JPS6355511B2 - - Google Patents
Info
- Publication number
- JPS6355511B2 JPS6355511B2 JP13805385A JP13805385A JPS6355511B2 JP S6355511 B2 JPS6355511 B2 JP S6355511B2 JP 13805385 A JP13805385 A JP 13805385A JP 13805385 A JP13805385 A JP 13805385A JP S6355511 B2 JPS6355511 B2 JP S6355511B2
- Authority
- JP
- Japan
- Prior art keywords
- test
- methoxybenzoyl
- pyrrolidinone
- treated
- avoidance
- 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
Links
- DZTVZKSCFQIBMV-UHFFFAOYSA-N 4-[(4-methoxybenzoyl)amino]butanoic acid Chemical compound COC1=CC=C(C(=O)NCCCC(O)=O)C=C1 DZTVZKSCFQIBMV-UHFFFAOYSA-N 0.000 claims description 7
- 239000000203 mixture Substances 0.000 description 20
- 238000009472 formulation Methods 0.000 description 17
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 10
- ZXNRTKGTQJPIJK-UHFFFAOYSA-N aniracetam Chemical compound C1=CC(OC)=CC=C1C(=O)N1C(=O)CCC1 ZXNRTKGTQJPIJK-UHFFFAOYSA-N 0.000 description 8
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000001569 carbon dioxide Substances 0.000 description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 241000282695 Saimiri Species 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000007903 gelatin capsule Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 229960003878 haloperidol Drugs 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 208000000044 Amnesia Diseases 0.000 description 2
- 208000031091 Amnestic disease Diseases 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000006986 amnesia Effects 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- 210000005069 ears Anatomy 0.000 description 2
- 230000005611 electricity Effects 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- -1 tetrahydrofuran Chemical compound 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 238000009423 ventilation Methods 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- HKMWGQRYPXHZEN-UHFFFAOYSA-N 2-[(4-methoxybenzoyl)amino]butanoic acid Chemical compound CCC(C(O)=O)NC(=O)C1=CC=C(OC)C=C1 HKMWGQRYPXHZEN-UHFFFAOYSA-N 0.000 description 1
- UAMMMFTXGWKQLG-UHFFFAOYSA-N 5-(4-methoxyphenyl)-5-oxopentanoic acid Chemical class COC1=CC=C(C(=O)CCCC(O)=O)C=C1 UAMMMFTXGWKQLG-UHFFFAOYSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000005156 Dehydration Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010020591 Hypercapnia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 241000282696 Saimiri sciureus Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000008011 inorganic excipient Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000008012 organic excipient Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229960001844 tubocurarine Drugs 0.000 description 1
- JFJZZMVDLULRGK-URLMMPGGSA-O tubocurarine Chemical compound C([C@H]1[N+](C)(C)CCC=2C=C(C(=C(OC3=CC=C(C=C3)C[C@H]3C=4C=C(C(=CC=4CCN3C)OC)O3)C=21)O)OC)C1=CC=C(O)C3=C1 JFJZZMVDLULRGK-URLMMPGGSA-O 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940072358 xylocaine Drugs 0.000 description 1
Landscapes
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は式
の4―(p―メトキシベンゾイルアミノ)酪酸に
関する。
式の化合物は式
を有し、そして価値ある薬理学的性質を有する新
規な化合物である1―(p―メトキシベンゾイ
ル)―2―ピロリジノンの製造のための中間体と
して使用することができる。
上記式の1―(p―メトキシベンゾイル)―
2―ピロリジノンは、式の化合物、すなわち、
4―(p―メトキシベンゾイルアミノ)酪酸を環
化することによつて製造することができる。
4―(p―メトキシベンゾイルアミノ)酪酸の
環化において、1モルの水が脱離し、それゆえこ
の環化には、このような脱水環化にそれ自体一般
に慣用されている方法、すなわち、加熱および/
または水脱離剤、たとえば、ポリリン酸、五塩化
リン、塩化チオニルなどによる処理を用いる。使
用する方法に依存して、該環化は不活性有機溶
媒、たとえば、芳香族炭化水素(たとえば、トル
エンなど)、エーテル(たとえば、テトラヒドロ
フランなど)、ハロゲン化炭化水素(たとえば、
クロロホルムなど)など中で行なうことが有利で
あることがある。本発明の目的であるこの4―
(p―メトキシベンゾイルアミノ)酪酸は、4―
アミノ酪酸を(たとえば、水酸化ナトリウムのよ
うな酸結合剤の存在下でp―メトキシベンゾイル
クロライドを使用して)適当にアシル化すること
によつて製造することができる。
前述のように、式の1―(p―メトキシベン
ゾイル)―2―ピロリジノンは価値ある薬理学的
性質を有する新規な化合物である。式の化合物
は毒性が極めて少なく、そして後述する動物実験
において、種々の方法で実験的に生じさせた脳不
全症(cerebral insufficiency)に拮抗作用
(counteracting)しうることが示された。
A 炭酸過剰症後の「回避」の修得
(POSTHYPERCAPNIC“AVOIDANCE”
ACQISITION)
試験結果は中央に10cmの高さの障害物と電気を
通じることができる格子の床とを有する「シヤツ
トル・ボツクス(shuttle box)」である。拡声器
が防音室内に取り付けられている。対照または試
験製剤を注射により投与してから1または3時間
後、訓練しないラツト(120〜150g;1グループ
当り10匹)を純粋な二酸化炭素の環境中に12秒間
置く。10匹のラツトの第3のグループは試験製剤
または二酸化炭素のいずれでも処理しない。二酸
化炭素で処理後3分で、すべての3グループのラ
ツトは次のプログラムにおいて「シヤツトル・ボ
ツクス」中で条件反射と非条件反射を学ばなくて
はならない:10秒の沈黙−5秒の騒音〔「回避の
応答(avoidance response)」〕−15秒の騒音+足
のシヨツク〔「逃避の応答(escape
response)」〕;6回の連続。6回の個々の実験の
おのおのに対して、各ラツトの反応時間(ラツト
が障害物を飛び越える時間)を測定し、そして
種々のグループの間の差の統計的有意性をラング
(Rang)試験により計算する。
試験製剤の「活性な」投与量は6回の個々の実
験の間で有意の活性を示す投与量である;これに
より試験製剤と二酸化炭素で処理した動物は、二
酸化炭素のみで処理した動物よりも有意によく、
そして試験製剤または二酸化炭素のいずれによつ
ても処理されない動物と同じように等しく良好に
必ず学ぶ。
B 電気シヨツク健忘症による「受動的回避」
(“PASSIVE AVOIDANCE”TEST WITH
ELECTROSHOCK AMNESIA)
試験装置は電気を通ずることができる格子の床
と1つの隅に灰色の四角のプラツトフオームとを
有するスキンナー(Skinner)・ボツクスである。
体重100〜120gの訓練しない雄のラツトを灰色の
プラツトフオーム上に置く。ラツトは格子の床上
へはい下りる時ごとに、電気シヨツクを受ける。
3〜5回の実験後、ラツトはいわゆる「受動的回
避の応答」、すなわち、プラツトフオームからは
い下りることの拒否を示す。拒否の修得の直後、
各20匹のラツトの3つのグループを形成する。1
つのグループは耳の間の電気シヨツク(45mA、
2秒)と、塩化ナトリウムの腹膜内注射とを受け
る。第2グループは耳の間の電気シヨツクと試験
製剤の腹膜内注射とを受ける。第3グループは塩
化ナトリウムのみを受ける。3時間後、各ラツト
をもう一度プラツトフオーム上に置き、そして保
持時間(最高60秒間)を測定する。2つの対照の
グループと比較した試験製剤の有意の活性をラン
グ試験により計算する。
試験製剤の「活性な」投与量は電気シヨツクに
対する有意な保護活性を示す投与量である(試験
製剤の活性投与量および電気シヨツクで処理した
動物は電気シヨツクで処理しない動物とちようど
同じように長い保持時間を示すが、これに対して
塩化ナトリウムと電気シヨツクで処理した動作は
短かい保持時間を示す)。
C リスザルによる「連続回避」プログラムにお
けるハロペリドール誘発「ノツクアウト」の抑
制
(INHIBITION OF THE
HALOPERIDOLINDUCED“KNOCK OUT”
IN A“CONTINUOUS AVOIDANCE”
PROGRAME WITH SQUIRREL
MONKEYS)
1匹ずつ収容した体重0.6〜1.2Kgの雄の訓練さ
れていないリスザル(Saimiri sciureus)を、次
の「連続回避」プログラムにおいて2レバー式の
スキンナー・ボツクス中で訓練する:「回避―シ
ヨツク」―間隔40秒;「シヨツク―シヨツク」―
間隔20秒;足―シヨツク最高5秒。正常の基本的
動作を有するリスザルにハロペリドール1.0mg/
Kg経口を投与して「ノツクアウト」時間を測定す
る(「回避」および「逃避」のブロツク)。安定な
「ノツクアウト」時間を有するリスザルを、有力
な(potential)脳不全症改善剤としての試験製
剤の評価のために選ぶ。試験製剤はハロペリドー
ルを用いる処理前の種々の時間に注射することが
できる。
試験製剤の「活性な」投与量は、ハロペリドー
ルで処理する前の投与時に、3時間の試験におい
て「ノツクアウト」時間の有意遅延を生ずる量で
ある。
D 抗酸素欠乏症(ANTI―ANOXIA TEST)
体重300〜350gの雄のラツトをこの試験に使用
する。動物をハロタン(halothane)の麻酔下に
気管切開し、そして硬膜外皮質電極(epidural
cortical electrode)をおのおの中に位置させる。
この手術の完了後、麻酔を中止し、すべての創傷
と圧力点をライドカイン(xylocaine)で浸潤し、
d―ツボクラリン(d―tubocurarine)を注入
し、そして動物を人工的に換気する。EEGをこ
の試験の全期間中連続的に記録する。酸素欠乏は
1時間の間隔で、等電のEEGに到達するまで、
99.9%の窒素で動物を換気することによつて実施
する。等電のEEGで30秒の期間後、動物を再び
正常の室内空気で換気する。
試験のパラメーターとして、次のものを定義す
る:
1 「生存時間」=ST:窒素の換気下に等電
EEGに到達するまでの時間。
2 「回復時間」=RT:室内の空気によるさら
に続けての換気と皮質
(cortex)からの最初の電気
的活性との間の時間。
試験製剤を最初の酸素欠乏の60分または120分
前に投与する。処理したラツトのST値とRT値
を、ラング試験により偽薬処理した対照と比較す
る。STの延長および/またはRTの短縮は、酸
素欠乏に対する保護活性とみなす。
試験製剤の「活性」な投与量は、有意な保護活
性を示す投与量である。
前述の試験において、非常に低い急性毒性
〔LD50>5000mg/Kg経口(マウス)〕を有する、
1―(p―メトキシベンゾイル)―2―ピロリジ
ノンは、すでに次の投与量で有意な活性を示す:
The present invention is based on the formula 4-(p-methoxybenzoylamino)butyric acid. A compound with the formula and can be used as an intermediate for the preparation of 1-(p-methoxybenzoyl)-2-pyrrolidinone, a new compound with valuable pharmacological properties. 1-(p-methoxybenzoyl)- of the above formula
2-pyrrolidinone is a compound of the formula, namely:
It can be produced by cyclizing 4-(p-methoxybenzoylamino)butyric acid. In the cyclization of 4-(p-methoxybenzoylamino)butyric acid, 1 mole of water is eliminated, and this cyclization therefore requires the methods commonly customary per se for such cyclization dehydrations, namely heating. and/
Alternatively, treatment with a water desorbing agent such as polyphosphoric acid, phosphorus pentachloride, thionyl chloride, etc. is used. Depending on the method used, the cyclization is carried out in an inert organic solvent, such as an aromatic hydrocarbon (e.g. toluene, etc.), an ether (e.g. tetrahydrofuran, etc.), a halogenated hydrocarbon (e.g.
It may be advantageous to carry out the process in a medium such as chloroform. This 4-- which is the purpose of the present invention
(p-methoxybenzoylamino)butyric acid is 4-
Aminobutyric acid can be prepared by appropriate acylation (eg, using p-methoxybenzoyl chloride in the presence of an acid binder such as sodium hydroxide). As mentioned above, the formula 1-(p-methoxybenzoyl)-2-pyrrolidinone is a novel compound with valuable pharmacological properties. The compound of the formula has very low toxicity and was shown in the animal experiments described below to be capable of counteracting experimentally induced cerebral insufficiency in various ways. A. Acquiring “AVOIDANCE” after hypercapnia (POSTHYPERCAPNIC “AVOIDANCE”)
ACQISITION) The test result is a ``shuttle box'' with a 10 cm high obstacle in the center and a grid floor capable of conducting electricity. A loudspeaker is installed inside the soundproof room. One or three hours after administration of the control or test formulation by injection, untrained rats (120-150 g; 10 per group) are placed in an environment of pure carbon dioxide for 12 seconds. A third group of 10 rats is not treated with either the test formulation or carbon dioxide. Three minutes after treatment with carbon dioxide, all three groups of rats must learn conditioned and unconditioned reflexes in the "shuttle box" with the following program: 10 seconds of silence - 5 seconds of noise. “avoidance response” - 15 seconds of noise + foot shot
6 times in a row. For each of six individual experiments, each rat's reaction time (the time it took for the rat to jump over the obstacle) was measured and the statistical significance of the differences between the various groups was determined by a Rang test. calculate. An "active" dose of a test formulation is the dose that exhibits significant activity over six individual experiments; this causes animals treated with the test formulation and carbon dioxide to have a higher level of activity than animals treated with carbon dioxide alone. is also significantly better,
and necessarily learn equally well as animals not treated with either the test formulation or carbon dioxide. B. “Passive avoidance” due to electric shock amnesia
(“PASSIVE AVOIDANCE” TEST WITH
ELECTROSHOCK AMNESIA) The test apparatus is a Skinner box with a grid floor capable of conducting electricity and a gray square platform in one corner.
Untrained male rats weighing 100-120 g are placed on a gray platform. Each time the rat crawls onto the floor of the grid, it receives an electric shock.
After 3-5 trials, the rats exhibit a so-called "passive avoidance response", ie, a refusal to crawl off the platform. Immediately after learning Denial,
Form 3 groups of 20 rats each. 1
One group is the electric shock between the ears (45mA,
2 seconds) and an intraperitoneal injection of sodium chloride. The second group will receive an electric shock between the ears and an intraperitoneal injection of the test formulation. The third group receives only sodium chloride. After 3 hours, each rat is placed on the platform again and the retention time (maximum 60 seconds) is measured. The significant activity of the test formulation compared to the two control groups is calculated by Lang's test. The "active" dose of the test formulation is the dose that exhibits significant protective activity against electric shock (the active dose of the test formulation and the animals treated with electric shock are just the same as the animals not treated with electric shock). shows long retention times, whereas motions treated with sodium chloride and electric shock show short retention times). C. Suppression of haloperidol-induced ``knockout'' in a ``continuous avoidance'' program by squirrel monkeys (INHIBITION OF THE
HALOPERIDOLINDUCED “KNOCK OUT”
IN A “CONTINUOUS AVOIDANCE”
PROGRAME WITH SQUIRREL
MONKEYS) Single untrained male squirrel monkeys (Saimiri sciureus) weighing 0.6-1.2 kg are trained in a two-lever Skinner box in the following ``continuous avoidance'' program: ``Avoidance - Shock''. ” - Interval 40 seconds; "Shotsk - shot" -
Interval 20 seconds; foot-shot maximum 5 seconds. Haloperidol 1.0 mg per day to squirrel monkeys with normal basic behavior.
Kg orally is administered and the "knockout" time is measured (blocks of "avoidance" and "escape"). Squirrel monkeys with stable "knockout" times are selected for evaluation of the test formulation as a potential brain failure ameliorating agent. Test formulations can be injected at various times prior to treatment with haloperidol. An "active" dose of a test formulation is that amount that, when administered prior to treatment with haloperidol, produces a significant delay in "knockout" time in a 3 hour test. D ANTI-ANOXIA TEST Male rats weighing 300-350 g are used for this test. The animal was tracheostomized under halothane anesthesia, and an epidural cortical electrode (epidural
cortical electrode) is placed in each.
After this surgery is completed, anesthesia is discontinued and all wounds and pressure points are infiltrated with xylocaine.
d-tubocurarine is injected and the animal is artificially ventilated. EEG is recorded continuously during the entire duration of the study. Oxygen deprivation occurs at intervals of 1 hour until reaching isoelectric EEG.
This is done by ventilating the animal with 99.9% nitrogen. After a 30 sec period with isoelectric EEG, ventilate the animal again with normal room air. The following test parameters are defined: 1 “Survival time” = ST: isoelectrically controlled under nitrogen ventilation.
Time to reach EEG. 2 "Recovery time" = RT: time between further ventilation with room air and the first electrical activation from the cortex. Test formulations are administered 60 or 120 minutes before the first oxygen deprivation. ST and RT values of treated rats are compared to placebo-treated controls by Lang's test. ST prolongation and/or RT shortening is considered a protective activity against oxygen deprivation. An "active" dose of a test formulation is a dose that exhibits significant protective activity. In the aforementioned test, it has very low acute toxicity [LD 50 >5000mg/Kg oral (mouse)].
1-(p-Methoxybenzoyl)-2-pyrrolidinone shows significant activity already at the following doses:
【表】
式の1―(p―メトキシベンゾイル)―2―
ピロリジノンは薬物として、たとえば、製剤
(pharmaceutical preparation)の形で使用でき
る。該製剤は経口的に、たとえば錠剤、被覆した
錠剤、糖剤、硬質ゼラチンカプセル剤、軟質ゼラ
チンカプセル剤、溶液、エマルジヨンまたは懸濁
液の形で投与することができる。しかしながら、
投与は経直腸的に(たとえば、坐薬の形で)、あ
るいは非経口的に(たとえば、注射溶液の形で)
行なうこともできる。
錠剤、被覆した錠剤、糖剤および硬質ゼラチン
カプセル剤の製造のためには、1―(p―メトキ
シベンゾイル)―2―ピロリジノンを製薬学的に
不活性な無機または有機の賦形剤と共に加工する
ことができる。このような賦形剤として、たとえ
ば、錠剤、糖剤および硬質ゼラチンカプセル剤に
対しては、ラクトース、トウモロコシデンプンま
たはそれらの誘導体、タルク、ステアリン酸また
はそれらの塩類などを使用することができる。
軟質ゼラチンカプセル剤のための適当な賦形剤
は、たとえば、植物油、ワツクス、油脂、半固体
および液状のポリオールなどである。
溶液およびシロツプ剤の製造に適した賦形剤
は、たとえば、水、ポリオール、サツカロール、
不活性砂糖、グルコースなどである。
注射用溶液に適した賦形剤は、たとえば、水、
アルコール、ポリオール、グリセリン、植物油な
どである。
坐薬に適した賦形剤は、たとえば、天然または
硬化した油、ワツクス、油脂、半液体または液体
のポリオールなどである。
その上、該製剤は防腐剤、溶解剤、安定剤、湿
潤剤、乳化剤、甘味剤、着色剤、香味剤、浸透圧
を変えるための塩類、緩衝剤、被覆剤または酸化
防止剤を含有することができる。該製剤はまた他
の治療上価値ある物質を含有することもできる。
式の1―(p―メトキシベンゾイル)―2―
ピロリジノンは脳不全症の抑制または予防に、あ
るいは知能力(intellectual capacity)の改善
に、たとえば脳性発作(cerebral seizure)の場
合、老人病(geriatry)、アルコール中毒
(alcoholism)などにおいて使用することができ
る。投与量は広い範囲に亘つて変えることがで
き、そして各特定の場合における個々の要件にも
ちろん適合せしめられる。一般に、経口投与の場
合において、約10mg〜2500mgの1日量の1―(p
―メトキシベンゾイル)―2―ピロリジノンが適
当でありうるが、その上限はそれが1―(p―メ
トキシベンゾイル)―2―ピロリジノンの低い毒
性を考慮して指示されたとき、容易に越えること
ができる。
次の実施例によつて本発明をさらに説明する
が、本発明はこれらの実施例に限定されるもので
はない。
実施例
10.2gのp―メトキシベンゾイルクロライド
を、よくかきまぜながら、30.9gの4―アミノ酪
酸、24.0gの水酸化ナトリウムおよび300mlのイ
オン不含水へ、30℃において一度に加える。2時
間後、この混合物を75mlの濃塩酸で10℃以下の温
度で酸性とする。沈殿を過し、イオン不含水で
洗い、乾燥炉中で65℃において五酸化リン上で乾
燥し、次いで45mlのアセトン/低沸点石油エーテ
ル(3:1)から再結晶する。融点120.5〜122℃
の4―(p―メトキシベンゾイルアミノ)酪酸が
得られる。
この4―(p―メトキシベンゾイル)酪酸は下
記の如くして1―(p―メトキシベンゾイル)―
2―ピロリジノンに変えることができる:
a 10gの五酸化リンと6mlのオルトリン酸(少
なくとも85%)を互に加温する。2.0gの4―
(p―メトキシベンゾイルアミノ)酪酸を室温
で生ずる溶液に加える。混合物を50℃に60分間
加温し、次いで氷で処理し、酢酸エチルで抽出
する。有機相を最初に冷水で、次いで冷炭酸水
素ナトリウム溶液で、最後に再び水で洗い、そ
して硫酸ナトリウム上で乾燥する。残留物をジ
エチルエーテルとともに磨砕すると、融点120
〜122℃の1―(p―メトキシベンゾイル)―
2―ピロリジノンが得られる。
b 20.0gの4―(p―メトキシベンゾイルアミ
ノ)酪酸、50mlのトルエンと9.2mlのチオニル
クロライドを還流下に2時間加熱し、次いで混
合物を脱色用木炭で処理し、蒸発させる。残留
物を塩化メチレン中に溶かし、中性の酸化アル
ミニウムでクロマトグラフ処理する。塩化メチ
レンで溶離した1―(p―メトキシベンゾイ
ル)―2―ピロリジノンをアルコールから再結
晶し、119〜120℃の融点を有する。[Table] Formula 1-(p-methoxybenzoyl)-2-
Pyrrolidinone can be used as a drug, for example in the form of a pharmaceutical preparation. The formulations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard gelatin capsules, soft gelatin capsules, solutions, emulsions or suspensions. however,
Administration can be rectally (e.g. in the form of suppositories) or parenterally (e.g. in the form of injection solutions)
You can also do it. For the production of tablets, coated tablets, dragees and hard gelatin capsules, 1-(p-methoxybenzoyl)-2-pyrrolidinone is processed with pharmaceutically inert inorganic or organic excipients. be able to. As such excipients, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof, etc. can be used for tablets, dragees and hard gelatin capsules. Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols. Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, sutucarol,
Inert sugar, glucose, etc. Suitable excipients for injectable solutions include, for example, water,
Alcohol, polyol, glycerin, vegetable oil, etc. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, and the like. In addition, the formulation may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts to modify the osmotic pressure, buffers, coating agents or antioxidants. I can do it. The formulation may also contain other therapeutically valuable substances. 1-(p-methoxybenzoyl)-2- of the formula
Pyrrolidinone can be used to suppress or prevent brain failure or to improve intellectual capacity, such as in cases of cerebral seizures, geriatry, alcoholism, etc. . The dosage can vary over a wide range and will of course be adapted to the individual requirements in each particular case. Generally, for oral administration, a daily dose of about 10 mg to 2500 mg of 1-(p
-methoxybenzoyl)-2-pyrrolidinone may be suitable, but its upper limit can be easily exceeded when it is indicated considering the low toxicity of 1-(p-methoxybenzoyl)-2-pyrrolidinone. . The present invention will be further illustrated by the following examples, but the present invention is not limited to these examples. Example 10.2 g of p-methoxybenzoyl chloride are added in one portion at 30° C. to 30.9 g of 4-aminobutyric acid, 24.0 g of sodium hydroxide and 300 ml of ion-free water with good stirring. After 2 hours, the mixture is acidified with 75 ml of concentrated hydrochloric acid at a temperature below 10°C. The precipitate is filtered, washed with ion-free water, dried over phosphorus pentoxide at 65° C. in a drying oven, and then recrystallized from 45 ml of acetone/low-boiling petroleum ether (3:1). Melting point 120.5~122℃
4-(p-methoxybenzoylamino)butyric acid is obtained. This 4-(p-methoxybenzoyl)butyric acid is converted to 1-(p-methoxybenzoyl)-
Can be converted to 2-pyrrolidinone: a. Warm together 10 g of phosphorus pentoxide and 6 ml of orthophosphoric acid (at least 85%). 2.0g of 4-
(p-methoxybenzoylamino)butyric acid is added to the resulting solution at room temperature. The mixture is warmed to 50° C. for 60 minutes, then treated with ice and extracted with ethyl acetate. The organic phase is washed first with cold water, then with cold sodium bicarbonate solution and finally again with water and dried over sodium sulfate. The residue is triturated with diethyl ether, melting point 120
1-(p-methoxybenzoyl)- at ~122℃
2-pyrrolidinone is obtained. b 20.0 g of 4-(p-methoxybenzoylamino)butyric acid, 50 ml of toluene and 9.2 ml of thionyl chloride are heated under reflux for 2 hours, then the mixture is treated with decolorizing charcoal and evaporated. The residue is dissolved in methylene chloride and chromatographed on neutral aluminum oxide. 1-(p-methoxybenzoyl)-2-pyrrolidinone, eluted with methylene chloride, is recrystallized from alcohol and has a melting point of 119-120°C.
Claims (1)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH140378 | 1978-02-10 | ||
CH1403/78 | 1978-02-10 | ||
CH11981/78 | 1978-11-22 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS6133167A JPS6133167A (en) | 1986-02-17 |
JPS6355511B2 true JPS6355511B2 (en) | 1988-11-02 |
Family
ID=4209610
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP13805385A Granted JPS6133167A (en) | 1978-02-10 | 1985-06-26 | P_methoxybenzoyl derivative |
Country Status (5)
Country | Link |
---|---|
JP (1) | JPS6133167A (en) |
ES (3) | ES483755A1 (en) |
IS (1) | IS1222B6 (en) |
MT (1) | MTP839B (en) |
ZA (1) | ZA79457B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH04104691U (en) * | 1991-02-15 | 1992-09-09 | アイエスデイ株式会社 | Suction tool |
-
1979
- 1979-01-03 MT MT839A patent/MTP839B/en unknown
- 1979-02-02 ZA ZA79457A patent/ZA79457B/en unknown
- 1979-02-09 IS IS2478A patent/IS1222B6/en unknown
- 1979-08-31 ES ES483755A patent/ES483755A1/en not_active Expired
- 1979-08-31 ES ES483757A patent/ES483757A1/en not_active Expired
- 1979-08-31 ES ES483758A patent/ES483758A1/en not_active Expired
-
1985
- 1985-06-26 JP JP13805385A patent/JPS6133167A/en active Granted
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH04104691U (en) * | 1991-02-15 | 1992-09-09 | アイエスデイ株式会社 | Suction tool |
Also Published As
Publication number | Publication date |
---|---|
IS2478A7 (en) | 1979-08-11 |
ES483755A1 (en) | 1980-09-01 |
IS1222B6 (en) | 1986-06-30 |
ES483757A1 (en) | 1980-09-01 |
ES483758A1 (en) | 1980-09-01 |
MTP839B (en) | 1980-01-24 |
ZA79457B (en) | 1980-02-27 |
JPS6133167A (en) | 1986-02-17 |
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