JPH01203368A - Thioimidazole derivative - Google Patents
Thioimidazole derivativeInfo
- Publication number
- JPH01203368A JPH01203368A JP63027771A JP2777188A JPH01203368A JP H01203368 A JPH01203368 A JP H01203368A JP 63027771 A JP63027771 A JP 63027771A JP 2777188 A JP2777188 A JP 2777188A JP H01203368 A JPH01203368 A JP H01203368A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- thioimidazole
- tables
- represented
- acid addition
- 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
- ZMPAPJBFYQSNFM-UHFFFAOYSA-N 1-sulfanylimidazole Chemical class SN1C=CN=C1 ZMPAPJBFYQSNFM-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 239000002253 acid Substances 0.000 claims abstract description 38
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims description 41
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 230000000144 pharmacologic effect Effects 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 210000004556 brain Anatomy 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 33
- 150000001875 compounds Chemical class 0.000 abstract description 32
- 230000003925 brain function Effects 0.000 abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- UPWAZIFLPCUTOU-UHFFFAOYSA-N s-[(5-phenyl-1h-imidazol-2-yl)] n,n-dimethylcarbamothioate Chemical compound N1C(SC(=O)N(C)C)=NC(C=2C=CC=CC=2)=C1 UPWAZIFLPCUTOU-UHFFFAOYSA-N 0.000 abstract description 2
- -1 ethoxyl Chemical group 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 230000004083 survival effect Effects 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- XHLKOHSAWQPOFO-UHFFFAOYSA-N 5-phenyl-1h-imidazole Chemical compound N1C=NC=C1C1=CC=CC=C1 XHLKOHSAWQPOFO-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000004020 conductor Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- MIJXJOXGACCWTR-UHFFFAOYSA-N 1-(5-phenyl-2-sulfanylidene-1h-imidazol-3-yl)ethanone Chemical compound N1=C(S)N(C(=O)C)C=C1C1=CC=CC=C1 MIJXJOXGACCWTR-UHFFFAOYSA-N 0.000 description 1
- SEULWJSKCVACTH-UHFFFAOYSA-N 1-phenylimidazole Chemical compound C1=NC=CN1C1=CC=CC=C1 SEULWJSKCVACTH-UHFFFAOYSA-N 0.000 description 1
- HXVNBWAKAOHACI-UHFFFAOYSA-N 2,4-dimethyl-3-pentanone Chemical group CC(C)C(=O)C(C)C HXVNBWAKAOHACI-UHFFFAOYSA-N 0.000 description 1
- FXPJQESWXQDJOW-UHFFFAOYSA-N 4-(4-chlorophenyl)-1,3-dihydroimidazole-2-thione Chemical compound C1=CC(Cl)=CC=C1C1=CNC(=S)N1 FXPJQESWXQDJOW-UHFFFAOYSA-N 0.000 description 1
- ISOLPDRTYOTMTO-UHFFFAOYSA-N 4-phenyl-1,3-dihydroimidazole-2-thione Chemical compound N1C(S)=NC(C=2C=CC=CC=2)=C1 ISOLPDRTYOTMTO-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000004129 EU approved improving agent Substances 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- SSOARRDCGRZMSU-UHFFFAOYSA-N n,n-diethylcarbamoyl chloride;n,n-dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O.CCN(CC)C(Cl)=O SSOARRDCGRZMSU-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000001034 respiratory center Anatomy 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001457 vasomotor Effects 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (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、新規なチオイミダゾール誘導体、およびその
塩類、ならびにそれを有効成分とする医薬に関するもの
で、より詳細には、脳機能改善薬として有用なチオイミ
ダゾール誘導体、およびその薬理上許容しつる酸付加塩
、またはそれらの混合物を有効成分とする脳機能改善作
用を有する医薬に関する。Detailed Description of the Invention (Field of Industrial Application) The present invention relates to a novel thioimidazole derivative, its salts, and a medicine containing the same as an active ingredient. The present invention relates to a medicament that has a brain function improving effect and contains a useful thioimidazole derivative, a pharmacologically acceptable phosphoric acid addition salt thereof, or a mixture thereof as an active ingredient.
（従来の技術）
従来、例えばドイツ特許第２８０５１６６号、同第２８
２３１９７号、および米国特許第４２１８４５８号明細
書には、ある種のチオイミダゾール誘導体が開示されて
おり、これらの化合物は、抗菌作用及び抗バクテリヤ作
用などの薬理作用を有するものであることが知られてい
る。(Prior Art) Conventionally, for example, German Patent Nos. 2805166 and 28
No. 23197 and US Pat. No. 4,218,458 disclose certain thioimidazole derivatives, and these compounds are known to have pharmacological effects such as antibacterial and antibacterial effects. ing.
（発明の概要）
本発明のチオイミダゾ−）Ｖ誘導体は、前記従来知られ
ているチオイミダゾール誘導体とは全く異なる置換基を
有し、従来のチオイミダゾール誘導体においては知られ
ていなかった、優れた脳機能改善薬として有用である。(Summary of the Invention) The thioimidazo-)V derivative of the present invention has a completely different substituent from the previously known thioimidazole derivatives, and has an excellent brain effect that has not been known in the conventional thioimidazole derivatives. It is useful as a function-improving drug.
すなわち、本発明は、−数式［Ｉ］
［式中、ＲＩ 、 Ｒ２は低級アルキル基であるか、ま
たはＲｌ 、 Ｒ２はそれらが結合している窒素原子と
共に員数５ないし７の環を形成してもよく、その環内に
窒素原子、イオウ原子又は酸素原子を含んでいてもよく
、環の置換基として低級アルキル基、低級アルコキシ基
を有していてもよく、環の置換基が環上の隣接する炭素
上にある場合は一緒になってそれらが結合している炭素
と共にベンゼン環を形成してもよく、Ｒ３は水素原子、
低級アルキル基、シクロアルキル基、フェニル基、低級
アルキルカルボニル基、低級アルコキシカルボニル基、
低級ジアルキルアミノカルボニル基、環状アミノカルボ
ニル基もしくはハロゲン原子またはニトロ基で置換され
ていてもよいピリジル基であり、または、Ｒ２とＲ３は
ひとつのカルボニル基となって環を形成してもよく、Ｒ
４は水素原子、低級アルキル基または低級アルコキシカ
ルボニル基であり、Ｒ５は低級アルキル基、低級アルコ
キシル基、ハロゲンで置換されていてもよいフェニル基
または水素原子である。］で表わされるチオイミダゾー
ル誘導体および、その薬理上許容しつる酸付加塩、また
はそれらの混合物を有効成分とする脳機能改善作用を有
する医薬を要旨とするものである。That is, the present invention provides - formula [I] [wherein RI and R2 are lower alkyl groups, or Rl and R2 together with the nitrogen atom to which they are bonded form a 5- to 7-membered ring] The ring may contain a nitrogen atom, a sulfur atom, or an oxygen atom, and may have a lower alkyl group or a lower alkoxy group as a substituent on the ring, and the substituent on the ring may contain a nitrogen atom, a sulfur atom, or an oxygen atom. If they are on adjacent carbons, they may be combined together to form a benzene ring with the carbon to which they are bonded, R3 is a hydrogen atom,
lower alkyl group, cycloalkyl group, phenyl group, lower alkylcarbonyl group, lower alkoxycarbonyl group,
A lower dialkylaminocarbonyl group, a cyclic aminocarbonyl group, or a pyridyl group which may be substituted with a halogen atom or a nitro group, or R2 and R3 may become one carbonyl group to form a ring, R
4 is a hydrogen atom, a lower alkyl group, or a lower alkoxycarbonyl group, and R5 is a lower alkyl group, a lower alkoxyl group, a phenyl group optionally substituted with halogen, or a hydrogen atom. The gist of this invention is a medicament having a brain function-improving effect that contains as active ingredients a thioimidazole derivative represented by the following formula, a pharmacologically acceptable phosphoric acid addition salt thereof, or a mixture thereof.
上記チオイミダゾール誘導体において、式［Ｉコ中のＲ
１、Ｒ２、Ｒ３、Ｒ４およびＲ５が示す低級アルキル基
としては、メチル基、エチル基、プロピル基、イソプロ
ピル基、ブチル基、イソブチル基、ｔ−ブチル基などを
例示することができ、Ｒ３のシクロアルキル基としては
シクロペンチル基、シクロヘキシル基、シクロへブチル
基などを例示することができ、Ｒ３，Ｒ５の置換基とし
てのハロゲン原子としては、塩素原子、臭素原子、フッ
素原子などを例示することができ、Ｒｌ 、 Ｒ２およ
びＲ５の低級アルコキシル基としてはメトキシル基、エ
トキシル基、プロポキシル基、イソプロポキシル基、ブ
トキシル基などを例示することができ、Ｒ３の低級アル
キルカルボニル基としてはアセチル基、プロピオニル基
、イソプロピオニル基、ブチロイル基などを例示するこ
とができ、低級アルコキシカルボニル基としてはメトキ
シカルボニル基、エトキシカルボニル基、プロポキシカ
ルボニル基、イソプロポキシカルボニル基、ブトキシカ
ルボニル基などを例示することができ、低級ジアルキル
アミノカルボニル基としてはジメチルアミノカルボニル
基、ジエチルアミノカルボニル基、ジプロピルアミノカ
ルボニル基、ジイソプロピルカルボニル基、ジブチルア
ミノカルボニル基などを例示することができ、環状アミ
ノカルボニル基としてはピロリジノカルボニル基、ピペ
リジノカルボニル基などを例示することができる。In the above thioimidazole derivative, R in the formula [I
Examples of lower alkyl groups represented by 1, R2, R3, R4, and R5 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl groups. Examples of the alkyl group include a cyclopentyl group, cyclohexyl group, and cyclohebutyl group. Examples of the halogen atom as a substituent for R3 and R5 include a chlorine atom, a bromine atom, and a fluorine atom. Examples of lower alkoxyl groups for , Rl, R2 and R5 include methoxyl, ethoxyl, propoxyl, isopropoxyl and butoxyl groups, and lower alkylcarbonyl groups for R3 include acetyl and propionyl groups. , isopropionyl group, butyroyl group, etc. Examples of the lower alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, etc. Examples of the dialkylaminocarbonyl group include dimethylaminocarbonyl group, diethylaminocarbonyl group, dipropylaminocarbonyl group, diisopropylcarbonyl group, and dibutylaminocarbonyl group, and examples of the cyclic aminocarbonyl group include pyrrolidinocarbonyl group and piperidinocarbonyl group. Examples include a nocarbonyl group.
本発明の化合物は、遊離の状態であっても、塩の形、た
とえば酸付加塩の形になっていてもよい。酸付加塩とし
ては、塩化物、臭化物、硫酸塩、硝酸塩、燐酸塩、スル
ホン酸塩、蟻酸塩、酒石酸塩、マレイン酸塩、クエン酸
塩、安息香酸塩、サリチル酸塩、アスコルビン酸塩など
の薬理上許容しつる酸付加塩を例示することができる。The compounds of the invention may be in the free state or in the form of a salt, such as an acid addition salt. Acid addition salts include chloride, bromide, sulfate, nitrate, phosphate, sulfonate, formate, tartrate, maleate, citrate, benzoate, salicylate, and ascorbate. The above-accepted vine acid addition salts can be exemplified.
（作 用）
本発明のチオイミダゾール話導体およびその酸付加塩は
、単独、あるいは混合物の形で優れた抗脳虚血作用およ
び抗低圧低酸素作用を示し、脳機能改善剤として有用で
ある。該化合物は、それ自体を単独で投与してもよいが
、必要に応じて種々の剤型として、経口的または非経口
的に投与することができる。(Function) The thioimidazole conductor and its acid addition salt of the present invention, alone or in the form of a mixture, exhibit excellent anti-cerebral ischemic activity and anti-low pressure hypoxic activity, and are useful as brain function improving agents. The compound itself may be administered alone, but it can also be administered orally or parenterally in various dosage forms as required.
（好適態様の説明）
本発明のチオイミダゾール話導体を表１に具体的に例示
する。(Description of preferred embodiments) Table 1 specifically illustrates the thioimidazole conductors of the present invention.
表 １
表 １（続き）
表 １ （絖き）
表 １（続き）
表 １（続き）
［製造方法］
本発明の上記−数式［１１で表わされる新規なチオイミ
ダゾール誘導体は次の反応式に従って製造することがで
きる。Table 1 Table 1 (Continued) Table 1 (Continued) Table 1 (Continued) Table 1 (Continued) [Production method] The novel thioimidazole derivative represented by the above-mentioned formula [11] of the present invention is produced according to the following reaction formula. can do.
［ｎ ］ ［ＩＩＩ ］ＯＨ
［ＩＶ］
［ＩＶ］ ＋ Ｒ３Ｃｊ２ − ［Ｉ ］ ・
（１）［■］ ［■］
Ｒ３
［■コ
（式［！Ｉ］乃至［■］におけるＲ１〜Ｒｆｉの定義は
、式［Ｉコと同じである。）
（１）化合物［Ｉ］のＲ３がアルキルカルボニル基、ア
ルコキシカルボニル基、ジアルキルアミノカルボニル基
の場合は、化合物［ＩＩ ］と［ＩＩＩ ］を炭酸カリ
ウム、炭酸ナトリウム、水酸化ナトリウム、水酸化カリ
ウム、ｔ−ブトキシカリウムなどの無機塩基またはピリ
ジン、トリエチルアミンなどの有機塩基存在下、不活性
溶媒中または前述の有機塩基を溶媒として０℃から２０
０℃、好ましくは室温から１５０℃で反応させ化合物〔
■］を得た後、これと［Ｖ］を再び上記と同様な条件で
反応させることによって化合物［１］が得られる。[n] [III]OH [IV] [IV] + R3Cj2 - [I] ・
(1) [■] [■] R3 [■co (The definitions of R1 to Rfi in formulas [!I] to [■] are the same as in formula [Ico.) (1) R3 of compound [I] is an alkylcarbonyl group, an alkoxycarbonyl group, or a dialkylaminocarbonyl group, compounds [II] and [III] can be treated with an inorganic base such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, or t-butoxypotassium, or with pyridine. , in the presence of an organic base such as triethylamine, in an inert solvent or using the above-mentioned organic base as a solvent from 0°C to 20°C.
The compound [
[2]] is then reacted with [V] again under the same conditions as above to obtain compound [1].
（２）化合物［Ｉ］のＲ２，Ｒ３がひとつのカルボニル
基となって環を形成している場合は化合物［ＶＩ］と［
■］をＮ、Ｎ−ジメチルホルムアミドなどの不活性溶媒
中、トリエチルアミンなどの有機塩基存在下で０℃から
１００℃、好ましくは室温から５０℃で反応させること
によって化合物［１］が得られる。(2) When R2 and R3 of compound [I] become one carbonyl group to form a ring, compound [VI] and [
Compound [1] can be obtained by reacting [1]] in an inert solvent such as N,N-dimethylformamide in the presence of an organic base such as triethylamine at a temperature of 0°C to 100°C, preferably room temperature to 50°C.
（３）その他の場合は化合物［■］と［ＩＩＩ ］を炭
酸カリウム、炭酸ナトリウム、水酸化ナトリウム、水酸
化カリウムなどの無機塩基またはピリジン、トリエチル
アミンなどの有機塩基存在下、不活性溶媒中または前述
の有機塩基を溶媒として０℃から２００℃、好ましくは
室温から１５０℃で反応させることによって化合物［１
］が得られる。(3) In other cases, compounds [■] and [III] are mixed in the presence of an inorganic base such as potassium carbonate, sodium carbonate, sodium hydroxide, or potassium hydroxide, or an organic base such as pyridine or triethylamine, in an inert solvent or as described above. The compound [1
] is obtained.
原料として使用される、上記式［ＩＩ ］、［ＶＩ］及
び［■］で表わされる化合物として具体的には、
２−メルカプトイミダゾール
２−メルカプト−４−フェニルイミダゾール１−アセチ
ル−４−フェニル−２−メルカプトイミダゾール
２−メルカプト−４−（２−メチルフェニル）イミダゾ
ール
２−メルカプト−４−（４−メトキシフェニル）イミダ
ゾール
２−メルカプト−４−（４−クロロフェニル）イミダゾ
ール
２−メルカプト−４−（ｐ−ビフエニル）イミダゾール
等が例示され、
式［ＩＩＩ ］で表わされる化合物として具体的には、
Ｎ、Ｎ−ジメチルカルバモイルクロリドＮ、Ｎ−ジエチ
ルカルバモイルクロリドＮ、Ｎ−ジ−ｎ−プロピルカル
バモイルクロリド１−ピペリジルカルボニルクロリド
モルホリノカルボニルクロリド
チオモルホリノカルボニルクロリド
１．２．：１．４−テトラヒドロキノリルカルボニルク
ロリド
等が例示される。Specifically, the compounds represented by the above formulas [II], [VI] and [■] used as raw materials include 2-mercaptoimidazole 2-mercapto-4-phenylimidazole 1-acetyl-4-phenyl-2 -Mercapto-imidazole 2-mercapto-4-(2-methylphenyl)imidazole 2-mercapto-4-(4-methoxyphenyl)imidazole 2-mercapto-4-(4-chlorophenyl)imidazole 2-mercapto-4-(p- Biphenyl)imidazole, etc. are exemplified, and specific examples of the compound represented by the formula [III] include N,N-dimethylcarbamoyl chloride N, N-diethylcarbamoyl chloride N, and N-di-n-propylcarbamoyl chloride 1-piperidyl. Carbonyl chloride morpholino carbonyl chloride thiomorpholino carbonyl chloride 1.2. :1.4-Tetrahydroquinolylcarbonyl chloride and the like are exemplified.
（実施例） 以下、実施例により本発明を具体的に説明する。(Example) Hereinafter, the present invention will be specifically explained with reference to Examples.
実施例１
２−メルカプト−４−フェニルイミダゾール５．０ ｇ
（２８，４ミリモル）をピリジン５０＋ａｊ！に：溶
解し、Ｎ、Ｎ−ジメチルカルバモイルクロリド３，１３
ｍｊｌ （３４，１ミリモル）ヲ加え、７０℃で３時間
加熱した。これを減圧下濃縮して、水２００１１１Ｊ２
、クロロホルム２００ｍｊ！を加えて抽出した。クロロ
ホルム層を濃縮した後、エタノールから再結晶し、目的
物である２−（Ｎ、Ｎ−ジメチルカルバモイルチオ）−
４−フェニルイミダゾール（化合物番号１）を無色結晶
として２．４ ｇ （収率３４％）得た。Example 1 2-mercapto-4-phenylimidazole 5.0 g
(28.4 mmol) in pyridine 50+aj! In: Dissolve N,N-dimethylcarbamoyl chloride 3,13
mjl (34.1 mmol) was added and heated at 70°C for 3 hours. This was concentrated under reduced pressure to obtain water 200111J2.
, chloroform 200mj! was added and extracted. After concentrating the chloroform layer, it was recrystallized from ethanol to obtain the target product, 2-(N,N-dimethylcarbamoylthio)-
2.4 g (yield 34%) of 4-phenylimidazole (compound number 1) was obtained as colorless crystals.
融点 １８３〜１８５℃
ＩＨ−核磁気共鳴スペクトル（重クロロホルム、δｐｐ
ｍ ）
３．０８（Ｓ、６Ｈ）、 ７．３０（０１，３Ｈ）
７．７０（ｍ、３）１）以下同様にして前記化合物番号
の置換基の異なる化合物を反応せしめ、化合物番号２〜
７，１４〜３０を合成した。その収率および物性を表２
に示した。Melting point 183-185°C IH-nuclear magnetic resonance spectrum (deuterochloroform, δpp
m) 3.08 (S, 6H), 7.30 (01, 3H)
7.70 (m, 3) 1) In the same manner, react the compounds with different substituents of the above compound number to form compound numbers 2 to 7.70(m,3)1)
7,14-30 were synthesized. Table 2 shows the yield and physical properties.
It was shown to.
表２
表 ２（続き）
表 ２（続き）
実施例２
２− （Ｎ、Ｎ−ジメチルカルバモイルチオ）−４＝フ
ェニルイミダゾール０．２５ｇ （１，０ミリモル）の
１０ ｎｕ Ｎ、Ｎ−ジメチルホルムアミド溶液に水素
化ナトリウム０．０４ｇ （１，０ミリモル）を加え、
室温で１時間攪拌した。これに２−クロロ−５−二トロ
ビリジン０．１６ｇ （１，０ミリモル）を加え、室温
で３時間攪拌した。これを減圧下濃縮し、次に水、酢酸
エチルで洗浄し、目的物である２−（Ｎ、Ｎ−ジメチル
カルバモイルチオ）−１−（５−ニトロピリジニル）−
４−フェニルイミダゾール（化合物番号８）を黄色粉末
として０．２７ｇ （収率７３％）得た。Table 2 Table 2 (continued) Table 2 (continued) Example 2 A solution of 0.25 g (1.0 mmol) of 2-(N,N-dimethylcarbamoylthio)-4=phenylimidazole in 10 nu N,N-dimethylformamide Add 0.04 g (1.0 mmol) of sodium hydride to
Stirred at room temperature for 1 hour. To this was added 0.16 g (1.0 mmol) of 2-chloro-5-nitroviridine, and the mixture was stirred at room temperature for 3 hours. This was concentrated under reduced pressure, then washed with water and ethyl acetate, and the desired product, 2-(N,N-dimethylcarbamoylthio)-1-(5-nitropyridinyl)-
0.27 g (yield 73%) of 4-phenylimidazole (compound number 8) was obtained as a yellow powder.
融点 ２００〜２０１℃
１Ｈ−核磁気共鳴スペクトル（重ジメチルスルホキシド
δｐｐｍ ）
２．６０（ｂｒ、ｓ、８１（）、 ７．４０〜７．７
０（４Ｈ，ｍ）７．８０〜８．０（２）１．ｍ）、
１３．１６（ＩＨ，ｍ）。Melting point 200-201°C 1H-nuclear magnetic resonance spectrum (deuterium dimethyl sulfoxide δppm) 2.60 (br, s, 81(), 7.40-7.7
0 (4H, m) 7.80-8.0 (2) 1. m),
13.16 (IH, m).
８．５２（ＩＨ，ｄ、Ｊ−８Ｈｚ）、 ９．２０（Ｌ
Ｈ，ｍ）同様にして前記化合物番号の置換基の異なる化
合物を反応せしめ、化合物番号９，３１．３２を得た。8.52 (IH, d, J-8Hz), 9.20 (L
H, m) Compounds with different substituents of the above compound number were reacted in the same manner to obtain compound number 9, 31.32.
その収率および物性を表３に示した。The yield and physical properties are shown in Table 3.
表３
実施例３
２− （Ｎ、Ｎ−ジメチルカルバモイルチオ）−４−フ
ェニルイミダゾール０．７０ｇ （２，８４ミリモル）
をピリジン５ ｒｎＪｌに溶解し、Ｎ、Ｎ−ジメチルカ
ルバモイルクロリド０．２８ ｎＪ！ （２，１３４ミ
リモル）を加え、１２０℃で５時間加熱した。これを減
圧下濃縮して、水２０ ｍｌ、クロロホルム２０ｍＪ２
を加えて抽出した。クロロホルム層を乾燥後、減圧下濃
縮し、目的物である１−（Ｎ、Ｎ−ジメチルカルバモイ
ル）−２−（Ｎ、Ｎ−ジメチルカルバモイルチオ）−４
−フェニルイミダゾール（化合物番号１０）を淡褐色油
状物として０．９ ｇ （収率１００％）得た。Table 3 Example 3 2-(N,N-dimethylcarbamoylthio)-4-phenylimidazole 0.70 g (2,84 mmol)
was dissolved in 5 rnJl of pyridine and 0.28 nJ! of N,N-dimethylcarbamoyl chloride! (2,134 mmol) was added and heated at 120°C for 5 hours. Concentrate this under reduced pressure and add 20 ml of water and 20 mJ of chloroform.
was added and extracted. After drying the chloroform layer, it was concentrated under reduced pressure to obtain the target product 1-(N,N-dimethylcarbamoyl)-2-(N,N-dimethylcarbamoylthio)-4.
-Phenylimidazole (Compound No. 10) was obtained as a light brown oil in an amount of 0.9 g (yield: 100%).
’Ｈ−核磁気共鳴スベクトル（重クロロホルム、δｐｐ
ｍ ）
３．０２（６Ｎ、ｓ）、３．０８（６Ｈ，ｓ） ７．
１〜７．６（４Ｈ，ｍ）。'H-nuclear magnetic resonance vector (deuterochloroform, δpp
m) 3.02 (6N, s), 3.08 (6H, s) 7.
1-7.6 (4H, m).
７．８０（２）１．ｍ）
同様にして前記化合物番号の置換基の異なる化合物を反
応せしめ、化合物番号１１，１２．１３を得た。その収
率および物性を表４に示した。7.80(2)1. m) Compounds with different substituents of the above compound numbers were reacted in the same manner to obtain compound numbers 11, 12.13. The yield and physical properties are shown in Table 4.
表４
実施例４
の製造
１−アセチル−４−フェニル−２−メルカプトイミダゾ
ール０．６ ｇ （２，７５ミリモル）をＮ、Ｎ−ジメ
チルホルムアミド１０ｍ１に溶解し、トリエチルアミン
１．０ ｔａｉｌを加えた。これにメチルイソシアネ
ート０．６５ ｍｌ！ （１０，９ミリモル）を加え、
室温で終夜攪拌した。これに木２０＋＋＋Ｊｌを加え、
１時間攪拌後、結晶をろ過し、目的物である３−メチル
−７−フェニル−１，３，５−チアシアジノ（３，２−
ａ］イミダゾール−２，４（３）１）−ジオン（化合物
番号３３）を０．４ ｇ （収率５６％）得た。Table 4 Preparation of Example 4 0.6 g (2.75 mmol) of 1-acetyl-4-phenyl-2-mercaptoimidazole was dissolved in 10 ml of N,N-dimethylformamide, and 1.0 tail of triethylamine was added. Add 0.65 ml of methyl isocyanate to this! (10,9 mmol) was added,
Stirred overnight at room temperature. Add wood 20+++Jl to this,
After stirring for 1 hour, the crystals were filtered to obtain the target product, 3-methyl-7-phenyl-1,3,5-thiacyazino(3,2-
a] 0.4 g (yield 56%) of imidazole-2,4(3)1)-dione (compound number 33) was obtained.
融点 ２２８〜２２９℃
＋Ｈ〜核磁気共鳴スペクトル（３１クロロホルム、δｐ
ｐｍ ）
３．４０（３Ｈ，ｓ）、 ７．５０（３Ｈ，ｎ＋）、
８．０（２８，ｍ）。Melting point 228-229℃ +H~Nuclear magnetic resonance spectrum (31 chloroform, δp
pm) 3.40 (3H, s), 7.50 (3H, n+),
8.0 (28, m).
８．５８ （１Ｂ、ｓ） 。8.58 (1B, s).
同様にして前記化合物番号の置換基の異なる化金物を反
応せしめ、化合物番号３４を無色結晶として得た。（収
率１６％）。Similarly, metal compounds having different substituents of the above compound number were reacted to obtain compound number 34 as colorless crystals. (Yield 16%).
融点 ２１３〜２１５℃
ＩＨ−核磁気共鳴スペクトル（重クロロホルム、δｐｐ
ｍ ）
１．３５（３Ｈ，ｔ、Ｊ＝７．２８ｘ）、 ４．２０
（２８，ｑ、Ｊ−７，２Ｈｚ）７．４０（３Ｈ，ｍ）、
７．８０（２Ｈ，ｍ）、 ８．０４（１）１．ｓ）次
に、上記化合物（化合物番号１乃至３４）について、抗
ハイボキシア作用の評価結果を延命率（比）として下記
表５に示した。なお、抗ハイボキシア作用の評価は次の
方法によって行なった。Melting point 213-215°C IH-nuclear magnetic resonance spectrum (deuterochloroform, δpp
m) 1.35 (3H, t, J=7.28x), 4.20
(28, q, J-7, 2Hz) 7.40 (3H, m),
7.80 (2H, m), 8.04 (1) 1. s) Next, the evaluation results of the anti-hyboxia effect of the above compounds (compound numbers 1 to 34) are shown in Table 5 below as survival prolongation rates (ratios). The anti-hyboxia effect was evaluated by the following method.
評価方法
材料および方法
５〜８週令のｄｄＹ系雄性マウスを１群７〜１０匹とし
て用いた。被検薬物は生理食塩液に溶解するか、あるい
は、不溶性のものは、１％アラビアゴム゛に懸濁し、２
５ 、ｍｇ／ｋｇを腹腔内に投与した。Evaluation Method Materials and Methods DDY male mice aged 5 to 8 weeks were used in groups of 7 to 10 mice. The test drug is dissolved in physiological saline, or if it is insoluble, it is suspended in 1% gum arabic.
5, mg/kg was administered intraperitoneally.
投与３０分後にマウスをデシケータ（容量：１１）内に
１匹ずつ入れ、真空ポンプでデシケータ内を１８０ ｍ
ｍＨｇまで減圧した。30 minutes after administration, mice were placed one by one in a desiccator (capacity: 11), and the inside of the desiccator was moved 180 m using a vacuum pump.
The pressure was reduced to mHg.
減圧開始から、呼吸停止までの時間を生存時間とし、１
５分以上生存した場合は、１５分として計算した。The survival time is the time from the start of decompression to the stop of breathing, and is 1
If the animal survived for more than 5 minutes, it was calculated as 15 minutes.
なお、生存時間の有意差検定は、生理食塩液投与群を対
照として、５ｔｕｄｅｎｔ １−ｔｅｓｔを用いた。そ
れらの結果から生食投与群の生存時間に対する薬物投与
群の生存時間の比を求め、延命率（比）とした。In addition, for the significant difference test of survival time, 5student 1-test was used with the physiological saline administration group as a control. From these results, the ratio of the survival time of the drug-administered group to the survival time of the saline-administered group was determined, and this was defined as the survival rate (ratio).
次に、延命率と脳機能改善との関係について説明する。Next, the relationship between life extension rate and brain function improvement will be explained.
脳は酸素不足（ハイホキシア）に対して最も抵抗性の弱
い組織である。減圧により酸素濃度を低下させる（ｈｙ
ｐｏｂａｒｉｃ ｈｙｐｏｘｉａ 、高い山に登った時
の状態）と、脳細胞機能（電気的興奮や伝達物質の合成
、分泌能など）が低下する。その為、生命維持に重要な
脳幹部（呼吸中枢や血管運動中枢などが存在する）機能
も低下し、動物は死に至る。したがって、脳機能改善作
用をもつ薬物は延命率も改善する。The brain is the tissue with the least resistance to oxygen deprivation (hyphoxia). Reduce oxygen concentration by reducing pressure (hy
pobaric hypoxia (the state you get when you climb a high mountain) and brain cell function (electrical excitation, transmitter synthesis, secretory ability, etc.) decline. As a result, the functions of the brain stem (home to the respiratory center, vasomotor center, etc.), which are important for life support, also decline, leading to the animal's death. Therefore, drugs that improve brain function also improve survival rates.
なお、抗ハイボキシア作用とは、ハイホキシア負荷によ
り死亡までの時間を延長させる薬物の効果をいう。Note that the antihypoxia effect refers to the effect of a drug that prolongs the time until death due to hyperxia loading.
表５
傘車 投与量５０ｍｇ／ｋｇの値
手続補正書（０釦
平成 １年 １月１１日
特許庁長官 吉 １）文 毅 殿
１、事件の表示
昭和６３年特許願第２７７７１号
事件との関係 特許出願人
住所 東京都千代田区霞が関三丁目２番５号名称 （５
８８）三井石油化学工業株式会社４、代理人〒１０５
７、補正の内容
（１）明細書第３０頁下から３行の式
％式％Table 5 Umbrella Car Dosage 50mg/kg Value Procedural Amendment (0 Button January 11, 1999 Director General of the Patent Office Yoshi 1) Moon Takeshi 1, Incident Indication Relationship with Patent Application No. 27771 of 1988 Patent applicant address: 3-2-5 Kasumigaseki, Chiyoda-ku, Tokyo Name (5
88) Mitsui Petrochemical Industries Co., Ltd. 4, Agent 〒105 7. Contents of amendment (1) Formula % formula % in the 3rd line from the bottom of page 30 of the specification
Claims (33)
たはＲ＾１、Ｒ＾２はそれらが結合している窒素原子と
共に員数５ないし７の環を形成してもよく、その環内に
窒素原子、イオウ原子又は酸素原子を含んでいてもよく
、環の置換基として低級アルキル基、低級アルコキシ基
を有していてもよく、環の置換基が環上の隣接する炭素
上にある場合は一緒になってそれらが結合している炭素
と共にベンゼン環を形成してもよく、Ｒ＾３は水素原子
、低級アルキル基、シクロアルキル基、フェニル基、低
級アルキルカルボニル基、低級アルコキシカルボニル基
、低級ジアルキルアミノカルボニル基、環状アミノカル
ボニル基もしくはハロゲン原子またはニトロ基で置換さ
れていてもよいピリジル基であり、または、Ｒ＾２とＲ
＾３はひとつのカルボニル基となって環を形成してもよ
く、Ｒ＾４は水素原子、低級アルキル基または低級アル
コキシカルボニル基であり、Ｒ＾５は低級アルキル基、
低級アルコキシル基、ハロゲンで置換されていてもよい
フェニル基または水素原子である。］で表わされるチオ
イミダゾール誘導体、およびその薬理上許容しうる酸付
加塩。(1) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, R^1 and R^2 are lower alkyl groups, or R^1 and R^2 are their may form a ring having 5 to 7 members with the nitrogen atom to which it is bonded, and the ring may contain a nitrogen atom, sulfur atom, or oxygen atom, and as a substituent of the ring, a lower alkyl group, a lower It may have an alkoxy group, and if the ring substituents are on adjacent carbons on the ring, they may be taken together to form a benzene ring with the carbon to which they are bonded, R^3 is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower dialkylaminocarbonyl group, a cyclic aminocarbonyl group, or a pyridyl group which may be substituted with a halogen atom or a nitro group. or R^2 and R
^3 may become one carbonyl group to form a ring, R^4 is a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group, R^5 is a lower alkyl group,
It is a lower alkoxyl group, a phenyl group which may be substituted with halogen, or a hydrogen atom. ] A thioimidazole derivative represented by the following, and a pharmacologically acceptable acid addition salt thereof.
される請求項１記載のチオイミダゾール誘導体およびそ
の薬理上許容しうる酸付加塩。(2) The thioimidazole derivative according to claim 1 represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein R^1 to R^4 are the same as formula [I]) and its pharmacologically acceptable Possible acid addition salts.
される請求項１記載のチオイミダゾール誘導体、および
その薬理上許容しうる酸付加塩。(3) The thioimidazole derivative according to claim 1, which is represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein R^1 to R^4 are the same as formula [I]), and its pharmacological Acceptable acid addition salts.
される請求項１記載のチオイミダゾール誘導体、および
その薬理上許容しうる酸付加塩。(4) The thioimidazole derivative according to claim 1, which is represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R^1 to R^4 are the same as formula [I]), and its pharmacological Acceptable acid addition salts.
される請求項１記載のチオイミダゾール誘導体、および
その薬理上許容しうる酸付加塩。(5) The thioimidazole derivative according to claim 1, which is represented by the general formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ (wherein R^1 to R^4 are the same as formula [I]), and its pharmacological Acceptable acid addition salts.
される請求項１記載のチオイミダゾール誘導体、および
その薬理上許容しうる酸付加塩。(6) The thioimidazole derivative according to claim 1, which is represented by the general formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ (wherein R^1 to R^4 are the same as formula [I]), and its pharmacological Acceptable acid addition salts.
される請求項１記載のチオイミダゾール誘導体、および
その薬理上許容しうる酸付加塩。(7) The thioimidazole derivative according to claim 1, which is represented by the general formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ (wherein R^1 to R^4 are the same as formula [I]), and its pharmacological Acceptable acid addition salts.
される請求項１記載のチオイミダゾール誘導体、および
その薬理上許容しうる酸付加塩。(8) The thioimidazole derivative according to claim 1, which is represented by the general formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ (wherein R^1 to R^4 are the same as formula [I]), and its pharmacological Acceptable acid addition salts.
同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(9) The thioimidazole derivative according to claim 1, which is represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 to R^3 and R^5 are the same as the formula [I])
and pharmacologically acceptable acid addition salts thereof.
同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(10) The thioimidazole derivative according to claim 1, represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein R^1 to R^3 and R^5 are the same as formula [I]),
and pharmacologically acceptable acid addition salts thereof.
同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(11) The thioimidazole derivative according to claim 1, represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein R^1 to R^3 and R^5 are the same as formula [I]),
and pharmacologically acceptable acid addition salts thereof.
同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(12) The thioimidazole derivative according to claim 1, represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein R^1 to R^3 and R^5 are the same as formula [I]),
and pharmacologically acceptable acid addition salts thereof.
I ］に同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(13) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^4 and R^5 are the formula [
The thioimidazole derivative according to claim 1, represented by
and pharmacologically acceptable acid addition salts thereof.
I ］に同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(14) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^4 and R^5 are the formula [
The thioimidazole derivative according to claim 1, represented by
and pharmacologically acceptable acid addition salts thereof.
I ］に同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(15) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^4 and R^5 are the formula [
The thioimidazole derivative according to claim 1, represented by
and pharmacologically acceptable acid addition salts thereof.
I ］に同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(16) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^4 and R^5 are the formula [
The thioimidazole derivative according to claim 1, represented by
and pharmacologically acceptable acid addition salts thereof.
I ］に同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(17) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^4 and R^5 are the formula [
The thioimidazole derivative according to claim 1, represented by
and pharmacologically acceptable acid addition salts thereof.
I ］に同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(18) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^4 and R^5 are the formula [
The thioimidazole derivative according to claim 1, represented by
and pharmacologically acceptable acid addition salts thereof.
I ］に同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(19) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^4 and R^5 are the formula [
The thioimidazole derivative according to claim 1, represented by
and pharmacologically acceptable acid addition salts thereof.
I ］に同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(20) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^4 and R^5 are the formula [
The thioimidazole derivative according to claim 1, represented by
and pharmacologically acceptable acid addition salts thereof.
I ］に同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(21) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^4 and R^5 are the formula [
The thioimidazole derivative according to claim 1, represented by
and pharmacologically acceptable acid addition salts thereof.
I ］に同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(22) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^4 and R^5 are the formula [
The thioimidazole derivative according to claim 1, represented by
and pharmacologically acceptable acid addition salts thereof.
I ］に同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(23) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^4 and R^5 are the formula [
The thioimidazole derivative according to claim 1, represented by
and pharmacologically acceptable acid addition salts thereof.
I ］に同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(24) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^4 and R^5 are the formula [
The thioimidazole derivative according to claim 1, represented by
and pharmacologically acceptable acid addition salts thereof.
I ］に同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(25) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^4 and R^5 are the formula [
The thioimidazole derivative according to claim 1, represented by
and pharmacologically acceptable acid addition salts thereof.
I ］に同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(26) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^4 and R^5 are the formula [
The thioimidazole derivative according to claim 1, represented by
and pharmacologically acceptable acid addition salts thereof.
I ］に同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(27) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^4 and R^5 are the formula [
The thioimidazole derivative according to claim 1, represented by
and pharmacologically acceptable acid addition salts thereof.
同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(28) The thioimidazole derivative according to claim 1, which is represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein R^1 and R^3 to R^5 are the same as formula [I]);
and pharmacologically acceptable acid addition salts thereof.
同じ） で表わされる請求項１記載のチオイミダゾール誘導体、
およびその薬理上許容しうる酸付加塩。(29) The thioimidazole derivative according to claim 1, which is represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein R^1 and R^3 to R^5 are the same as the formula [I]);
and pharmacologically acceptable acid addition salts thereof.
される請求項１記載のチオイミダゾール誘導体、および
その薬理上許容しうる酸付加塩。(30) The thioimidazole derivative according to claim 1, which is represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein R^2 to R^5 are the same as formula [I]), and its pharmacological Acceptable acid addition salts.
される請求項１記載のチオイミダゾール誘導体、および
その薬理上許容しうる酸付加塩。(31) The thioimidazole derivative according to claim 1, which is represented by the general formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ (wherein R^2 to R^5 are the same as formula [I]), and its pharmacological Acceptable acid addition salts.
じ）で表わされる請求項１記載のチオイミダゾール誘導
体、およびその薬理上許容しうる酸付加塩。(32) The thioimidazole derivative according to claim 1, represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein R^1, R^4 and R^5 are the same as the formula [I]), and pharmacologically acceptable acid addition salts thereof.
たはＲ＾１、Ｒ＾２はそれらが結合している窒素原子と
共に員数５ないし７の環を形成してもよく、その環内に
窒素原子、イオウ原子又は酸素原子を含んでいてもよく
、環の置換基として低級アルキル基、低級アルコキシ基
を有していてもよく、環の置換基が環上の隣接する炭素
上にある場合は一緒になってそれらが結合している炭素
と共にベンゼン環を形成してもよく、Ｒ＾３は水素原子
、低級アルキル基、シクロアルキル基、フェニル基、低
級アルキルカルボニル基、低級アルコキシカルボニル基
、低級ジアルキルアミノカルボニル基、環状アミノカル
ボニル基もしくはハロゲン原子またはニトロ基で置換さ
れていてもよいピリジル基であり、または、Ｒ＾２とＲ
＾３はひとつのカルボニル基となって環を形成してもよ
く、Ｒ＾４は水素原子、低級アルキル基または低級アル
コキシカルボニル基であり、Ｒ＾５は低級アルキル基、
低級アルコキシル基、ハロゲンで置換されていてもよい
フェニル基または水素原子である。］で表わされるチオ
イミダゾール誘導体、およびその薬理上許容しうる酸付
加塩またはそれらの混合物を有効成分とする脳機能改善
作用を有する医薬。(33) General formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R^1 and R^2 are lower alkyl groups, or R^1 and R^2 are their may form a ring having 5 to 7 members with the nitrogen atom to which it is bonded, and the ring may contain a nitrogen atom, sulfur atom, or oxygen atom, and as a substituent of the ring, a lower alkyl group, a lower It may have an alkoxy group, and if the ring substituents are on adjacent carbons on the ring, they may be taken together to form a benzene ring with the carbon to which they are bonded, R^3 is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower dialkylaminocarbonyl group, a cyclic aminocarbonyl group, or a pyridyl group which may be substituted with a halogen atom or a nitro group. or R^2 and R
^3 may become one carbonyl group to form a ring, R^4 is a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group, R^5 is a lower alkyl group,
It is a lower alkoxyl group, a phenyl group which may be substituted with halogen, or a hydrogen atom. A medicament having a brain function-improving effect, which contains a thioimidazole derivative represented by the following, a pharmacologically acceptable acid addition salt thereof, or a mixture thereof as an active ingredient.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63027771A JPH01203368A (en) | 1988-02-10 | 1988-02-10 | Thioimidazole derivative |
| AU29780/89A AU2978089A (en) | 1988-02-10 | 1989-02-08 | Novel imidazole derivative |
| EP19890301281 EP0332295A3 (en) | 1988-02-10 | 1989-02-10 | Novel imidazole derivative |
| KR1019910011164A KR910007240B1 (en) | 1988-02-10 | 1991-07-02 | Deriveritives thioimidazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63027771A JPH01203368A (en) | 1988-02-10 | 1988-02-10 | Thioimidazole derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01203368A true JPH01203368A (en) | 1989-08-16 |
Family
ID=12230243
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63027771A Pending JPH01203368A (en) | 1988-02-10 | 1988-02-10 | Thioimidazole derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01203368A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2015528013A (en) * | 2012-07-27 | 2015-09-24 | ビアル−ポルテラ エ コンパニア，ソシエダッド アノニマ | Method for synthesizing substituted urea compounds |
-
1988
- 1988-02-10 JP JP63027771A patent/JPH01203368A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2015528013A (en) * | 2012-07-27 | 2015-09-24 | ビアル−ポルテラ エ コンパニア，ソシエダッド アノニマ | Method for synthesizing substituted urea compounds |
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