JPS61238775A - Peptidase-inhibiting compound, production and use thereof - Google Patents
Peptidase-inhibiting compound, production and use thereofInfo
- Publication number
- JPS61238775A JPS61238775A JP8087185A JP8087185A JPS61238775A JP S61238775 A JPS61238775 A JP S61238775A JP 8087185 A JP8087185 A JP 8087185A JP 8087185 A JP8087185 A JP 8087185A JP S61238775 A JPS61238775 A JP S61238775A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- formulas
- tables
- mathematical
- chemical formulas
- 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.)
- Granted
Links
Abstract
Description
【発明の詳細な説明】 〈産業上の利用分野〉 本発明は、プロリルエンドペプチダーゼ（ＥＣ。[Detailed description of the invention] <Industrial application field> The present invention uses prolyl endopeptidase (EC).
３、４．２１．２６ Ｐｒｏｌｙｌ ｅｎｄｏ ｐｅ
ｐｔｉｄａａｅ ）に対して酵素阻害活性を示す新規な
化合物に関し、さらにその化学合成法、ならびにそれを
有効成分として含有するプロリルエンドペプチダーゼ活
性阻害剤及び薬剤、特に抗健忘症剤としての利用に関す
るものである。3, 4.21.26 Prolyl endo pe
The present invention relates to a novel compound that exhibits enzyme inhibitory activity against P. ptidaae), as well as its chemical synthesis method and its use as an active ingredient in prolyl endopeptidase activity inhibitors and drugs, particularly as anti-amnestic agents. be.
〈従来技術〉
プロリルエンドペプチダーゼは、神経伝達物質とされて
いるサブスタンスＰ、ＴＲＨ（甲状腺刺激ホルモン）及
びノイロテンシンや、記憶と関係があると考えられてい
るバンプレシンに作用し、これらを不活性化することが
知られている。一方、長崎大学薬学部の鶴、芳本両氏は
、プロリルエンドペプチダーゼ活性を阻害する化合物が
、ラットのスコポラミンによる実験的健忘症を予防する
ことを見い出し、プロリルエンドペプチダーゼ活性阻害
剤質の抗健忘症剤への応用の可能性を示唆している。<Prior art> Prolyl endopeptidase acts on substance P, TRH (thyroid stimulating hormone), and neurotensin, which are considered neurotransmitters, as well as vanpressin, which is thought to be related to memory, and inactivates them. It is known that On the other hand, Tsuru and Yoshimoto of the Nagasaki University School of Pharmacy found that a compound that inhibits prolyl endopeptidase activity prevents experimental amnesia caused by scopolamine in rats. This suggests the possibility of application as a drug.
〈発明が解決しようとする技術課題〉
本発明者らは、上記の知見に基づき、抗健忘症活性が強
く、かつ毒性の充分低い新規な化合物を見出すべく研究
した結果、下記一般式ＣＩ）で表わされる抗プロリルエ
ンドペプチダーゼ化合物を見い出した。その活性は現在
まで見い出されている抗プロリルエンドペプチダーゼ化
合物〔芳本忠、日本農芸化学会、講演要旨集ｐ７５２〜
７５４（１９８３）及び昭和５９年７月３１日付の特願
昭５９−１６０９９４号〕の中で最も強い阻害活性を示
す。また、本化合物、特にＳＵＡＭＩ １１７およびＳ
ＵＡＭ１１１５は低濃度で抗健忘作用に優れた成績を示
す。本発明はこれらの知見に基づき完成した。<Technical Problems to be Solved by the Invention> Based on the above findings, the present inventors conducted research to find a novel compound with strong anti-amnestic activity and sufficiently low toxicity, and as a result, the following general formula CI) was found. An anti-prolyl endopeptidase compound has been found. Its activity is compared with the anti-prolyl endopeptidase compounds found to date [Tadashi Yoshimoto, Japanese Society of Agricultural Chemistry, Lecture Abstracts p752~
754 (1983) and Japanese Patent Application No. 59-160994 dated July 31, 1982], it shows the strongest inhibitory activity. Also, the present compounds, especially SUAMI 117 and S
UAM1115 shows excellent anti-amnestic effects at low concentrations. The present invention was completed based on these findings.
本発明のプロリルエンドペプチダーゼインヒビター活性
を有する化合物は、一般式〔Ｉ〕：ＣＨＯ
で表わされる。The compound having prolyl endopeptidase inhibitor activity of the present invention is represented by the general formula [I]: CHO.
式（Ｉ）の化合物のうち、プロリルエンドペプチダーゼ
インヒビター活性の大きい点で好ましい化合物は次のも
のである。なお、以下これらをカッコ内の番号で呼ぶこ
とがある。Among the compounds of formula (I), the following compounds are preferred in terms of high prolyl endopeptidase inhibitor activity. Note that these may be referred to below by numbers in parentheses.
ＣＨＯ
本発明化合物の製造は、一般的ペプチド合成法によシ行
なうことができるが、以下に説明する本発明の合成法に
よれば都合よく合成される。CHO The compound of the present invention can be produced by a general peptide synthesis method, but it is conveniently synthesized by the synthetic method of the present invention described below.
なお、各略号は次の意味を表わす。In addition, each abbreviation represents the following meaning.
Ｚ ：ベンジルオキシカルボニル基
Ａｌａ：アラニン残基
Ｖａ ｌ ：バリン残基
Ｌｅｖ ：ロイシン残基
ＯＭｅ ：メチルエステル基
ＷＳＣＩ ： Ｎ−エチル−Ｎ’、 Ｎ’−ジメチルア
ミノプロピルカルボジイミド
ＴＥＡ：ｌ−リエチルアミン
０ＯＣＲ３
本発明の合成法により、式（Ｉ）の化合物を製造するに
は、次の一般式（■）：
（式中、Ｒは前記式（１）で示された意味を表わし、Ｒ
′は メチル基、又は低級アルキル基を表わす。〕
で表わされるエステルを第三ブチルアルコールに溶解し
、水素化ホウ素す） ＩＪウムを加え、還流下メタノー
ルを滴下することによシ、次の一般式で表わされるアル
コールに変換し、次いで該アルコールをジメチルスルホ
キシド中、二酸化イオウ−ピリジン錯体で酸化すること
によシ前記一般式（１）で表わされる化合物を得ること
が出来る。また、一般式（ＩＦ）で表わされる出発物賞
はカルボキシ末端をエステル基等で保護した相当するペ
プチドと４−フェニル−ｎ−酪酸を適宜反応させて得る
ことが出来る。目的の化合物はいずれもオイル状で取得
できる。Z: benzyloxycarbonyl group Ala: alanine residue Val: valine residue Lev: leucine residue OMe: methyl ester group WSCI: N-ethyl-N', N'-dimethylaminopropylcarbodiimide TEA: l-liethylamine 0OCR3 In order to produce the compound of formula (I) by the synthesis method of the present invention, the following general formula (■): (wherein R represents the meaning shown in the above formula (1), R
' represents a methyl group or a lower alkyl group. ] An ester represented by the following general formula is dissolved in tert-butyl alcohol, borohydride is added thereto, and methanol is added dropwise under reflux to convert it into an alcohol represented by the following general formula, and then the alcohol is converted into an alcohol represented by the following general formula. The compound represented by the general formula (1) can be obtained by oxidizing with a sulfur dioxide-pyridine complex in dimethyl sulfoxide. Further, the starting material represented by the general formula (IF) can be obtained by appropriately reacting a corresponding peptide whose carboxy terminus is protected with an ester group, etc., and 4-phenyl-n-butyric acid. All of the target compounds can be obtained in oil form.
本化合物の２−グリシル−プロリル−β−ナフチルアミ
ドのプロリルエンドペプチターゼによる分解を阻止する
効力について調べた結果、後述の試験例に示されるごと
く非常に強い抗プロリルエンドペプチダーゼ活性を示し
、パパイン、プロメライン、トリプシン、キモトリプシ
ン、サーモライシン・ゝプシン等のプロテイナーゼには
全く阻害活性を示さなかった。As a result of examining the efficacy of this compound in inhibiting the decomposition of 2-glycyl-prolyl-β-naphthylamide by prolyl endopeptidase, it showed very strong anti-prolyl endopeptidase activity, as shown in the test example below. It showed no inhibitory activity against proteinases such as papain, promelain, trypsin, chymotrypsin, and thermolysin/epsin.
また、このようにして得た本化合物は新規であυ、実施
例で示すように抗健忘症作用を有する。Furthermore, the present compound thus obtained is novel and has anti-amnestic effects as shown in the Examples.
次に参考例および実施例をもって本発明の詳細な説明す
る。Next, the present invention will be explained in detail using reference examples and examples.
参考例
式（Ｉｆ）で表わされる出発物質［Ｎ−（４−フェニル
−Ｈ−ブタ／イル） −Ａｌａ−Ｐｒｏ −ＯＭｅ（Ｓ
ＵＡＭ１０９８））の合成
ａ） Ｚ −Ａｌａ−Ｐｒｏ −ＯＭｅＺ−Ａｌａ−
ＯＨ（ｌ ｄ量〕、Ｐｒｏ −ＯＭｅ ” ＨｃＬ（１
当量）及びＴＥＡ （１当量〕を乾燥地化メチレンに溶
解し、水冷下にＷＳＣＩ（１当量〕を加える。室温で２
０時間攪拌したのち、反応液をＩＮ塩酸、水、飽和重曹
水、水、及び飽和食塩水で洗い、無水硫酸マグネシウム
で乾燥する。溶媒を減圧留去して目的化合物を得る。Reference Example Starting material represented by formula (If) [N-(4-phenyl-H-buta/yl)-Ala-Pro-OMe(S
Synthesis of UAM1098)) a) Z -Ala-Pro -OMeZ-Ala-
OH (l d amount), Pro-OMe” HcL (1
Dissolve WSCI (1 eq.) and TEA (1 eq.) in dry methylene and add WSCI (1 eq.) under water cooling.
After stirring for 0 hour, the reaction solution was washed with IN hydrochloric acid, water, saturated aqueous sodium bicarbonate, water, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain the target compound.
ｂ）Ｎ−（４−フェニル−ｎ−ブタメイル） −Ａｌａ
−Ｐｒｏ−ＯＭｅ （ＳＵＡＭ、１０９８ ）Ｚ−Ａｌ
ａ−Ｐｒｏ−ＯＭｅ （１当量）をエタノールに溶解
し、ＩＮ悸弁塩酸（１当量〕と、パラジウムカーボン（
少量〕を加えて接触還元により２基を除去する。反応液
を濾過したのち、溶媒を減圧留去して得られた残渣（１
当量）と、４−フェニル−ｎ−酪酸（１当量）及びＴＥ
Ａ（１当量〕を乾燥塩化メチレンに溶解し、水冷下にＷ
ＳＣＩ（１当量）を加える。室温で２０時間攪拌したの
ち、反応液をＩＮ塩酸、水、飽和１１水、水、及び飽和
食塩水で洗い、無水硫酸マグネシウムで乾燥する。溶媒
を減圧留去して得られる残渣を、シリカゲルを用いた中
圧カラムクロマトグラフィーで精製し、目的化合物を得
る。b) N-(4-phenyl-n-butamyl) -Ala
-Pro-OMe (SUAM, 1098)Z-Al
a-Pro-OMe (1 eq.) was dissolved in ethanol, IN-hydrochloric acid (1 eq.) and palladium on carbon (
A small amount] is added and the two groups are removed by catalytic reduction. After filtering the reaction solution, the solvent was distilled off under reduced pressure to obtain a residue (1
equivalent), 4-phenyl-n-butyric acid (1 equivalent) and TE
Dissolve A (1 equivalent) in dry methylene chloride and add W under water cooling.
Add SCI (1 eq.). After stirring at room temperature for 20 hours, the reaction solution was washed with IN hydrochloric acid, water, saturated 11 water, water, and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure is purified by medium pressure column chromatography using silica gel to obtain the target compound.
上記ａ）で、Ｚ−Ａｌａ−ＯＨのかわりに、７） Ｚ
−Ｖａｌ−ＯＨ，イ） Ｚ−Ｌｅｕ−０’Ｈを用いるこ
とによシ、それぞれア’） Ｚ Ｖａｌ ｐｒｏ
ＯＭｅｓイつＺ−Ｌｅｕ −Ｐｒｏ −ＯＭｅを得る
ことができる。In a) above, instead of Z-Ala-OH, 7) Z
-Val-OH, a) By using Z-Leu-0'H, a') Z Val pro
Z-Leu-Pro-OMe can be obtained.
また、ｂ〕において、Ｚ −Ａｌａ −ｐｒｏ −ＯＭ
ｅのかわシに、ア） Ｚ−Ｖａｌ−ｐｒｏ −ＯＭｅ
、イ） Ｚ −Ｌｅｕ −Ｐｒｏ−ＯＭｅを用いること
によシ、それぞれア’）Ｎ−（４−）ｘ ＝ ／Ｉ／
−ｙｌ−ブタノイｈ ） −Ｖａｌ −Ｐｒｏ −ＯＭ
ｅ（ＳＵＡＭ １１１２ ）、イつＮ−（４−フェニル
−■−ブタノイｈ ） −Ｌｅｕ−Ｐｒｏ−ＯＭｅ（Ｓ
ＵＡＭ １１１．３）を得ることができる。In addition, in [b], Z -Ala -pro -OM
To the edge of e, a) Z-Val-pro -OMe
, b) By using Z -Leu -Pro-OMe, respectively, a') N-(4-)x = /I/
-yl-butanoih) -Val -Pro -OM
e(SUAM 1112), ItsuN-(4-phenyl-■-butanoih)-Leu-Pro-OMe(S
UAM 111.3) can be obtained.
実施例Ｉ
Ｎ−（４−フェニル−ｎ″−″ブタノイル） −Ａｌａ
−Ｐｒｏ−ａｔ（ＳＵＡＭ １１１０ ） Ｏ合成ａ
）Ｎ−（４−フェニル−ｎ−ブタノイル） −人１ａ−
Ｐｒｏ−ｏＬ （ＳＵＡＭ １１１０ ）の−ＣＨｏの
代シに一〇ＨｓＯＨを有する中間体（ＳＵＡＭ参考例で
得た、Ｎ−（４−フェニル−ｎ−ブタノイル） −Ａｌ
ａ−Ｐｒｏ−ＯＭｅ （２００Ｗ９ ）と水素化ホウ素
ナトリウム（６６ｖ）を第三ブチルアルコール（２−）
に溶解し、加熱攪拌する。Example I N-(4-phenyl-n''-''butanoyl) -Ala
-Pro-at (SUAM 1110) O synthesis a
)N-(4-phenyl-n-butanoyl) -person 1a-
An intermediate having 10HsOH in place of -CHO of Pro-oL (SUAM 1110) (N-(4-phenyl-n-butanoyl) -Al obtained in SUAM reference example)
a-Pro-OMe (200W9) and sodium borohydride (66v) in tert-butyl alcohol (2-)
Dissolve and heat with stirring.
次いで還流下、無水メタノール（０，４８ｍｊ）を滴下
し、滴下終了後、１時間還流攪拌する。反応液を室温に
もどし、水冷下に水（１−）を加える。メタノールと第
三ブチルアルコールを減圧留去した後、酢酸エチルで抽
出後、有機層を飽和食塩水で洗浄し、無水硫酸マグネシ
ウムで乾燥する。溶蝉を減圧留去して得られる粗生成物
をシリカゲルの中圧カラムクロマトグラフィー（溶媒系
；クロロホルム−メタノール〕で精製し、目的化合物（
１４０ｔＩｌｉ）を得る。Then, anhydrous methanol (0.48 mj) was added dropwise under reflux, and after the addition was completed, the mixture was stirred under reflux for 1 hour. The reaction solution was returned to room temperature, and water (1-) was added while cooling with water. After methanol and tert-butyl alcohol were distilled off under reduced pressure, the organic layer was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the molten cicada under reduced pressure was purified by medium pressure column chromatography on silica gel (solvent system: chloroform-methanol), and the target compound (
140tIli).
更に上記 ａ）において、原料化合物としてＮ−（４−
フェニル−ｎ−ブタノイル） −Ａｌａ −ｐｒｏ−Ｏ
Ｍｅの代シに
ア）Ｎ−（４−フェニル−ｎ−ブタノイル） −Ｖａｌ
−Ｐｒｏ−ＯＭｅ（ＳＵＡＭ １１１２）イ）Ｎ−（４
−フエ＝ Ａ、 −ｎ−ブタノイ＃）−Ｌｅｕ−Ｐｒｏ
−ＯＭｅ（ＳＵＡＭ １１１３）を使用すると、目的化
合物として、夫々ア’）Ｎ −（４−フェニル−ｎ−ブ
タノイル） −Ｖａｌ−Ｐｒｏ−ｏｔ（ＳＵＡＭ １１
１６）イ’）Ｎ−（４−フェニル−ｎ−ブタノイル）
−Ｌｅｕ−Ｐｒｏ−ｏｔ（ＳＵＡＭ １１１４）を得る
ことができる。Furthermore, in a) above, N-(4-
phenyl-n-butanoyl) -Ala -pro-O
Me substitute a) N-(4-phenyl-n-butanoyl) -Val
-Pro-OMe (SUAM 1112) a) N- (4
-Hue=A, -n-Butanoi#) -Leu-Pro
When -OMe (SUAM 1113) is used, each target compound is a')N-(4-phenyl-n-butanoyl) -Val-Pro-ot (SUAM 11
16) i') N-(4-phenyl-n-butanoyl)
-Leu-Pro-ot (SUAM 1114) can be obtained.
ｂ） ＳＵＡＭ １１１Ｏ
Ｎ−（４−フェニル−ｎ−ブタノイル） −人１ａ−Ｐ
ｒｏ−ｏｔ（１３０１’１９ ）と、ＴＥＡ（０，１７
ｗ）を無水ジメチルスルホキシド（１−）に溶解し、攪
拌下に三酸化イオウ−ピリジン錯体（１２９η〕のジメ
チルスルホキシド（１−）溶液を加えた。室温で１５分
攪拌後、氷水（１０ｍ）に注ぎ、酢酸エチルで抽出し、
１０％クエン酸水溶液、水、飽和重曹水、水、及び飽和
食塩水で洗い、無水硫酸す） ＩＪウムで乾燥した。溶
媒を減圧で留去し、得られる粗生成物を、シリカゲルの
中圧カラムクロマトグラフィー（溶媒系；四塩化炭素−
クロロホルム）で精製し、目的化合物（１０８■）を得
た。b) SUAM 111O N-(4-phenyl-n-butanoyl) -Human 1a-P
ro-ot (1301'19) and TEA (0,17
w) was dissolved in anhydrous dimethyl sulfoxide (1-), and a solution of sulfur trioxide-pyridine complex (129η) in dimethyl sulfoxide (1-) was added under stirring. After stirring at room temperature for 15 minutes, it was dissolved in ice water (10 m). Pour, extract with ethyl acetate,
It was washed with a 10% aqueous citric acid solution, water, saturated aqueous sodium bicarbonate, water, and saturated brine, and dried over anhydrous sulfuric acid. The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to medium pressure column chromatography on silica gel (solvent system: carbon tetrachloride-
chloroform) to obtain the target compound (108■).
上記ｂ）において出発中間体化合物としてＮ−（４−７
ｘ＝ルーｎ−ブタノイ／’ ） Ａｌａ −Ｐｒ。In b) above, N-(4-7
x=Ru n-butanoi/') Ala-Pr.
−ｏＬ Ｏ代シに、
ア）Ｎ−（４−フェニル−ｎ−ブタノイル） −■ａｌ
−Ｐｒｏ−ｏＬ（ＳＵＡＭ １１１６）イ）Ｎ−（４−
７エールーｎ−ブタノイル） −Ｌｅｕ−Ｐｒｏ−ｏｔ
（ＳＵＡＭ １１１４ ）を使用することにより、目
的化合物として、夫々ア’）Ｎ−（４−フェニル−ｎ−
ブタノイＡ、） −Ｖａｌ−Ｐｒｏ−ａｔ（ＳＵＡＭ
１１１７）イ’）Ｎ−（４−フェニル−ｎ−ブタノイル
） −Ｉ、ｅｕ−Ｐｒｏ−ａｔ（ＳＵＡＭ １１１５）
を得ることができる。-oL On the O side, a) N-(4-phenyl-n-butanoyl) -■al
-Pro-oL(SUAM 1116)i)N-(4-
7 aeru-n-butanoyl) -Leu-Pro-ot
(SUAM 1114), each target compound was a')N-(4-phenyl-n-
Butanoi A,) -Val-Pro-at (SUAM
1117) i') N-(4-phenyl-n-butanoyl) -I, eu-Pro-at (SUAM 1115)
can be obtained.
得られた化合物の物性は後記光１に示す。The physical properties of the obtained compound are shown in Light 1 below.
実施例２
抗プロリルエンドペプチダーゼ活性の測定抗プロリルエ
ンドペプチターゼ活性の測定は、芳本（Ｔ、 Ｙｏｓｈ
ｉｍｏｔｏおよびり、 Ｔｓｕｒｕ、 Ａｇｒ−Ｂｉｏ
ｌ、 （：ｈｅｍ、 ４２．２４１７．１９７８）等の
方法で行った。即ち、０゜００２５Ｍ Ｚ−グリシル
−プロリン−β−ナフチルアミド０．２５ｍ１．０．１
Ｍリン酸緩衝液（ＰＨ７，０） ０．９９−および本発
明の抗プロリルエンドペプチダーゼ化合物の溶液０．０
１−を含む混合液を試験管中で３７℃、３分間加温した
後、プロリルエンドペプチダーゼ＃液（０，２単位／−
１）を０．１−加え、３５℃で１０分間反応させた。そ
の後、１Ｍ酢酸緩衝液（ｐＨ４，０）中のトリトンＸ
−１００（Ｔｒｉｔｏｎ Ｘ −１００９溶液２．０ツ
を界面活性剤の最終濃度が１０％となるように加え、室
温に１５分間放置したのち、４１０ ｎｍにおける吸光
度（ａ）を測定した０
同時に抗プロリルエンドペプテグーゼ化合物の溶液の代
りに緩衝液のみを用いた盲検の吸光度（ｂ）を測定し、
プロリルエンドペプチダーゼ阻害率を、次式：
％式％
によシ計算し、５０チ阻害に必要な量（ＩＣｓｏ’：］
を求めた。試験結果を表２に示す。Example 2 Measurement of anti-prolyl endopeptidase activity Measurement of anti-prolyl endopeptidase activity was carried out by Yoshimoto (T, Yoshimoto).
imoto and Tori, Tsuru, Agr-Bio
It was carried out by the method of 1, (:hem, 42.2417.1978), etc. That is, 0°0025M Z-glycyl-proline-β-naphthylamide 0.25ml 1.0.1
M phosphate buffer (PH 7,0) 0.99- and a solution of the anti-prolyl endopeptidase compound of the invention 0.0
After heating the mixture containing 1- in a test tube at 37°C for 3 minutes, prolyl endopeptidase # solution (0.2 units/-
1) was added and reacted at 35°C for 10 minutes. Triton X in 1M acetate buffer (pH 4,0) was then
-100 (Triton Measuring the blind absorbance (b) using only the buffer solution instead of the solution of the riluendopeptegose compound;
The inhibition rate of prolyl endopeptidase was calculated according to the following formula: % formula %, and the amount required for inhibition of 50% (ICso':]
I asked for The test results are shown in Table 2.
表２
実施例３
ラットを用いたスコポラミンによる実験的健忘症の予防
効果の測定（腹腔内投与〕
本発明の抗プロリルエンドペプテダーゼ化合物について
、スコポラミンによる長期記憶、固定阻害を防止する効
果を検討した。即ち、本発明の化合物を１〜／Ｋｆ、０
．２５η／胸、０．１■／ Ｋｇ、０．０２５■／Ｋｆ
になるよう調整し、生理食塩水に溶解し、夫々ウィスタ
ー（ｗｉｓｔｅｒ ）系雄性ラツ）（１００〜１２０？
）の腹腔に１回投与し、投与１時間後に電気ショック（
１，７ｍＡ）による受動的回避学習を行い、直後にスコ
ポラミン（３η／Ｋｙ）を腹腔内投与した。Table 2 Example 3 Measurement of the preventive effect of experimental amnesia by scopolamine in rats (intraperitoneal administration) The anti-prolyl endopeptidase compound of the present invention was tested for the effect of preventing long-term memory and consolidation inhibition by scopolamine. That is, the compound of the present invention was studied at a concentration of 1 to /Kf, 0
．． 25η/chest, 0.1■/Kg, 0.025■/Kf
Dissolved in physiological saline, and dissolved in physiological saline, respectively.
) once into the peritoneal cavity, and 1 hour after administration, an electric shock (
Passive avoidance learning was performed using 1.7 mA), and immediately thereafter scopolamine (3η/Ky) was administered intraperitoneally.
効果の判定は、２４時間後および４８時間後の受動的回
避テストで供試化合物を投与しないで、スコポラミンお
よび生理食塩水を腹腔内投与した対照の動物群と、供試
化合物の投与およびスコポラミンの投与を共に行った動
物群の各々につき、健忘症ラットおよび非健忘症ラット
の数を対比することによシ行った。Efficacy was determined in a passive avoidance test 24 hours and 48 hours later in a control group of animals in which scopolamine and saline were administered intraperitoneally without administration of the test compound, and in a control group of animals administered intraperitoneally with scopolamine and saline. This was done by comparing the number of amnestic and non-amnestic rats in each group of animals treated together.
試験結果を８表３に示す。ＳＵＡＭＩＩＩＯ１ＳＵＡＭ
１１１５、ＳＵＡＭ １１１７は１Ｍ９７に１１では顕
著な効果を示さカかったが、ｏ、ｉ１Ｎ？／初、０．０
２５■／駒の化合物投与で大変強い抗健忘症効果を示し
た。The test results are shown in Table 8. SUAMIIIO1SUAM
1115, SUAM 1117 showed a remarkable effect on 1M97 at 11, but o, i1N? /first, 0.0
A very strong anti-amnestic effect was shown when the compound was administered at a dose of 25 cm/piece.
これらの化合物は一定の低濃度域で大変強い抗健忘症効
果を示すが、投与濃度を１００４／ＫＩｉに上昇させて
もラットには外見上変化が見られなかつｆｃ。These compounds exhibit very strong anti-amnestic effects at a certain low concentration range, but even when the administered concentration was increased to 1004/KIi, no changes were observed in the appearance of rats.
手 続 補 正 書 昭和６０年６月ｒ日Handbook continuation supplementary book June 1985
Claims (4)
す▼、または ▲数式、化学式、表等があります▼の基を表わす。） で表わされる化合物。(1) The following general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R is -CH_3, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, or ▲Mathematical formulas, chemical formulas, tables, etc.) etc. Represents the group ▼.) A compound represented by.
はメチル基又は低級アルキル基を表わす。）で表わされ
るエステルを第三ブチルアルコールに溶解し、水素化ホ
ウ素ナトリウムを加え、還流下メタノールを滴下するこ
とにより、次の一般式（III）：▲数式、化学式、表等
があります▼（III） で表わされるアルコールに変換し、次いで該アルコール
をジメチルスルホキシド中、三酸化イオウ−ピリジン錯
体で酸化することよりなる一般式（ I ）： ▲数式、化学式、表等があります▼（ I ） （式中Ｒは−ＣＨ＿３、▲数式、化学式、表等がありま
す▼、または ▲数式、化学式、表等があります▼の基を表わす。） で表わされる化合物の製造方法。(2) The following general formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R represents the meaning given in the following formula I, and R'
represents a methyl group or a lower alkyl group. ) is dissolved in tert-butyl alcohol, sodium borohydride is added, and methanol is added dropwise under reflux to form the following general formula (III): ▲Mathematical formula, chemical formula, table, etc.▼(III ) and then oxidizing the alcohol with a sulfur trioxide-pyridine complex in dimethyl sulfoxide. The middle R represents a group of -CH_3, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼.) A method for producing a compound represented by.
す▼、または ▲数式、化学式、表等があります▼の基を表わす。） で表わされる化合物を有効成分として含有するプロリル
エンドペプチダーゼ活性阻害剤。(3) The following general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R is -CH_3, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, or ▲Mathematical formulas, chemical formulas, tables, etc.) A prolyl endopeptidase activity inhibitor containing a compound represented by ▼ as an active ingredient.
す▼、または ▲数式、化学式、表等があります▼の基を表わす。） で表わされる化合物を有効成分として含有する抗健忘症
剤。(4) The following general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R is -CH_3, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, or ▲Mathematical formulas, chemical formulas, tables, etc.) An anti-amnestic agent containing the compound represented by ▼ as an active ingredient.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60080871A JPH0623191B2 (en) | 1985-04-16 | 1985-04-16 | Peptidase-inhibiting active compound, its production method and use |
| AT86105231T ATE65782T1 (en) | 1985-04-16 | 1986-04-16 | DIPEPTIDE DERIVATIVES, METHOD OF MANUFACTURE, PHARMACEUTICAL COMPOSITIONS AND THEIR APPLICATIONS. |
| US06/852,710 US4873342A (en) | 1985-04-16 | 1986-04-16 | Dipeptide derivative and synthesis and use thereof |
| DE8686105231T DE3680578D1 (en) | 1985-04-16 | 1986-04-16 | DIPEPTIDE DERIVATIVES, METHOD FOR THE PRODUCTION, PHARMACEUTICAL COMPOSITIONS AND THEIR USE. |
| CA000506770A CA1309805C (en) | 1985-04-16 | 1986-04-16 | Dipeptide derivative and synthesis and use thereof |
| EP86105231A EP0201741B1 (en) | 1985-04-16 | 1986-04-16 | Dipeptide derivatives, processes for preparing them, pharmaceutical composition and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60080871A JPH0623191B2 (en) | 1985-04-16 | 1985-04-16 | Peptidase-inhibiting active compound, its production method and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61238775A true JPS61238775A (en) | 1986-10-24 |
| JPH0623191B2 JPH0623191B2 (en) | 1994-03-30 |
Family
ID=13730403
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60080871A Expired - Lifetime JPH0623191B2 (en) | 1985-04-16 | 1985-04-16 | Peptidase-inhibiting active compound, its production method and use |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0623191B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01156957A (en) * | 1986-11-20 | 1989-06-20 | Ono Pharmaceut Co Ltd | Novel prolinal derivative, production thereof and antiamnesia containing said derivative |
| JP2008521853A (en) * | 2004-12-02 | 2008-06-26 | プロビオドルグ エージー | Novel compounds for the treatment of neurological diseases |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60188317A (en) * | 1984-03-09 | 1985-09-25 | Yakult Honsha Co Ltd | Antiamnestic agent |
-
1985
- 1985-04-16 JP JP60080871A patent/JPH0623191B2/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60188317A (en) * | 1984-03-09 | 1985-09-25 | Yakult Honsha Co Ltd | Antiamnestic agent |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01156957A (en) * | 1986-11-20 | 1989-06-20 | Ono Pharmaceut Co Ltd | Novel prolinal derivative, production thereof and antiamnesia containing said derivative |
| JP2008521853A (en) * | 2004-12-02 | 2008-06-26 | プロビオドルグ エージー | Novel compounds for the treatment of neurological diseases |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0623191B2 (en) | 1994-03-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0172458B1 (en) | Novel biologically active compound having anti-prolyl endopeptidase activity | |
| JPH0623190B2 (en) | N-acylpyrrolidine derivative having inhibitor activity, process for producing the same and use thereof | |
| JP2021519766A (en) | Factor XIIa inhibitor | |
| JPS61236770A (en) | Novel amino acid derivative | |
| IE50261B1 (en) | Antihypertensive amides | |
| JPS63130579A (en) | Novel pyrrolidine amide derivative having prolylendopeptidase inhibiting activity | |
| JPS62129278A (en) | Novel pyrrolidinylimide ester derivative having inhibitory activity against prolylendopeptidase, production and use thereof | |
| JPH01143897A (en) | Thiazolidine derivative | |
| DK149063B (en) | METHOD OF ANALOGUE FOR THE PREPARATION OF TRH-ANALOGUE DERIVATIVES OF HISTIDYL PROLINAMIDE OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. | |
| JPH0680077B2 (en) | Novel peptide compound having proline endopeptidase inhibitor activity | |
| JPH0714878B2 (en) | Prolyl endopeptidase inhibitor containing pyrrolidine amide as an active ingredient | |
| JPH05505820A (en) | new compound | |
| JPH01287068A (en) | 4, 4-disubstituted proline or 4-monosubstituted dehydroproline derivative | |
| JPS61238775A (en) | Peptidase-inhibiting compound, production and use thereof | |
| JPS62148467A (en) | Dipeptide derivative, production and use thereof | |
| DE3113610A1 (en) | S-ACYLATION PRODUCTS OF A MERCAPTOACYLAMINO ACID AND A DIURETIC CONTAINING A CARBOXYL GROUP | |
| JPH03176478A (en) | New diketopiperazine derivative and immunosuppressive agent containing the same as active ingredient | |
| CN101724016B (en) | Peptide compound and preparation method and application thereof | |
| JPH04117396A (en) | Tripeptide derivative having pyroglutamic acid residue | |
| JPS6333361A (en) | Dipeptide derivative, its production and use thereof | |
| CN102924567B (en) | Peptide compound and preparation method and use of peptide compound | |
| US3700651A (en) | L-leucyl-l-leucyl-l-valyl-l-tyrosinol | |
| JPS61238799A (en) | Novel compound with inhibitory action production and use thereof | |
| JPS6284058A (en) | Novel compound having peptidase-inhibiting action, its preparation and use | |
| JPS59137451A (en) | Indane derivative |