrin, the elution time is 39 minutes. In addition, when the title compound was reduced with dithioerythritol and eluted using the above method, tiopronin (elution time 27 minutes) and glutathione (elution time 48 minutes) were obtained.
minute) can be detected in equivalent quantities.
Claims (1)
その塩類。 式中、R1は１〜８個の炭素原子を有する直鎖
または分枝の飽和アルキル基又はアリル基又はグ
ルタチオンよりメルカプト基を除いた基を示し、
前記アルキル基はカルボキシ基、アミノ基および
テトラヒドロフリル基から選択される同一かまた
は異なる１〜２個の基で置換されていてもよい。
ｎは１または２の整数を示す。[Claims] 1. Compounds represented by the following general formula [] and salts thereof. In the formula, R 1 represents a linear or branched saturated alkyl group or allyl group having 1 to 8 carbon atoms, or a group obtained by removing a mercapto group from glutathione,
The alkyl group may be substituted with 1 to 2 groups, which may be the same or different, selected from carboxy groups, amino groups, and tetrahydrofuryl groups.
n represents an integer of 1 or 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4131979A JPS55133343A (en) | 1979-04-04 | 1979-04-04 | Thiopronine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4131979A JPS55133343A (en) | 1979-04-04 | 1979-04-04 | Thiopronine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS55133343A JPS55133343A (en) | 1980-10-17 |
| JPS6257619B2 true JPS6257619B2 (en) | 1987-12-02 |
Family
ID=12605186
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4131979A Granted JPS55133343A (en) | 1979-04-04 | 1979-04-04 | Thiopronine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS55133343A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1305845C (en) * | 2005-05-16 | 2007-03-21 | 河南省新谊药业股份有限公司 | Anhydrous tiopronin natrium for curing acute or chronic liver disease and preparation method |
| CN100383521C (en) * | 2005-09-23 | 2008-04-23 | 复旦大学 | Method for determining concentration of tiopronin |
| EP2961733B1 (en) * | 2013-02-28 | 2021-01-13 | Tufts University | Disulfide compounds for delivery of pharmaceutical agents |
-
1979
- 1979-04-04 JP JP4131979A patent/JPS55133343A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS55133343A (en) | 1980-10-17 |
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