JPH04198165A - 2-pyrrolidinone derivative - Google Patents
2-pyrrolidinone derivativeInfo
- Publication number
- JPH04198165A JPH04198165A JP2326530A JP32653090A JPH04198165A JP H04198165 A JPH04198165 A JP H04198165A JP 2326530 A JP2326530 A JP 2326530A JP 32653090 A JP32653090 A JP 32653090A JP H04198165 A JPH04198165 A JP H04198165A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- glutamic acid
- diethyl ester
- action
- 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.)
- Pending
Links
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical class O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 title claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 23
- 230000003042 antagnostic effect Effects 0.000 abstract description 5
- WSEQLMQNPBNMSL-FJXQXJEOSA-N diethyl (2s)-2-aminopentanedioate;hydron;chloride Chemical compound Cl.CCOC(=O)CC[C@H](N)C(=O)OCC WSEQLMQNPBNMSL-FJXQXJEOSA-N 0.000 abstract description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 abstract description 3
- 229960002989 glutamic acid Drugs 0.000 abstract description 3
- 235000013922 glutamic acid Nutrition 0.000 abstract description 3
- 239000004220 glutamic acid Substances 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 206010012289 Dementia Diseases 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 125000003431 oxalo group Chemical group 0.000 abstract description 2
- 230000001965 increasing effect Effects 0.000 abstract 2
- 229940024606 amino acid Drugs 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 238000002955 isolation Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 8
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 7
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 6
- 229940122459 Glutamate antagonist Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 5
- 229940049906 glutamate Drugs 0.000 description 5
- 229930195712 glutamate Natural products 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 229960003638 dopamine Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000002708 enhancing effect Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003194 amino acid receptor blocking agent Substances 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- -1 cyclic GABA derivative Chemical class 0.000 description 2
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000003825 glutamate receptor antagonist Substances 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 2
- 229960001252 methamphetamine Drugs 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000010902 straw Substances 0.000 description 2
- NQRKYASMKDDGHT-UHFFFAOYSA-N (aminooxy)acetic acid Chemical compound NOCC(O)=O NQRKYASMKDDGHT-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VGUWZCUCNQXGBU-UHFFFAOYSA-N 3-[(4-methylpiperazin-1-yl)methyl]-5-nitro-1h-indole Chemical compound C1CN(C)CCN1CC1=CNC2=CC=C([N+]([O-])=O)C=C12 VGUWZCUCNQXGBU-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- SOWBFZRMHSNYGE-UHFFFAOYSA-N Monoamide-Oxalic acid Natural products NC(=O)C(O)=O SOWBFZRMHSNYGE-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- LHNKBXRFNPMIBR-UHFFFAOYSA-N Picrotoxin Natural products CC(C)(O)C1(O)C2OC(=O)C1C3(O)C4OC4C5C(=O)OC2C35C LHNKBXRFNPMIBR-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000002205 anti-dementic effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 210000000877 corpus callosum Anatomy 0.000 description 1
- HERPVHLYIHBEFW-ZETCQYMHSA-N diethyl (2s)-2-aminopentanedioate Chemical compound CCOC(=O)CC[C@H](N)C(=O)OCC HERPVHLYIHBEFW-ZETCQYMHSA-N 0.000 description 1
- 230000000706 effect on dopamine Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000035863 hyperlocomotion Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940035429 isobutyl alcohol Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VJKUPQSHOVKBCO-AHMKVGDJSA-N picrotoxin Chemical compound O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(=C)C)[C@@H]1C(=O)O2.O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(C)(O)C)[C@@H]1C(=O)O2 VJKUPQSHOVKBCO-AHMKVGDJSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〈産業上の利用分野〉
本発明はＹ−アミノ酪酸（Ｇ Ａ Ｂ Ａ）拮抗作用、
ドーパミン遊離抑制作用及びグルタミン酸増強作用を示
す２−ピロリジノン誘導体に関する。[Detailed description of the invention] <Industrial application field> The present invention provides Y-aminobutyric acid (GABA) antagonism,
The present invention relates to 2-pyrrolidinone derivatives that exhibit dopamine release inhibiting action and glutamic acid enhancing action.
〈従来の技術〉
グルタミン酸拮抗薬またはＧＡＢＡの作用増強薬は抗痴
呆症またはアルツハイマー症治療薬としての可能性が考
えられているが、現在知られているＭＫ−８０１；Ｐｒ
ｏｃ Ｎａｔｌ、ＡｃａｄＳｃｉ、ＵＳＡ、、 第８
３巻、７１０４−７１０８頁、１９８６年（グルタミン
酸拮抗薬）、ＮＣ−１２００；Ｂｒ、Ｊ、Ｐｈａｒｍａ
ｃｏｌ、。<Prior art> Glutamate antagonists or GABA action enhancers are considered to have potential as anti-dementia or Alzheimer's disease therapeutics, but the currently known MK-801;Pr
oc Natl, AcadSci, USA, 8th
3, pp. 7104-7108, 1986 (glutamate antagonists), NC-1200; Br, J, Pharma
col.
第８９巻、２１９〜２２８頁（グルタミン酸拮抗薬）、
ビラセタム（ＧＡＢＡ増強薬増強子ニラセタム（ＧＡＢ
Ａ増強薬増強子は充分な作用が得られていない。Volume 89, pages 219-228 (glutamate antagonists),
viracetam (GABA potentiator niracetam (GAB
A-enhancing agent enhancer does not have sufficient effect.
〈発明が解決しようとする課題〉
本発明は、優れたＧＡＢＡ拮抗作用、ドーパミン遊離抑
制作用及びグルタミン酸増強作用を示す化合物を提供す
ることを目的とする。<Problems to be Solved by the Invention> An object of the present invention is to provide a compound that exhibits excellent GABA antagonistic activity, dopamine release inhibiting activity, and glutamate enhancing activity.
〈課題を解決するための手段〉
本発明者らは、環状ＧＡＢＡ誘導体である２−ピロリジ
ノン誘導体とグルタミン酸拮抗作用を有するグルタミン
酸ジエチルエステルの構造を同一分子内に有する化合物
について鋭意検討した結果、ＧＡＢＡの拮抗作用、ドー
パミンの遊離抑制作用及びグルタミン酸増強作用を有す
る全く新しい作用様式を有する本発明の化合物を見い吊
した。<Means for Solving the Problems> As a result of intensive studies by the present inventors on compounds having the structures of a 2-pyrrolidinone derivative, which is a cyclic GABA derivative, and a glutamic acid diethyl ester, which has a glutamic acid antagonistic effect, in the same molecule, We have discovered a compound of the present invention which has a completely new mode of action, having antagonistic action, dopamine release inhibiting action, and glutamate enhancing action.
本発明の化合物は、下記式１
［式中、Ａは式−（ＣＨ２）ｎ−（式中、ｎはＯ〜８の
整数を示す。）で表わされる基またはフェニレン基を示
し、Ｒ１およびＲ２は同一または異なって低級アルキル
基を示す。］で表わされる２−ピロリジノン誘導体であ
る。The compound of the present invention has the following formula 1 [wherein A represents a group represented by the formula -(CH2)n- (wherein n represents an integer of O to 8] or a phenylene group, R1 and R2 are the same or different and represent a lower alkyl group. ] It is a 2-pyrrolidinone derivative represented by.
本発明において、低級アルキル基とは炭素数１〜４のア
ルキル基であり、例えばメチル基、エチル基、プロピル
基、イソプロピル基などである。In the present invention, a lower alkyl group is an alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and the like.
好ましくはエチル基である。Preferably it is an ethyl group.
式１の化合物は、例えば式
（式中、Ａは前記と同！！義であり、Ｈａｌはハロゲン
原子を示す。）で表わされる化合物とし一グルタミン酸
ジエチルエステル塩酸塩を塩基の存在下に反応すること
によって製造することができる。The compound of formula 1 is, for example, a compound represented by the formula (wherein A has the same meaning as above and Hal represents a halogen atom), and monoglutamic acid diethyl ester hydrochloride is reacted in the presence of a base. It can be manufactured by
ここで用いられる塩基としては、例えば炭酸カリウム、
炭酸ナトリウム、水酸化ナトリウム、水酸化力υラム等
のアルカリ塩類、トリエチルアミン、ジイソプロピルエ
チルアミン、Ｎ−メチルモルホリン、ピリジン等のアミ
ン類等を挙げることができ、反応溶媒としては水、酢酸
、メタノール、エタノール、イソブＯビルアルコール、
第三ブチルアルコール等のアルコール類、ジオキサン、
テトラヒドロフラン等のエーテル類、ジメチルホルムア
ミド、ジメチルスルホキシド、塩化メチレン、クロロホ
ルム、アセトン等の反応に不活性な溶媒を挙げることが
できる。Examples of the base used here include potassium carbonate,
Examples of the reaction solvent include alkali salts such as sodium carbonate, sodium hydroxide, and hydroxide, amines such as triethylamine, diisopropylethylamine, N-methylmorpholine, and pyridine, and reaction solvents such as water, acetic acid, methanol, and ethanol. , isobutyl alcohol,
Alcohols such as tertiary butyl alcohol, dioxane,
Examples include ethers such as tetrahydrofuran, and solvents inert to the reaction such as dimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, and acetone.
〈発明の効果〉
本発明の化合物は優れＧＡＢＡ拮抗作用、ドーパミン遊
離抑制作用及びグルタミン酸増強作用を示すことから、
痴呆患者の意識水準の上昇及び記銘力の増強をもたらす
医薬として有用である。<Effects of the Invention> Since the compound of the present invention exhibits excellent GABA antagonistic activity, dopamine release inhibiting activity, and glutamate enhancing effect,
It is useful as a medicine that raises the level of consciousness and enhances memory in dementia patients.
以下に試験例を示す。Test examples are shown below.
なお、試験例中の化合物番号は実施例中の化合物番号と
同一である。In addition, the compound number in the test example is the same as the compound number in the example.
試験例１ ［ビクロトキシン誘発痙彎に対する作用］
ＩｃＲ系雄性マウス１群７０匹（体１１２５−３０ｇ
）を用い、被検薬を経口投与した３０分後にピクロトキ
シン７５ｍｇ／に９を腹腔的投与し痙彎の発現を観察し
た。Test Example 1 [Effect on bicrotoxin-induced convulsions] Group 70 male IcR mice (body weight 1125-30g)
), 30 minutes after oral administration of the test drug, picrotoxin 75 mg/9 was administered intraperitoneally, and the development of spasticity was observed.
その結果、化合物１、化合物２、化合物３、化合物４及
び化合物６は、２〜ｌ００ｍｇ／ｋｇの腹腔的投与で用
量依存的にビクロトキシン誘発痙彎を増強した。 一方
、ＧＡＢＡ増強藁であるアミノオキシ酢酸及びグルタミ
ン酸拮抗薬であるグルタミン酸ジエチルエステルはビク
ロトキシン誘発１ｍ”Ｊを抑制した。As a result, Compound 1, Compound 2, Compound 3, Compound 4, and Compound 6 dose-dependently enhanced bicrotoxin-induced convulsions when administered intraperitoneally at 2 to 100 mg/kg. On the other hand, aminooxyacetic acid, a GABA-enhancing straw, and glutamate diethyl ester, a glutamate antagonist, suppressed bicrotoxin-induced 1 m''J.
＋００ ６０
コントロール １０試験例２［ドー
パミン遊離に対する作用ＪＩｃＲ系雄性マウス１群１０
匹（休１ｉ２５−３０ｇ）を用い、２時開以上測定箱に
入れ充分に順応させた。+00 60 Control 10 Test Example 2 [Effect on dopamine release JIcR male mice group 1 10
A mouse (25-30 g per day) was placed in a measurement box that was open at least 2 o'clock and allowed to acclimatize sufficiently.
被検薬を経口投与した３０分後にメタンフェタミンＩｍ
ｇ／ｋｇを腹腔内に投与し、運動量をアニメックス（室
町機械製）で測定した。Methamphetamine Im 30 minutes after oral administration of the test drug
g/kg was administered intraperitoneally, and the amount of exercise was measured using Animex (manufactured by Muromachi Kikai).
その結果、化合物４、化合物５及び化合物６は２〜２０
０ｍｇ／ｋｇの投与量で用量依存的にメタンフェタミン
誘発運動過多を抑制した。As a result, compound 4, compound 5 and compound 6 were found to have 2 to 20
A dose of 0 mg/kg inhibited methamphetamine-induced hyperlocomotion in a dose-dependent manner.
また、これらの被検藁を２〜２００ｍｇ／に９を経口投
与した際には自発運動量に対する影響は認められなかっ
た。Moreover, when 9 was orally administered to these test straws at 2 to 200 mg/day, no effect on locomotor activity was observed.
試験例３［半球間伝達に対する作用コ
１２週令のウィスター系雄性ラット１群６匹（体重＋６
０−２２０ｇ ）を用い、ウレタン麻酔下に一側脳梁を
電気刺激し対側大脳皮質より半球間伝達電位を記録した
。この電位はグルタミン酸拮抗薬であるグルタミン酸ジ
エチルエステル１００μ９／ラツトを脳室内に投与する
ことにより抑制された。Test Example 3 [Effect on interhemispheric transmission] 1 group of 6 male Wistar rats (body weight +6
0-220g), one side of the corpus callosum was electrically stimulated under urethane anesthesia, and interhemispheric transmission potentials were recorded from the contralateral cerebral cortex. This potential was suppressed by intracerebroventricularly administering 100 μ9/rat of glutamate diethyl ester, a glutamate antagonist.
その結果、化合物４、化合物５及び化合物６は１０〜５
０ｍｇ／ｋｇの静脈内投与により用量依存的に半球間伝
達電位を増強した。As a result, Compound 4, Compound 5 and Compound 6 were 10 to 5
Intravenous administration of 0 mg/kg enhanced interhemispheric transmission potential in a dose-dependent manner.
〈実施例〉 以下、実施例を挙げて本発明の詳細な説明する。<Example> Hereinafter, the present invention will be explained in detail by giving examples.
実施例１
Ｎ−［（２−ピロリジン−１−イル）オギザリル１−し
一グルタミン酸ジエチルエステル（化合物１）の製造
塩化オギザリル（５１）の塩化メチレン（５ｍｌ）溶液
に室温下２−ビＯリジノン（１，７９）の塩化メチレン
（５１）溶液を滴下し、室温で１０分間攪拌した。反応
後２０℃で溶媒を減圧留去し、残渣を塩化メチレン（Ｉ
Ｏｍｌ）に溶解し、Ｌ−グルタミン酸ジエチルエステル
塩酸塩（４，８９）とトリエチルアミン（６、９ｍｌ）
の塩化メチレン（１５０ｍｌ）溶液中に１０℃で滴下し
５分間攪拌した。反応溶液を２０℃以下で減圧留去し、
残渣をシリカゲルカラムクロマトグラフィー（展開溶媒
、酢酸エチル ヘキサン＝２・ １）に付し目的の画分
を集め、エーテル−塩化メチレン混合液で結晶化して標
記の化合物（３，０９）を得た。Example 1 Preparation of N-[(2-pyrrolidin-1-yl)oxalyl 1-monoglutamic acid diethyl ester (Compound 1) A solution of oxalyl chloride (51) in methylene chloride (5 ml) was added with 2-biOlidinone ( A solution of 1,79) in methylene chloride (51) was added dropwise, and the mixture was stirred at room temperature for 10 minutes. After the reaction, the solvent was distilled off under reduced pressure at 20°C, and the residue was dissolved in methylene chloride (I
L-glutamic acid diethyl ester hydrochloride (4,89) and triethylamine (6,9 ml)
The mixture was added dropwise to a methylene chloride (150 ml) solution at 10°C and stirred for 5 minutes. The reaction solution was distilled off under reduced pressure at 20°C or lower,
The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate hexane = 2.1), the desired fractions were collected, and crystallized from an ether-methylene chloride mixture to obtain the title compound (3,09).
融点 ８４５〜８６℃
＋ａ＋ｇ５（メタノール ｃ ＝ Ｏ，１５％）；−２
２，８゜実施例２
Ｎ−［４−（２−ピロリジン−１−イル）−４−オキソ
ブタノイル１−Ｌ−グルタミン酸ジエチルエステル（化
合物２）の製造
４−（２−ピロリジン−１−イル）−４−オキソブタノ
イルクロリド（４９）の塩化メチレン（Ｉｏｎｌ）溶液
をＬ−グルタミン酸ジエチルエステル塩酸塩（４，８９
）とトリエチルアミン（６、９ｉｔ）の塩化メチレン（
１５０＋ｎｌ）溶液中に１０℃で滴下し５分間攪拌した
。反応溶液を２０℃以下で減圧留去し、残渣をシリカゲ
ルカラムクロマトグラフィー（展開溶媒：クロロホルム
、メタノール＝＋ＯＯ： ｉ）に付し目的の両分を集め
、エーテル−塩化メチレン混合液で結晶化して標記の化
合物（１，９２ｇ）を得た。Melting point 845-86℃ +a+g5 (methanol c = O, 15%); -2
2,8゜Example 2 Preparation of N-[4-(2-pyrrolidin-1-yl)-4-oxobutanoyl 1-L-glutamic acid diethyl ester (compound 2) 4-(2-pyrrolidin-1-yl) )-4-oxobutanoyl chloride (49) in methylene chloride (Ionl) was added to L-glutamic acid diethyl ester hydrochloride (4,89
) and triethylamine (6,9it) in methylene chloride (
150+nl) solution at 10° C. and stirred for 5 minutes. The reaction solution was distilled off under reduced pressure at below 20°C, and the residue was subjected to silica gel column chromatography (developing solvent: chloroform, methanol = +OO: i) to collect both desired fractions, and crystallized with an ether-methylene chloride mixture. The title compound (1.92 g) was obtained.
融点 ２７〜２９℃
［Ｑ］６５（メタノール ｃ＝０．１４％）； −＋２
ゆ同様の操作を行い以下の化合物を得た。Melting point 27-29°C [Q]65 (methanol c=0.14%); -+2
The following compound was obtained by carrying out the same operation as above.
Ｎ −１５−（２−ビＯリジンー１−イル）−５−オキ
ソペンタノイル］−１−グルタミン酸ジエチルエステル
（化合物３）
融点 ５２〜５４℃
ｔｏ＋ｇ５＋メタノールｃ＝０．１８％）；−１８，５
゜Ｎ −［６−（２−ピロリジン−１−イル）−６−オ
キソヘキサノイル］−Ｌ−グルタミン酸ジエチルエステ
ル（化合物４）
ｌ Ｈ−Ｎ Ｍ Ｒ（ＣＤＣｌ２） ろ（ｐｐｍ） ；
１２８（３Ｈ，ｔ、Ｊ＝７Ｈ２）
１３０（３Ｈ，ｔ、Ｊ＝７Ｈｚ）
１．７０（４Ｈ，ｍ）
１．９−２．５ （８Ｈ，ｍ）
２．６０（２Ｈ，ｔ、Ｊ＝７Ｈｚ）
２．９０（２Ｈ，ｂｒｔ）
３．８０（２Ｈ，ｔ、Ｊ＝７．５Ｈｚ１４．１２（２Ｈ
，ｑ、Ｊ＝７Ｈｚ）
４．２０（２Ｈ，ｑ、Ｊ＝７Ｈｚ）
４．６０（ＩＨ，ｄｔ、Ｊ、１＝５Ｈｚ、Ｊｔ＝８Ｈｚ
）
６．３２（ＩＨ，ｂｒｄ、Ｊ＝８Ｈｚ）６．５０（Ｉ
Ｈ，ｂｒｄ、Ｊ＝８Ｈｚ）ｔｏ＋ｇ５（メタノール、ｃ
−０，１８％）；−２０’Ｎ −［８−（２−ピロリジ
ン−１−イル）−８−オキソオクタノイル］−Ｌ−グル
タミン酸ジエチルエステル（化合物５）
’ Ｈ−Ｎ Ｍ Ｒ（ＣＤＣｌ２） ろ（ｐｐｍ） ：
１ ２６（３１−１，ｔ、Ｊ＝７Ｈｚ）１．３０（３）
−１，ｔ、Ｊ ＝７Ｈ２１１，３４（４Ｈ，ｍ）
１６ ２ （４Ｈ，ｍ）
２．０ ５ （２Ｈ，ｍ）
２．２０（２）−１，ｍ）
２．３ ７ （２Ｈ，ｍ）
２．６０（２Ｈ，ｔ、Ｊ＝７．５Ｈｚ）２．８９（２Ｈ
，ｔ、Ｊ＝７．５Ｈ２）３．８０（２Ｈ，ｔ、Ｊ＝９．
５Ｈｚ）４、＋ ５（２Ｈ，ｑ、Ｊ＝７Ｈｚ）４．２
０（２Ｈ，ｑ、Ｊ＝７Ｈｚ）
４．６０（ＩＨ，ｄｔ、Ｊ、＝５Ｈｚ、Ｊ、＝８Ｈｚ）
６．２ ０ Ｈｌ−１，ｂ ｒ ｄ、Ｊ＝８Ｈｚ
）６．４０（ＩＨ，ｂｒｄ、Ｊ＝ＪＨｚ）＋ａ＋ｇ５（
メタノール Ｃ＝０．４７％）ｊ−１５゜Ｎ−１１０−
（２−ピロリジン−１−イル）−１０−オキソデカノイ
ル］−Ｌ−グルタミン酸ジエチルエステル（化合物６）
融点 ６６〜６８℃
Ｎ −［４−（２〜ピロリジン−１−イル）フェニルカ
ルボニル］−Ｌ−グルタミン酸ジエチルエステル（化合
物７）
融ｆ５．１１２〜１１４℃N-15-(2-biOlysin-1-yl)-5-oxopentanoyl]-1-glutamic acid diethyl ester (compound 3) Melting point 52-54°C to+g5+methanol c=0.18%); -18,5
゜N-[6-(2-pyrrolidin-1-yl)-6-oxohexanoyl]-L-glutamic acid diethyl ester (compound 4) l H-NMR(CDCl2) filter (ppm);
128 (3H, t, J=7H2) 130 (3H, t, J=7Hz) 1.70 (4H, m) 1.9-2.5 (8H, m) 2.60 (2H, t, J= 7Hz) 2.90 (2H, brt) 3.80 (2H, t, J = 7.5Hz 14.12 (2H
, q, J=7Hz) 4.20 (2H, q, J=7Hz) 4.60 (IH, dt, J, 1=5Hz, Jt=8Hz
) 6.32 (IH, brd, J=8Hz) 6.50 (I
H,brd,J=8Hz)to+g5(methanol,c
-0,18%); -20'N-[8-(2-pyrrolidin-1-yl)-8-oxooctanoyl]-L-glutamic acid diethyl ester (compound 5)' H-N M R (CDCl2) ro (ppm):
1 26 (31-1, t, J=7Hz) 1.30 (3)
-1,t,J =7H211,34(4H,m) 16 2 (4H,m) 2.0 5 (2H,m) 2.20(2)-1,m) 2.3 7 (2H,m ) 2.60 (2H, t, J=7.5Hz) 2.89 (2H
, t, J=7.5H2) 3.80(2H, t, J=9.
5Hz) 4, + 5 (2H, q, J=7Hz) 4.2
0 (2H, q, J = 7Hz) 4.60 (IH, dt, J, = 5Hz, J, = 8Hz) 6.2 0 Hl-1, b r d, J = 8Hz
)6.40(IH,brd,J=JHz)+a+g5(
Methanol C=0.47%)j-15°N-110-
(2-pyrrolidin-1-yl)-10-oxodecanoyl]-L-glutamic acid diethyl ester (compound 6) Melting point 66-68°C N-[4-(2-pyrrolidin-1-yl)phenylcarbonyl]-L-glutamic acid Diethyl ester (compound 7) Melting f5.112-114℃
Claims (1)
８の整数を示す。）で表わされる基またはフェニレン基
を示し、Ｒ＾１およびＲ＾２は同一または異なつて低級
アルキル基を示す。］で表わされる２−ピロリジノン誘
導体(1) Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, A is the formula -(CH_2)_n-(In the formula, n is 0 to
Indicates an integer of 8. ) or a phenylene group, and R^1 and R^2 are the same or different and represent a lower alkyl group. 2-pyrrolidinone derivative represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2326530A JPH04198165A (en) | 1990-11-28 | 1990-11-28 | 2-pyrrolidinone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2326530A JPH04198165A (en) | 1990-11-28 | 1990-11-28 | 2-pyrrolidinone derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04198165A true JPH04198165A (en) | 1992-07-17 |
Family
ID=18188867
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2326530A Pending JPH04198165A (en) | 1990-11-28 | 1990-11-28 | 2-pyrrolidinone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04198165A (en) |
-
1990
- 1990-11-28 JP JP2326530A patent/JPH04198165A/en active Pending
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