JPH02131454A - Oxamic acid compound and improver for cerebral function disorder - Google Patents
Oxamic acid compound and improver for cerebral function disorderInfo
- Publication number
- JPH02131454A JPH02131454A JP16994889A JP16994889A JPH02131454A JP H02131454 A JPH02131454 A JP H02131454A JP 16994889 A JP16994889 A JP 16994889A JP 16994889 A JP16994889 A JP 16994889A JP H02131454 A JPH02131454 A JP H02131454A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- acid
- carbon atoms
- acid compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- SOWBFZRMHSNYGE-UHFFFAOYSA-N Monoamide-Oxalic acid Natural products NC(=O)C(O)=O SOWBFZRMHSNYGE-UHFFFAOYSA-N 0.000 title claims abstract description 25
- -1 Oxamic acid compound Chemical class 0.000 title claims abstract description 17
- 230000002490 cerebral effect Effects 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 18
- 238000006243 chemical reaction Methods 0.000 abstract description 14
- 208000002381 Brain Hypoxia Diseases 0.000 abstract description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003960 organic solvent Substances 0.000 abstract description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 abstract description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 abstract description 2
- YMUUFPRLUJMRPK-UHFFFAOYSA-N 2-[ethyl(propyl)amino]-2-oxoacetic acid Chemical compound CCCN(CC)C(=O)C(O)=O YMUUFPRLUJMRPK-UHFFFAOYSA-N 0.000 abstract 1
- 208000018152 Cerebral disease Diseases 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000003223 protective agent Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 239000003814 drug Substances 0.000 description 18
- 229940079593 drug Drugs 0.000 description 16
- 230000005978 brain dysfunction Effects 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 206010021143 Hypoxia Diseases 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 230000001146 hypoxic effect Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 230000001681 protective effect Effects 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 208000000044 Amnesia Diseases 0.000 description 5
- 208000031091 Amnestic disease Diseases 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 230000006986 amnesia Effects 0.000 description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 230000037149 energy metabolism Effects 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 159000000001 potassium salts Chemical class 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- YKFGLGXRUVEMNF-UHFFFAOYSA-N 2-(dimethylamino)-2-oxoacetic acid Chemical compound CN(C)C(=O)C(O)=O YKFGLGXRUVEMNF-UHFFFAOYSA-N 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 206010039966 Senile dementia Diseases 0.000 description 3
- 235000011089 carbon dioxide Nutrition 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 206010027175 memory impairment Diseases 0.000 description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- CVNQWQMAEUQRCT-UHFFFAOYSA-N 2-(dibutylamino)-2-oxoacetic acid Chemical compound CCCCN(C(=O)C(O)=O)CCCC CVNQWQMAEUQRCT-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 206010002660 Anoxia Diseases 0.000 description 2
- 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 2
- 241000124008 Mammalia Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000007721 medicinal effect Effects 0.000 description 2
- 125000005394 methallyl group Chemical group 0.000 description 2
- ZXUQEPZWVQIOJE-UHFFFAOYSA-N methyl 2-chloro-2-oxoacetate Chemical compound COC(=O)C(Cl)=O ZXUQEPZWVQIOJE-UHFFFAOYSA-N 0.000 description 2
- 230000008450 motivation Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Inorganic materials O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- DCGDRZCGQSDERQ-UHFFFAOYSA-N 2-(diethylamino)-2-oxoacetic acid Chemical compound CCN(CC)C(=O)C(O)=O DCGDRZCGQSDERQ-UHFFFAOYSA-N 0.000 description 1
- JSGDDGGRQZCRFZ-UHFFFAOYSA-N 2-(dipropylamino)-2-oxoacetic acid Chemical compound CCCN(CCC)C(=O)C(O)=O JSGDDGGRQZCRFZ-UHFFFAOYSA-N 0.000 description 1
- RMOUHWPZZGSLOT-UHFFFAOYSA-N 2-(n-methylanilino)-2-oxoacetic acid Chemical compound OC(=O)C(=O)N(C)C1=CC=CC=C1 RMOUHWPZZGSLOT-UHFFFAOYSA-N 0.000 description 1
- PZKODNAVADLMMO-UHFFFAOYSA-N 2-[butyl(ethyl)amino]-2-oxoacetic acid Chemical compound CCCCN(CC)C(=O)C(O)=O PZKODNAVADLMMO-UHFFFAOYSA-N 0.000 description 1
- GUIHAIUPQZQZNV-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]-2-oxoacetic acid Chemical compound CC(C)N(C(C)C)C(=O)C(O)=O GUIHAIUPQZQZNV-UHFFFAOYSA-N 0.000 description 1
- ICGPMBQSXZEPSW-UHFFFAOYSA-N 2-oxo-2-(n-phenylanilino)acetic acid Chemical compound C=1C=CC=CC=1N(C(=O)C(=O)O)C1=CC=CC=C1 ICGPMBQSXZEPSW-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
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- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 239000004129 EU approved improving agent Substances 0.000 description 1
- 208000027534 Emotional disease Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
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- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010038669 Respiratory arrest Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
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- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
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- 150000003973 alkyl amines Chemical class 0.000 description 1
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- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
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- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
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- CZPONAUVEIVCTN-UHFFFAOYSA-M sodium;2-[ethyl(propyl)amino]-2-oxoacetate Chemical compound [Na+].CCCN(CC)C(=O)C([O-])=O CZPONAUVEIVCTN-UHFFFAOYSA-M 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
Description
【発明の詳細な説明】
(産業上の利用分野)
本発明は低酸素状態に置かれた啼乳動物の脳に起るアノ
キシア(血液酸素欠乏)に対して保護作用を有し且つこ
の保護作用をもつことから,脳内エネルギー代謝障害に
起因する脳機能障害の種々の症状を改善する医薬作用を
有する有用な新規なオキザミド酸化合物に関する.また
、本発明はこれらの新規オキザミド酸化合物及びこれと
同じ医薬作用を有する既知のオキザミド酸化合物を有効
成分とする脳機能障害改善薬に関する,更に、本発明は
新規なオキザミド酸化合物の製造法に関する。Detailed Description of the Invention (Field of Industrial Application) The present invention has a protective effect against anoxia (blood oxygen deficiency) that occurs in the brains of mammals placed in hypoxic conditions, and This invention relates to a useful new oxamidic acid compound that has medicinal effects to improve various symptoms of brain dysfunction caused by disorders of brain energy metabolism. The present invention also relates to drugs for improving brain dysfunction containing these new oxamic acid compounds and known oxamic acid compounds having the same medicinal effects as active ingredients.Furthermore, the present invention relates to a method for producing novel oxamic acid compounds. .
(従来の技術及び本発明が解決しようとする課題)高齢
化社会の到来にともない、脳血管障害や脳内エネルギー
の代謝障害が原因とされる脳機能障害に起因する老人性
痴呆症の対策が大きな社会間頭になってきており、従来
の種々の薬剤が抗痴呆薬として開発されてきた.老人性
痴呆や、脳血管障害に起因する記憶障害ならびにその障
害の発生の機序が明確にされていない現状において、有
効な薬物を見出す方法は未だ十分には確立されていない
.正常動物に記憶障害(アムネシアamnesia)を
惹起させる方法として、核酸や蛋白質の合成を阻害する
薬物や抗コリン薬の投与、あるいは脳アノキシア(an
oxia)や虚血負荷等によって惹起されたアムネシア
のモデル動物を用いて記憶障害を改善あるいは予防する
薬物の開発が試みられている。(Prior Art and Problems to be Solved by the Present Invention) With the advent of an aging society, countermeasures against senile dementia caused by brain dysfunction caused by cerebrovascular disorders and intracerebral energy metabolism disorders are becoming more and more important. It has become a major social issue, and various conventional drugs have been developed as anti-dementia drugs. At present, the mechanisms of senile dementia and memory impairment caused by cerebrovascular disorders and their occurrence are not clear, and methods for finding effective drugs have not yet been fully established. Methods of inducing memory impairment (amnesia) in normal animals include administration of drugs that inhibit nucleic acid and protein synthesis, anticholinergic drugs, or cerebral anoxia (amnesia).
Attempts have been made to develop drugs that improve or prevent memory impairment using animal model animals of amnesia induced by amnesia (amnesia) or ischemic stress.
また、致死量の青酸カリ投与により、あるいは低圧又は
常圧下で低酸素の状態下に置くことにより、即ち低酸素
負荷条件下で惹起した脳アノキシアのモデル動物を用い
て脳循環代謝又は脳内エネルギー代謝を改善する薬物の
開発も試みられている(例えば「日薬理誌」閃,323
〜328頁(1985) ;同誌86, 445〜45
6頁(1986) ;特開昭54−117468号公報
;参照)。In addition, we investigated cerebral circulation metabolism and intracerebral energy metabolism using model animals of cerebral anoxia induced under hypoxic loading conditions, such as by administering a lethal dose of potassium cyanide or by placing them under hypoxic conditions under low pressure or normal pressure. Attempts are also being made to develop drugs that improve
~328 pages (1985); Same Magazine 86, 445-45
6 (1986); see Japanese Unexamined Patent Publication No. 117468/1986).
しかし、従来提供された薬剤は、脳機能障害改善薬とし
ての効果も万全とはいい難い。このような状況下では、
従来提供された薬剤よりも更に効力が強く且つより安全
な脳機能障害改善薬の創出が要望されている。However, the drugs that have been provided so far cannot be said to be completely effective as drugs for improving brain function disorders. Under such circumstances,
There is a demand for the creation of drugs for improving brain dysfunction that are more effective and safer than the drugs that have been provided so far.
他方,特開昭54−24823号公報には、ポリマーの
安定剤又は溶剤としての用途をもつN,N−ジ置換グリ
コールアミドの製造法が記載され、その際に副生成物と
してN,N−ジ置換オキザミド酸が生成されることか記
載されているが、ここで具体的に副成されたことが確認
された化合物は、N,N−ジメチルオキザミド酸、N,
N−ジェチルオキザミド酸、N,N−ジーn−プロピル
オキザミド酸、N,N−ジーn−プチルオキザミド酸、
N,N−ジアリルオキザミド酸、N,N−シクロペンチ
ルオキザミド酸、N−メチルーN−フェニルオキザミド
酸及びN,N−ジフエニルオキザミド酸に限られている
。しかも、これらの例のN,N−ジ置換オキザミド酸の
用途や,生理活性について上記公報は記載する処がない
。更にN,N−ジイソプロビルオキザミド酸は、文献「
ジャーナル・オブ・オルガノメタリック・ケミストリー
」297巻379−390頁(1985)に記載されて
あるが、この化合物の生理活性についての記載はない。On the other hand, JP-A-54-24823 describes a method for producing N,N-disubstituted glycolamides that are used as polymer stabilizers or solvents. It is described that di-substituted oxamic acid is produced, but the compounds specifically confirmed to be produced as by-products are N,N-dimethyloxamic acid, N,N-dimethyloxamic acid,
N-jethyloxamic acid, N,N-di-n-propyloxamic acid, N,N-di-n-butyloxamic acid,
Limited to N,N-diallyloxamic acid, N,N-cyclopentyloxamic acid, N-methyl-N-phenyloxamic acid and N,N-diphenyloxamic acid. Moreover, the above-mentioned publication does not describe the uses or physiological activities of the N,N-disubstituted oxamic acids of these examples. Furthermore, N,N-diisoprobyl oxamic acid is described in the literature “
Journal of Organometallic Chemistry, Vol. 297, pp. 379-390 (1985), but there is no description of the physiological activity of this compound.
(課題を解決するための手段)
本発明の目的は,優れた脳機能障害改善の薬理作用を有
し且つ副作用のない安全な新規化合物を創成して提供す
ることにあり、また新規な脳機能障害改善薬を提供する
ことにある。前記の目的を達成するために,本発明者ら
は研究を重ねて来た.その結果、低圧性低酸素負荷条件
下に置がれて脳アノキシアを起したマウスをモデル動物
として用いる実験において、この脳アノキシア・マウス
の生存時間を有意に延長できる効果をもつ点で抗アノキ
シア作用、即ち脳アノキシアに対する保護作用を有する
化合物は、人間を含めて、晴乳動物の脳機能障害を改善
できる薬効をもつ薬物として有用乃至有望であるとの知
見を得た。そこで、本発明者らは,特開昭54−248
23号公報に記載される若干のN,N−ジアルキルオキ
ザミド酸(N,N−ジアルキルオキサミン酸ともいう)
について着目し,これらの化合物の脳アノキシアに対す
る保護作用を試験した。しかも、従来の文献に記載され
ていない新規なN,N−ジ置換オキザミド酸化合物を新
らたに合成し,これらの新規化合物についても脳アノキ
シアに対する保護作用を試験した。(Means for Solving the Problems) The purpose of the present invention is to create and provide a safe new compound that has an excellent pharmacological effect of improving brain dysfunction and has no side effects, and The aim is to provide drugs that improve disorders. In order to achieve the above objective, the present inventors have conducted repeated research. As a result, in experiments using mice that developed cerebral anoxia under hypobaric hypoxic stress conditions as model animals, the anti-anoxia effect was found to significantly prolong the survival time of these cerebral anoxia mice. In other words, it has been found that a compound having a protective effect against cerebral anoxia is useful or promising as a medicinal drug capable of improving brain dysfunction in mammals including humans. Therefore, the inventors of the present invention have proposed
Some N,N-dialkyloxamic acids (also referred to as N,N-dialkyloxamic acids) described in Publication No. 23
We focused on the following and tested the protective effects of these compounds against cerebral anoxia. In addition, novel N,N-disubstituted oxamidic acid compounds not described in conventional literature were newly synthesized, and these novel compounds were also tested for their protective effects against brain anoxia.
以上の研究と試験の結果、後記の式(Ia)で表わされ
る一群の新規なオキザミド酸化合物を包含して、後記の
式(I)で表わされるN,N−ジ置換オキザミド酸化合
物は脳アノキシアに対する保護作用を有すること及び低
毒性であるζとを発見し,また脳機能障害改善薬として
、また特に脳アノキシア保護剤として,有用であること
を期待できることを認めた.
更に、本発明者は,式(Ia)の新規化合物を工業的に
有利に製造できる方法を提供することに成功した.
従って、第1の本発明は、次式(Ia)n
(式中、R1a及びR!aは互に異なる基であり、それ
ぞれ炭素数1〜4の直鎖冬は分岐鎖状のアルキル基もし
くは炭素数2〜4のアルケニル基を示す)で表わされる
オキザミド酸化合物を要旨とするものである。As a result of the above research and tests, it has been found that N,N-disubstituted oxamic acid compounds represented by the below-mentioned formula (I), including a group of new oxamic acid compounds represented by the below-mentioned formula (Ia), have brain anoxia. They discovered that it has a protective effect against ζ and has low toxicity, and also recognized that it can be expected to be useful as a drug for improving brain dysfunction, and especially as a brain anoxia protectant. Furthermore, the present inventors have succeeded in providing a method for producing the novel compound of formula (Ia) industrially and advantageously. Therefore, the first invention is based on the following formula (Ia)n (wherein R1a and R!a are mutually different groups, and each linear group having 1 to 4 carbon atoms is a branched alkyl group or The gist thereof is an oxamidic acid compound represented by (representing an alkenyl group having 2 to 4 carbon atoms).
更に,第2の本発明は、次の一般式(1)(式中,Ri
及びR2は互に同一又は異なってもよい炭素数1〜4の
直鎖又は分岐鎖状のアルキル基もしくは炭素数2〜4の
アルケニル基を示す)で表わされるオキザミド酸化合物
を有効成分とする脳機能障害改善薬を要旨とするもので
ある。Furthermore, the second invention provides the following general formula (1) (wherein, Ri
and R2 represents a linear or branched alkyl group having 1 to 4 carbon atoms or an alkenyl group having 2 to 4 carbon atoms, which may be the same or different from each other. The main focus is drugs that improve functional disorders.
前記の式( I a)の化合物のHla及びR2″、並
びに一般式(I)の化合物の81及びR2で示される炭
素数1〜4の直鎖又は分岐鎖状のアルキル基の具体例と
しては、メチル基,エチル基、n−プロビル基、iso
−プロビル基、n−ブチル基、iso−ブチル基、Se
G−ブチル基、tart−ブチル基等が挙げられ、また
炭素数2〜4のアルケニル基の具体例としては,アリル
基,メタリル基、クロチル基等が挙げられる.
本発明による式(Ia)の新規化合物の例には、N−エ
チルーN−n−プロビルオキザミド酸及びそれのナトリ
ウム又はカリウム塩; N一エチルーN−イソプロビル
オキザミド酸及びそれのナトリウム又はカリウム塩;
N一エチルーN−n−プチルオキザミド酸及びそれのナ
トリウム又はカリウム塩;並びにN一エチルーN−イン
ブチルオキザミド酸及び牛れのナトリウム又はカリウム
塩、等がある.第2の本発明による一般式(1)の化合
物は、第1の本発明による一般式( I a)の新規化
合物を包含し、更にまた、公知のN,N−ジ置換オキザ
ミド酸のうちの適当な例として、N,N−ジメチルオキ
ザミド酸、N,N−ジエチルオキザミド酸、N,N−ジ
ーn−プロビルオキザミド酸、N,N−ジーイソプロビ
ルオキザミド酸、N,N−ジーn−プチルオキザミド酸
、N,N−ジーアリルオキザミド酸、並びにこれらのナ
トリウム又はカリウム塩も包含する。Specific examples of the straight or branched alkyl group having 1 to 4 carbon atoms represented by Hla and R2'' of the compound of formula (Ia) and 81 and R2 of the compound of general formula (I) are: , methyl group, ethyl group, n-probyl group, iso
-probyl group, n-butyl group, iso-butyl group, Se
Examples include G-butyl group and tart-butyl group, and specific examples of alkenyl groups having 2 to 4 carbon atoms include allyl group, methallyl group, crotyl group, and the like. Examples of novel compounds of formula (Ia) according to the invention include N-ethyl-N-n-probyloxamic acid and its sodium or potassium salts; N-ethyl-N-isoprobyloxamic acid and its sodium or potassium salts; sodium or potassium salt;
N-ethyl-N-n-butyloxamic acid and its sodium or potassium salt; and N-ethyl-N-imbutyloxamic acid and its sodium or potassium salt. The compounds of general formula (1) according to the second invention include novel compounds of general formula (Ia) according to the first invention, and furthermore, compounds of the general formula (Ia) according to the first invention, Suitable examples include N,N-dimethyloxamic acid, N,N-diethyloxamic acid, N,N-di-n-probyloxamic acid, N,N-diisoprobyloxamic acid. , N,N-di-n-butyloxamic acid, N,N-diallyloxamic acid, and their sodium or potassium salts.
本発明の式( I a)又は式(1)で示される化合物
の薬理学上許容される塩としては,一般に、該化合物の
カルボン酸基における医薬上許容される金属との塩類、
とくに慣用の非毒性塩、例えばナトリウム塩、カリウム
塩等のアルカリ金属塩、カルシウム塩,マグネシウム塩
等のアルカリ土類金属塩、アンモニウム塩があり、また
有機塩基との付加塩類、例えばトリエチルアミンの如き
低級アルキルアミンとの塩、ピリジン塩、エタノールア
ミン塩、トリエタノールアミン塩、ジシクロヘキシルア
ミン塩等の有機アミンとの付加塩及びリジン、アルギニ
ンのような塩基性アミノ酸との付加塩が挙げられる。The pharmacologically acceptable salts of the compound represented by formula (Ia) or formula (1) of the present invention generally include salts of the carboxylic acid group of the compound with a pharmaceutically acceptable metal;
In particular, there are customary non-toxic salts, such as alkali metal salts such as sodium salts, potassium salts, alkaline earth metal salts such as calcium salts, magnesium salts, ammonium salts, and addition salts with organic bases, such as lower salts such as triethylamine. Examples include salts with alkylamines, addition salts with organic amines such as pyridine salts, ethanolamine salts, triethanolamine salts, and dicyclohexylamine salts, and addition salts with basic amino acids such as lysine and arginine.
本発明による式(Ia)の新規化合物は以下に示す反応
式により下記の式(n)のオキザミド酸エステル化合物
を加水分解することから成る方法により製造できる。The novel compound of formula (Ia) according to the invention can be prepared by a process consisting of hydrolyzing an oxamic acid ester compound of formula (n) below according to the reaction scheme shown below.
(II ) (Ia)上記
の反応式において、Hl&及びBa&は互に異なり,そ
れぞれ炭素数1〜4の直鎖又は分岐鎖状のアル午ル基、
もしくは炭素数2〜4のアルケニル基を示し、R3は炭
素数1〜4の直鎖又は分岐鎖状の7ルキル基又はベンジ
ル基の如きアラルキル基又はフェニル基の如きアリール
基を示す。(II) (Ia) In the above reaction formula, Hl& and Ba& are different from each other, and each is a linear or branched almer group having 1 to 4 carbon atoms,
Alternatively, it represents an alkenyl group having 2 to 4 carbon atoms, and R3 represents a linear or branched heptalkyl group having 1 to 4 carbon atoms, an aralkyl group such as a benzyl group, or an aryl group such as a phenyl group.
一般式(II)で示される原料のエステル化合物のR1
I″及びRIMで示される炭素数1〜4の直鎖又は分岐
鎖状のアルキル基の具体例としては、メチル基,エチル
基、n−プロピル基. iso−プロビル基,n−ブチ
ル基、iso−ブ乏ル基、see−ブチル基、tart
−ブチル基があり、またアルケニル基の具体例としては
、アリル基,メタリル基、クロチル基等が挙げられる。R1 of the raw material ester compound represented by general formula (II)
Specific examples of linear or branched alkyl groups having 1 to 4 carbon atoms represented by I'' and RIM include methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-propyl group, n-butyl group, iso-propyl group, n-butyl group, -butol group, see-butyl group, tart
-butyl group, and specific examples of alkenyl groups include allyl group, methallyl group, crotyl group, etc.
R3で示される炭素数1〜4の直鎖又は分岐鎖状のアル
キル基の具体例としては、メチル基、エチル基、n−プ
ロビル基、iso−プロビル基,n−ブチル基、iso
−ブチル基、see−ブチル基、tert−ブチル基等
が挙げられ、またアラルキル基の例としてはベンジル又
はフェネチル基の如きフェニル−(Cエ〜C4)一アル
キル基がある。更に R3がアリール基である場合の例
には、非置換又は置換されたフェニル基がある。Specific examples of the linear or branched alkyl group having 1 to 4 carbon atoms represented by R3 include methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso
-butyl group, see-butyl group, tert-butyl group, etc. Examples of aralkyl group include phenyl-(C-C4)monoalkyl group such as benzyl or phenethyl group. Further examples of R3 being an aryl group include unsubstituted or substituted phenyl groups.
式(II)のエステル化合物の加水分解反応は、水中又
は含水有機溶媒中で塩基の存在下に−10℃〜50℃で
0.1時間から数時間行なわれる.有機溶媒としては、
メタノール、エタノール、プロパノール等のアルコール
類,又は1,4−ジオキサン、テトラヒドロフラン、ピ
リジン、等の非プロトン性溶媒が使用できる。塩基とし
ては、水酸化ナトリウム,水酸化カリウム等のアルカリ
金属の水酸化物、水酸化マグネシウム、水酸化カルシウ
ム等のアルカリ土類金属水酸化物、水酸化テトラブチル
アンモニウム、水酸化ベンジルトリメチルアンモニウム
等の第四級アンモニウム水酸化物等の第四級アンモニウ
ム水酸化物,炭酸ナトリウム、炭酸カリウム等のアルカ
リ金属の炭酸塩等,トリエチルアミンの如きトリアルキ
ルアミン.N−メチルピペリジン、4−(N,N−ジメ
チルアミ,ノ)ピリジン等の第三級アミン等が挙げられ
る.
式(II)で表わされる原料エステル化合物は,例えば
下記の式(II)で示されるアミン化合物に対して(r
V)で示される(クロロホルミル)ギ酸エステルを縮合
させる反応に従って製造される。The hydrolysis reaction of the ester compound of formula (II) is carried out in water or a water-containing organic solvent in the presence of a base at -10°C to 50°C for 0.1 to several hours. As an organic solvent,
Alcohols such as methanol, ethanol, and propanol, or aprotic solvents such as 1,4-dioxane, tetrahydrofuran, and pyridine can be used. Examples of bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide, etc. Quaternary ammonium hydroxides such as quaternary ammonium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, trialkylamines such as triethylamine. Examples include tertiary amines such as N-methylpiperidine and 4-(N,N-dimethylami,no)pyridine. The raw material ester compound represented by formula (II) is, for example, (r
It is produced according to the reaction of condensing (chloroformyl)formic acid ester shown in V).
(III) (mV)
(II)(式中、Hla. Ra&及びR3は前述
と同じ意味を有する)
次に、式(II)の原料エステルの調製を示す参考合成
例並びに式( I a)の本発明化合物の製造を示す実
施例により本発明を更に詳しく説明する.査双
マグネシウムを加えて脱水した。その后に濾過した有機
層を減圧濃縮してN一エチルーN−n−プロピルーオキ
ザミド酸メチル955mg(5.5ミリモル)を無色油
状物質として得た.
”I{−NMR, δイ直(CDCQ,):0.90
(311, dt, J=8Hz, 311z), 1
.19(3H, dt, J =7Hz,3Hz),
1.62(2H, sext, J=71{z), 3
.05〜3.53(4H, m)N一エチル−N−n−
プロビルアミンIg(11.5ミリモル)を塩化メチレ
ン30++flに加え、ドライアイス/アセトン浴で−
78℃に冷却下にかくはんしておく。ここに(クロロホ
ルミル)ギ酸メチル703mg (5.7ミリモル)を
滴下する.反応容器の温度を徐々に室温まで上げながら
2時間かくはんする。反応液を氷水にあけ、塩化メチレ
ン10vaQで抽出、10%クエン酸水溶液、水、飽和
炭酸水素ナトリウム水溶液、水、飽和食塩水の順に有機
層を洗浄し、無水硫酸ーJ文
N一エチルーN−n−プチルアミンを出発化合物として
用い,参考合成例1と同様にして表題化合物を得た.
1H−NMR,δ値(CDCI2,) :0.92(3
H, t, J=7Hz)* 1.19(3H, dt
, J=7Hz,311z), 1.15〜1.90(
4H, m), 3.50〜3.60(4H, m)去
遣1り,
N一エチルーN−n−プロビルオキザミド の去】u1
4
/
rrC,H,
N一エチルーN−n−プロビルオキザミド酸メチル87
0mg(5.0ミリモル)をメタノール201Ωに溶か
し、水浴上で水冷下に撹拌しておく.この得られた溶液
へ水酸化ナトリウム594鳳g(15ミリモル)を水l
O■Ωに溶かした水液を滴下する.滴下後に、水浴をは
ずし、室温で1時間かくはんする.反応液にIN塩酸水
溶液10mfiを加えた後,溶媒を減圧下留去する.残
渣にエタノーメBOvxQを加え、溶けない固体を濾去
する.有機層を濃縮してN一エチルーN−n−プロビル
オキザミド酸305■g(1.9ミリモル)を無色油状
物質として得た.
” H−NMR ,δ値(D,0) :0.93(3H
, t, J=7Hz), 1.22(3肌dt, J
:7Hz, 6Hz),1.40〜2.00(2}1,
m), 3.10〜3.60(2H, m)IR吸収
(cm−’, neat) :1635, 1440,
1230, 1200, 1145/
rr−C,H,
N一エチルーN−n−プチルーオキザミド酸メチルより
上記の実施例1と同様にして表題化合物を合成した.
”II−NMR.δ値(D,O,):
0.70〜1.20(3}1, II), 1.00〜
1.90(7H, m),3.41(21{, t,
J=71Iz), 3.46(2}1, q, J=7
Hz)IR吸収(am−1, neat) :1710
, 1630, 1460, 1380, 1280,
1250/
n−C3H,
N一エチルーN−n−プロビルオキザミド酸メチル47
5mg(2−75−:リモル)を,+E タ/−ルLO
ml:溶がし,得られたメタノール溶液を水冷下かく体
をしておく.水酸化ナトリウムIQmg(2.75ミリ
モル)を水51gに溶かし、この水溶液を前記メタノー
ル檀液に滴下後、その混合液を室温″!!3時間かくは
んする.反応液からメタノールを減圧で留去し、残った
水層を塩化メチレン5mMで洗浄する。水層を分離し、
減圧留去すると、N一エチルーN−n−プロビルオキザ
ミド酸ナトリウム495B(2.7ミリモル)が白色固
体として得られた.
’I−NNR,δ値(ago) :
3−75〜3−20(411− m)t 2−10〜1
−35(2H− ml)?1.50〜1.OO(311
, m), 1.20−0.75(3H, dt, J
=8Hz, 2Hz)(iso−C,HJr−N−Co
−COOHC4) N,N−ジイソプ口ビルアミンのI
g(9.9ミリモル)を塩化メチレン30@Qに加え、
ドライアイス/アセトン浴で−78℃に冷却、かくはん
しておく.ここに(クロロホノレミノレ)ギ酸メチノレ
605腸g(4.9ミリモル)を滴下する。反応容器の
温度を徐々に室温まで上げながら2時間かくはんした。(III) (mV)
(II) (wherein Hla.Ra& and R3 have the same meanings as above) Next, a reference synthesis example showing the preparation of the raw material ester of formula (II) and the production of the present compound of formula (Ia) will be described. The present invention will be explained in more detail with reference to the following examples. Magnesium was added to dehydrate the mixture. Thereafter, the filtered organic layer was concentrated under reduced pressure to obtain 955 mg (5.5 mmol) of methyl N-ethyl-N-n-propyl-oxamate as a colorless oil. "I{-NMR, δI direct (CDCQ,): 0.90
(311, dt, J=8Hz, 311z), 1
.. 19 (3H, dt, J = 7Hz, 3Hz),
1.62 (2H, sext, J=71{z), 3
.. 05-3.53(4H, m)N-ethyl-N-n-
Probylamine Ig (11.5 mmol) was added to 30++ fl of methylene chloride and dried in a dry ice/acetone bath.
Stir while cooling to 78°C. Add 703 mg (5.7 mmol) of methyl (chloroformyl)formate to this solution dropwise. Stir for 2 hours while gradually raising the temperature of the reaction vessel to room temperature. The reaction solution was poured into ice water, extracted with 10 vaQ of methylene chloride, and the organic layer was washed with a 10% aqueous citric acid solution, water, a saturated aqueous sodium bicarbonate solution, water, and saturated brine in that order, and diluted with sulfuric anhydride, ethyl chloride, and sulfuric anhydride. The title compound was obtained in the same manner as in Reference Synthesis Example 1 using n-butylamine as the starting compound. 1H-NMR, δ value (CDCI2,): 0.92 (3
H, t, J=7Hz)* 1.19(3H, dt
, J=7Hz, 311z), 1.15~1.90(
4H, m), 3.50-3.60 (4H, m) 1, N-ethyl-N-n-probyl oxamide u1
4/rrC,H,N-ethyl-N-n-methylpropyloxamate 87
Dissolve 0 mg (5.0 mmol) in methanol 201Ω and stir on a water bath while cooling with water. To this obtained solution, add 594 g (15 mmol) of sodium hydroxide to 1 liter of water.
Drop a solution of water dissolved in O■Ω. After dropping, remove the water bath and stir at room temperature for 1 hour. After adding 10 mfi of IN aqueous hydrochloric acid to the reaction solution, the solvent was distilled off under reduced pressure. Add ethanolome BOvxQ to the residue and filter off the undissolved solids. The organic layer was concentrated to obtain 305 g (1.9 mmol) of N-ethyl-N-n-probyl oxamic acid as a colorless oil. "H-NMR, δ value (D, 0): 0.93 (3H
, t, J=7Hz), 1.22 (3 skin dt, J
:7Hz, 6Hz), 1.40~2.00(2}1,
m), 3.10-3.60 (2H, m) IR absorption (cm-', neat): 1635, 1440,
The title compound was synthesized from methyl 1230, 1200, 1145/rr-C,H,N-ethyl-N-n-butyl-oxamate in the same manner as in Example 1 above. "II-NMR. δ value (D, O,): 0.70 ~ 1.20 (3}1, II), 1.00 ~
1.90 (7H, m), 3.41 (21{, t,
J=71Iz), 3.46(2}1, q, J=7
Hz) IR absorption (am-1, neat): 1710
, 1630, 1460, 1380, 1280,
1250/ n-C3H, N-ethyl-N-n-probyloxamate methyl 47
5 mg (2-75-: rimole), +E tar/- LO
ml: Dissolve and keep the resulting methanol solution cooled in water. Dissolve IQmg (2.75 mmol) of sodium hydroxide in 51 g of water, drop this aqueous solution into the methanol solution, and stir the mixture for 3 hours at room temperature. Methanol is distilled off from the reaction solution under reduced pressure. , wash the remaining aqueous layer with 5mM methylene chloride. Separate the aqueous layer,
Distillation under reduced pressure gave sodium N-ethyl-N-n-propyloxamate 495B (2.7 mmol) as a white solid. 'I-NNR, δ value (ago): 3-75 to 3-20 (411-m)t 2-10 to 1
-35 (2H-ml)? 1.50-1. OO(311
, m), 1.20-0.75 (3H, dt, J
=8Hz, 2Hz) (iso-C, HJr-N-Co
-COOHC4) I of N,N-diisopropylamine
g (9.9 mmol) to methylene chloride 30@Q,
Cool to -78°C in a dry ice/acetone bath and stir. To this, 605 g (4.9 mmol) of chloroformic acid (chlorophonoleminole) was added dropwise. The reaction vessel was stirred for 2 hours while gradually raising the temperature to room temperature.
反応液を氷水にあけ,塩化メチレン10mmで抽出した
。lO%クエン酸水溶液、水、飽和炭酸水素ナトリウム
水溶液、水、飽和食塩水の順に有機層を洗浄し,無水硫
酸マグネシウムを加えて脱水した。濾過した有機層を減
圧濃縮してN,N−ジイソプロビルオキザミド酸メチル
800mg (4.3ミリモル)を無色油状物質として
得た。The reaction solution was poured into ice water and extracted with 10 mm of methylene chloride. The organic layer was washed successively with 1O% citric acid aqueous solution, water, saturated sodium hydrogen carbonate aqueous solution, water, and saturated brine, and dehydrated by adding anhydrous magnesium sulfate. The filtered organic layer was concentrated under reduced pressure to obtain 800 mg (4.3 mmol) of methyl N,N-diisoprobyl oxamate as a colorless oil.
(a) N, N−ジイソプロビルオキザミド酸メチル
500mgをメタノール20mflに溶かし,水冷下か
くはんしておく。このメタノール溶液へIN水酸化ナト
リウム水溶液15−を滴下する。滴下後、室温で1時間
かくはんする.反応液から溶媒を減圧留去して、残留物
にIN−HCQの20mMを加え、溶けない白色沈澱を
濾取し、冷水、n−ヘキサンで洗って乾燥し、表題のN
,N−ジイソプロピルオキザミド酸180 mgを白色
固体として得た。(a) Dissolve 500 mg of methyl N,N-diisoprobyl oxamate in 20 mfl of methanol and stir under water cooling. IN aqueous sodium hydroxide solution 15- is added dropwise to this methanol solution. After addition, stir at room temperature for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, 20mM of IN-HCQ was added to the residue, and the insoluble white precipitate was collected by filtration, washed with cold water and n-hexane, dried, and the title N
, N-diisopropyloxamic acid (180 mg) was obtained as a white solid.
″H−NMR ,δ値(Cfl,00) :1−23(
61{e d= J==71Iz), 1−40(6H
,d− J==71lz),3.40〜4.00(2H
, m)
IR吸収(cn+7’, KBr) :1720, 1
565, 1370, 1230, 1190?施例4
と同様の方法でN,N−ジーn−プロビルアミンから出
発してN,N−ジーn−プロビルオキザミド酸を得た。″H-NMR, δ value (Cfl, 00): 1-23 (
61{ed= J==71Iz), 1-40(6H
, d- J==71lz), 3.40~4.00(2H
, m) IR absorption (cn+7', KBr): 1720, 1
565, 1370, 1230, 1190? Example 4
Starting from N,N-di-n-probylamine, N,N-di-n-probyl oxamic acid was obtained in the same manner as described above.
’!{−NMR,δ値CCDCQ■):0.92(61
1, t, J=7Hz), 1.30”1.90(4
H, m)3.35(2}1, t, J=71{z)
, 3.66(2H, t, J==7Hz),5.9
4(Ill, broad)
IR吸収(cm−’ ,ヌジョール):1730, 1
600, 1265, 1125(CH2=CH−CH
2),−N−CO−COOH(イ) N,N−ジアリル
アミンの1gを塩化メチレン301に加え、ドライアイ
ス/アセトン浴で−78℃に冷却下にかくはんしておく
。ここに(クロロホルミル)ギ酸メチル630mgを滴
下する.反応容器の温度を徐々に室温まで上げながら2
時間かくはんした.反応液を氷水にあけ、塩化メチレン
’10mQで抽出した。10%クエン酸水溶液,水、飽
和炭酸水素ナトリウム水溶液、水、飽和食塩水の順に有
機層を洗浄し,無水硫酸マグネシウムを加えて脱水した
.濾過した有機層を減圧濃縮してN,N−ジアリルオキ
ザミド酸メチル875mgを無色油状物質として得た.
’H−NMR,δ値(CDCI,) :3.85(31
{, s) 4.07〜4.36(4H,m), 4
.98〜5.33(4H, m),5.49〜6.00
(2H, m)
(a) N, N−ジアリルオキザミド酸メチル6ΩO
mgをメタノール20+oQに溶かし、水冷下かぐはん
しておく.このメタノール溶液にIN水酸化ナトリウム
水溶液15n+Qを滴下する.滴下後、室温で1時間撹
拌する.反応液を室温で10mQ程度まで減圧濃縮し、
IN塩酸水溶液を加えて液のpHを4にする.酢酸エチ
ル50+++Qで抽出して飽和食塩水で洗浄し、無水硫
酸マグネシウムを加えて脱水する。濾過した有機層を減
圧濃縮してN,N−ジアリルオキザミド酸460mgを
白色固体として得た.’ 11−NMR ,δ値(CD
CI,) :4.03(21L d, J =7Hz)
, 4.18(2N, d, J =711z),5.
10〜5.40(4H, m), 5.65〜5.95
(2H, m)IR吸収(cm−1,スジョール):
1735, 1640, 1500, 1420, 1
300, 1288, 1210本発明に用いる一般式
(1)の化合物の毒性を、一例として、 N,N−ジー
イソプ口ピルオ・キザミド酸について評価した。すなわ
ち、ddY系マウス(雄、5週令、体重25g)の一群
3匹に供試化合物を1000B/kgの投与量で静脈内
投与したところ、全例が生存し、本発明に用いる化合物
が低毒性であり脳機能障害改善剤として有用なことを示
している。'! {-NMR, δ value CCDCQ■): 0.92 (61
1, t, J=7Hz), 1.30"1.90 (4
H, m) 3.35 (2}1, t, J=71{z)
, 3.66 (2H, t, J==7Hz), 5.9
4 (Ill, broad) IR absorption (cm-', Nujol): 1730, 1
600, 1265, 1125 (CH2=CH-CH
2), -N-CO-COOH (a) Add 1 g of N,N-diallylamine to methylene chloride 301, and stir while cooling to -78°C in a dry ice/acetone bath. Add 630 mg of methyl (chloroformyl)formate dropwise to this. 2 while gradually raising the temperature of the reaction vessel to room temperature.
I stirred for hours. The reaction solution was poured into ice water and extracted with 10 mQ of methylene chloride. The organic layer was washed successively with 10% citric acid aqueous solution, water, saturated sodium bicarbonate aqueous solution, water, and saturated brine, and dehydrated by adding anhydrous magnesium sulfate. The filtered organic layer was concentrated under reduced pressure to obtain 875 mg of methyl N,N-diallyloxamate as a colorless oil. 'H-NMR, δ value (CDCI,): 3.85 (31
{, s) 4.07-4.36 (4H, m), 4
.. 98-5.33 (4H, m), 5.49-6.00
(2H, m) (a) Methyl N, N-diallyloxamide 6ΩO
Dissolve mg in 20+oQ methanol and keep it cooled in water. Add 15n+Q of IN sodium hydroxide aqueous solution dropwise to this methanol solution. After addition, stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure at room temperature to about 10 mQ,
Add IN aqueous hydrochloric acid to bring the pH of the solution to 4. Extract with ethyl acetate 50+++Q, wash with saturated brine, and dehydrate by adding anhydrous magnesium sulfate. The filtered organic layer was concentrated under reduced pressure to obtain 460 mg of N,N-diallyloxamic acid as a white solid. '11-NMR, δ value (CD
CI, ): 4.03 (21L d, J = 7Hz)
, 4.18 (2N, d, J = 711z), 5.
10-5.40 (4H, m), 5.65-5.95
(2H, m) IR absorption (cm-1, sujoor): 1735, 1640, 1500, 1420, 1
300, 1288, 1210 The toxicity of the compound of general formula (1) used in the present invention was evaluated for N,N-diisopropyrokizamic acid, as an example. Specifically, when the test compound was intravenously administered to a group of three ddY mice (male, 5 weeks old, body weight 25 g) at a dose of 1000 B/kg, all mice survived, indicating that the compound used in the present invention has a low It has been shown to be toxic and useful as an agent for improving brain dysfunction.
一般式(1)で示される化合物またはその塩を有効成分
として含有する脳機能障害改善剤は、主として静注等の
注射剤、カプセル剤、錠剤、散剤等の経口剤もしくは直
腸投与剤、油脂性座薬、水溶性座薬等の種々の剤形で使
用される。これらの各種製剤は通常用いられている賦形
剤、増量剤,結合剤,湿潤化剤、崩壊剤、表面活性剤、
滑沢剤,分散剤、緩衝剤,保存剤,溶解補助剤,防腐剤
、矯味矯臭剤、無痛化剤等を用いて常法によりB5製す
ることができる。製剤法の具体例は後記の実施例7〜9
によってさらに詳細に説明する。Brain dysfunction improving agents containing the compound represented by general formula (1) or a salt thereof as an active ingredient are mainly used for injections such as intravenous injection, oral or rectal preparations such as capsules, tablets, and powders, and oil-based preparations. It is used in various dosage forms such as suppositories and water-soluble suppositories. These various preparations contain commonly used excipients, fillers, binders, wetting agents, disintegrants, surfactants,
B5 can be produced by a conventional method using a lubricant, a dispersant, a buffer, a preservative, a solubilizing agent, a preservative, a flavoring agent, a soothing agent, and the like. Specific examples of the formulation method are given in Examples 7 to 9 below.
This will be explained in more detail.
式(r)の化合物の投与量は症状や年齢、性別等を考慮
して、個々の場合に応じて適宜決定されるが、通常は成
人1日あたり250〜3000mgであり、これを1日
1〜4回に分けて投与する。The dosage of the compound of formula (r) is appropriately determined depending on the individual case, taking into account the symptoms, age, gender, etc., but it is usually 250 to 3000 mg per day for adults, and this is administered once per day. Administer in ~4 doses.
以下の実施例では各種の製剤の調製法を述べるが、本発
明は何らこれらに限定されるものではない。The following Examples describe methods for preparing various formulations, but the present invention is not limited thereto.
去遼1』1
N, N−ジーイソプ口ピルオキザミド酸1重量部、乳
糖2.7重量部、コーンスターチ0.8重量部、ポリビ
ニルビロリドン0.05重景部を混合し、エタノールで
湿して常法により造粒し、乾燥及び整粒し、これに0。Mix 1 part by weight of N, N-diisopropyroxamic acid, 2.7 parts by weight of lactose, 0.8 parts by weight of cornstarch, and 0.05 parts by weight of polyvinylpyrrolidone, and moisten with ethanol. Pelletize by conventional method, dry and sieve, and add 0.
5%のステアリン酸マグネシウムを加え混合後、常法に
より1錠100mgの錠剤とする。After adding 5% magnesium stearate and mixing, each tablet is made into 100 mg tablets using a conventional method.
去JLLも
N,N−ジーイソプロビルオキザミド酸5g,マンニト
ール5gを蒸留水に溶解して1000 mnとし、常法
により除菌した後、2mQずつバイアルに分注し、凍結
乾燥する.本剤は使用に際し注射用蒸留水で溶解し注射
液とする。For JLL, 5 g of N,N-diisoprobyl oxamidic acid and 5 g of mannitol were dissolved in distilled water to make 1000 mn, and after sterilization by the usual method, 2 mQ each was dispensed into vials and freeze-dried. Before use, this drug is dissolved in distilled water for injection to form an injection solution.
災胤I
N, N−ジーイソプロビルオキザミド酸1重量部、乳
糖4重量部をよく混合し,これを50メッシュの篩で篩
別して散剤とする。1 part by weight of N,N-diisoprobyl oxamic acid and 4 parts by weight of lactose are thoroughly mixed, and the mixture is sieved through a 50 mesh sieve to obtain a powder.
k腹旌よ
減圧低酸素負荷により脳アノキシアを起したマウスの生
存時間の延長効果を指標として、一般式(1)による本
発明化合物の脳機能障害改善作用を調べた。The effect of improving brain dysfunction of the compound of the present invention according to general formula (1) was investigated using as an indicator the effect of prolonging the survival time of mice that had developed cerebral anoxia due to a vacuum-induced hypoxic load.
1群6匹(7)ddY系マウス(6週令、体重25〜3
0g)を用い,本発明の化合物(投与液量が0.1 m
Q/10gとなるように再蒸留水に溶解した)を腹腔内
に投与した,30分間後に透明な密閉容器に1匹ずつ入
れ、真空ポンプで190 mmlgに急速に減圧した。6 mice per group (7) ddY mice (6 weeks old, weight 25-3
0 g), and the compound of the present invention (administered solution volume was 0.1 m
Q/10g (dissolved in double-distilled water) was administered intraperitoneally. After 30 minutes, each animal was placed in a transparent sealed container and the pressure was rapidly reduced to 190 mmlg using a vacuum pump.
減圧開始からマウスが呼吸停止により死亡するまでの時
間を測定し,生存時間(秒)とした。The time from the start of decompression until the mouse died due to respiratory arrest was measured and defined as survival time (seconds).
薬剤を何も投与しない対照群の生存時間に対する本発明
の供試化合物投与群の生存時間の比を求め、次の表−1
に記載した。The ratio of the survival time of the test compound administration group of the present invention to the survival time of the control group to which no drug was administered was determined, and the ratio was determined in the following Table-1.
Described in.
表−1
(発明の効果)
本発明による式(1)の化合物は前記の試験例から明ら
かなように、低圧性低酸素負荷条件で惹起された脳アノ
キシアの動物の生存時間を延長することから,脳アノキ
シアに対する保護作用を有するものであり,そして脳へ
の酸素の供給を促進、脳のムダな酸素やATP消費の減
少あるいは脳のATP生成の増加作用をもつことにより
、脳のエネルギー代謝や循環を改善していることが考え
られる。Table 1 (Effects of the Invention) As is clear from the above test examples, the compound of formula (1) according to the present invention prolongs the survival time of animals with cerebral anoxia induced under hypobaric hypoxic loading conditions. , has a protective effect against cerebral anoxia, promotes the supply of oxygen to the brain, reduces wasted oxygen and ATP consumption in the brain, and increases ATP production in the brain, thereby improving brain energy metabolism. It is thought that it improves circulation.
特に臨床においては、脳梗塞後遺症や脳出血後遺症など
における意欲低下や情緒障害等の改善に有用であると考
えられる.また、本発明による式(I)の化合物は,意
欲低下を改善することが考えられることから、老人性痴
呆症破の治療薬としても効果を示すと思われる。Particularly in clinical practice, it is thought to be useful for improving motivation and emotional disorders caused by cerebral infarction and cerebral hemorrhage sequelae. Furthermore, since the compound of formula (I) according to the present invention is thought to improve motivation loss, it is thought to be effective as a therapeutic agent for senile dementia.
Claims (1)
り、それぞれ炭素数1〜4の直鎖又は分岐鎖状のアルキ
ル基もしくは炭素数2〜4のアルケニル基を示す)で表
わされる新規オキザミド酸化合物又はその薬理学的に許
容される塩。 2、一般式 ▲数式、化学式、表等があります▼( I ) (式中、R^1及びR^2は互に同一又は異なってもよ
く、炭素数1〜4の直鎖又は分岐鎖状のアルキル基もし
くは炭素数2〜4のアルケニル基を示す)で表わされる
オキザミド酸化合物又はその薬理学的に許容される塩を
有効成分とする脳機能障害改善薬。 3、一般式 ▲数式、化学式、表等があります▼(II) (式中、R^1^a及びR^2^aは互に異なる基であ
り、炭素数1〜4の直鎖又は分岐鎖状のアルキル基もし
くは炭素数2〜4のアルケニル基を示し、R^3は炭素
数1〜4の直鎖又は分岐鎖状のアルキル基、アラルキル
基又はアリール基を示す)で表わされるオキザミド酸エ
ステル化合物を加水分解することを特徴とする請求項1
に記載の式( I a)のオキザミド酸化合物の製造法。[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I a) (In the formula, R^1^a and R^2^a are mutually different groups, and each has a carbon number A novel oxamic acid compound represented by a linear or branched alkyl group having 1 to 4 carbon atoms or an alkenyl group having 2 to 4 carbon atoms, or a pharmacologically acceptable salt thereof. 2. General formulas ▲ Numerical formulas, chemical formulas, tables, etc. An oxamidic acid compound represented by (representing an alkyl group or an alkenyl group having 2 to 4 carbon atoms) or a pharmacologically acceptable salt thereof as an active ingredient. 3. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (In the formula, R^1^a and R^2^a are mutually different groups, and are straight chain or branched groups with 1 to 4 carbon atoms. Oxamide acid represented by a chain alkyl group or an alkenyl group having 2 to 4 carbon atoms, and R^3 represents a linear or branched alkyl group having 1 to 4 carbon atoms, an aralkyl group, or an aryl group. Claim 1 characterized in that the ester compound is hydrolyzed.
A method for producing an oxamic acid compound of formula (Ia) as described in .
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1169948A JPH0818979B2 (en) | 1988-07-04 | 1989-07-03 | Brain dysfunction improving drug containing oxamidic acid compound |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP63-164938 | 1988-07-04 | ||
JP16493888 | 1988-07-04 | ||
JP1169948A JPH0818979B2 (en) | 1988-07-04 | 1989-07-03 | Brain dysfunction improving drug containing oxamidic acid compound |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH02131454A true JPH02131454A (en) | 1990-05-21 |
JPH0818979B2 JPH0818979B2 (en) | 1996-02-28 |
Family
ID=26489862
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP1169948A Expired - Fee Related JPH0818979B2 (en) | 1988-07-04 | 1989-07-03 | Brain dysfunction improving drug containing oxamidic acid compound |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0818979B2 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5424823A (en) * | 1977-07-28 | 1979-02-24 | Tokuyama Soda Co Ltd | Preparation of n,n-di-substituted glycolic amide |
-
1989
- 1989-07-03 JP JP1169948A patent/JPH0818979B2/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5424823A (en) * | 1977-07-28 | 1979-02-24 | Tokuyama Soda Co Ltd | Preparation of n,n-di-substituted glycolic amide |
Also Published As
Publication number | Publication date |
---|---|
JPH0818979B2 (en) | 1996-02-28 |
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