JPH0730020B2 - N-substituted amino acid imide derivative, production method and use - Google Patents
N-substituted amino acid imide derivative, production method and useInfo
- Publication number
- JPH0730020B2 JPH0730020B2 JP61043821A JP4382186A JPH0730020B2 JP H0730020 B2 JPH0730020 B2 JP H0730020B2 JP 61043821 A JP61043821 A JP 61043821A JP 4382186 A JP4382186 A JP 4382186A JP H0730020 B2 JPH0730020 B2 JP H0730020B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- carbon atoms
- phenyl
- substituted
- integer
- 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
Links
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 78
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- 150000001875 compounds Chemical class 0.000 claims description 55
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 16
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000003277 amino group Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
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Description
【発明の詳細な説明】 (産業上の利用分野) 本発明は一般式(1) (式中、mは0または1〜7の整数を表わし、nは0ま
たは1〜8の整数を表わし、 Rはフェニル基、置換フェニル基、フェノキシ基または
置換フェノキシ基を表わし(ここで、置換フェニル基ま
たは置換フェノキシ基の置換基は、ハロゲン原子、炭素
数8〜10のアリールアルケニル基、炭素数6〜10のアリ
ールオキシ基、炭素数7〜10のアリールアルキル基、炭
素数7〜11のアリールアルキルオキシ基、ベンゾイル
基、炭素数2〜5のアルキルオキソ基、アリルオキシ
基、シンナモイル基、スチリルオキソ基、ヒドロキシ
基、炭素数3〜6のアルケニル基または炭素数1〜10の
アルキル基である)、 R1は水素原子を表わし、R2は水素原子、炭素数3〜5の
分岐アルキル基、フエニル基、ヒドロキシフエニル基、
ベンジルオキシフエニル基、炭素数1〜3のアルキル基
を有するアルキルチオ基、アミノ基、ベンジルオキシカ
ルボニルアミノ基、カルボキシル基、カルボン酸ベンジ
ルエステル基、水酸基、ベンジルオキシ基、インドリル
基、イミダゾリル基を表わすかまたはR1およびR2はいつ
しよになつて炭素・窒素間の結合を表わし、但し、 mが0のとき、Rは炭素数7〜9のアリールアルキルオ
キシ基であり、R1およびR2はいつしよになつて炭素・窒
素間の結合を表わす) を有する新規なN置換アミノ酸イミド誘導体、その製造
法およびその用途に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention relates to general formula (1) (In the formula, m represents 0 or an integer of 1 to 7, n represents an integer of 0 or 1 to 8, R represents a phenyl group, a substituted phenyl group, a phenoxy group or a substituted phenoxy group (wherein, The substituent of the phenyl group or the substituted phenoxy group includes a halogen atom, an arylalkenyl group having 8 to 10 carbon atoms, an aryloxy group having 6 to 10 carbon atoms, an arylalkyl group having 7 to 10 carbon atoms, and an arylalkyl group having 7 to 11 carbon atoms. Arylalkyloxy group, benzoyl group, alkyloxo group having 2 to 5 carbon atoms, allyloxy group, cinnamoyl group, styryloxo group, hydroxy group, alkenyl group having 3 to 6 carbon atoms or alkyl group having 1 to 10 carbon atoms ), R 1 represents a hydrogen atom, R 2 represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, a phenyl group, a hydroxyphenyl group,
Represents a benzyloxyphenyl group, an alkylthio group having an alkyl group having 1 to 3 carbon atoms, an amino group, a benzyloxycarbonylamino group, a carboxyl group, a carboxylic acid benzyl ester group, a hydroxyl group, a benzyloxy group, an indolyl group and an imidazolyl group. Or R 1 and R 2 always represent a bond between carbon and nitrogen, provided that when m is 0, R is an arylalkyloxy group having 7 to 9 carbon atoms, R 1 and R 2 2 always represents a bond between carbon and nitrogen), a novel N-substituted amino acid imide derivative, a process for producing the same and a use thereof.
さらに詳しく述べれば、本発明の前記一般式(1)を有
する新規な化合物はプロリルエンドペプチダーゼ(EC,
3.4,21.26,Prolyl−endopeptidase)に対し、酵素阻害
活性を示すのみならず、脳内における器質性障害にもと
ずく症状の改善・治療に有効な化合物である。More specifically, the novel compound of the present invention having the general formula (1) is a prolyl endopeptidase (EC,
3.4,21.26, Prolyl-endopeptidase), it is a compound that not only exhibits enzyme inhibitory activity, but is also effective in improving / treating the symptoms of organic disorders in the brain.
ここで「脳内の器質性障害」とは脳梗塞後遺症、脳出血
後遺症、脳動脈硬化後遺症などの脳虚血性障害に由来す
る諸症状および老年痴呆、初老期痴呆、健忘症、頭部外
傷後遺症、脳手術後遺症などに由来する各種器質的障害
を意味する。Here, "organic disorder in the brain" is a cerebral infarction sequelae, sequelae of cerebral hemorrhage, various symptoms derived from cerebral ischemic disorders such as sequelae of cerebral arteriosclerosis and senile dementia, presenile dementia, amnesia, sequelae of head trauma, It means various organic disorders caused by aftereffects of brain surgery.
(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、サプスタンス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、バソプレシンに作用し、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
がラツトのスコポラミンによる実験的健忘症を予防する
ことを見出し、記憶の固定にプロリルエンドペプチダー
ゼ インヒビターが関与すると推論した。またこの結果
プロリルエンドペプチザーゼ インヒビターが健忘症の
予防および治療に利用できる可能性を示唆している。(Prior Art) Prolyl endopeptidase acts on vasopressin, which is considered to be related to neurotransmitters such as Supstance P, TRH (thyroid stimulating hormone) and neurotensin, and memory, and these are impaired. It is known to activate. On the other hand, Dr. Tsuru and Mr. Yoshimoto of Nagasaki University found that compounds that inhibit prolyl endopeptidase activity prevent experimental amnesia caused by rat scopolamine, and reasoned that prolyl endopeptidase inhibitors are involved in memory consolidation. . The results also suggest that prolyl endopeptidase inhibitors may be useful in the prevention and treatment of amnesia.
事実、本発明の前記一般式(1)で表わされる新規N置
換アミノ酸イミド誘導体は実験動物を用いた実験によ
り、その健忘症に対する効果が確認された。In fact, the novel N-substituted amino acid imide derivative represented by the general formula (1) of the present invention was confirmed to have an effect on amnesia by experiments using experimental animals.
脳細胞は、その周囲の環境(細胞外液)と全くかけ離れ
た細胞内環境を保持し、その差を維持し乍ら生きている
が、そのためには絶えずエネルギーを産出し供給し続け
なければならない。脳の神経細胞が必要とするエネルギ
ーの大部分は酸素とブドウ糖により供給されており、こ
れらのエネルギー源は脳内にはほとんど貯蔵されていな
いため、常時血液から補強されている。Brain cells maintain an intracellular environment that is completely different from the surrounding environment (extracellular fluid), maintain the difference, and live, but in order to do so, they must continually produce and supply energy. . Most of the energy needed by the nerve cells in the brain is supplied by oxygen and glucose, and since these energy sources are scarcely stored in the brain, they are constantly supplemented with blood.
仮りに脳に障害が起こり、酸素とブドウ糖の供給が杜絶
したとすると、一般的にはエネルギー代謝障害が段階的
に進行し、時間の経過とともに細胞は機能を失い、やが
て器質的にも崩壊し、その機能を正常に営むことができ
なくなる。If the brain is damaged and the supply of oxygen and glucose is cut off, the energy metabolism disorder generally progresses in stages, and the cells lose their function over time and eventually collapse organically. However, the function cannot be normally performed.
このため、脳組織のエネルギー源を安定供給し、脳神経
細胞の外部環境を一定に保つために、脳血管自身の脳血
流を調整する機構がよく発達している。Therefore, in order to stably supply the energy source of the brain tissue and keep the external environment of the cerebral nerve cells constant, a mechanism for adjusting the cerebral blood flow of the cerebral blood vessels themselves is well developed.
脳血管障害を内科的に治療する場合、これまで各種の脳
循環改善剤、脳血管拡張剤、脳代謝改善剤などが使用さ
れてきた。しかしながら、これらの薬剤は自覚症状の改
善は認められるものの、神経症状の改善はほとんど認め
られないのが現状である。When treating cerebrovascular disorders medically, various cerebral circulation improving agents, cerebral vasodilators, cerebral metabolism improving agents and the like have been used so far. However, although these drugs improve the subjective symptoms, they hardly improve the neurological symptoms at present.
(発明が解決しようとする問題点) 本発明者らは、前記の脳内の各種障害に起因する症状の
改善・治療に対して密接に関与していると考えられるプ
ロリルエンドペプチダーゼ阻害活性および抗健忘症活性
を有する化合物を見出すべく鋭意研究を重ねてきた。さ
らに、毒性の充分低い新規な化合物を見出すべく、天然
化合物として安全性の高い脂肪酸さらにアミノ酸、ペプ
チド系化合物の組合せにより天然物に近似した化合物を
合成し、前記一般式(1)で表わされる化合物が抗プロ
リルエンドペプチダーゼ活性を有する事を見出した。(Problems to be Solved by the Invention) The inventors of the present invention have a prolyl endopeptidase inhibitory activity which is considered to be closely involved in the improvement / treatment of symptoms caused by various disorders in the brain. We have conducted intensive research to find compounds having antiamnestic activity. Further, in order to find a novel compound having sufficiently low toxicity, a compound similar to a natural product is synthesized by combining a highly safe fatty acid, an amino acid and a peptide compound as a natural compound, and the compound represented by the general formula (1) Was found to have anti-prolyl endopeptidase activity.
(問題点を解決するための手段) 本発明者は鋭意研究の結果、前記一般式(1)で表わさ
れる新規なN置換アミド酸イミド誘導体が抗プロリンエ
ンドペプチダーゼ活性を有し、またこの新規N置換アミ
ノ酸イミド誘導体が実験モデル動物に対し抗健忘症作用
も併せ持つという全く新しい知見を得、本発明を完成す
るに至つた。(Means for Solving Problems) As a result of earnest research by the present inventor, the novel N-substituted amidamide derivative represented by the general formula (1) has antiproline endopeptidase activity, and The present invention was completed by obtaining completely new knowledge that a substituted amino acid imide derivative also has an anti-amnestic effect on experimental model animals.
(発明の構成) すなわち、本発明の式(1)で表わされる新規N置換ア
ミノ酸イミド誘導体は脳内の器質性障害に起因する精神
機能症状の改善・治療に有効であり、特に健忘症に対し
有効な化合物である。(Structure of the Invention) That is, the novel N-substituted amino acid imide derivative represented by the formula (1) of the present invention is effective for ameliorating and treating mental functional symptoms caused by organic disorders in the brain, and particularly for amnesia. It is an effective compound.
本発明の式(1)の化合物は、アミノ酸残基、及びアシ
ル基を含む点で、従来よく知られているピラセタム誘導
体系の抗健忘症剤とは大きく異なつており、さらにアミ
ノ酸誘導体であるため、生体に対する毒性も極めて低い
ものである。The compound of the formula (1) of the present invention is greatly different from the conventionally well-known anti-amnestic agent of the piracetam derivative type in that it contains an amino acid residue and an acyl group, and is further an amino acid derivative. The toxicity to the living body is also extremely low.
式(1)の化合物のうち、抗プロリルエンドペプチダー
ゼ活性が大きい点で好ましい化合物は次のものである。
なお、以下これらの化合物をかつこ内の番号で呼ぶこと
がある。Among the compounds of formula (1), the following compounds are preferable because of their high antiprolyl endopeptidase activity.
In the following, these compounds may be referred to by the numbers in the cutlet.
以下 と表記する。 Less than It is written as.
以下 と表記する。 Less than It is written as.
本発明化合物は、一般的なペプチドの合成法により合成
することができるが、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。なお略記号は次の意味を表
わす。 The compound of the present invention can be synthesized by a general peptide synthetic method, but is conveniently synthesized by the synthetic method of the present invention described below. The abbreviations have the following meanings.
L−Pro:L−プロリン残基 L−Val:L−バリン残基 L−Phe:L−フエニルアラニン残基 L−Met:L−メチオニン残基 L−nLeu:L−ノルロイシン残基 L−Leu:L−ロイシン残基 L−Ser:L−セリン残基 L−Tyr:L−チロシン残基 L−Lys:L−リジン残基 L−Glu:L−グルタミン酸残基 L−Ser(OBzl):L−セリン−O−ベンジルエーテル残
基 L−Tyr(OBzl):L−チロシン−O−ベンジルエーテル
残基 L−Glu(BOzl):Cγ−ベンジル−L−グルタミン酸エ
ステル残基 Z:ベンジルオキシカルボニル基 BoC:三級ブトキシカルボニル基 WSCD: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:トリエチルアミン TFA:トリフルオロ酢酸 本発明の前記一般式(1)の化合物は、以下のようにし
て合成することができる。L-Pro: L-proline residue L-Val: L-valine residue L-Phe: L-phenylalanine residue L-Met: L-methionine residue L-nLeu: L-norleucine residue L-Leu : L-leucine residue L-Ser: L-serine residue L-Tyr: L-tyrosine residue L-Lys: L-lysine residue L-Glu: L-glutamic acid residue L-Ser (OBzl): L - serine -O- benzyl ether residue L-Tyr (OBzl): L- tyrosine -O- benzyl ether residue L-Glu (BOzl): C γ - benzyl -L- glutamate residues Z: benzyloxycarbonyl group BoC: tertiary butoxycarbonyl group WSCD: N-ethyl-N, N'-dimethylaminopropylcarbodiimide TEA: triethylamine TFA: trifluoroacetic acid The compound of the general formula (1) of the present invention is synthesized as follows. be able to.
まず一般式(2)または(2′) R−(CH2)m−COX(2)または〔R−(CH2)m−CO
2O (2′) (式中、Rおよびmは前記定義の通りであり、Xはハロ
ゲン原子を表わす) を有するカルボン酸ハライドまたはカルボン酸無水物と
一般式(3) (式中R1は水素原子を表わし、nは0または1〜8の整
数を表わし、R2aは水素原子、炭素数3〜5の分岐アル
キル基、フエニル基、ヒドロキシフエニル基、ベンジル
オキシフエニル基、炭素数1〜3のアルキル基を有する
アルキルチオ基、ベンジルオキシカルボニルアミノ基、
カルボン酸ベンジルエステル基、ベンジルオキシ基、イ
ンドリル基、イミダゾリル基を表わすか、またはR1およ
びR2aはいつしよになつて炭素・窒素間の結合を表わ
す) を有するアミノ酸と塩基存在下または非存在下で反応さ
せ、次いでピロリジンと縮合させることにより、一般式
(Ia) (式中、mが1〜7の整数、nが0または1〜8の整数
のとき、R1およびR2aは前記定義の通りであり、Rはフ
ェニル基、置換フェニル基、フェノキシ基または置換フ
ェノキシ基を表わし(ここで、置換フェニル基または置
換フェノキシ基の置換基は、ハロゲン原子、炭素数8〜
10のアリールアルケニル基、炭素数6〜10のアリールオ
キシ基、炭素数7〜10のアリールアルキル基、炭素数7
〜11のアリールアルキルオキシ基、ベンゾイル基、炭素
数2〜5のアルキルオキソ基、アリルオキシ基、シンナ
モイル基、スチリルオキソ基、ヒドロキシ基、炭素数3
〜6のアルケニル基または炭素数1〜10のアルキル基で
ある)、 mが0のとき、Rは炭素原子数7〜9のアリールアルキ
ルオキシ基であり、R1およびR2aはいつしよになつて炭
素と窒素との間の結合を表わす) を有する本発明のN置換アミド酸イミド誘導体は得られ
る。First the general formula (2) or (2 ') R- (CH 2 ) m-COX (2) or [R- (CH 2) m-CO
A carboxylic acid halide or carboxylic acid anhydride having 2 O (2 ′) (wherein R and m are as defined above, and X represents a halogen atom), and the general formula (3) (In the formula, R 1 represents a hydrogen atom, n represents 0 or an integer of 1 to 8, R 2 a represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, a phenyl group, a hydroxyphenyl group, benzyloxy. A phenyl group, an alkylthio group having an alkyl group having 1 to 3 carbon atoms, a benzyloxycarbonylamino group,
A carboxylic acid benzyl ester group, a benzyloxy group, an indolyl group, an imidazolyl group, or R 1 and R 2 a always represent a carbon-nitrogen bond) in the presence of a base and The compound of the general formula (Ia) (In the formula, when m is an integer of 1 to 7 and n is an integer of 0 or 1 to 8, R 1 and R 2 a are as defined above, and R is a phenyl group, a substituted phenyl group, a phenoxy group or Represents a substituted phenoxy group (wherein the substituent of the substituted phenyl group or the substituted phenoxy group is a halogen atom, a carbon number of 8 to
10 arylalkenyl group, 6-10 carbon aryloxy group, 7-10 carbon arylalkyl group, 7 carbon atom
To 11 arylalkyloxy groups, benzoyl groups, C2 to C5 alkyloxo groups, allyloxy groups, cinnamoyl groups, styryloxo groups, hydroxy groups, and 3 carbon atoms
Is an alkenyl group having 6 to 6 carbon atoms or an alkyl group having 1 to 10 carbon atoms), when m is 0, R is an arylalkyloxy group having 7 to 9 carbon atoms, and R 1 and R 2 a are all To N-substituted amidamic acid imide derivatives of the invention having a ## STR3 ## representing the bond between the carbon and the nitrogen.
この反応で用いる塩基はアルカリ金属の水酸化物、アル
カリ金属の炭酸塩、トリアルキルアミンまたは芳香族ア
ミンなどがあげられる。又、反応温度は室温以下が好ま
しく、溶媒は上記の塩基をとかすものであるばよい。Examples of the base used in this reaction include alkali metal hydroxides, alkali metal carbonates, trialkylamines and aromatic amines. The reaction temperature is preferably room temperature or lower, and the solvent may be one that dissolves the above base.
一方、ピロリジンとの縮合において、縮合剤としてはペ
プチド合成において一般に用いられている試薬、例えば
N,N′−ジシクロヘキシルカルボジイミド、WSCD等があ
げられるが、他の方法、例えば酸クロリド法、混合酸無
水物法、活性エステル法などの一般に常用されている方
法でもよい。On the other hand, in the condensation with pyrrolidine, as a condensing agent, a reagent generally used in peptide synthesis, for example,
Examples thereof include N, N′-dicyclohexylcarbodiimide, WSCD and the like, but other commonly used methods such as acid chloride method, mixed acid anhydride method and active ester method may be used.
この化合物(Ia)の水酸基、アミノ基、およびカルボキ
シル基を保護している基は常法により容易に除去でき
る。この脱保護は例えば、接触還元などがベンジルエー
テルの場合好ましく、酸処理による方法ではベンジルオ
キシカルボニル基、三級ブトキシカルボニル基の除去が
できる。ここで用いられる酸としてはトリフルオロ酢
酸、塩酸、フツ化水素酸または臭化水素酸がよい。The group protecting the hydroxyl group, amino group and carboxyl group of this compound (Ia) can be easily removed by a conventional method. This deprotection is preferable, for example, when benzyl ether is used for the catalytic reduction, and the benzyloxycarbonyl group and the tertiary butoxycarbonyl group can be removed by the method by acid treatment. The acid used here is preferably trifluoroacetic acid, hydrochloric acid, hydrofluoric acid or hydrobromic acid.
このような方法で化合物(Ia)を処理すると、一般式
(Ib) (式中、mは0または1〜7の整数を表わし、 nは0または1〜8の整数を表わし、 R1は水素原子を表わし、 R2bは水素原子、炭素数3〜5の分岐アルキル基、フエ
ニル基、ヒドロキシフエニル基、炭素数1〜3のアルキ
ル基を有するアルキルチオ基、アミノ基、カルボキシル
基、水酸基、インドリル基またはイミダゾリル基を表わ
すか、またはR1およびR2bはいつしよになつて炭素・窒
素間の結合を表わし、但し、 mが0のとき、Rは炭素原子数7〜9のアリールアルキ
ルオキシ基であり、R1およびR2bはいつしよになつて炭
素・窒素間の結合を表わす) を有する本発明の新規N置換アミノ酸イミド誘導体が得
られる。When the compound (Ia) is treated by such a method, the compound of the general formula (Ib) (In the formula, m represents 0 or an integer of 1 to 7, n represents an integer of 0 or 1 to 8, R 1 represents a hydrogen atom, R 2 b represents a hydrogen atom, and a branched chain having 3 to 5 carbon atoms. An alkyl group, a phenyl group, a hydroxyphenyl group, an alkylthio group having an alkyl group having 1 to 3 carbon atoms, an amino group, a carboxyl group, a hydroxyl group, an indolyl group or an imidazolyl group, or when R 1 and R 2 b are It represents a bond between carbon and nitrogen, provided that when m is 0, R is an arylalkyloxy group having 7 to 9 carbon atoms and R 1 and R 2 b are , Which represents a bond between carbon and nitrogen, and a novel N-substituted amino acid imide derivative of the present invention is obtained.
前記式(1b)でmが0で、Rがベンジルオキシ基の場合
には脱保護によりベンジルオキシカルボニル基が脱離す
る。When m is 0 and R is a benzyloxy group in the above formula (1b), the benzyloxycarbonyl group is eliminated by deprotection.
これら新規な一般式(1)で表わされる化合物は、例え
ばアミノ酸のカルボキシル基を常法によりピロリジンと
処理してピロリジンイミド体としたのち、前記と同じ方
法によりアミノ基をアシル化することによつても得られ
る。These novel compounds represented by the general formula (1) are prepared, for example, by treating a carboxyl group of an amino acid with pyrrolidine by a conventional method to give a pyrrolidine imide, and then acylating the amino group by the same method as described above. Can also be obtained.
前述の化合物(2)または(2′)と(3)との反応に
おける合成法は一般に用いられているアミノ基のアシル
化反応であり、式(2)または(2′)を有する出発成
分が酸ハライドまたは酸無水物のいづれであるかによ
り、用いられる塩基等の試薬は異なる。例えば酸ハライ
ドを用いる場合、塩基としてトリエチルアミンなどのト
リアルキルアミンが好ましいが、アルカリ金属の水酸化
物の水溶液、アルカリ金属の炭酸塩などでもよい。The synthetic method in the reaction of the above-mentioned compounds (2) or (2 ') and (3) is a commonly used acylation reaction of an amino group, and the starting component having the formula (2) or (2') is The reagent such as a base used differs depending on whether it is an acid halide or an acid anhydride. For example, when an acid halide is used, a trialkylamine such as triethylamine is preferable as the base, but an aqueous solution of an alkali metal hydroxide, an alkali metal carbonate or the like may be used.
酸無水物の用いる場合、前述のアルカリ金属の水酸化物
の水溶液、例えば水酸化ナトリウム、水酸化カリウムな
ど又はアルカリ金属の炭酸塩、例えば炭酸ナトリウム、
炭酸カリウムなどがあげられる。When using an acid anhydride, an aqueous solution of the above-mentioned alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide or the like, or an alkali metal carbonate such as sodium carbonate,
Examples include potassium carbonate.
化合物(2)または(2′)の代りに、例えば一般式
(2″) R−(CH2)m−COOH (2″) (式中、Rおよびmは前記定義の通りである) を用いる場合、反応に関与しない有機溶媒中で縮合剤、
例えばWSCD、ジシクロヘキシルカルボジイミドなどが用
いられる。In place of compound (2) or (2 '), using for example the general formula (2 ") R- (CH 2 ) m-COOH (2") ( wherein, R and m are as defined above) In the case, a condensing agent in an organic solvent that does not participate in the reaction,
For example, WSCD, dicyclohexylcarbodiimide and the like are used.
次に実施例をもつて本発明をさらに詳しく説明するが、
本発明がこれら実施例の範囲に限定されるものでないこ
とはいうまでもない。Next, the present invention will be described in more detail with reference to Examples.
It goes without saying that the present invention is not limited to the scope of these examples.
実施例 1. (a) N−(γ−フエニル)ブタノイル−L−Val−
ピロリジンイミド(SUAM 1252) L−バリン(10mモル)を1規定水酸化ナトリウム溶液2
0mlに溶解し、これを水で30mlに希釈した。この水溶液
を氷冷下攪拌しながら(γ−フエニル)ブタノイルクロ
リド(10mモル)を、あらかじめ10mlのベンゼンに溶か
した溶液をゆつくりと滴下した。その直後にさらに1規
定水酸化ナトリウム溶液を10ml加えた。室温にもどした
後、混合物を一昼夜攪拌した。Example 1. (a) N- (γ-phenyl) butanoyl-L-Val-
Pyrrolidine imide (SUAM 1252) L-valine (10 mmol) 1N sodium hydroxide solution 2
It was dissolved in 0 ml and diluted with water to 30 ml. A solution of (γ-phenyl) butanoyl chloride (10 mmol) previously dissolved in 10 ml of benzene was slowly added dropwise while stirring the aqueous solution under ice cooling. Immediately thereafter, 10 ml of 1N sodium hydroxide solution was added. After returning to room temperature, the mixture was stirred overnight.
位応終了後、混合物を2回エチルエーテルで抽出し、未
反応の酸クロリドを除去した。水層を塩酸酸性にして沈
澱する化合物を酢酸エチルで3回抽出し、溶媒を減圧留
去することにより、N−(γ−フエニルブタノイル−L
−バリンを得る。次にこのN−(γ−フエニル)ブタノ
イル−L−バリン(1当量)とピロリジン(1当量)を
乾燥塩化メチレンに溶解し(約100ml)、1当量のWSCD
を加え、一昼夜攪拌する。反応終了後、1規定塩酸、飽
和食塩水、飽和炭酸水素ナトリウム溶液、飽和食塩水の
順に洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃
縮したのち、残渣をシリカゲルを用いたカラムクロマト
グラフイーで精製して目的化合物を得た。After completion of the reaction, the mixture was extracted twice with ethyl ether to remove unreacted acid chloride. The aqueous layer was acidified with hydrochloric acid and the precipitated compound was extracted three times with ethyl acetate, and the solvent was evaporated under reduced pressure to give N- (γ-phenylbutanoyl-L).
-Get Valine. The N- (γ-phenyl) butanoyl-L-valine (1 eq) and pyrrolidine (1 eq) were then dissolved in dry methylene chloride (about 100 ml) and 1 eq WSCD.
And stir all day and night. After completion of the reaction, the mixture was washed with 1N hydrochloric acid, saturated saline solution, saturated sodium hydrogen carbonate solution and saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography using silica gel to obtain the target compound.
上記(a)に於いてL−バリンのかわりにL−ロイシン
を用いることにより、(b) N−(γ−フエニル)ブ
タノイル−L−Leu−ピロリジンイミド(SUAM 1253)
を;L−メチオニンを用いることにより、(c) N−
(γ−フエニル)ブタノイル−L−Met−ピロリジンイ
ミド(SUAM 1254)を;L−フエニルアラニンを用いるこ
とにより、(d) N−(γ−フエニル)ブタノイル−
L−Phe−ピロリジンイミド(SUAM 1255)を;L−ノル
ロイシンを用いることにより、(e) N−(γ−フエ
ニル)ブタノイル−L−nLeu−ピロリジンイミド(SUAM
1256)を;L−セリン−O−ベンジルエーテルを用いる
ことにより、(f) N−(γ−フエニル)ブタノイル
−L−Ser(OBzl)−ピロリジンイミド(SUAM 1261)
を;L−チロシン−O−ベンジルエーテルを用いることに
より、(g) N−(γ−フエニル)ブタノイル−L−
Tyr(OBzl)−ピロリジンイミド(SUAM 1268)を;Nε
−カルボベンゾキシ−L−リジンを用いることにより、
(h) N−(γ−フエニル)ブタノイル−L−Lys
(Z)−ピロリジンイミド(SUAM 1272)を;Cγ−ベン
ジル−L−グルタミン酸エステルを用いることにより、
(i) N−(γ−フエニルブタノイル)−L−Glu(O
Bzl)−ピロリジンイミド(SUAM 1278)を;それぞれ
得ることができた。得られた化合物の物理化学的データ
は表1に示す。By using L-leucine in place of L-valine in (a) above, (b) N- (γ-phenyl) butanoyl-L-Leu-pyrrolidine imide (SUAM 1253)
By using L-methionine, (c) N-
(Γ-phenyl) butanoyl-L-Met-pyrrolidineimide (SUAM 1254); by using L-phenylalanine, (d) N- (γ-phenyl) butanoyl-
L-Phe-pyrrolidine imide (SUAM 1255); by using L-norleucine, (e) N- (γ-phenyl) butanoyl-LnLeu-pyrrolidine imide (SUAM
1256) by using; L-serine-O-benzyl ether, (f) N- (γ-phenyl) butanoyl-L-Ser (OBzl) -pyrrolidine imide (SUAM 1261)
By using L-tyrosine-O-benzyl ether, (g) N- (γ-phenyl) butanoyl-L-
Tyr (OBzl) -pyrrolidine imide (SUAM 1268); N ε
By using -carbobenzoxy-L-lysine,
(H) N- (γ-phenyl) butanoyl-L-Lys
By using (Z) -pyrrolidine imide (SUAM 1272); C γ -benzyl-L-glutamic acid ester,
(I) N- (γ-phenylbutanoyl) -L-Glu (O
Bzl) -pyrrolidine imide (SUAM 1278); respectively could be obtained. Physicochemical data of the obtained compound are shown in Table 1.
実施例 2. (a) N−(γ−フエニル)ブタノイル−L−Pro−
ピロリジンイミド(SUAM 1221) L−プロリン(10mモル)を1規定水酸化ナトリウム溶
液20mlに溶解し、これを水で30mlに希釈した。この水溶
液を氷例下攪拌しながら、(γ−フエニル)ブタノイル
クロリド(10mモル)を、あらかじめ10mlのベンゼンに
溶かした溶液をゆつくりと滴下した。その直後にさらに
1規定水酸化ナトリウム溶液を10ml加えた。室温にもど
した後、混合物を一昼夜攪拌した。Example 2. (a) N- (γ-phenyl) butanoyl-L-Pro-
Pyrrolidine imide (SUAM 1221) L-proline (10 mmol) was dissolved in 20 ml of 1N sodium hydroxide solution, and this was diluted to 30 ml with water. A solution of (γ-phenyl) butanoyl chloride (10 mmol) dissolved in 10 ml of benzene was slowly added dropwise while stirring this aqueous solution under ice. Immediately thereafter, 10 ml of 1N sodium hydroxide solution was added. After returning to room temperature, the mixture was stirred overnight.
反応終了後、混合物を2回エチルエーテルで抽出し、未
反応の酸クロリドを除去した。水層を塩酸酸性にして沈
澱する化合物を酢酸エチルで3回抽出し、溶媒を減圧留
去することにより、N−(γ−フエニル)ブタノイル−
L−プロリンを得、次にこのN−(γ−フエニル)ブタ
ノイル−L−プロリン(1当量)を乾燥塩化メチレンに
溶解し、(約100ml)、1当量のWSCDを加え、一昼夜攪
拌した。反応終了後、1規定塩酸、飽和食塩水、飽和炭
酸水素ナトリウム溶液、飽和食塩水の順に洗浄し、無水
硫酸マグネシウムで乾燥した。減圧濃縮したのち残渣を
シリカゲルを用いたカラムクロマトグラフイーで精製し
て目的化合物を得た。After completion of the reaction, the mixture was extracted twice with ethyl ether to remove unreacted acid chloride. The aqueous layer was acidified with hydrochloric acid and the precipitated compound was extracted three times with ethyl acetate, and the solvent was evaporated under reduced pressure to give N- (γ-phenyl) butanoyl-
L-Proline was obtained, then this N- (γ-phenyl) butanoyl-L-proline (1 eq) was dissolved in dry methylene chloride (about 100 ml), 1 eq WSCD was added and stirred overnight. After completion of the reaction, the mixture was washed with 1N hydrochloric acid, saturated saline solution, saturated sodium hydrogen carbonate solution and saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography using silica gel to obtain the target compound.
上記(a)に於いて(γ−フエニル)ブタノイルクロリ
ドのかわりに(δ−フエニル)ペンタノイルクロリドを
用いることにより、(b) N−(δ−フエニル)ペン
タノイル−L−Pro−ピロリジンイミド(SUAM 1264)
を;また(p−クロロフエノキシ)アセチルクロリドを
用いることにより、(c) N−(p−クロロフエノキ
シ)アセチル−L−Pro−ピロリジンイミド(SUAM 125
8)を;それぞれ得た。得られた化合物の物理化学的デ
ータは表1に示す。By using (δ-phenyl) pentanoyl chloride in place of (γ-phenyl) butanoyl chloride in (a) above, (b) N- (δ-phenyl) pentanoyl-L-Pro-pyrrolidine imide ( SUAM 1264)
By using (p-chlorophenoxy) acetyl chloride, (c) N- (p-chlorophenoxy) acetyl-L-Pro-pyrrolidine imide (SUAM 125
8); respectively obtained. Physicochemical data of the obtained compound are shown in Table 1.
実施例 3. (a) N−(γ−フエニル)ブタノイル−L−Ser−
ピロリジンイミド(SUAM 1270) 実施例1(f)に於いて得たSUAM 1261の化合物をエチ
ルアルコールに溶解し、触媒量のパラジウムカーボンと
ともに常圧水素雰囲気下、二昼夜攪拌した。反応終了後
パラジウムカーボンを過して除き、溶媒を減圧留去
後、残渣をシリカゲルを用いたカラムクロマトグラフイ
ーで精製して目的化合物を得た。Example 3. (a) N- (γ-phenyl) butanoyl-L-Ser-
Pyrrolidine imide (SUAM 1270) The compound of SUAM 1261 obtained in Example 1 (f) was dissolved in ethyl alcohol and stirred with a catalytic amount of palladium carbon under a hydrogen atmosphere at atmospheric pressure for two days and nights. After completion of the reaction, palladium carbon was removed by filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography using silica gel to obtain the target compound.
上記(a)に於いてSUAM 1261のかわりにSUAM 1268を
用いることにより、(b) N−(γ−フエニル)ブタ
ノイル−L−Tyr−ピロリジンイミド(SUAM 1271)を
得ることができた。得られた化合物の物理化学的データ
は表1に示す。By using SUAM 1268 instead of SUAM 1261 in (a) above, (b) N- (γ-phenyl) butanoyl-L-Tyr-pyrrolidine imide (SUAM 1271) could be obtained. Physicochemical data of the obtained compound are shown in Table 1.
実施例 4. (a) N−(γ−フエニル)ブタノイル−L−Lys−
ピロリジンイミド(SUAM 1277) 実施例1(h)で得たSUAM 1272の化合物をエチルアル
コールに溶解し、触媒量のパラジウムカーボンとともに
常圧水素雰囲気下二昼夜攪拌した。反応終了後、パラジ
ウムカーボンを過して除き、溶媒を減圧留去して目的
化合物を得た。Example 4. (a) N- (γ-phenyl) butanoyl-L-Lys-
Pyrrolidine imide (SUAM 1277) The compound of SUAM 1272 obtained in Example 1 (h) was dissolved in ethyl alcohol and stirred with a catalytic amount of palladium carbon under a hydrogen atmosphere at atmospheric pressure for 24 hours. After the reaction was completed, the palladium carbon was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the target compound.
上記(a)に於いてSUAM 1272のかわりにSUAM 1278を
用いることにより、(b) N−(γ−フエニル)ブタ
ノイル−L−Glu−ピロリジンイミド(SUAM 1279)を
得た。得られた化合物の物理化学的データは表1に示
す。By using SUAM 1278 instead of SUAM 1272 in the above (a), (b) N- (γ-phenyl) butanoyl-L-Glu-pyrrolidine imide (SUAM 1279) was obtained. Physicochemical data of the obtained compound are shown in Table 1.
実施例 5. (a) o−(E)−スチルベニルオキシブタノイル−
L−Pro−ピロリジンイミド(SUAM 1289) オルトヒドロキシ−(E)−スチルベン(10mモル)と
水酸化カリウム(15mモル)を乾燥ジメチルスルホキシ
ド(10ml)に溶解した。この溶液に4−ブロモ酪酸エチ
ルエステル(11mモル)を加え、室温で一昼夜攪拌し
た。反応終了後、水とベンゼンで分液し、有機層を硫酸
マグネシウム上で乾燥し、溶媒を留去すると、オルトヒ
ドロキシ−(E)−スチルベニルオキシ酪酸エチルエス
テルを得た。これを少量のエタノールに溶解し、1Nの水
酸化ナトリウム水溶液約100mlを加え、室温で約3時間
攪拌した。反応終了後、10N塩酸で反応液を酸性(pH〜
2)にし、酢酸エチルで抽出した。この有機層を硫酸マ
グネシウム上で乾燥し、溶媒を留去し、o−(E)−ス
チルベニルオキシ酪酸を得た。次にこのオルト−(E)
−スチルベニルオキシ酪酸(5mモル)とL−プロリンメ
チルエステル塩酸塩(5mモル)を乾燥塩化メチレン約10
0mlに溶解し、等モルのトリエチルアミンを加えた。こ
の溶液に1.2当量のWSCDを加え、一昼夜室温にて攪拌し
た。反応終了後、反応液を1N塩酸、飽和食塩水、飽和炭
酸水素ナトリウム溶液及び飽和食塩水の順番に洗浄し、
有機層を無水硫酸ナトリウム上で乾燥後溶媒を留去し
た。残渣をシリカゲルを用いたカラムクロマトグラフイ
ーを用いて精製して、オルト−(E)−スチルベニルオ
キシブタノイル−L−プロリンメチルエステルを得た。
これを少量のメタノールに溶解し、1N水酸化ナトリウム
水溶液100mlを加えて室温で約3時間攪拌した。反応終
了後、10N塩酸で反応液を酸性にして(pH〜2)、酢酸
エチルで抽出した。この有機層を無水硫酸マグネシウム
上で乾燥し、溶媒を留去し、オルト−(E)−スチルベ
ニルオキシブタノイル−L−プロリンを得た。この様に
して得られたオルト−(E)−スチルベニルオキシブタ
ノイル−L−プロリンと、ピロリジン(各3mモル)を乾
燥塩化メチレン約100mlに溶解し、1.2当量のWSCDを加え
一昼夜室温で攪拌した。反応終了後、反応液を1N塩酸、
飽和食塩水、飽和炭酸水素ナトリウム水溶液、及び飽和
食塩水の順で洗浄し、有機層を無水硫酸ナトリウム上で
乾燥後、溶媒を留去した。残渣をシリカゲルを用いたカ
ラムクロマトグラフイーを用いて精製すると、目的のオ
ルト−(E)−スチルベニルオキシブタノイル−L−プ
ロリンピロリジンイミドが得られた。Example 5. (a) o- (E) -stilbenyloxybutanoyl-
L-Pro-Pyrrolidineimide (SUAM 1289) Orthohydroxy- (E) -stilbene (10 mmol) and potassium hydroxide (15 mmol) were dissolved in dry dimethyl sulfoxide (10 ml). 4-Bromobutyric acid ethyl ester (11 mmol) was added to this solution, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the mixture was partitioned with water and benzene, the organic layer was dried over magnesium sulfate, and the solvent was distilled off to obtain orthohydroxy- (E) -stilbenyloxybutyric acid ethyl ester. This was dissolved in a small amount of ethanol, about 100 ml of 1N sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for about 3 hours. After the reaction is complete, acidify the reaction solution with 10N hydrochloric acid (pH ~
2) and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was distilled off to obtain o- (E) -stilbenyloxybutyric acid. Next, this ortho- (E)
-Stilbenyloxybutyric acid (5 mmol) and L-proline methyl ester hydrochloride (5 mmol) in dry methylene chloride about 10
It was dissolved in 0 ml and equimolar triethylamine was added. To this solution, 1.2 equivalents of WSCD was added and stirred overnight at room temperature. After completion of the reaction, the reaction solution was washed with 1N hydrochloric acid, saturated saline solution, saturated sodium hydrogen carbonate solution and saturated saline solution in this order,
The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography using silica gel to obtain ortho- (E) -stilbenyloxybutanoyl-L-proline methyl ester.
This was dissolved in a small amount of methanol, 100 ml of a 1N sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for about 3 hours. After completion of the reaction, the reaction solution was acidified with 10N hydrochloric acid (pH ~ 2) and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain ortho- (E) -stilbenyloxybutanoyl-L-proline. The thus obtained ortho- (E) -stilbenyloxybutanoyl-L-proline and pyrrolidine (3 mmol each) were dissolved in about 100 ml of dry methylene chloride, 1.2 equivalents of WSCD was added, and the mixture was stirred overnight at room temperature. It was stirred. After the reaction was completed, the reaction solution was added with 1N hydrochloric acid,
The organic layer was washed with a saturated saline solution, a saturated sodium hydrogencarbonate aqueous solution and a saturated saline solution in this order, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography using silica gel to obtain the desired ortho- (E) -stilbenyloxybutanoyl-L-proline pyrrolidine imide.
(b) p−(E)−スチルベニルオキシブタノイル−
L−Pro−ピロリジン(イミド)(SUAM 1290) 実施例5(a)に於いてオルトヒドロキシ−(E)−ス
チルベンのかわりに、パラヒドロキシ−(E)−スチル
ベンを用いることにより目的化合物を得た。(B) p- (E) -stilbenyloxybutanoyl-
L-Pro-Pyrrolidine (imide) (SUAM 1290) The target compound was obtained by using parahydroxy- (E) -stilbene instead of orthohydroxy- (E) -stilbene in Example 5 (a). .
(c) o−(2−フエニルエチル)フエノキシブタノ
イル−L−Pro−ピロリジンイミド(SUAM 1293) 実施例5(a)に於いてオルトヒドロキシ−(E)−ス
チルベンのかわりに、o−(2−フエニルエチル)フエ
ノールを用いることにより得られた。(C) o- (2-Phenylethyl) phenoxybutanoyl-L-Pro-pyrrolidineimide (SUAM 1293) Instead of orthohydroxy- (E) -stilbene in Example 5 (a), o- ( Obtained by using 2-phenylethyl) phenol.
(d) o−アリルフエノキシブタノイル−L−Pro−
ピロリジンイミド(SUA 1294) 実施例5(a)に於いてオルトヒドロキシ−(E)−ス
チルベンのかわりに、o−アリルフエノールを用いるこ
とにより得られた。(D) o-allylphenoxybutanoyl-L-Pro-
Pyrrolidineimide (SUA 1294) Obtained by substituting o-allylphenol in place of orthohydroxy- (E) -stilbene in Example 5 (a).
(e) p−ノニルフエノキシブタノイル−L−Pro−
ピロリジンイミド(SUAM 1295) 実施例5(a)に於いてo−ヒドロキシ−(E)−スチ
ルベンのかわりに、p−ノニルフエノールを用いること
により得られた。(E) p-nonylphenoxybutanoyl-L-Pro-
Pyrrolidine imide (SUAM 1295) Obtained by substituting p-nonylphenol in place of o-hydroxy- (E) -stilbene in Example 5 (a).
(f) o−ベンジルオキシフエノキシブタノイル−L
−Pro−ピロリジンイミド(SUAM 1296) 実施例5(a)に於いてo−ヒドロキシ−(E)−スチ
ルベンのかわりに、o−ベンジルオキシフエノールを用
いることにより得られた。(F) o-benzyloxyphenoxybutanoyl-L
-Pro-Pyrrolidineimide (SUAM 1296) Obtained by substituting o-benzyloxyphenol in place of o-hydroxy- (E) -stilbene in Example 5 (a).
(g) o−ヒドロキシフエノキシブタノイル−L−Pr
o−ピロリジンイミド(SUAM 1298) 実施例5(a)に於いてo−ヒドロキシ−(E)−スチ
ルベンのかわりに、o−ヒドロキシフエノールを用いる
ことにより得られた。(G) o-Hydroxyphenoxybutanoyl-L-Pr
o-Pyrrolidineimide (SUAM 1298) Obtained by substituting o-hydroxyphenol in place of o-hydroxy- (E) -stilbene in Example 5 (a).
(h) p−フエノキシフエノキシブタノイル−L−Pr
o−ピロリジンイミド(SUAM 1299) 実施例5(a)に於いてo−ヒドロキシ−(E)−スチ
ルベンのかわりに、p−フエノキシフエノールを用いる
ことにより得られた。(H) p-phenoxyphenoxybutanoyl-L-Pr
o-Pyrrolidineimide (SUAM 1299) Obtained by substituting p-phenoxyphenol for o-hydroxy- (E) -stilbene in Example 5 (a).
(i) p−ベンゾイルフエノキシブタノイル−L−Pr
o−ピロリジンイミド(SUAM 1369) 実施例5(a)に於いてo−ヒドロキシ−(E)−スチ
ルベンのかわりに、p−ベンゾイルフエノールを用いる
ことにより得られた。(I) p-benzoylphenoxybutanoyl-L-Pr
o-Pyrrolidine imide (SUAM 1369) Obtained by substituting p-benzoylphenol in place of o-hydroxy- (E) -stilbene in Example 5 (a).
(j) o−ベンゾイルフエノキシブタノイル−L−Pr
o−ピロリジンイミド(SUAM 1370) 実施例5(a)に於いてo−ヒドロキシ−(E)−スチ
ルベンのかわりに、o−ベンゾイルフエノールを用いる
ことにより得られた。(J) o-benzoylphenoxybutanoyl-L-Pr
o-Pyrrolidineimide (SUAM 1370) Obtained by substituting o-benzoylphenol in place of o-hydroxy- (E) -stilbene in Example 5 (a).
(k) p−プロピオニルフエノキシブタノイル−L−
Pro−ピロリジンイミド(SUAM 1371) 実施例5(a)に於いてo−ヒドロキシ−(E)−スチ
ルベンのかわりに、p−プロピオニルフエノールを用い
ることにより得られた。(K) p-propionylphenoxybutanoyl-L-
Pro-Pyrrolidineimide (SUAM 1371) Obtained by substituting p-propionylphenol in place of o-hydroxy- (E) -stilbene in Example 5 (a).
(l) o−プロピオニルフエノキシブタノイル−L−
Pro−ピロリジンイミド(SUAM 1372) 実施例5(a)に於いてo−ヒドロキシ−(E)−スチ
ルベンのかわりに、o−プロピオニルフエノールを用い
ることにより得られた。(L) o-propionylphenoxybutanoyl-L-
Pro-Pyrrolidineimide (SUAM 1372) Obtained by substituting o-propionylphenol for o-hydroxy- (E) -stilbene in Example 5 (a).
(m) フエノキシブタノイル−L−Pro−ピロリジン
イミド(SUAM 1378) 実施例5(a)に於いて、o−ヒドロキシ−(E)−ス
チルベンのかわりに、フエノールを用いることにより得
られた。(M) Phenyloxybutanoyl-L-Pro-pyrrolidine imide (SUAM 1378) Obtained in Example 5 (a) by using phenol instead of o-hydroxy- (E) -stilbene. .
(n) p−ベンジルフエノキシブタノイル−L−Pro
−ピロリジンイミド(SUAM 1379) 実施例5(a)に於いてo−ヒドロキシ−(E)−スチ
ルベンのかわりに、p−ベンジルフエノールを用いるこ
とにより得られた。(N) p-benzylphenoxybutanoyl-L-Pro
-Pyrrolidineimide (SUAM 1379) Obtained by substituting p-benzylphenol in place of o-hydroxy- (E) -stilbene in Example 5 (a).
(o) o−ベンジルフエノキシブタノイル−L−Pro
−ピロリジンイミド(SUAM 1381) 実施例5(a)に於いてo−ヒドロキシ−(E)−スチ
ルベンのかわりに、o−ベンジルフエノールを用いるこ
とにより得られた。(O) o-Benzylphenoxybutanoyl-L-Pro
-Pyrrolidine imide (SUAM 1381) Obtained by substituting o-benzylphenol in place of o-hydroxy- (E) -stilbene in Example 5 (a).
(p) 2−カルコノキシブタノイル−L−Pro−ピロ
リジンイミド(SUAM 1383) 実施例5(a)に於いてo−ヒドロキシ−(E)−スチ
ルベンのかわりに、2−ヒドロキシカルコンを用いるこ
とにより得られた。(P) 2-Chalconoxybutanoyl-L-Pro-pyrrolidineimide (SUAM 1383) Use 2-hydroxychalcone instead of o-hydroxy- (E) -stilbene in Example 5 (a). Was obtained by
(q) 2′−カルコキシブタノイル−L−Pro−ピロ
リジンイミド(SUAM 1384) 実施例5(a)に於いてo−ヒドロキシ−(E)−スチ
ルベンのかわりに、2′−ヒドロキシカルコンを用いる
ことにより得られ。(Q) 2'-Chalkoxybutanoyl-L-Pro-pyrrolidineimide (SUAM 1384) In Example 5 (a), 2'-hydroxychalcone is used instead of o-hydroxy- (E) -stilbene. Obtained by
(r) o−(E)−スチルベニルオキシアセチル−L
−Pro−ピロリジンイミド(SUAM 1456) 実施例5(a)に於いて、4−ブロモ酪酸エチルエステ
ルのかわりに、ブロム酢酸エチルエステルを用いること
により目的化合物を得た。(R) o- (E) -stilbenyloxyacetyl-L
-Pro-Pyrrolidineimide (SUAM 1456) In Example 5 (a), the target compound was obtained by using bromoacetic acid ethyl ester instead of 4-bromobutyric acid ethyl ester.
また、ブロム酢酸エチルエステルのかわりに、夫々アク
リル酸エチルエステル、および5−ブロモ吉草酸メチル
エステルを用いることにより、(s)o−(E)−スチ
ルベニルオキシプロピル−L−Pro−ピロリジンアミド
(SUAM 1457);および(t) o−(E)−スチルベ
ニルオキシバレリル−L−Pro−ピロリジンアミド(SUA
M 1458);をそれぞれ得た。In addition, (s) o- (E) -stilbenyloxypropyl-L-Pro-pyrrolidineamide was obtained by using acrylic acid ethyl ester and 5-bromovaleric acid methyl ester, respectively, in place of bromoacetic acid ethyl ester. (SUAM 1457); and (t) o- (E) -stilbenyloxyvaleryl-L-Pro-pyrrolidineamide (SUA
M 1458); respectively.
(u) o−(E)−スチルベニルオキシブタノイル−
L−Phe−ピロリジンイミド(SUAM 1398) 実施例5(a)に於いて、L−プロリンメチルエステル
塩酸塩のかわりに、L−フエニルアラニンエチルエステ
ル塩酸塩を用いることにより目的化合物を得た。(U) o- (E) -stilbenyloxybutanoyl-
L-Phe-Pyrrolidineimide (SUAM 1398) In Example 5 (a), the target compound was obtained by using L-phenylalanine ethyl ester hydrochloride instead of L-proline methyl ester hydrochloride.
また、L−フエニルアラニンエチルエステル塩酸塩のか
わりに、夫々L−ロイシンエチルエステル塩酸塩、およ
びL−バリンエチルエステル塩酸塩を用いることによ
り、(v) o−(E)−スチルベニルオキシブタノイ
ル−L−Leu−ピロリジンイミド(SUAM 1399);およ
び(w) o−(E)−スチルベニルオキシブタノイル
−L−Val−ピロリジンイミド(SUAM 1400);をそれ
ぞれ得た。Further, by using L-leucine ethyl ester hydrochloride and L-valine ethyl ester hydrochloride instead of L-phenylalanine ethyl ester hydrochloride, respectively, (v) o- (E) -stilbenyloxy Butanoyl-L-Leu-pyrrolidine imide (SUAM 1399); and (w) o- (E) -stilbenyloxybutanoyl-L-Val-pyrrolidine imide (SUAM 1400); respectively were obtained.
(x) p−ベンジルフエノキシブタノイル−L−Phe
−ピロリジンイミド(SUAM 1401) 実施例5(n)に於いて、L−プロリンメチルエステル
塩酸塩のかわりに、L−フエニルアラニンエチルエステ
ル塩酸塩を用いることにより、目的化合物を得た。(X) p-benzylphenoxybutanoyl-L-Phe
-Pyrrolidine imide (SUAM 1401) The target compound was obtained by using L-phenylalanine ethyl ester hydrochloride in place of L-proline methyl ester hydrochloride in Example 5 (n).
また、L−フエニルアラニンエチルエステル塩酸塩のか
わりに、夫々L−ロイシンエチルエステル塩酸塩、およ
びL−バリンエチルエステル塩酸塩を用いることによ
り、(y) p−ベンジルフエノキシブタノイル−L−
Leu−ピロリジンイミド(SUAM 1402);および(z)
p−ベンジルフエノキシブタノイル−L−Val−ピロ
リジンイミド(SUAM 1403);をそれぞれ得た。Further, by using L-leucine ethyl ester hydrochloride and L-valine ethyl ester hydrochloride instead of L-phenylalanine ethyl ester hydrochloride, respectively, (y) p-benzylphenoxybutanoyl-L −
Leu-pyrrolidine imide (SUAM 1402); and (z)
p-Benzylphenoxybutanoyl-L-Val-pyrrolidineimide (SUAM 1403); was obtained respectively.
物理化学定数は表1にまとめて示す。Physical chemical constants are summarized in Table 1.
実施例 6. (a) m−フエノキシフエニルブタノイル−L−Pro
−ピロリジンイミド(SUAM 1291) m−フエノキシフエニル酪酸(5mモル)とL−プロリン
メチルエステル塩酸塩(5mモル)を乾燥塩化メチレン約
100mlに溶解し、等モルのトリエチルアミンを加えた。
この溶液に1.2当量のWSCDを加え、一昼夜室温にて攪拌
した。反応終了後、反応液を1N塩酸飽和食塩水、飽和炭
酸水素ナトリウム溶液及び飽和食塩水の順番に洗浄し、
有機層を無水硫酸ナトリウム上で乾燥後溶媒を留去し
た。残渣をシリカゲルを用いたカラムクロマトグラフイ
ーで精製すると、m−フエノキシフエニルブタノイル−
L−プロリンメチルエステルが得られた。これを少量の
メタノールに溶解し、1N水酸化ナトリウム水溶液100ml
を加えて室温で約3時間攪拌した。反応終了後、10N塩
酸で反応液を酸性にし(pH〜2)、酢酸エチルで抽出し
た。この有機層を硫酸マグネシウム上で乾燥し、溶媒を
留去すると、m−フエノキシフエニルブタノイル−L−
プロリンが得らえた。この様にして得られた。m−フエ
ノキシフエニルブタノイル−L−プロリンと、ピロリジ
ン(各3mモルずつ)を乾燥塩化メチレン約100mlに溶解
し、1.2当量のWSCDを加えて一昼夜室温で攪拌した。反
応終了後、反後液を1N塩酸、飽和食塩水、飽和炭酸水素
ナトリウム水溶液、及び飽和食塩水の順で洗浄し、有機
層を無水硫酸ナトリウム上で乾燥後、溶媒を留去した。
残渣をシリカゲルを用いたカラムクロマトグラフイーで
精製すると、目的のm−フエノキシフエニルブタノイル
−L−プロリンピロリジンイミドが得られた。Example 6. (a) m-Phenoxyphenylbutanoyl-L-Pro
-Pyrrolidine imide (SUAM 1291) m-phenoxyphenyl butyric acid (5 mmol) and L-proline methyl ester hydrochloride (5 mmol) in dry methylene chloride
It was dissolved in 100 ml and equimolar triethylamine was added.
To this solution, 1.2 equivalents of WSCD was added and stirred overnight at room temperature. After completion of the reaction, the reaction solution was washed with 1N hydrochloric acid saturated saline solution, saturated sodium hydrogen carbonate solution and saturated saline solution in this order,
The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography using silica gel to give m-phenoxyphenylbutanoyl-
L-proline methyl ester was obtained. Dissolve this in a small amount of methanol and add 100 ml of 1N sodium hydroxide solution.
Was added and the mixture was stirred at room temperature for about 3 hours. After the reaction was completed, the reaction solution was acidified with 10N hydrochloric acid (pH ~ 2) and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was distilled off to give m-phenoxyphenylbutanoyl-L-
I got proline. Obtained in this way. m-Phenoxyphenylbutanoyl-L-proline and pyrrolidine (3 mmol each) were dissolved in about 100 ml of dry methylene chloride, 1.2 equivalents of WSCD was added, and the mixture was stirred overnight at room temperature. After the reaction was completed, the solution was washed with 1N hydrochloric acid, saturated saline solution, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution in this order, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated.
The residue was purified by column chromatography using silica gel to obtain the target m-phenoxyphenylbutanoyl-L-prolinepyrrolidine imide.
(b) o−アリルオキシブタノイル−L−Pro−ピロ
リジンイミド(SUAM 1300) 上記実施例(a)に於いて、m−フエノキシフエニル酪
酸のかわりに、o−アリルオキシ酪酸を用いることによ
り目的化合物が得られた。物理化学的データは表1に示
す。(B) o-allyloxybutanoyl-L-Pro-pyrrolidineimide (SUAM 1300) In the above-mentioned Example (a), by using o-allyloxybutyric acid instead of m-phenoxyphenyl butyric acid, The compound is obtained. Physicochemical data are shown in Table 1.
実施例 7. ベンジルオキシカルボニル−L−Pro−ピロリジンイミ
ド(SUAM 1263) L−プロリン(10mモル)を1規定水酸化ナトリウム溶
液20mlに溶解し、これを水で30mlに希釈した。この水溶
液を氷冷下攪拌しながらZ−クロリド(10mモル)を、
あらかじめ10mlのベンゼンに溶かした溶液をゆつくりと
滴下した。その直後にさらに1規定水酸化ナトリウム溶
液を10ml加えた。室温にもどした後、混合物を一昼夜攪
拌した。Example 7. Benzyloxycarbonyl-L-Pro-pyrrolidineimide (SUAM 1263) L-proline (10 mmol) was dissolved in 20 ml of 1N sodium hydroxide solution, and this was diluted to 30 ml with water. While stirring this aqueous solution under ice cooling, Z-chloride (10 mmol) was added,
A solution previously dissolved in 10 ml of benzene was gently added dropwise. Immediately thereafter, 10 ml of 1N sodium hydroxide solution was added. After returning to room temperature, the mixture was stirred overnight.
反応終了後、混合物を2回エチルエーテルで抽出し、未
反応の酸クロリドを除去した。水層を塩酸酸性にして沈
澱する化合物を酢酸エチルで3回抽出し、溶媒を減圧留
去することにより、Z−L−プロリンを得た。次にこの
Z−L−プロリン(1当量)とピロリジン(1当量)を
乾燥塩化メチレンに溶解し(約100ml)、1当量のWSCD
を加え、一昼夜攪拌した。反応終了後、1規定塩酸、飽
和食塩水、飽和炭酸水素ナトリウム溶液、飽和食塩水の
順に洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃
縮したのち、残渣をシリカゲルを用いたカラムクロマト
グラフイーで精製して目的化合物を得た(油状化合
物)。得られた化合物の物理化学的データは表1に示
す。After completion of the reaction, the mixture was extracted twice with ethyl ether to remove unreacted acid chloride. The aqueous layer was acidified with hydrochloric acid and the precipitated compound was extracted three times with ethyl acetate, and the solvent was evaporated under reduced pressure to give ZL-proline. The ZL-proline (1 equivalent) and pyrrolidine (1 equivalent) were then dissolved in dry methylene chloride (about 100 ml) and 1 equivalent of WSCD.
Was added and stirred overnight. After completion of the reaction, the mixture was washed with 1N hydrochloric acid, saturated saline solution, saturated sodium hydrogen carbonate solution and saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography using silica gel to obtain the target compound (oil compound). Physicochemical data of the obtained compound are shown in Table 1.
実施例 8. 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ダーゼ活性の測定は、芳本(T.
YoshimotoおよびD.Tsuru,Arg.Biol.Chem.42、2417、197
8)等の方法で行つた。即ち、0.0025M Z−グリシル−
プロリン−β−ナフチルアミド0.25ml、0.1Mリン酸緩衝
液(pH7.0)0.99ml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0.01ml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
ゼ溶液(0.2単位/ml)を0.1ml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−100)溶液2.0mlを表面活性剤の
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、410nmにおける吸光度(a)を測定した。 Example 8. Measurement of anti-prolyl endopeptidase activity The anti-prolyl endopeptidase activity was measured by Yoshimoto (T.
Yoshimoto and D. Tsuru, Arg. Biol. Chem. 42, 2417, 197
8) and so on. That is, 0.0025M Z-glycyl-
A mixed solution containing 0.25 ml of proline-β-naphthylamide, 0.99 ml of 0.1 M phosphate buffer (pH 7.0) and 0.01 ml of the solution of the anti-prolyl endopeptidase compound of the present invention was placed in a test tube at 37 ° C for 3 minutes. After heating, 0.1 ml of prolyl endopeptidase solution (0.2 unit / ml) was added and reacted at 35 ° C for 10 minutes. Then, 2.0 ml of Triton X-100 (Triton X-100) solution in 1M acetate buffer (pH 4.0) was added so that the final concentration of the surfactant was 10%, and the mixture was allowed to stand at room temperature for 15 minutes. The absorbance (a) at 410 nm was measured.
同時に抗プロリルエンドペプチダ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: 〔(b−a)/b〕×100 により計算し、50%阻害に必要な量〔IC50〕を求めた。
試験結果を表2に示す。At the same time, a blind absorbance (b) was measured using only a buffer solution instead of the solution of the anti-prolyl endopeptidase compound,
The prolyl endopeptidase inhibition rate was calculated by the following formula: [(ba) / b] × 100, and the amount required for 50% inhibition [IC 50 ] was determined.
The test results are shown in Table 2.
実施例 9. マウスによる急性毒性試験 CDF−1系雄性マウス(体重27.2〜30.1g)を用い、本発
明化合物のLD50を算出した。マウスは1群5匹を用い、
薬物を腹腔内に投与した。 Using Example 9 Acute toxicity test CDF-1 male mice by mice (body weight 27.2~30.1g), was calculated LD 50 for the present invention compounds. Five mice are used per group,
The drug was administered intraperitoneally.
結果を表3に示す。The results are shown in Table 3.
実施例 10. ラツトを用いたスコポラミンにより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チ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25mg/kg、5mg/k
g、含有する生理食塩水を夫々ウイスター(Wister)系
雄性ラツト(100〜120g)の腹腔に1回投与し、投与1
時間後に電気シヨツクによる受動的回避学習を行ない、
直後にスコポラミン3mg/kgを腹腔内投与した。 Example 10. Measurement of experimental amnesia preventive effect by scopolamine using rat (intraperitoneal administration) With respect to the anti-prolyl endopeptidase compound of the present invention, the effect of preventing long-term memory fixation inhibition by scopolamine was examined. That is, the compound of the present invention is 25 mg / kg, 5 mg / k
g, containing physiological saline is administered once to each abdominal cavity of male Wistar rats (100 to 120 g), and administration 1
After a while, perform passive avoidance learning by electric shock,
Immediately after that, 3 mg / kg of scopolamine was intraperitoneally administered.
効果の判定は、24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及び生理食塩水を腹腔
内投与した対照動物群と、供試化合物の投与及びスコポ
ラミンの投与を共に行つた動物群の各々につき、健忘症
ラツト、非健忘症ラツトの数を対比する事により行なつ
た。試験結果を表4に示す。The effect was determined by a passive avoidance test after 24 hours, in which both the test compound and scopolamine were administered to a group of control animals that received intraperitoneal administration of scopolamine and physiological saline without administration of the test compound. For each animal group, the number of amnestic rats and non-amnestic rats was compared. The test results are shown in Table 4.
本発明はまた脳内における器質性障害にもとずく症状の
改善・治療に有効な本発明化合物および製薬上許容され
る補助剤を含有する医薬組成物を包含する。 The present invention also includes a pharmaceutical composition containing the compound of the present invention which is effective for ameliorating / treating the symptoms of organic disorders in the brain and a pharmaceutically acceptable adjuvant.
これら活性成分および医薬組成物は、カプセル、錠剤お
よび粉末のような固形投薬形態に、またはエリキシー
ル、シロツプおよび懸濁液のような液体投薬形態で経口
投与される。又非経口的に、例えば注射剤および坐薬と
しても用いられる。These active ingredients and pharmaceutical compositions are orally administered in solid dosage forms such as capsules, tablets and powders, or in liquid dosage forms such as elixirs, syrups and suspensions. It is also used parenterally, for example as an injection and a suppository.
医薬用組成物に含まれる固形投薬としての補助剤は、例
えば固形粉末状の担体、ラクトース、サツカロース、デ
キストロース、マンニツト、ソルビツト、セルロース、
グリシンなどが挙げられる。Auxiliary agents for solid dosage contained in the pharmaceutical composition include, for example, solid powder carriers, lactose, sucrose, dextrose, mannitol, sorbit, cellulose,
Examples include glycine.
又滑沢剤としては二酸化珪素、タルク、ステアリン酸マ
グネシウム、ポリエチレングリコール、結合剤として澱
粉、ゼラチン、トラガント、メチルセルロース、ナトリ
ウムカルボキシメチルセルロース、ポリビニルピロリド
ンなどが例示される。崩壊剤としては澱粉、寒天などが
ある。Examples of lubricants include silicon dioxide, talc, magnesium stearate, polyethylene glycol, and binders such as starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone. Disintegrators include starch and agar.
本発明の化合物の投与量は成人に対して1日当り、普通
10〜2000mg好ましくは100〜1000mgの服用量で経口投与
を行なうか、あるいは1〜1000mg、好ましくは50〜500m
gの服用量で非経口投与する。投与量は、投与される疾
患の種類・患者の年令、体重、症状の程度、投与形態に
よつても異なることは明らかである。The dose of the compound of the present invention is usually
Orally administered at a dose of 10 to 2000 mg, preferably 100 to 1000 mg, or 1 to 1000 mg, preferably 50 to 500 m
Administer parenterally at a dose of g. It is clear that the dose varies depending on the type of disease to be administered, the age of the patient, the body weight, the degree of symptoms, and the administration form.
製剤例 1. 活性物質 10部 乳糖 75部 重質酸化マグネシウム 15部 を均一に混合し、錠剤、カプセル剤とした。Formulation example 1. Active substance 10 parts Lactose 75 parts Heavy magnesium oxide 15 parts were uniformly mixed to obtain tablets and capsules.
製剤例 2. 活性物質 45部 澱粉 15部 乳糖 40部 を均一に混合し、散剤、顆粒剤とした。Formulation Example 2. 45 parts of active substance, 15 parts of starch, and 40 parts of lactose were uniformly mixed to obtain powder and granules.
製剤例 3. 活性物質 1部 界面活性剤 5部 生理食塩水 94部 を加温混合、滅菌して注射剤とした。Formulation example 3. Active substance 1 part Surfactant 5 parts Physiological saline 94 parts were mixed by heating and sterilized to obtain an injection.
(発明の効果) 以上に示した様に本発明による化合物は顕著な抗エンド
プロリルペプチダーゼ活性及び抗健忘症作用を示す。
又、急性毒性試験の結果から、毒性が弱い事が示され、
安全域も充分広く、健忘症の予防および治療のための医
薬として有用である。(Effects of the Invention) As described above, the compound according to the present invention exhibits remarkable anti-endoprolyl peptidase activity and anti-amnestic effect.
Moreover, the result of the acute toxicity test shows that the toxicity is weak,
The safety margin is wide enough and it is useful as a medicine for the prevention and treatment of amnesia.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 FI 技術表示箇所 C07D 209/20 8317−4C 233/61 103 295/18 Z (72)発明者 深見 治一 大阪府三島郡島本町若山台1丁目1番1号 サントリー株式会社応用微生物研究所内 (72)発明者 田中 隆治 大阪府三島郡島本町若山台1丁目1番1号 サントリー株式会社応用微生物研究所内─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 6 Identification number Office reference number FI technical display location C07D 209/20 8317-4C 233/61 103 295/18 Z (72) Inventor Shinichi Fukami Osaka Prefecture 1-1-1, Wakayamadai, Shimamoto-cho, Mishima-gun Suntory Co., Ltd. Applied Microbiology Laboratory (72) Inventor Ryuji Tanaka 1-1-1, Wakayamadai, Shimamoto-cho, Shimamoto-cho, Mishima-gun Suntory Ltd.
Claims (7)
たは1〜8の整数を表わし、 Rはフェニル基、置換フェニル基、フェノキシ基または
置換フェノキシ基を表わし(ここで、置換フェニル基ま
たは置換フェノキシ基の置換基は、ハロゲン原子、炭素
数8〜10のアリールアルケニル基、炭素数6〜10のアリ
ールオキシ基、炭素数7〜10のアリールアルキル基、炭
素数7〜11のアリールアルキルオキシ基、ベンゾイル
基、炭素数2〜5のアルキルオキソ基、アリルオキシ
基、シンナモイル基、スチリルオキソ基、ヒドロキシ
基、炭素数3〜6のアルケニル基または炭素数1〜10の
アルキル基である)、 R1は水素原子を表わし、R2は水素原子、炭素数3〜5の
分岐アルキル基、フェニル基、ヒドロキシフェニル基、
ベンジルオキシフェニル基、炭素数1〜3のアルキル基
を有するアルキルチオ基、アミノ基、ベンジルオキシカ
ルボニルアミノ基、カルボキシル基、カルボン酸ベンジ
ルエステル基、水酸基、ベンジルオキシ基、インドリル
基またはイミダゾリル基を表わすか、またはR1およびR2
は一緒になって炭素・窒素間の結合を表わし、但し、 mが0のとき、Rは炭素数7〜9のアリールアルキルオ
キシ基であり、R1およびR2は一緒になって炭素・窒素間
の結合を表わす〕 を有するN置換アミノ酸イミド誘導体。1. A general formula [In the formula, m represents 0 or an integer of 1 to 7, n represents an integer of 0 or 1 to 8, R represents a phenyl group, a substituted phenyl group, a phenoxy group or a substituted phenoxy group (wherein, The substituent of the phenyl group or the substituted phenoxy group includes a halogen atom, an arylalkenyl group having 8 to 10 carbon atoms, an aryloxy group having 6 to 10 carbon atoms, an arylalkyl group having 7 to 10 carbon atoms, and an arylalkyl group having 7 to 11 carbon atoms. Arylalkyloxy group, benzoyl group, alkyloxo group having 2 to 5 carbon atoms, allyloxy group, cinnamoyl group, styryloxo group, hydroxy group, alkenyl group having 3 to 6 carbon atoms or alkyl group having 1 to 10 carbon atoms ), R 1 represents a hydrogen atom, R 2 represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, a phenyl group, a hydroxyphenyl group,
Represents a benzyloxyphenyl group, an alkylthio group having 1 to 3 carbon atoms, an amino group, a benzyloxycarbonylamino group, a carboxyl group, a carboxylic acid benzyl ester group, a hydroxyl group, a benzyloxy group, an indolyl group or an imidazolyl group. , Or R 1 and R 2
Together represent a carbon-nitrogen bond, provided that when m is 0, R is an arylalkyloxy group having 7 to 9 carbon atoms, and R 1 and R 2 together are carbon-nitrogen. Which represents a bond between the N-substituted amino acid imide derivative.
8の整数を表わし、 Rはフェニル基、置換フェニル基、フェノキシ基または
置換フェノキシ基を表わし(ここで、置換フェニル基ま
たは置換フェノキシ基の置換基は、ハロゲン原子、炭素
数8〜10のアリールアルケニル基、炭素数6〜10のアリ
ールオキシ基、炭素数7〜10のアリールアルキル基、炭
素数7〜11のアリールアルキルオキシ基、ベンゾイル
基、炭素数2〜5のアルキルオキソ基、アリルオキシ
基、シンナモイル基、スチリルオキソ基、ヒドロキシ
基、炭素数3〜6のアルケニル基または炭素数1〜10の
アルキル基である)、 R2は水素原子、炭素数3〜5の分岐アルキル基、フェニ
ル基、ヒドロキシフェニル基、ベンジルオキシフェニル
基、炭素数1〜3のアルキル基を有するアルキルチオ
基、アミノ基、ベンジルオキシカルボニルアミノ基、カ
ルボキシル基、カルボン酸ベンジルエステル基、水酸
基、ベンジルオキシ基、インドリル基またはイミダゾリ
ル基を表わす〕 を有する特許請求の範囲第1項記載の化合物。2. General formula [In formula, m represents the integer of 1-7, n is 0 or 1-
Represents an integer of 8, R represents a phenyl group, a substituted phenyl group, a phenoxy group or a substituted phenoxy group (wherein the substituted phenyl group or the substituted phenoxy group has a halogen atom or an arylalkenyl having 8 to 10 carbon atoms). Group, aryloxy group having 6 to 10 carbon atoms, arylalkyl group having 7 to 10 carbon atoms, arylalkyloxy group having 7 to 11 carbon atoms, benzoyl group, alkyloxo group having 2 to 5 carbon atoms, allyloxy group, cinnamoyl Group, styryloxo group, hydroxy group, alkenyl group having 3 to 6 carbon atoms or alkyl group having 1 to 10 carbon atoms), R 2 is a hydrogen atom, branched alkyl group having 3 to 5 carbon atoms, phenyl group, hydroxy group Phenyl group, benzyloxyphenyl group, alkylthio group having an alkyl group having 1 to 3 carbon atoms, amino group, benzyloxycarbonyl Amino group, carboxyl group, carboxylic acid benzyl ester group, a hydroxyl group, benzyloxy group, compounds ranging first claim of claims having a represents an indolyl group or an imidazolyl group].
表わし、Rはフェニル基、置換フェニル基、フェノキシ
基または置換フェノキシ基を表わす(ここで、置換フェ
ニル基または置換フェノキシ基の置換基は、ハロゲン原
子、炭素数8〜10のアリールアルケニル基、炭素数6〜
10のアリールオキシ基、炭素数7〜10のアリールアルキ
ル基、炭素数7〜11のアリールアルキルオキシ基、ベン
ゾイル基、炭素数2〜5のアルキルオキソ基、アリルオ
キシ基、シンナモイル基、スチリルオキソ基、ヒドロキ
シ基、炭素数3〜6のアルケニル基または炭素数1〜10
のアルキル基である)〕 を有する特許請求の範囲第1項記載の化合物。3. General formula [In the formula, m represents an integer of 1 to 7, p represents 2 or 3, and R represents a phenyl group, a substituted phenyl group, a phenoxy group or a substituted phenoxy group (wherein the substituted phenyl group or the substituted phenoxy group is represented. Is a halogen atom, an arylalkenyl group having 8 to 10 carbon atoms, or a carbon atom having 6 to 10 carbon atoms.
10 aryloxy groups, C 7-10 arylalkyl groups, C 7-11 arylalkyloxy groups, benzoyl groups, C 2-5 alkyloxo groups, allyloxy groups, cinnamoyl groups, styryloxo groups, Hydroxy group, alkenyl group having 3 to 6 carbon atoms or 1 to 10 carbon atoms
The compound according to claim 1, which is an alkyl group of
のアリールアルキル基を表わす) を有する特許請求の範囲第1項記載の化合物。4. A general formula (In the formula, p represents 2 or 3, and R ′ represents 7 to 9 carbon atoms.
Represents an arylalkyl group of);
7の整数を表わし、 mが1〜7の整数のとき、Rはフェニル基、置換フェニ
ル基、フェノキシ基または置換フェノキシ基を表わし
(ここで、置換フェニル基または置換フェノキシ基の置
換基は、ハロゲン原子、炭素数8〜10のアリールアルケ
ニル基、炭素数6〜10のアリールオキシ基、炭素数7〜
10のアリールアルキル基、炭素数7〜11のアリールアル
キルオキシ基、ベンゾイル基、炭素数2〜5のアルキル
オキソ基、アリルオキシ基、シンナモイル基、スチリル
オキソ基、ヒドロキシ基、炭素数3〜6のアルケニル基
または炭素数1〜10のアルキル基である)、 mが0のとき、Rは炭素数7〜9のアリールオキシ基を
表わす〕 を有するカルボン酸ハライドまたはカルボン酸無水物と
一般式 (式中、R1は水素原子を表わし、nは0または1〜8の
整数を表わし、R2aは水素原子、炭素数3〜5の分岐ア
ルキル基、フェニル基、ヒドロキシフェニル基、ベンジ
ルオキシフェニル基、炭素数1〜3のアルキル基を有す
るアルキルチオ基、ベンジルオキシカルボニルアミノ
基、カルボン酸ベンジルエステル基、ベンジルオキシ
基、イミドリル基、イミダゾリル基を表わすか、または
R1およびR2aは一緒になって炭素・窒素間の結合を表わ
す) を有するアミノ酸を塩基存在下または非存在下で反応さ
せ、次いでピロリジンと縮合させ、必要によりさらに脱
保護させることを特徴とする、一般式 〔式中、mは0または1〜7の整数を表わし、nは0ま
たは1〜8の整数を表わし、 Rはフェニル基、置換フェニル基、フェノキシ基または
置換フェノキシ基を表わし(ここで、置換フェニル基ま
たは置換フェノキシ基の置換基は、ハロゲン原子、炭素
数8〜10のアリールアルケニル基、炭素数6〜10のアリ
ールオキシ基、炭素数7〜10のアリールアルキル基、炭
素数7〜11のアリールアルキルオキシ基、ベンゾイル
基、炭素数2〜5のアルキルオキソ基、アリルオキシ
基、シンナモイル基、スチリルオキソ基、ヒドロキシ
基、炭素数3〜6のアルケニル基または炭素数1〜10の
アルキル基である)、 R1は水素原子を表わし、R2は水素原子、炭素数3〜5の
分岐アルキル基、フェニル基、ヒドロキシフェニル基、
ベンジルオキシフェニル基、炭素数1〜3のアルキル基
を有するアルキルチオ基、アミノ基、ベンジルオキシカ
ルボニルアミノ基、カルボキシル基、カルボン酸ベンジ
ルエステル基、水酸基、ベンジルオキシ基、インドリル
基またはイミダゾリル基を表わすか、またはR1およびR2
は一緒になって炭素・窒素間の結合を表わし、但し、 mが0のとき、Rは炭素数7〜9のアリールアルキルオ
キシ基であり、R1およびR2は一緒になって炭素・窒素間
の結合を表わす〕 を有するN置換アミノ酸イミド誘導体の製造法。5. In the general formula R- (CH 2) m-COX or [R- (CH 2) m-CO 2 O [wherein, X represents a halogen atom, m is 0 or 1
Represents an integer of 7, when m is an integer of 1 to 7, R represents a phenyl group, a substituted phenyl group, a phenoxy group or a substituted phenoxy group (wherein the substituted phenyl group or the substituted phenoxy group is a halogen atom); Atom, C8-10 arylalkenyl group, C6-10 aryloxy group, C7-
10 arylalkyl group, C 7-11 arylalkyloxy group, benzoyl group, C 2-5 alkyloxo group, allyloxy group, cinnamoyl group, styryloxo group, hydroxy group, C 3-6 alkenyl A group or an alkyl group having 1 to 10 carbon atoms), m is 0, and R represents an aryloxy group having 7 to 9 carbon atoms]. (In the formula, R 1 represents a hydrogen atom, n represents 0 or an integer of 1 to 8, R 2 a represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, a phenyl group, a hydroxyphenyl group, benzyloxy. Represents a phenyl group, an alkylthio group having an alkyl group having 1 to 3 carbon atoms, a benzyloxycarbonylamino group, a carboxylic acid benzyl ester group, a benzyloxy group, an imidolyl group, an imidazolyl group, or
R 1 and R 2 a together represent a carbon-nitrogen bond) are reacted in the presence or absence of a base, then condensed with pyrrolidine, and optionally further deprotected. And the general formula [In the formula, m represents 0 or an integer of 1 to 7, n represents an integer of 0 or 1 to 8, R represents a phenyl group, a substituted phenyl group, a phenoxy group or a substituted phenoxy group (wherein, The substituent of the phenyl group or the substituted phenoxy group includes a halogen atom, an arylalkenyl group having 8 to 10 carbon atoms, an aryloxy group having 6 to 10 carbon atoms, an arylalkyl group having 7 to 10 carbon atoms, and an arylalkyl group having 7 to 11 carbon atoms. Arylalkyloxy group, benzoyl group, alkyloxo group having 2 to 5 carbon atoms, allyloxy group, cinnamoyl group, styryloxo group, hydroxy group, alkenyl group having 3 to 6 carbon atoms or alkyl group having 1 to 10 carbon atoms ), R 1 represents a hydrogen atom, R 2 represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, a phenyl group, a hydroxyphenyl group,
Represents a benzyloxyphenyl group, an alkylthio group having 1 to 3 carbon atoms, an amino group, a benzyloxycarbonylamino group, a carboxyl group, a carboxylic acid benzyl ester group, a hydroxyl group, a benzyloxy group, an indolyl group or an imidazolyl group. , Or R 1 and R 2
Together represent a carbon-nitrogen bond, provided that when m is 0, R is an arylalkyloxy group having 7 to 9 carbon atoms, and R 1 and R 2 together are carbon-nitrogen. Which represents a bond between the two.].
たは1〜8の整数を表わし、 Rはフェニル基、置換フェニル基、フェノキシ基または
置換フェノキシ基を表わし(ここで、置換フェニル基ま
たは置換フェノキシ基の置換基は、ハロゲン原子、炭素
数8〜10のアリールアルケニル基、炭素数6〜10のアリ
ールオキシ基、炭素数7〜10のアリールアルキル基、炭
素数7〜11のアリールアルキルオキシ基、ベンゾイル
基、炭素数2〜5のアルキルオキソ基、アリルオキシ
基、シンナモイル基、スチリルオキソ基、ヒドロキシ
基、炭素数3〜6のアルケニル基または炭素数1〜10の
アルキル基である)、 R1は水素原子を表わし、R2は水素原子、炭素数3〜5の
分岐アルキル基、フェニル基、ヒドロキシフェニル基、
ベンジルオキシフェニル基、炭素数1〜3のアルキル基
を有するアルキルチオ基、アミノ基、ベンジルオキシカ
ルボニルアミノ基、カルボキシル基、カルボン酸ベンジ
ルエステル基、水酸基、ベンジルオキシ基、インドリル
基またはイミダゾリル基を表わすか、またはR1およびR2
は一緒になって炭素・窒素間の結合を表わし、但し、 mが0のとき、Rは炭素数7〜9のアリールアルキルオ
キシ基であり、R1およびR2は一緒になって炭素・窒素間
の結合を表わす〕 を有するN置換アミノ酸イミド誘導体を有効成分として
含有するプロリルエンドペブチダーゼ活性阻害剤。6. A general formula [In the formula, m represents 0 or an integer of 1 to 7, n represents an integer of 0 or 1 to 8, R represents a phenyl group, a substituted phenyl group, a phenoxy group or a substituted phenoxy group (wherein, The substituent of the phenyl group or the substituted phenoxy group includes a halogen atom, an arylalkenyl group having 8 to 10 carbon atoms, an aryloxy group having 6 to 10 carbon atoms, an arylalkyl group having 7 to 10 carbon atoms, and an arylalkyl group having 7 to 11 carbon atoms. Arylalkyloxy group, benzoyl group, alkyloxo group having 2 to 5 carbon atoms, allyloxy group, cinnamoyl group, styryloxo group, hydroxy group, alkenyl group having 3 to 6 carbon atoms or alkyl group having 1 to 10 carbon atoms ), R 1 represents a hydrogen atom, R 2 represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, a phenyl group, a hydroxyphenyl group,
Represents a benzyloxyphenyl group, an alkylthio group having 1 to 3 carbon atoms, an amino group, a benzyloxycarbonylamino group, a carboxyl group, a carboxylic acid benzyl ester group, a hydroxyl group, a benzyloxy group, an indolyl group or an imidazolyl group. , Or R 1 and R 2
Together represent a carbon-nitrogen bond, provided that when m is 0, R is an arylalkyloxy group having 7 to 9 carbon atoms, and R 1 and R 2 together are carbon-nitrogen. Which represents a bond between the amino acid imide and the N-substituted amino acid imide derivative.
たは1〜8の整数を表わし、 Rはフェニル基、置換フェニル基、フェノキシ基または
置換フェノキシ基を表わし(ここで、置換フェニル基ま
たは置換フェノキシ基の置換基は、ハロゲン原子、炭素
数8〜10のアリールアルケニル基、炭素数6〜10のアリ
ールオキシ基、炭素数7〜10のアリールアルキル基、炭
素数7〜11のアリールアルキルオキシ基、ベンゾイル
基、炭素数2〜5のアルキルオキソ基、アリルオキシ
基、シンナモイル基、スチリルオキソ基、ヒドロキシ
基、炭素数3〜6のアルケニル基または炭素数1〜10の
アルキル基である)、 R1は水素原子を表わし、R2は水素原子、炭素数3〜5の
分岐アルキル基、フェニル基、ヒドロキシフェニル基、
ベンジルオキシフェニル基、炭素数1〜3のアルキル基
を有するアルキルチオ基、アミノ基、ベンジルオキシカ
ルボニルアミノ基、カルボキシル基、カルボン酸ベンジ
ルエステル基、水酸基、ベンジルオキシ基、インドリル
基またはイミダゾリル基を表わすか、またはR1およびR2
は一緒になって炭素・窒素間の結合を表わし、但し、 mが0のとき、Rは炭素数7〜9のアリールアルキルオ
キシ基であり、R1およびR2は一緒になって炭素・窒素間
の結合を表わす〕 を有するN置換アミノ酸イミド誘導体を有効成分として
含有する脳機能改善剤。7. General formula [In the formula, m represents 0 or an integer of 1 to 7, n represents an integer of 0 or 1 to 8, R represents a phenyl group, a substituted phenyl group, a phenoxy group or a substituted phenoxy group (wherein, The substituent of the phenyl group or the substituted phenoxy group includes a halogen atom, an arylalkenyl group having 8 to 10 carbon atoms, an aryloxy group having 6 to 10 carbon atoms, an arylalkyl group having 7 to 10 carbon atoms, and an arylalkyl group having 7 to 11 carbon atoms. Arylalkyloxy group, benzoyl group, alkyloxo group having 2 to 5 carbon atoms, allyloxy group, cinnamoyl group, styryloxo group, hydroxy group, alkenyl group having 3 to 6 carbon atoms or alkyl group having 1 to 10 carbon atoms ), R 1 represents a hydrogen atom, R 2 represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, a phenyl group, a hydroxyphenyl group,
Represents a benzyloxyphenyl group, an alkylthio group having 1 to 3 carbon atoms, an amino group, a benzyloxycarbonylamino group, a carboxyl group, a carboxylic acid benzyl ester group, a hydroxyl group, a benzyloxy group, an indolyl group or an imidazolyl group. , Or R 1 and R 2
Together represent a carbon-nitrogen bond, provided that when m is 0, R is an arylalkyloxy group having 7 to 9 carbon atoms, and R 1 and R 2 together are carbon-nitrogen. Representing a bond between each other], a brain function improving agent containing as an active ingredient an N-substituted amino acid imide derivative.
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP61043821A JPH0730020B2 (en) | 1986-02-28 | 1986-02-28 | N-substituted amino acid imide derivative, production method and use |
CA000528630A CA1320734C (en) | 1986-02-04 | 1987-01-30 | Pyrrolidineamide derivative of acylamino acid and pharmaceutical composition containing the same |
US07/010,490 US4826870A (en) | 1986-02-04 | 1987-02-03 | Pyrrolidineamide derivative of acylamino acid and pharmaceutical containing the same |
AU68228/87A AU588968B2 (en) | 1986-02-04 | 1987-02-03 | Pyrrolidineamide derivative of acylamino acid and pharmaceutical composition containing the same |
ES87101504T ES2056791T3 (en) | 1986-02-04 | 1987-02-04 | A PROCEDURE FOR PREPARING ACIL AMINO ACID PYRROLIDINAMIDE DERIVATIVES. |
AT87101504T ATE89000T1 (en) | 1986-02-04 | 1987-02-04 | PYRROLIDINAMIDE DERIVATIVES OF ACYLAMINOS ACID, PHARMACEUTICAL COMPOSITION AND USE. |
DE87101504T DE3785684T2 (en) | 1986-02-04 | 1987-02-04 | Pyrrolidinamide derivatives of acylamino acid, pharmaceutical composition and use. |
EP87101504A EP0232849B1 (en) | 1986-02-04 | 1987-02-04 | Pyrrolidineamide derivative of acylamino acid, pharmaceutical composition and use |
US07/638,148 US5198458A (en) | 1986-02-04 | 1991-01-09 | Pyrrolidineamide derivatives of acylamino acid and pharmaceutical composition containing the same |
GR920403167T GR3007789T3 (en) | 1986-02-04 | 1993-05-06 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP61043821A JPH0730020B2 (en) | 1986-02-28 | 1986-02-28 | N-substituted amino acid imide derivative, production method and use |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS62201877A JPS62201877A (en) | 1987-09-05 |
JPH0730020B2 true JPH0730020B2 (en) | 1995-04-05 |
Family
ID=12674412
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP61043821A Expired - Lifetime JPH0730020B2 (en) | 1986-02-04 | 1986-02-28 | N-substituted amino acid imide derivative, production method and use |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0730020B2 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0832704B2 (en) * | 1987-11-30 | 1996-03-29 | キッセイ薬品工業株式会社 | Prolyl endopeptidase inhibitor |
AU6983894A (en) * | 1993-06-30 | 1995-01-24 | Zeria Pharmaceutical Co., Ltd. | Thiazolidine derivative and medicine containing the same |
-
1986
- 1986-02-28 JP JP61043821A patent/JPH0730020B2/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
JPS62201877A (en) | 1987-09-05 |
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