JPS6213955B2 - - Google Patents
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- Publication number
- JPS6213955B2 JPS6213955B2 JP1251979A JP1251979A JPS6213955B2 JP S6213955 B2 JPS6213955 B2 JP S6213955B2 JP 1251979 A JP1251979 A JP 1251979A JP 1251979 A JP1251979 A JP 1251979A JP S6213955 B2 JPS6213955 B2 JP S6213955B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- carbon atoms
- acid
- compound
- 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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- 150000001875 compounds Chemical class 0.000 claims description 19
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 5
- -1 (4R)-2-(2-hydroxyphenyl)-3- (S-octanoyl-3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid Chemical compound 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- 239000002253 acid Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- BUZUHDJKQXPATC-UHFFFAOYSA-N 2-(3-sulfanylpropanoyl)-1,3-thiazolidine-4-carboxylic acid Chemical compound SCCC(=O)C1SCC(N1)C(=O)O BUZUHDJKQXPATC-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- DZLNHFMRPBPULJ-VKHMYHEASA-N L-thioproline Chemical compound OC(=O)[C@@H]1CSCN1 DZLNHFMRPBPULJ-VKHMYHEASA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- FWNWATHTRVGPDX-RITPCOANSA-N (4r)-3-[(2s)-2-methyl-3-sulfanylpropanoyl]-1,3-thiazolidine-4-carboxylic acid Chemical compound SC[C@@H](C)C(=O)N1CSC[C@H]1C(O)=O FWNWATHTRVGPDX-RITPCOANSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-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
- 229940126062 Compound A Drugs 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 241001465754 Metazoa Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000007073 chemical hydrolysis Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N linoleic acid group Chemical group C(CCCCCCC\C=C/C\C=C/CCCCC)(=O)O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000005473 octanoic acid group Chemical group 0.000 description 1
- REEZZSHJLXOIHL-UHFFFAOYSA-N octanoyl chloride Chemical compound CCCCCCCC(Cl)=O REEZZSHJLXOIHL-UHFFFAOYSA-N 0.000 description 1
- 235000019645 odor Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229950001139 timonacic Drugs 0.000 description 1
Description
本発明は下記一般式〔〕で表わされる含硫化
合物およびその塩類、ならびにこれらの化合物を
主成分とする血圧降下剤に関する。
〔式中、R1は６〜７個の炭素原子を有するシクロ
アルキル基または置換フエニル基を示し、該置換
フエニル基の置換基はヒドロキシ基または低級ア
ルキルカルボニルオキシ基を示す。R2は高級ア
ルカノイル基、６〜７個の炭素原子を有するシク
ロアルカンカルボニル基、フエニル低級アルカノ
イル基のいずれかを示す。Ｚ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。
尚式〔〕に示されている化合物のR1およびR2
における低級アルキル基または低級アルカノイル
基とは炭素原子１〜６を有する直鎖または分枝の
ものをいい、また高級アルカノイル基としては例
えばオクタン酸残基、リノール酸残基があげられ
る。以下同じ。〕
本発明化合物〔〕は高血圧症状に有効な公知
の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（例えば、（4R）−３−
〔（2S）−３−メルカプト−２−メチルプロパノイ
ル〕−４−チアゾリジンカルボン酸、（2S）−１−
〔（2S）−３−メルカプト−２−メチルプロパノイ
ル〕プロリン等）のＳ−アシルおよびＳ−アルキ
ル誘導体であつて、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加水分解を受け、
活性を発揮すべき部位において薬効の証明されて
いるメルカプルアシルアミノ酸を遊離するもので
ある。メルカプトアシルアミノ酸は分子中にスル
フヒドリル基を含むために、製剤中はたは経時的
に酸化等の反応を受けやすく、それゆえ活性の低
下、持続時間の短かさという問題を有している。
一方スルフヒドリル基をアシル基特にベンゾイル
基で保護することにより作用を持続させることが
でき、同時に親油性を増加させ、従つてその吸収
特性を改善することができる。しかしながら、従
来知られているＳ−ベンゾイル誘導体は吸収され
た後に生体中における加水分解反応あるいは代謝
により速やかに脱アシル化されるため望ましい程
度まで持続時間の延長を図ることができない。そ
こで本発明においては効果をできるだけ長く持続
させるという目的を達成するために、メルカプト
アシルアミノ酸のスルフヒドリン基を保護するア
シル基として、特定のアシル基を導入した。その
結果、Ｓ−ベンゾイル誘導体より更に持続時間を
延長することができ、スルフヒドリン基を保護す
るのに極めて適しているものである。また、本発
明化合物は不安定なスルフヒドリン基がアシルあ
るいはアルキル基で保護されているために、特に
酸化などによる力価の低下が起り難いという特長
を有し、その製剤は従来のメルカプトアシルアミ
ノ酸を成分とする血圧降下剤よりも安定で、製剤
化工程中あるいは経時的に分解して力価の低下、
異臭の発生等を示すことがない。
本発明化合物〔〕は、例えば次のＡ、Ｂのよ
うな方法で合成される。
(A) 一般式
R2−Ｓ−Ｚ−CO−Ｙ 〔〕
〔式中、Ｙは水酸基またはハロゲン原子を示
す。以下同じ。〕で示される化合物と一般式
〔式中、R3は前記R1に示される基と同一の基を
示すが、そのうち式〔〕よりR1を除いた基
においては、−CO−Ｚ−Ｓ−R2は−Ｈで置換
されたものを示す。〕で示される化合物から、
シヨツテンバウマン反応、混合酸無水物法等の
一般的方法により一般式〔〕で示される本発
明化合物を得ることができる。
(B) 一般式
R2−Ｙ 〔〕
で示される化合物と一般式
〔式中、R4は前記R1に示される基と同一の基を
示すが、そのうち式〔〕よりR1を除いた基
においては、−CO−Ｚ−Ｓ−R2は−CO−Ｚ−
SHで置換されたものを示す。〕で示される化合
物から、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一般式〔〕で示さ
れる本発明化合物を得ることができる。
上記のＡ、Ｂの方法により合成した一般式
〔〕で示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
ールアミンなど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
はそれ以上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。以下に実施例を示す。
実施例 １
（4R）−２−（２−ヒドロキシフエニル）−３−
（Ｓ−オクタノイル−３−メルカプトプロパノ
イル）−４−チアゾリジンカルボン酸Ａおよび
（4R）−２−（２−オクタノイルオキシフエニ
ル）−３−（Ｓ−オクタノイル−３−メルカプト
プロパノイル）−４−チアゾリジンカルボン酸
Ｂの製造
（4R）−２−（２−ヒドロキシフエニル）−３−
（３−メルカプトプロパノイル）−４−チアゾリジ
ンカルボン酸3.1ｇおよび炭酸カリウム2.8ｇを水
50mlに溶解し、氷冷下撹拌しながらオクタノイル
クロリド1.7ｇを滴下する。滴下終了後、氷冷下
１時間、さらに室温で１時間撹拌する。この反応
溶液を酢酸エチルで洗浄し、濃塩酸で酸性にした
後、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、減圧濃縮
して油状物を得る。この油状物をシリカゲルカラ
ムクロマトにより精製して標記化合物A1.7ｇ
（収率39％）およびB0.2ｇ（収率４％）を得る。
The present invention relates to sulfur-containing compounds represented by the following general formula [] and salts thereof, and antihypertensive agents containing these compounds as main ingredients. [In the formula, R 1 represents a cycloalkyl group or a substituted phenyl group having 6 to 7 carbon atoms, and the substituent of the substituted phenyl group represents a hydroxy group or a lower alkylcarbonyloxy group. R 2 represents any one of a higher alkanoyl group, a cycloalkanecarbonyl group having 6 to 7 carbon atoms, and a phenyl lower alkanoyl group. Z represents straight-chain or branched alkylene having 1 to 3 carbon atoms.
R 1 and R 2 of the compound shown in formula []
The lower alkyl group or lower alkanoyl group in the formula refers to a straight chain or branched one having 1 to 6 carbon atoms, and the higher alkanoyl group includes, for example, an octanoic acid residue and a linoleic acid residue. same as below. ] The compound of the present invention [ ] is a mercaptoacylamino acid (e.g., (4R)-3-
[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid, (2S)-1-
S-acyl and S-alkyl derivatives of [(2S)-3-mercapto-2-methylpropanoyl]proline, etc.) that undergo enzymatic and/or chemical hydrolysis when administered to humans or animals. ,
It releases mercapuruacyl amino acids, which have proven medicinal efficacy, at the site where they should exert their activity. Since mercaptoacylamino acids contain sulfhydryl groups in their molecules, they are susceptible to reactions such as oxidation during formulation or over time, and therefore have problems such as decreased activity and short duration.
On the other hand, by protecting the sulfhydryl group with an acyl group, especially a benzoyl group, it is possible to prolong the action and at the same time increase the lipophilicity and thus improve its absorption properties. However, since the conventionally known S-benzoyl derivatives are rapidly deacylated by hydrolysis reaction or metabolism in the living body after being absorbed, it is not possible to extend the duration to a desirable extent. Therefore, in the present invention, in order to achieve the purpose of sustaining the effect as long as possible, a specific acyl group was introduced as an acyl group to protect the sulfhydrin group of the mercaptoacylamino acid. As a result, it can last longer than S-benzoyl derivatives and is extremely suitable for protecting sulfhydrin groups. In addition, since the unstable sulfhydrin group of the compound of the present invention is protected by an acyl or alkyl group, it has the feature that it is difficult to reduce its potency due to oxidation, etc., and its formulation does not contain conventional mercaptoacylamino acids. It is more stable than the antihypertensive agents it contains, and may degrade during the formulation process or over time, resulting in a decrease in potency.
There is no occurrence of strange odors. The compound of the present invention [] can be synthesized, for example, by the following methods A and B. (A) General formula R 2 -S-Z-CO-Y [] [In the formula, Y represents a hydroxyl group or a halogen atom. same as below. ] Compounds and general formula [In the formula, R 3 represents the same group as the group shown in R 1 above, but in the group in which R 1 is removed from the formula [], -CO-Z-S-R 2 is substituted with -H. Show what was done. ] From the compounds shown in
The compound of the present invention represented by the general formula [] can be obtained by general methods such as the Schotten-Baumann reaction and the mixed acid anhydride method. (B) Compound represented by the general formula R 2 -Y [] and the general formula [In the formula, R 4 represents the same group as the group shown in R 1 above, but in the group in which R 1 is removed from the formula [], -CO-Z-S-R 2 is -CO-Z −
Shows substitution with SH. The compound of the present invention represented by the general formula [] can be obtained from the compound represented by the formula [] by a general method such as the Schotten-Baumann reaction or the mixed acid anhydride method. The compound of the present invention represented by the general formula [ ] synthesized by the methods A and B above may be combined with commonly used pharmaceutical salts such as sodium, potassium, calcium, aluminum, ammonium, diethylamine, and triethanolamine, if necessary. can do. 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 are shown below. Example 1 (4R)-2-(2-hydroxyphenyl)-3-
(S-octanoyl-3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid A and (4R)-2-(2-octanoyloxyphenyl)-3-(S-octanoyl-3-mercaptopropanoyl)-4 -Production of thiazolidinecarboxylic acid B (4R)-2-(2-hydroxyphenyl)-3-
Add 3.1 g of (3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate to water.
Dissolve in 50 ml and add 1.7 g of octanoyl chloride dropwise while stirring under ice cooling. After completion of the dropwise addition, the mixture was stirred for 1 hour under ice-cooling and further stirred at room temperature for 1 hour. The reaction solution is washed with ethyl acetate, made acidic with concentrated hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain an oil. This oily substance was purified by silica gel column chromatography to obtain 1.7 g of the title compound A.
(yield 39%) and B0.2 g (yield 4%) are obtained.
【表】
実施例 ２
（4R）−３−〔（2S）−Ｓ−シクロヘキサンカルボ
ニル−３−メルカプト−２−メチルプロパノイ
ル〕−２−シクロヘキシル−４−チアゾリジン
カルボン酸の製造
（4R）−２−シクロヘキシル−３−〔（2S）−３
−メルカプト−２−メチルプロパノイル〕−４−
チアゾリジンカルボン酸3.2ｇおよび炭酸カリウ
ム2.8ｇを水40mlに溶解し、氷冷下撹拌しながら
シクロヘキサンカルボニルクロリド1.8ｇを滴下
し、実施例２と同様に操作して標記化合物3.4ｇ
（収率80％）を得る。
〔α〕２５ Ｄ−114.5゜（ｃ＝1.0、メタノール）
IR（CHCl3、cm-1） 1728、1680、1640、1418、
973
実施例 ３
（4R）−２−（２−ヒドロキシフエニル）−３−
（Ｓ−フエニルアセチル−３−メルカプトプロ
パノイル）−４−チアゾリジンカルボン酸の製
造
（4R）−２−（２−ヒドロキシフエニル）−３−
（３−メルカプトプロパノイル）−４−チアゾリジ
ンカルボン酸3.1ｇおよび炭酸ナトリウム2.1ｇを
水40mlに溶解し、氷冷下撹拌しながらフエニル酢
酸クロリド2.0ｇを滴下し、実施例２と同様に操
作して標記化合物3.7ｇ（収率85％）を得る。
融点 57〜59℃
〔α〕２５ Ｄ＋120.9゜（ｃ＝1.0、メタノール）
IR（CHCl3、cm-1） 1724、1680、1650、1602、
1403
実施例 ４
（4R）−２−（２−アセトキシフエニル）−３−
（Ｓ−フエニルアセチル−３−メルカプトプロ
パノイル）−４−チアゾリジンカルボン酸の製
造
窒素雰囲気下、50％水素化ナトリウム0.6ｇの
無水Ｎ・Ｎ−ジメチルホルムアミド15ml懸濁液
に、実施例８で得られた（4R）−２−（２−ヒド
ロキシフエニル）−３−（Ｓ−フエニルアセチル−
３−メルカプトプロパノイル）−４−チアゾリジ
ンカルボン酸2.2ｇの無水Ｎ・Ｎ−ジメチルホル
ムアミド溶液20mlを滴下し、室温で30分間撹拌す
る。これに塩化アセチル0.6ｇを滴下し、さらに
室温で３時間撹拌後、酢酸0.5mlを加え減圧濃縮
する。濃縮液に炭酸カリウム水溶液とエーテルを
加え、水層円を分取し、濃塩酸で酸性にした後酢
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、減圧濃縮して得
られる油状物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1.5ｇ（収率63％）を得る。
〔α〕２５ Ｄ＋72.0゜（ｃ＝0.8、メタノール）
IR（neat、cm-1） 1763、1727、1653、1637、
1605、1400、1198[Table] Example 2 Production of (4R)-3-[(2S)-S-cyclohexanecarbonyl-3-mercapto-2-methylpropanoyl]-2-cyclohexyl-4-thiazolidinecarboxylic acid (4R)-2- Cyclohexyl-3-[(2S)-3
-Mercapto-2-methylpropanoyl]-4-
3.2 g of thiazolidine carboxylic acid and 2.8 g of potassium carbonate were dissolved in 40 ml of water, 1.8 g of cyclohexane carbonyl chloride was added dropwise with stirring under ice cooling, and the same procedure as in Example 2 was carried out to obtain 3.4 g of the title compound.
(yield 80%). [α] 25 D −114.5° (c=1.0, methanol) IR (CHCl 3 , cm −1 ) 1728, 1680, 1640, 1418,
973 Example 3 (4R)-2-(2-hydroxyphenyl)-3-
Production of (S-phenylacetyl-3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid (4R)-2-(2-hydroxyphenyl)-3-
3.1 g of (3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid and 2.1 g of sodium carbonate were dissolved in 40 ml of water, and 2.0 g of phenylacetic acid chloride was added dropwise with stirring under ice cooling, and the procedure was repeated in the same manner as in Example 2. 3.7 g (yield 85%) of the title compound is obtained. Melting point 57-59℃ [α] 25 D +120.9゜ (c=1.0, methanol) IR (CHCl 3 , cm -1 ) 1724, 1680, 1650, 1602,
1403 Example 4 (4R)-2-(2-acetoxyphenyl)-3-
Production of (S-phenylacetyl-3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid In a nitrogen atmosphere, a suspension of 0.6 g of 50% sodium hydride in 15 ml of anhydrous N.N-dimethylformamide was added as described in Example 8. The obtained (4R)-2-(2-hydroxyphenyl)-3-(S-phenylacetyl-
A solution of 2.2 g of 3-mercaptopropanoyl)-4-thiazolidinecarboxylic acid in 20 ml of anhydrous N.N-dimethylformamide was added dropwise, and the mixture was stirred at room temperature for 30 minutes. To this was added dropwise 0.6 g of acetyl chloride, and after further stirring at room temperature for 3 hours, 0.5 ml of acetic acid was added and concentrated under reduced pressure. Add an aqueous potassium carbonate solution and ether to the concentrate, separate the aqueous layer, make it acidic with concentrated hydrochloric acid, and then extract with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and the resulting oil is purified by silica gel column chromatography to obtain 1.5 g (yield: 63%) of the title compound. [α] 25 D +72.0° (c=0.8, methanol) IR (neat, cm -1 ) 1763, 1727, 1653, 1637,
1605, 1400, 1198
Claims (1)
その塩類。 式中、R1は６〜７個の炭素原子を有するシク
ロアルキル基または置換フエニル基を示し、該置
換フエニル基の置換基はヒドロキシ基または低級
アルキルカルボニルオキシ基を示す。R2は高級
アルカノイル基、６〜７個の炭素原子を有するシ
クロアルカンカルボニル基、フエニル低級アルカ
ノイル基のいずれかを示す。Ｚ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. Compounds represented by the following general formula [] and salts thereof. In the formula, R 1 represents a cycloalkyl group or a substituted phenyl group having 6 to 7 carbon atoms, and a substituent of the substituted phenyl group represents a hydroxy group or a lower alkylcarbonyloxy group. R 2 represents any one of a higher alkanoyl group, a cycloalkanecarbonyl group having 6 to 7 carbon atoms, and a phenyl lower alkanoyl group. Z represents straight-chain or branched alkylene having 1 to 3 carbon atoms.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1251979A JPS55104275A (en) | 1979-02-06 | 1979-02-06 | Sulfur-containing compound |
| US06/086,996 US4483861A (en) | 1978-10-31 | 1979-10-22 | Antihypertensive sulfur-containing compounds |
| GB7936988A GB2038800B (en) | 1978-10-31 | 1979-10-25 | Antihypertensive sulphurcontaining compounds |
| IT26923/79A IT1124841B (en) | 1978-10-31 | 1979-10-30 | COMPOUNDS CONTAINING SULFUR ANTI-HYPERTENSION |
| SE7908994A SE448541B (en) | 1978-10-31 | 1979-10-30 | NEW TIAZOLIDINE AND PYRROLIDINE DERIVATIVES AND A PHARMACEUTICAL PREPARATION THEREOF |
| CH977979A CH642351A5 (en) | 1978-10-31 | 1979-10-31 | Antihypertensive, SULPHUR CONTAINING COMPOUNDS, PROCESS FOR PRODUCING THE SAME AND CONTAINING THEM Pharmaceutical Compositions. |
| DE19792944037 DE2944037A1 (en) | 1978-10-31 | 1979-10-31 | ANTI-HYPERTENSIVE SULFURING COMPOUNDS |
| FR7926983A FR2440365A1 (en) | 1978-10-31 | 1979-10-31 | NOVEL MERCAPTO-AZOLIDINE-CARBOXYLIC ACID DERIVATIVES USEFUL AS HYPERTENSORS |
| US06/395,128 US4496578A (en) | 1978-10-31 | 1982-07-06 | Antihypertensive sulfur-containing compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1251979A JPS55104275A (en) | 1979-02-06 | 1979-02-06 | Sulfur-containing compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS55104275A JPS55104275A (en) | 1980-08-09 |
| JPS6213955B2 true JPS6213955B2 (en) | 1987-03-30 |
Family
ID=11807584
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1251979A Granted JPS55104275A (en) | 1978-10-31 | 1979-02-06 | Sulfur-containing compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS55104275A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57112381A (en) * | 1980-12-29 | 1982-07-13 | Santen Pharmaceut Co Ltd | Five-membered heterocyclic compound |
| IT1153963B (en) * | 1982-03-22 | 1987-01-21 | Montedison Spa | ACID DERIVATIVES 2 0 4-THIAZOLIDIN-CARBOXYL 3-ACYL SUBSTITUTED FOR FITOREGULATING AND BIOSTIMULANT ACTION |
-
1979
- 1979-02-06 JP JP1251979A patent/JPS55104275A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS55104275A (en) | 1980-08-09 |
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