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JPH0670023B2 - Thiazolidine derivative - Google Patents

Thiazolidine derivative

Info

Publication number
JPH0670023B2
JPH0670023B2 JP19838087A JP19838087A JPH0670023B2 JP H0670023 B2 JPH0670023 B2 JP H0670023B2 JP 19838087 A JP19838087 A JP 19838087A JP 19838087 A JP19838087 A JP 19838087A JP H0670023 B2 JPH0670023 B2 JP H0670023B2
Authority
JP
Japan
Prior art keywords
compound
general formula
present
formula
thiazolidine
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 - Lifetime
Application number
JP19838087A
Other languages
Japanese (ja)
Other versions
JPS6442475A (en
Inventor
淳 古川
忠 芳本
幸義 味澤
聖一 池口
幸彦 木下
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kissei Pharmaceutical Co Ltd
Original Assignee
Kissei Pharmaceutical Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Kissei Pharmaceutical Co Ltd filed Critical Kissei Pharmaceutical Co Ltd
Priority to JP19838087A priority Critical patent/JPH0670023B2/en
Priority to US07/227,864 priority patent/US4857524A/en
Priority to EP88307334A priority patent/EP0303434A1/en
Publication of JPS6442475A publication Critical patent/JPS6442475A/en
Publication of JPH0670023B2 publication Critical patent/JPH0670023B2/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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  • Thiazole And Isothizaole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

【発明の詳細な説明】 〔産業上の利用分野〕 本発明は医薬品として有用なチアゾリジン誘導体に関す
るものである。
DETAILED DESCRIPTION OF THE INVENTION [Industrial Application] The present invention relates to a thiazolidine derivative useful as a medicine.

さらに詳しく述べれば、本発明はプロリルエンドペプチ
ダーゼ(Prolyl Endopeptidase、以下PEPという)阻害
活性を有し、健忘症治療剤として有用な、一般式 (式中の はN以外の異項原子を含むこともある5〜6員環の飽和
異項環であり、Rは水素原子またはアルコキシカルボニ
ル基である)で表わされるチアゾリジン誘導体を提供す
るものである。
More specifically, the present invention has a prolyl endopeptidase (hereinafter referred to as PEP) inhibitory activity and is useful as a therapeutic agent for amnesia having the general formula: (In the formula Is a 5- to 6-membered saturated heterocyclic ring which may contain heteroatoms other than N, and R is a hydrogen atom or an alkoxycarbonyl group).

〔従来の技術〕[Conventional technology]

人口の高齢化に伴って老人医療の問題が重要視されてき
ている。なかでも老人性痴呆は社会的にも深刻な問題で
あることから効果的な治療剤の早急な開発が望まれてい
る。
With the aging of the population, the problem of medical care for the elderly has been emphasized. Among them, senile dementia is a serious social problem, and therefore, the immediate development of an effective therapeutic agent is desired.

これまで健忘症や痴呆等の治療剤としては、脳血管拡張
作用などによる脳循環改善剤、脳細胞酸素消費量亢進作
用などによる脳代謝賦活剤等が用いられている。しかし
ながら、これらの薬剤は脳血管障害による痴呆には有効
であるが、その他の原因による痴呆には効果が確実でな
いことが難点とされていた。
Hitherto, as therapeutic agents for amnesia and dementia, there have been used cerebral circulation improving agents due to cerebral vasodilatory action, cerebral metabolism activating agents due to cerebral cell oxygen consumption enhancing action and the like. However, although these agents are effective for dementia due to cerebrovascular disorder, it has been considered difficult to be surely effective for dementia due to other causes.

PEPはプロリンを含む生理活性ペプチドや合成基質に作
用し、プロリンのカルボキシル側を特異的に切断する酵
素として知られている。この酵素は記憶と関係があると
されているバゾプレシン(Vasopressin)やサイロトロ
ピン放出ホルモン(Thyrotropin Releasing Hormone,TR
H)等を分解することから、この酵素の阻害活性と抗健
忘効果の関連性について種々検討が行われ、その結果、
PEP阻害剤は痴呆や健忘の治療剤となり得ることが示唆
されている(生化学、55巻、8号、831ページ、1983
年)。
PEP is known as an enzyme that acts on a physiologically active peptide containing proline and a synthetic substrate to specifically cleave the carboxyl side of proline. This enzyme is associated with memory vasopressin (Vasopressin) and thyrotropin releasing hormone (Thyrotropin Releasing Hormone, TR
H) and the like are decomposed, various studies have been conducted on the relationship between the inhibitory activity of this enzyme and the anti-amnestic effect.
It has been suggested that a PEP inhibitor may be a therapeutic agent for dementia and amnesia (Biochemistry, 55, No. 8, page 831, 1983.
Year).

これまで、PEPを阻害する化合物としては、式 で表される化合物などが知られているが、これらの化合
物は本発明の化合物とは全く構成を異にするものである
(公開特許公報昭60-188317号)。
So far, compounds that inhibit PEP have the formula: Compounds represented by the following are known, but these compounds have completely different constitutions from the compound of the present invention (Japanese Patent Laid-Open No. 60-188317).

本発明のようなチアゾリジン誘導体として、式 で表される化合物〔ケミカルアブストラクツ(Chem.Abs
tr.)86巻、17号、117082v(1977年)〕、式 で表される化合物〔ケミカル アブストラクツ(Chem.A
bstr.)105巻、25号、227322s(1986年)〕、式 および、式 で表される化合物〔ケミカル アブストラクツ(Chem.A
bstr.)95巻、19号、169173f(1981年)、同、96巻、15
号、123303r(1982年)〕などが知られている。
The thiazolidine derivative as in the present invention has the formula: Compound represented by [Chem.Abs
tr.) 86, No. 17, 117082v (1977)], formula The compound represented by [Chemical Abstracts (Chem.A
bstr.) 105, No. 25, 227322s (1986)], formula formula And the expression The compound represented by [Chemical Abstracts (Chem.A
bstr.) Volume 95, Issue 19, 169173f (1981), Volume 96, 15
No. 123303r (1982)] and the like are known.

これらの化合物で一番目の化合物はマススペクトルにお
けるフラグメントの研究のために合成されたものであ
り、それ自体の薬理作用については全く記載されていな
い。また、二番目の化合物は肝疾患治療作用を示す一連
の化合物の製造中間体の一つとして用いられており、そ
れ自体の薬理作用については何も記載されていない。三
番目の化合物群は、血圧効果作用を示し、高血圧症治療
薬剤として有用な一連の化合物の一部として合成された
ものであるが、本発明のようなPEP阻害活性に関しては
全く記載されていない。
The first of these compounds was synthesized for the study of fragments in the mass spectrum and no description of its own pharmacological action. In addition, the second compound is used as one of the intermediates for the production of a series of compounds having a therapeutic effect on liver diseases, and nothing is described about the pharmacological effect of itself. The third group of compounds has a blood pressure effect and was synthesized as a part of a series of compounds useful as a drug for treating hypertension, but there is no description about the PEP inhibitory activity as in the present invention. .

〔発明が解決しようとする問題点〕[Problems to be solved by the invention]

従来より健忘症や痴呆症治療剤として用いられている脳
循環改善剤や脳代謝賦活剤はあまり効果が確実でないこ
とから、新しい作用による抗健忘症治療剤の開発が望ま
れていた。
Since a cerebral circulation improving agent and a cerebral metabolism activating agent which have been conventionally used as a therapeutic agent for amnesia and dementia are not so effective, development of an anti-amnestic therapeutic agent with a new action has been desired.

本発明者らは従来の治療剤とは別の作用による健忘症治
療剤を見出すべく検討した結果、ある種のチアゾリジン
誘導体が強いPEP阻害活性を示し、目的が達成できるこ
とを見出した。
As a result of investigations to find out a therapeutic agent for amnesia which has an action different from that of conventional therapeutic agents, the present inventors have found that a certain thiazolidine derivative exhibits a strong PEP inhibitory activity and can achieve the object.

本発明はこれらの知見に基づくものである。The present invention is based on these findings.

〔問題点を解決するための手段〕[Means for solving problems]

本発明の前記一般式(I)で表されるチアゾリジン誘導
体は強いPEP阻害活性を示し、毒性も低く、健忘症治療
剤として有用である。
The thiazolidine derivative represented by the above general formula (I) of the present invention has a strong PEP inhibitory activity and low toxicity, and is useful as a therapeutic agent for amnesia.

本発明の前記一般式(I)において、 の飽和異項環とは、ピロリジン、チアゾリジン、ペプリ
ジン、モルホリンなどのような5〜6員環の飽和異項環
である。
In the general formula (I) of the present invention, The saturated heterocyclic ring of is a 5- to 6-membered saturated heterocyclic ring such as pyrrolidine, thiazolidine, pepidine and morpholine.

アルコキシカルボニル基とは例えば、メトキシカルボニ
ル基、エトキシカルボニル基、プロポキシカルボニル
基、ブトキシカルボニル基などのような炭素数2〜6の
アルコキシカルボニル基であり、アルコキシ部分のアル
キル基は直鎖状でも枝分かれ状でもよい。
The alkoxycarbonyl group is, for example, an alkoxycarbonyl group having 2 to 6 carbon atoms such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, etc., and the alkyl group of the alkoxy moiety is linear or branched. But it's okay.

本発明の前記一般式(I)の化合物は新規な化合物であ
り、以下のようにして製造することができる。
The compound of the general formula (I) of the present invention is a novel compound and can be produced as follows.

例えば、式 で表されるカルボン酸またはその反応性官能的誘導体
と、一般式 (式中の およびRは前記と同じ意味をもつ)で表される環状アミ
ンとを反応させることにより製造することができる。
For example, the expression A carboxylic acid or a reactive functional derivative thereof represented by the general formula (In the formula And R have the same meanings as described above).

本発明の製造方法において、出発原料として用いられる
式(II)および一般式(III)の化合物は公知化合物で
あり、市販品として入手できるか、あるいは文献記載の
方法により容易に製造することができる。
In the production method of the present invention, the compounds of formula (II) and general formula (III) used as starting materials are known compounds and can be obtained as commercial products, or can be easily produced by the methods described in the literature. .

本発明の一般式(I)の化合物を一般式(II)のカルボ
ン酸と一般式(III)の化合物を用いて製造する場合は
縮合剤の存在下に反応を行うが、このような縮合剤とし
てはペプチド合成において一般に用いられる縮合剤、例
えばN,N′−ジシクロヘキシカルボジイミドなどが用い
られる。
When the compound of the general formula (I) of the present invention is produced by using the carboxylic acid of the general formula (II) and the compound of the general formula (III), the reaction is carried out in the presence of a condensing agent. As the condensing agent, a condensing agent generally used in peptide synthesis, such as N, N'-dicyclohexylcarbodiimide, is used.

本発明の一般式(I)の化合物の製造方法において用い
られる一般式(II)の化合物の反応性官能的誘導体とし
ては、酸ハロゲン化物、酸無水物、混合酸無水物、活性
エステルなどをあげることができる。
Examples of the reactive functional derivative of the compound of the general formula (II) used in the method for producing the compound of the general formula (I) of the present invention include acid halides, acid anhydrides, mixed acid anhydrides and active esters. be able to.

本発明の一般式(I)の化合物はチアゾリジン−4−カ
ルボン酸部分を含め1〜2個の不斉炭素を有するが、本
発明においては、それぞれの不斉炭素上の置換基の配置
がR、Sのいずれでも、またそれらの混合物であっても
よい。それぞれの光学活性化合物は光学活性な化合物を
出発原料として用い、立体保持的に縮合することによっ
て得ることができる。
The compound of the general formula (I) of the present invention has 1 to 2 asymmetric carbons including the thiazolidine-4-carboxylic acid moiety, but in the present invention, the configuration of the substituent on each asymmetric carbon is R. , S, or a mixture thereof. Each optically active compound can be obtained by using an optically active compound as a starting material and condensing sterically.

本発明の一般式(I)の化合物は常法に従い、種々の医
薬品製剤とすることできる。すなわち、必要に応じて賦
形剤、崩壊剤、縮合剤、滑沢剤等の医薬品添加物を加
え、常法に従って調剤することにより種々の製剤、例え
ば、錠剤、散剤、顆粒剤、カプセル剤等とすることがで
きる。
The compound of the general formula (I) of the present invention can be made into various pharmaceutical preparations according to a conventional method. That is, if necessary, pharmaceutical additives such as an excipient, a disintegrant, a condensing agent, a lubricant, etc. are added, and various preparations are prepared according to a conventional method, for example, tablets, powders, granules, capsules, etc. Can be

本発明の前記一般式(I)の化合物を健忘症治療剤とし
て使用する場合、その投与量は患者の年令、体重、性
別、症状の度合等により適宜決定されるが、概ね成人1
日当たり経口投与の場合50〜1000mg、非経口投与の場合
1〜500mgの範囲内で使用される。
When the compound of the general formula (I) of the present invention is used as a therapeutic agent for amnesia, its dosage is appropriately determined according to the age, weight, sex, degree of symptoms of the patient, etc.
It is used within the range of 50 to 1000 mg for oral administration and 1 to 500 mg for parenteral administration per day.

〔発明の効果〕〔The invention's effect〕

本発明の前記一般式(I)の化合物はN−カルボベンゾ
キシ−L−グリシル−L−プロリルβ−ナフチルアミド
(以下Z−Gly−Pro−β−NAという)を基質とした牛脳
由来プロリルエンドペプチダーゼに対する阻害活性測定
試験において、概ね、7×10−5〜3×10−10モル濃度
で50%阻害活性を示す。
The compound of the general formula (I) of the present invention is a bovine brain-derived prodrug using N-carbobenzoxy-L-glycyl-L-prolyl β-naphthylamide (hereinafter referred to as Z-Gly-Pro-β-NA) as a substrate. In a test for measuring the inhibitory activity against rill endopeptidase, it shows 50% inhibitory activity at a molar concentration of 7 × 10 −5 to 3 × 10 −10 .

特に3-((R)-(-)-3-カルボベンゾキシチアゾリジン−4
−カルボニル)チアゾリジンのIC50値は2.6×10−10
ルである。このように、本発明の前記一般式(I)の化
合物は強いPEP阻害活性を示し、しかも毒性も低いの
で、安全で優れた健忘症治療剤として有用な化合物であ
る。
Especially 3-((R)-(-)-3-carbobenzoxythiazolidine-4
The IC 50 value of -carbonyl) thiazolidine is 2.6 × 10 -10 mol. As described above, the compound of the general formula (I) of the present invention has a strong PEP inhibitory activity and low toxicity, and is therefore a safe and excellent compound useful as a therapeutic agent for amnesia.

〔実施例〕〔Example〕

本発明をさらに詳細に説明するために以下に参考例およ
び実施例をあげる。なお、各参考例および実施例中の化
合物の融点はすべて未補正である。
Reference examples and examples will be given below to describe the present invention in more detail. The melting points of the compounds in Reference Examples and Examples are all uncorrected.

参考例 (R)-(-)-3-カルボベンゾキシチアゾリジン−4−カルボ
ン酸 (R)-(-)-チアゾリジン−4−カルボン酸2.66gを2N−水
酸化ナトリウム水溶液10mlに溶解し、氷冷下に撹拌しつ
つ、塩化カルボベンゾキシ4.1gと2N−水酸化ナトリウム
水溶液15mlとを同時に滴下した。滴下後さらに室温で2
時間撹拌したのち、ジエチルエーテルで洗い、氷冷下に
濃塩酸を加えて酸性とした。30分間放置したのち酢酸エ
チルで抽出し、有機層を飽和食塩水で洗い、無水硫酸ナ
トリウムで乾燥した。減圧下に溶媒を留去し、(R)-(-)-
3-カルボベンゾキシチアゾリジン−4−カルボン酸4.14
g(77.5%)を得た。この無色透明粘稠な液体を冷却放置し
て固化させ、ジエチルエーテル−石油エーテルより再結
晶して、無色針状結晶を得た。
Reference example (R)-(-)-3-carbobenzoxythiazolidine-4-carboxylic acid (R)-(-)-thiazolidine-4-carboxylic acid 2.66 g was dissolved in 2N-sodium hydroxide aqueous solution 10 ml and iced. While stirring under cooling, 4.1 g of carbobenzoxy chloride and 15 ml of 2N-sodium hydroxide aqueous solution were simultaneously added dropwise. 2 more at room temperature after dropping
After stirring for an hour, the mixture was washed with diethyl ether and acidified by adding concentrated hydrochloric acid under ice cooling. After standing for 30 minutes, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, (R)-(-)-
3-carbobenzoxy thiazolidine-4-carboxylic acid 4.14
Obtained g (77.5%). This colorless transparent viscous liquid was left to cool and solidify, and recrystallized from diethyl ether-petroleum ether to give colorless needle crystals.

融点:58〜63℃ ▲〔α〕22 D▼=−97.5°(c=1,酢酸エチル) MS=m/z=267(M) IR(KBr):νco 1742,1664 cm−1 NMR(CDCl) δ:3.30(d,2H),4.58(AB−q,2H),4.90(br−s,1H),
5.18(s,2H),7.34(s,5H),8.50(s,1H) 元素分析値:(C1213NDSとして) C%H% N% 計算値 53.93 4.90 5.24 実測値 53.86 4.87 5.19 実施例1 3-((R)-(-)-3-カルボベンゾキシチアゾリジン−4−カ
ルボニル)チアゾリジンの(化合物A) (R)-(-)-3-カルボベンゾキシチアゾリジン−4−カルボ
ン酸2.67gをN−ヒドロキシコハク酸イミド1.15gとをジ
オキサン20mlに溶解し、冷却下に撹拌しつつ、N,N′−
ジシクロヘキシカルボジイミド2.06gとジオキサン5mlの
溶液を滴下した。冷所に一夜放置したのち、析出した結
晶をろ去し、ろ液を減圧下に濃縮した。残留油状物をジ
メトキシエタン15mlに溶解し、氷冷下に撹拌しつつ、チ
アゾリジン0.89gを滴下した。一夜放置したのち減圧下
に溶媒を留去し、残留物に水5mlを加え、30分間かきま
ぜたのち、酢酸エチルで抽出した。有機層を1N−塩酸、
55炭酸水素ナトリウム水溶液および飽和食塩水で順次洗
い、無水硫酸ナトリウムで乾燥後減圧下に溶媒を留去し
た。
Melting point: 58 to 63 ° C ▲ [α] 22 D ▼ = -97.5 ° (c = 1, ethyl acetate) MS = m / z = 267 (M + ) IR (KBr): νco 1742, 1664 cm -1 NMR ( CDCl 3 ) δ: 3.30 (d, 2H), 4.58 (AB-q, 2H), 4.90 (br-s, 1H),
5.18 (s, 2H), 7.34 (s, 5H), 8.50 (s, 1H) Elemental analysis value: (as C 12 H 13 ND 4 S) C% H% N% Calculated value 53.93 4.90 5.24 Measured value 53.86 4.87 5.19 Example 1 3-((R)-(-)-3-Carbobenzoxythiazolidine-4-carbonyl) thiazolidine (Compound A) (R)-(-)-3-Carbobenzoxythiazolidine-4-carboxylic acid 2.67 g of N-hydroxysuccinimide 1.15 g was dissolved in 20 ml of dioxane, and N, N'- was added while stirring under cooling.
A solution of 2.06 g of dicyclohexylcarbodiimide and 5 ml of dioxane was added dropwise. After standing overnight in a cold place, the precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure. The residual oily substance was dissolved in 15 ml of dimethoxyethane, and 0.89 g of thiazolidine was added dropwise while stirring under ice cooling. After leaving it overnight, the solvent was distilled off under reduced pressure, 5 ml of water was added to the residue, and the mixture was stirred for 30 minutes and then extracted with ethyl acetate. The organic layer was 1N-hydrochloric acid,
55 The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.

残留物をシリカゲルカラムクロマトグラフィー(溶出溶
媒:酢酸エチル/ベンゼン=6/4)で精製して無色針状
結晶の3-((R)-(-)-3-カルボベンゾキシチアゾリジン−
4−カルボニル)チアゾリジンを得た。
The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / benzene = 6/4) to give colorless needle crystals of 3-((R)-(-)-3-carbobenzoxythiazolidine-
4-Carbonyl) thiazolidine was obtained.

融点:73〜75℃ ▲〔α〕20 D▼=−83.0°(c=1,酢酸エチル) MS=m/z=338(M) IR(KBr):νco 1701,1640 cm-1 NMR(CDCl) δ:2.8〜3.2(br−m,2H),3.25(m,2H),3.4〜4.0(br
−m,2H),4.5〜5.0(m,5H),5.13(s,2H),7.34(s,5
H) 元素分析値:(C1518として) C% H% N% 計算値 53.25 5.36 8.28 実測値 53.61 5.55 8.01 実施例2 対応する原料を用い、実施例1と同様に反応を行って下
記の化合物を合成した。
Melting point: 73 to 75 ° C ▲ [α] 20 D ▼ = -83.0 ° (c = 1, ethyl acetate) MS = m / z = 338 (M + ) IR (KBr): νco 1701,1640 cm -1 NMR ( CDCl 3 ) δ: 2.8 to 3.2 (br-m, 2H), 3.25 (m, 2H), 3.4 to 4.0 (br
-M, 2H), 4.5 to 5.0 (m, 5H), 5.13 (s, 2H), 7.34 (s, 5
H) Elemental analysis value: (as C 15 H 18 N 2 O 3 S 2 ) C% H% N% Calculated value 53.25 5.36 8.28 Measured value 53.61 5.55 8.01 Example 2 Same as Example 1 using corresponding raw materials Reaction was performed to synthesize the following compound.

実施例3 PEP阻害活性測定実験 Z-Gly-Pro-β-NAを基質として用い、牛脳由来PEPに対す
る阻害活性を測定した。
Example 3 PEP Inhibitory Activity Measurement Experiment Using Z-Gly-Pro-β-NA as a substrate, the inhibitory activity against bovine brain-derived PEP was measured.

(測定方法) 10mMのEDTAと10mMの2-メルカプトエタノールを含む20mM
トリス塩酸緩衝液(20mM−Tris HCl Buffer,pH=7.0)
0.7mlにPEP(約0.14u/ml)100μlおよび各濃度(0、1
0-9〜10-4M)に調整した被験化合物の溶液100μlを加
え、37℃で5分間プレインキューベーション(Preincub
ation)した。次いでこれに100μlの40%ジオキサンに
溶かした各々の濃度(5.0、2.5、1.25、0.625、0.3125mM)の
基質を加え、再び37℃で15分間インキューベーションを
行い、酵素反応を進行させた。25%トリクロ酢酸で反応
を停止させ、3000r.p.m.で10分間遠心分離を行い、上清
0.5mlを分取し、これに0.5mlの0.1%亜硝酸を加え、さ
らに、3分間0.05%のN-(1-ナフチル)エチレンジアミ
ンジヒドロクロリドエタノール溶液を加えた。混合液を
37℃で25分放置した後、570nmでの吸光度を測定し、次
式によって各濃度での酵素活性を試算し、阻害活性の活
性値から50%阻害濃度(IC50値)を求めた。
(Measurement method) 20 mM containing 10 mM EDTA and 10 mM 2-mercaptoethanol
Tris-HCl buffer (20 mM-Tris HCl Buffer, pH = 7.0)
100 μl of PEP (about 0.14 u / ml) in 0.7 ml and each concentration (0, 1
100 μl of a solution of the test compound adjusted to 0 −9 to 10 −4 M) was added, and preincubation (Preincubation) was performed at 37 ° C. for 5 minutes.
ation). Then, the substrate of each concentration (5.0, 2.5, 1.25, 0.625, 0.3125 mM) dissolved in 100 μl of 40% dioxane was added thereto, and incubation was carried out again at 37 ° C. for 15 minutes to allow the enzymatic reaction to proceed. Stop the reaction with 25% trichloroacetic acid, centrifuge at 3000 rpm for 10 minutes, and remove the supernatant.
0.5 ml was taken out, 0.5 ml of 0.1% nitrous acid was added thereto, and 0.05% N- (1-naphthyl) ethylenediamine dihydrochloride ethanol solution was further added for 3 minutes. The mixture
After leaving at 37 ° C. for 25 minutes, the absorbance at 570 nm was measured, the enzyme activity at each concentration was calculated by the following formula, and the 50% inhibitory concentration (IC 50 value) was determined from the activity value of the inhibitory activity.

酵素活性単位(μmol/min/ml)=Δ0D×0.42×希釈率 (結果) 化合物 IC50値 化合物 A 260 pM 化合物 B 72 μM 化合物 C 160 nM 化合物 F 0.23mM 化合物 G 0.21μMEnzyme activity unit (μmol / min / ml) = Δ0D × 0.42 × dilution rate (Result) Compound IC 50 value Compound A 260 pM Compound B 72 μM Compound C 160 nM Compound F 0.23 mM Compound G 0.21 μM

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 FI 技術表示箇所 A61K 31/54 C12N 9/99 ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification code Internal reference number FI Technical display area A61K 31/54 C12N 9/99

Claims (2)

【特許請求の範囲】[Claims] 【請求項1】一般式 (式中の はN以外の異項原子を含むこともある5〜6員環の飽和
異項環であり、Rは水素原子またはアルコキシカルボニ
ル基である)で表されるチアゾリジン誘導体。
1. A general formula (In the formula Is a 5- to 6-membered saturated heterocyclic ring which may contain a heteroatom other than N, and R is a hydrogen atom or an alkoxycarbonyl group).
【請求項2】式 で表される特許請求の範囲第1項記載のチアゾリジン誘
導体。
2. A formula The thiazolidine derivative according to claim 1, which is represented by:
JP19838087A 1987-08-08 1987-08-08 Thiazolidine derivative Expired - Lifetime JPH0670023B2 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP19838087A JPH0670023B2 (en) 1987-08-08 1987-08-08 Thiazolidine derivative
US07/227,864 US4857524A (en) 1987-08-08 1988-08-03 Thiazolidine compounds and therapeutic method
EP88307334A EP0303434A1 (en) 1987-08-08 1988-08-08 Thiazolidine compounds

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP19838087A JPH0670023B2 (en) 1987-08-08 1987-08-08 Thiazolidine derivative

Publications (2)

Publication Number Publication Date
JPS6442475A JPS6442475A (en) 1989-02-14
JPH0670023B2 true JPH0670023B2 (en) 1994-09-07

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Country Status (1)

Country Link
JP (1) JPH0670023B2 (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0662591B2 (en) * 1988-12-14 1994-08-17 株式会社ヤクルト本社 Novel thioproline derivative
WO1991018877A1 (en) * 1990-06-07 1991-12-12 Zeria Pharmaceutical Co., Ltd. Novel arylalkanoylamine derivative and drug containing the same
JPH05186498A (en) * 1991-12-27 1993-07-27 Japan Tobacco Inc Proline derivative
CA2149892C (en) 1992-11-20 1998-12-08 Koji Kobayashi Compound having prolyl endopeptidase inhibitory activity and pharmaceutical use thereof
JP2973271B2 (en) * 1994-01-18 1999-11-08 参天製薬株式会社 Endopeptidase 24.15 inhibitor
JP4786590B2 (en) * 2007-05-10 2011-10-05 日本エンジニアリング株式会社 Semiconductor device transfer device

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