JPH02178289A - Imidazo(2,1-b)thiazoles - Google Patents
Imidazo(2,1-b)thiazolesInfo
- Publication number
- JPH02178289A JPH02178289A JP63329341A JP32934188A JPH02178289A JP H02178289 A JPH02178289 A JP H02178289A JP 63329341 A JP63329341 A JP 63329341A JP 32934188 A JP32934188 A JP 32934188A JP H02178289 A JPH02178289 A JP H02178289A
- Authority
- JP
- Japan
- Prior art keywords
- group
- hydrogen atom
- compound
- lower alkyl
- formula
- 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
- UFBBWLWUIISIPW-UHFFFAOYSA-N imidazo[2,1-b][1,3]thiazole Chemical class C1=CSC2=NC=CN21 UFBBWLWUIISIPW-UHFFFAOYSA-N 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- -1 propargyl halide Chemical class 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 239000000126 substance Substances 0.000 claims abstract description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 150000003557 thiazoles Chemical class 0.000 claims description 10
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000003172 aldehyde group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 63
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 51
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 abstract description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 15
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003795 chemical substances by application Substances 0.000 abstract description 7
- 239000002904 solvent Substances 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 5
- 238000010992 reflux Methods 0.000 abstract description 5
- 239000003699 antiulcer agent Substances 0.000 abstract description 4
- 238000007911 parenteral administration Methods 0.000 abstract description 4
- QBOQDEKQZFSQBT-UHFFFAOYSA-N 3-prop-2-ynyl-1,3-thiazol-2-imine Chemical class N=C1SC=CN1CC#C QBOQDEKQZFSQBT-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 125000005599 alkyl carboxylate group Chemical group 0.000 abstract 1
- 230000002490 cerebral effect Effects 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 15
- 238000002844 melting Methods 0.000 description 13
- 230000008018 melting Effects 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000013078 crystal Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 230000004083 survival effect Effects 0.000 description 11
- 229920000084 Gum arabic Polymers 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 10
- 241000978776 Senegalia senegal Species 0.000 description 10
- 208000025865 Ulcer Diseases 0.000 description 10
- 239000000205 acacia gum Substances 0.000 description 10
- 235000010489 acacia gum Nutrition 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 231100000397 ulcer Toxicity 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 238000010998 test method Methods 0.000 description 8
- 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 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 210000004051 gastric juice Anatomy 0.000 description 6
- 230000003925 brain function Effects 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 230000035882 stress Effects 0.000 description 5
- 206010002091 Anaesthesia Diseases 0.000 description 4
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 229960001138 acetylsalicylic acid Drugs 0.000 description 4
- 230000037005 anaesthesia Effects 0.000 description 4
- 230000000767 anti-ulcer Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 206010021143 Hypoxia Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229940099112 cornstarch Drugs 0.000 description 3
- 230000003628 erosive effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 3
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- OXFSTTJBVAAALW-UHFFFAOYSA-N 1,3-dihydroimidazole-2-thione Chemical class SC1=NC=CN1 OXFSTTJBVAAALW-UHFFFAOYSA-N 0.000 description 2
- ORECNKBJIMKZNX-UHFFFAOYSA-N 1,3-thiazol-3-ium;chloride Chemical compound Cl.C1=CSC=N1 ORECNKBJIMKZNX-UHFFFAOYSA-N 0.000 description 2
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 206010038669 Respiratory arrest Diseases 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 206010042220 Stress ulcer Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 208000000718 duodenal ulcer Diseases 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000001146 hypoxic effect Effects 0.000 description 2
- 238000007654 immersion Methods 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 description 2
- KJFMBFZCATUALV-UHFFFAOYSA-N phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- JXPDNDHCMMOJPC-UHFFFAOYSA-N 2-hydroxybutanedinitrile Chemical compound N#CC(O)CC#N JXPDNDHCMMOJPC-UHFFFAOYSA-N 0.000 description 1
- PMJUTPWDBHQESG-UHFFFAOYSA-N 2-methylimidazo[2,1-b][1,3]thiazole Chemical compound C1=CN=C2SC(C)=CN21 PMJUTPWDBHQESG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- MCWDDAAVFNMHKO-UHFFFAOYSA-N 6-methylimidazo[2,1-b][1,3]thiazole-5-carbaldehyde Chemical compound S1C=CN2C(C=O)=C(C)N=C21 MCWDDAAVFNMHKO-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
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- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
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- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
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- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
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- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
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- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000001490 effect on brain Effects 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- WZHUPCREDVWLKC-UHFFFAOYSA-N ethyl 2-amino-4-methyl-1,3-thiazole-5-carboxylate Chemical compound CCOC(=O)C=1SC(N)=NC=1C WZHUPCREDVWLKC-UHFFFAOYSA-N 0.000 description 1
- RDULEYWUGKOCMR-UHFFFAOYSA-N ethyl 2-chloro-3-oxobutanoate Chemical compound CCOC(=O)C(Cl)C(C)=O RDULEYWUGKOCMR-UHFFFAOYSA-N 0.000 description 1
- XOBQIIBCIWMREU-UHFFFAOYSA-N ethyl 5-methyl-2-sulfanylidene-1,3-dihydroimidazole-4-carboxylate Chemical compound CCOC(=O)C=1NC(=S)NC=1C XOBQIIBCIWMREU-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002431 foraging effect Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- RGZRSLKIOCHTSI-UHFFFAOYSA-N hydron;n-methylhydroxylamine;chloride Chemical compound Cl.CNO RGZRSLKIOCHTSI-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- UVNXNSUKKOLFBM-UHFFFAOYSA-N imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=CSC2=NC=CN21 UVNXNSUKKOLFBM-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- YVGLSUJNDXBZBM-UHFFFAOYSA-N propan-2-one;hydrobromide Chemical compound Br.CC(C)=O YVGLSUJNDXBZBM-UHFFFAOYSA-N 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
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- 239000004094 surface-active agent Substances 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
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Abstract
Description
上の
本発明は新規なイミダゾ［２，１−ｂｌチアゾール類に
関し、更に詳細には、一般式（１）［式中、Ｒ及びＲ２
はそれぞれ同−又は異なり、冨
水素原子、低級アルキル基、アセチル基、ヒドロキシア
ルキル基、カルボン酸アルキルエステ（Ｒ５及びＲ６は
それぞれ同−又は異なり、水素原子、低級アルキル基、
ヒドロキシアルキル基、ベンジル基あるいはＲ６とＲ６
はこれらが結合している窒素原子と一緒にモルホリノ基
などの環を形成することができる基を表す）、−ＣＨ（
ＯＨ） Ｒ７（Ｒ７は水素原子、低級アルキル基、フ
ェニル基、シクロアルキル基を表す）、−ＣＨなり、水
素原子、シアノ基、カルボン酸アルキルエステル基を表
す）、−ＣＨ＝Ｎ−Ｒ，０（Ｒ，。
は水酸基、低級アルコキシ基を表す）、２−シアノ−３
−ヒドロキシプロピル基、テトラゾリル基を；Ｒ１は水
素原子、低級アルキル基を表す１で示されるイミダゾ［
２，１−ｂｌチアゾール類又はその薬理学的に許容され
る塩に関する。
鵞ｊ四目り断
従来より、イミダゾ［２，１−ｂｌチアゾール類につい
ては種々の化合物が単離され公知となっている。これら
化合物のうち、幾つかは医薬としての有用性が示唆され
、その薬理作用については鎮痛・消炎作用（特公昭５９
−４０８３５号、同５９−５３２７８号など）、抗血栓
作用（特開昭５６−１１５７８０号）、抗高血圧作用・
利尿作用（特開昭５７−２１３８９号）などに対する効
果が既に公知となっている。しかしながら、イミダゾ［
２，１−ｂｌチアゾール類の脳機能改善作用あるいは抗
潰瘍作用に関しては未だ具体的な開示はなく、示唆さえ
見当たらない。
が し ”と る 履古
本発明者らは、公知のイミダゾール類あるいはチアゾー
ル類を出発物質として多くの化合物を合成し、これら化
合物につき種々検討を重ねた結果、一般式（１）で示さ
れるイミダゾ［２，１−ｂｌチアゾール類が公知の脳機
能改善作用あるいは抗潰瘍作用を示す薬剤とは化学構造
的に異なるにも拘らず優れた脳機能改善作用あるいは抗
潰瘍作用を有するとの知見を得、本発明を完成するに至
った。
即ち、本発明は一般式（Ｉ）で示される新規なイミダゾ
［２，１−ｂｌチアゾール類又はその薬理学的に許容さ
れる塩を提供することを目的とする。
履古を ° るための
本発明によって提供される一般式（１）で示されるイミ
ダゾ［２，１−ｂｌチアゾール類は、新規化合物であり
、以下の方法に従って製造することができる。
第−法
第二法
（■） （Ｉ−ｂ）ＣＩ）
〔式中、Ｒ，、Ｒｔ、 Ｒ３及びＲ４は前記と同じ意味
を表すＪ
第三法
（ｎ） （ＩＩ−ａ）（ト１）
［式中、Ｒ６、Ｒ２、Ｒ１及びＲ４は前記と同じ意味を
、Ｘはハロゲンを表す１
［式中、Ｒ３、Ｒ９、Ｒ３及びＲ４は前記と同じ意味を
表す］
即ち、一般式（ＩＩ）若しくは（ＩＩＩ）で示される２
−アミノチアゾール類若しくは２−メルカプトイミダゾ
ール類を出発物質として、一般式（Ｉ）で示されるイミ
ダゾ［２，１−ｂ］チアゾール類を製造することができ
る。
これら製造方法を更に詳細に検討すると、 ■２−アミ
ノチアゾール類（ＩＩ）とハロゲン化プロパルギルをエ
タノール、ｎ−ブタノール、エチレングリコール、モノ
メチルアルコールなどのアルコール類若しくはメチルエ
チルケトンなどの溶媒中、還流下若しくは室温で２時間
乃至４日間反応させて２−イミノ−３−プロパルギルチ
アゾール類（ＩＩ−ａ）とし、これを水酸化ナトリウム
、アルコキシナトリウムなどの縮合剤の存在下に前記ア
ルコール中で閉環させる方法（第一法） ■２−アミノ
チアゾール類（ｎ）とクロルアセトアルデヒド水溶液を
エタノール、ｎ−ブタノールなどのアルコール類中、還
流下若しくは９０〜１２０℃で反応させて閉環させる方
法（第二法）■２−メルカプトイミダゾールｆｌ（ＩＩ
Ｉ）を、２−クロルアセト酢酸エチルなどのハロゲン化
ケトン化合物とアセトン、メチルエチルケトン、メチル
イソブチルケトンなどのケトン系溶媒中で還流下、２〜
８時間反応させ閉環させる方法（第三法） などを適宜
選択して使用することができる。
これらの方法において使用される一般式（ＩＩ）及び（
Ｉ［［）で示される出発物質は、当業者が必要に応じて
容易に入手若しくは合成することができるものであり、
例えば、ジャーナル・イン・ザ・アメリカン・ケミカル
・ソサエティー（Ｊｏｕｒｎａｌ ｏｆｔｈｅ Ａ＋ｗ
ｅｒｉｃａｎ Ｃｈｅｍｉｃａｌ ５ｏｃｉｅｔｙ）
６８巻、４５７頁（１９４６年）、同７１巻、４００７
頁（１９４９年）などの文献記載の方法に準じて合成す
ることができる。
また、例えば、一般式（１−ａ）の化合物の５位に置換
基を導入する場合には、ウィルスマイヤー （Ｖｉｌｓ
ａ＋ｙｅｒ ）反応、マンニッヒ（Ｍａｎｎｉｃｈ）反
応あるいは還元反応などの公知の方法に従い所望の置換
基を導入して、目的とする化合物を取得することができ
る。
上記の製造方法により合成される一般式（１）で示され
るイミダゾ［２，１−ｂｌチアゾール類は、例えば、溶
媒抽出、クロマトグラフィー、結晶化などの常法を用い
て反応混合物から分離、精製することができる。
更に、上記の製造方法により取得される一般式（Ｉ）の
化合物は、所望に応じて薬理学的に許容される各種塩に
変換することができ、これら化合物の酸付加塩としては
、塩酸、硫酸、硝酸、臭化水素酸などの無機酸の付加塩
、シュウ酸、クエン酸、メタンスルホン酸、パラトルエ
ンスルホン酸などの有機酸の付加塩が、あるいはこれら
化合物の塩基の塩としては、例えば（ナトリウム、カリ
ウムなどの）アルカリ金属、（カルシウムなどの）アル
カリ土類金属などの無機塩基との塩、アンモニウム塩、
アルキルアミン類、ピリジンなどの有機塩基との塩が挙
げられる。
従って、一般式（１）で示されるイミダゾ［２゜１−ｂ
］チアゾール類を薬理学的に許容される各種塩に変換す
る場合には、例えば、酸付加塩を形成する場合には、本
発明化合物を化学量論量に対応する酸と適当な溶媒中で
反応させることにより取得することができる。
なお１本発明により取得される化合物には、右旋性、左
旋性あるいはこれらの混合物などの光学興・性体やシス
型、トランス型の立体異性体が存在する場合もあるが、
いずれの化合物も本発明の範囲内に包含されるものであ
る。
本発明に係わる化合物の幾つかは、低酸素負荷時の生存
時間の延長およびシアン化カリウム（ＫＣＮ）による生
存時間の延長を示し、かつ脳虚血に対しても有意な効果
を示すことから、脳機能改善剤として有用である。
また、本発明に係わる化合物の幾つかは、アスピリン潰
瘍、水浸拘束ストレス潰瘍並びにエタノール潰瘍に対し
て有意な効果を示し、かつ胃酸分泌抑制作用も強いこと
から、抗潰瘍剤としても有用である。
本発明に係わる化合物を脳機能改善剤あるいは抗潰瘍剤
として使用する場合には、経口又は非経口などの適当な
投与方法により投与することができる。経口投与用の形
態としては、例えば錠剤、顆粒、カプセル剤、丸剤、散
剤などが、また、非経口投与用の形態としては、例えば
、注射剤、坐剤、液剤などが挙げられる。これら医薬投
与用組成物の製剤化に際しては、本発明の化合物（及び
その塩）を常法に従い調製することができ、例えば経口
剤の場合には乳糖、ブドウ糖、コーンスターチ、ショ糖
などの賦形剤、カルボキシメチルセルロースカルシウム
、ヒドロキシプロピルセルロースなどの崩壊剤、ステア
リン酸カルシウム、ステアリン酸マグネシウム、タルク
、ポリエチレングリコール、硬化油などの滑沢剤、ヒド
ロキシプロピルセルロース、ヒドロキシプロピルメチル
セルロース、カルボキシメチルセルロース、ポリビニル
アルコール、ゼラチン、アラビアゴムなどの結合剤、グ
リセリン、エチレングリコールなどの湿潤剤、その他必
要に応じて界面活性剤、矯味剤などを使用して所望の投
与剤型に調製することができる。
また、非経口剤の場合には、水、エタノール、グリセリ
ン、プロピレングリコール、ポリエチレングリコール、
寒天、トラガラントガムなどの稀釈剤を用いて、必要に
応じて溶解補助剤、緩衝剤、保存剤、香料、着色剤など
を使用することができる。
本発明の化合物を脳機能改善剤あるいは抗潰瘍剤として
処方する場合、その投与単位は本発明化合物として、成
人−人当たり、経口投与の場合、１日５Ｎ乃至８００■
、好ましくは５ｍｇ乃至４００■、非経口投与の場合、
１日１■乃至３００ｍｇ。
好ましくは１■乃至２０ＯＮの範囲で投与され、それぞ
れ−日１乃至３回の分割投与により所望の治療効果が期
待できる。
ｌユΩ羞呈
本発明化合物は強い低酸素障害に対する抑制作用を有し
、脳卒中などにより発生する脳障害に対して有効な脳機
能改善作用を示す。
また、本発明化合物は強い胃酸分泌抑制作用を有し、ア
スピリン潰瘍、水浸拘束ストレス潰瘍並びにエタノール
潰瘍に対しても強い抗潰瘍作用を示す。
更に、本発明化合物の毒性は低（、経口および非経口投
与のどちらにおいても効果を示すことから、人に使用す
るための医療用薬剤としても有用である。
び
以下に、本発明化合物の実施例並びに試験例を記載し、
更に詳細かつ具体的に説明する。但し、本発明はその要
旨を越えない限り、これら実施例などにより限定される
ものではない。
実施例１
３．６−シメチルー２−エトキシカルボニルイミダゾ［
２，１−ｂｌチアゾール
２−アミノ−５−エトキシカルボニル−４−メチルチア
ゾール９．３ｇ、臭化プロパルギル７．１ｇをｎ−ブタ
ノール２０Ｗｉ中１００℃で７時間加熱した。冷後、析
出した２−イミノ−５−エトキシカルボニル−３−プロ
パルギル−４−メチルチアゾール臭化水素酸塩６．０ｇ
を炉取、これをナトリウムエトキシド（ナトリウム０．
７ｇ、エタノール２０ｄ）中で５時間還流した。反応終
了後、乾固して得た残渣に酢酸エチルと水を加え分液し
、酢酸エチル相より表記化合物４．０ｇを得た。
融点 １２８．５〜１２９．５℃
ＮＭＲδ（ＣＤＣＩ、）
１．３７ （ｔ、３Ｈ。
２．３６ （ｄ、３Ｈ。
２．７１ （ｓ、３Ｈ。
４．３２ （ｑ、２Ｈ。
７．０６ （ｑ、ＩＨ。
ＣＨ３ＣＯ，）
ＣＨ，）
ＣＨ，）
ＣＨ，ＣＨ，）
骨格）
実施例２
３−エトキシカルボニルイミダゾ［２，１−ｂｌチアゾ
ール
２−アミノ−４−エトキシカルボニルチアゾール１５．
４ｇ、クロルアセトアルデヒド２２−をｎ−ブタノール
１４〇−中１１０℃で６．５時間加熱した。反応終了後
、反応液を乾固して得た残渣をアセトンで結晶化して表
記化合物１２．２ｇを得た。
融点 −一一一一−
ＮＭＲ（塩酸塩） δ（ＤＭＳＯ−ｄ、）１．３７
（ｔ、３Ｈ，ＣＨ２ＣＨ，）４．４１ （ｑ、２Ｈ，
ＣＨ２ＣＨ，）７．７７ （ｑ、ＩＨ，骨格）
８．２０ （ｄ、ＩＨ，骨格）
８．３９ （ｄ、ＬＨ，骨格）
実施例３
２−エトキシカルボニル−３−メチルイミダゾ［２，１
−ｂｌチアゾール
２−アミノ−５−エトキシカルボニル−４−メチルチア
ゾールを用いて、実施例２と同様に反応を行い、表記化
合物を８３．１％収率で得た。
融 点（塩酸塩） ２１３℃（分解）
ＮＭＲ（塩酸塩） δ（ＤＭＳＯ−ｄ、）２．７２
（ｓ、３Ｈ，ＣＨ８）
４．３９ （ｑ、２Ｈ，ＣＨ２ＣＨ，）６．９１
（ｄ、ＩＨ，骨格）
７．２８ （ｄ、ＩＨ，骨格）
実施例４
２−アセチル−３，６−シメチルー５−エトキシカルボ
ニルイミダゾ［２，１−ｂｌチアゾール４−エトキシカ
ルボニル−５−メチル−２−メルカプトイミダゾール４
．０ｇと臭化アセトン３゜６ｇをメチルエチルケトン５
０ｄ中で２時間還流した。冷浸、析出した結晶を炉底し
、この結晶を水酸化ナトリウムで遊離化し、無水酢酸３
０艷−ビリジン６０ｗ１中１００℃で２時間撹拌した。
冷浸、析出した結晶を炉底し、エタノールより再結晶し
、表記化合物３．８ｇを得た。
融点 ２０６．０℃〜２０７．０℃
ＮＭＲδ（ＤＭＳＯ−ｄ、）
２．３０ （ｔ、３Ｈ，ＣＨ，ＣＨ，）２．６２
（ｓ、３Ｈ，ＣＨ３）
２、９０ （ｓ 、３ Ｈ、ＣＨｓ＞３．０９ （
ｓ、３Ｈ，Ｃ０ＣＨ，）４．３０ （ｑ、２Ｈ，ＣＨ
，ＣＨ，）実施例５
３．６−シメチルー５−ホルミルイミダゾ［２゜１−ｂ
］チアゾール
３．６−シメチルイミダゾ［２，１−ｂｌチアゾールの
塩酸塩３．３４ｇをオキシ塩化リン５ＩＩ＋！、ジメチ
ルホルムアミド２０Ｉｌｉ！より調製した混液中へ加え
、６０℃で７時間加熱した。反応終了後、反応液を氷水
中へ注ぎアンモニア水で中和し、クロロホルム抽出した
。クロロホルム相より表記化合物３．０ｇを得た。
融点 １４３．０℃〜１４４．０℃
ＮＭＲδ（ＣＤＣ１３）
２．６３ （ｓ、３Ｈ，ＣＨ８）
２．７５ （ｄ、３Ｈ，ＣＨ，）
６．４１ （ｑ、ＩＨ，骨格）
９．７０ （ｓ、ＩＨ，ＣＨＯ）
実施例６
５−ホルミルイミダゾ［２，１−ｂｌチアゾール
イミダゾ［２，１−ｂｌチアゾールを用いて、実施例５
と同様にホルミル化反応を行い、表記化合物を３１．１
％収率で得た。
融点 −一一一一−
ＮＭＲδ（ＣＤＣｌ２）
７．０６ （ｄ、ＩＨ，骨格）
７．９９ （ｓ、ＩＨ，骨格）
８．２１ （ｄ、ＩＨ，骨格）
９．６９ （ｓ、ＩＨ，ＣＨＯ）
実施例７
５−アミノメチル−６−メチルイミダゾ［２゜１−ｂ］
チアゾール塩酸塩
５−ヒドロキシイミノメチレン−６−メチルイミダゾ［
２，１−ｂｌチアゾール３．６ｇをＩＮ塩酸５０−に懸
濁し、これに水冷下亜鉛末３．６ｇを３回に分けて加え
た。水冷下での撹拌を１時間行った後、アンモニア水で
アルカリとし、酢酸エチルで抽出した。酢酸エチル相よ
り得た結晶を塩酸塩にしエタノールより再結晶し、表記
化合物１．５ｇを得た。
融 点 −一一一一−
ＮＭＲδ（ＣＤＣ１３）
２．５３ （ｓ、３Ｈ，ＣＨ３）
７．５６ （ｄ、ＬＨ，骨格）
８．４２ （ｄ、ＬＨ，骨格）
実施例８
３．６−シメチルー５−ヒドロキシメチルイミダゾ［２
，１−ｂｌチアゾール
３．６−シメチルー５−ホルミルイミダゾ［２゜１−ｂ
］チアゾール１．８ｇをエタノール４０−に懸濁した後
、水素化ホウ素ナトリウム１．８９ｇを加え、５０℃で
３０分温めた後、反応液を乾固して得た残渣を水洗して
表記化合物１．７８ｇを得た。
融 点 １６９．０〜１７１．０℃ＮＭＲδ（Ｄ
ＭＳＯ−ｄ、）
２．０〜２．７ （ｂ、ＬＨ，０Ｈ）２．２２ （
ｓ、３Ｈ，ＣＨ，）
２．６１ （ｄ、３Ｈ，ＣＨ３）
４．７３ （ｓ、２Ｈ，ＣＨ２）
６．２７ （ｑ、ＬＨ，骨格）
実施例９〜１４
次表に、実施例８に準じて合成した各実施例化合物を掲
げる。
実施例１５〜２０
６−メチルイミダゾ［２，１−ｂｌチアゾールあるいは
３，６−シメチルイミダゾ［２，１−ｂｌチアゾール５
ｓＭをエタノール２０−に溶かし、酢酸ニー、対応する
アミン６ｍＭ、３７％ホルマリン７ＩＩＭを加え、室温
で２時間撹拌した。反応液を乾固し、残渣を水に溶かし
、塩基で中和後クロロホルム抽出した。クロロホルム相
より該化合物の遊離塩基を得、次いで塩酸で塩とした。
次表に、上記に準じて合成した各実施例化合物を掲げる
。
実施例２１〜２７
５−ホルミル−６−メチルイミダゾ［２，１−ｂｌチア
ゾール、３，６−シメチルー５−ホルミルイミダゾ［２
，１−ｂｌチアゾールあるいは２−ブチル−３，６−シ
メチルー５−ホルミルイミダゾ［２，１−ｂｌチアゾー
ル２０醜りをテトラヒドロフラン３０ｍに溶かし、冷却
下、対応するグリニヤール試薬を加え、３０分間撹拌、
その後室温で３時間若しくは５０℃で３０分間加熱した
。
冷浸、塩酸で中和し、酢酸エチルで抽出し、酢酸エチル
相より該化合物を得た。
次表に、上記に準じて合成した各実施例化合物を掲げる
。
実施例２８〜３０
３，６−シメチルー５−ホルミルイミダゾ［２゜１−ｂ
１チアゾールあるいは５−ホルミルイミダゾ［２，１−
ｂｌチアゾール１０−ｈをエタノール、ピリジンの混液
に溶解し、塩酸メチルヒドロキシルアミンあるいは塩酸
ヒドロキシルアミンの１１ａＭを加え、３０分間還流後
、乾固して得た残渣を場合に応じて塩酸塩とする。
次表に、上記に準じて合成した各実施例化合物を掲げる
。
実施例３１
６−メチル−５−テトラゾリルイミダゾThe above invention relates to novel imidazo[2,1-bl thiazoles, more specifically, compounds of the general formula (1) [wherein R and R2
are the same or different, hydrogen atom, lower alkyl group, acetyl group, hydroxyalkyl group, carboxylic acid alkyl ester (R5 and R6 are the same or different, hydrogen atom, lower alkyl group,
Hydroxyalkyl group, benzyl group or R6 and R6
represents a group that can form a ring such as a morpholino group together with the nitrogen atom to which they are bonded), -CH(
OH) R7 (R7 represents a hydrogen atom, a lower alkyl group, a phenyl group, or a cycloalkyl group), -CH, represents a hydrogen atom, a cyano group, or a carboxylic acid alkyl ester group), -CH=N-R, 0 (R,. represents a hydroxyl group or a lower alkoxy group), 2-cyano-3
-Hydroxypropyl group, tetrazolyl group; R1 represents a hydrogen atom, a lower alkyl group; imidazo[
The present invention relates to 2,1-bl thiazoles or pharmacologically acceptable salts thereof. Various compounds have been isolated and known as imidazo[2,1-bl thiazoles]. Some of these compounds have been suggested to be useful as medicines, and their pharmacological effects are known to have analgesic and anti-inflammatory effects (Special Publication No. 59
-40835, No. 59-53278, etc.), antithrombotic effect (Japanese Patent Application Laid-open No. 115780/1983), antihypertensive effect,
Its diuretic effect (Japanese Patent Application Laid-Open No. 57-21389) is already known. However, imidazo [
There has been no specific disclosure or even suggestion regarding the brain function improving effect or anti-ulcer effect of 2,1-bl thiazoles. The present inventors have synthesized many compounds using known imidazoles or thiazoles as starting materials, and have conducted various studies on these compounds. Obtained the knowledge that 2,1-bl thiazoles have excellent brain function-improving effects or anti-ulcer effects despite their chemical structure being different from known drugs that exhibit brain function-improving effects or anti-ulcer effects; The present invention has been completed.That is, an object of the present invention is to provide a novel imidazo[2,1-bl thiazole represented by general formula (I) or a pharmacologically acceptable salt thereof. The imidazo[2,1-bl thiazoles represented by the general formula (1) provided by the present invention for aging purposes are novel compounds and can be produced according to the following method. - Method 2 (■) (I-b) CI) [In the formula, R,, Rt, R3 and R4 represent the same meanings as above J Method 3 (n) (II-a) (G1) [In the formula, R6, R2, R1 and R4 have the same meanings as above, and X represents a halogen 1 [In the formula, R3, R9, R3 and R4 have the same meanings as above] That is, general formula (II) or (III) 2
Imidazo[2,1-b]thiazoles represented by general formula (I) can be produced using -aminothiazoles or 2-mercaptoimidazoles as starting materials. A more detailed study of these production methods shows that: (1) 2-aminothiazoles (II) and propargyl halides are mixed in alcohols such as ethanol, n-butanol, ethylene glycol, and monomethyl alcohol, or in solvents such as methyl ethyl ketone, under reflux or at room temperature; A method of reacting for 2 hours to 4 days to obtain 2-imino-3-propargylthiazoles (II-a), and ring-closing this in the alcohol in the presence of a condensing agent such as sodium hydroxide or sodium alkoxy. Method 1) ■Method of ring-closing by reacting 2-aminothiazoles (n) with an aqueous solution of chloroacetaldehyde in an alcohol such as ethanol or n-butanol under reflux or at 90 to 120°C (Second method) ■2- Mercaptoimidazole fl(II
I) under reflux in a halogenated ketone compound such as ethyl 2-chloroacetoacetate and a ketone solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.
A method of reacting for 8 hours to close the ring (third method) can be appropriately selected and used. General formula (II) and (
The starting material represented by I[[) can be easily obtained or synthesized as needed by a person skilled in the art,
For example, the Journal of the American Chemical Society (Journal of the A+w
erican Chemical 5ociety)
Volume 68, page 457 (1946), Volume 71, 4007
It can be synthesized according to the method described in literature such as P. (1949). Furthermore, for example, when introducing a substituent into the 5-position of the compound of general formula (1-a), Vilsmeier (Vilsmeier)
A desired compound can be obtained by introducing a desired substituent according to a known method such as a+yer ) reaction, Mannich reaction, or reduction reaction. The imidazo[2,1-bl thiazoles represented by the general formula (1) synthesized by the above production method are separated and purified from the reaction mixture using conventional methods such as solvent extraction, chromatography, and crystallization. can do. Furthermore, the compound of general formula (I) obtained by the above production method can be converted into various pharmacologically acceptable salts as desired, and acid addition salts of these compounds include hydrochloric acid, hydrochloric acid, Addition salts of inorganic acids such as sulfuric acid, nitric acid, and hydrobromic acid; addition salts of organic acids such as oxalic acid, citric acid, methanesulfonic acid, and para-toluenesulfonic acid; and salts of bases of these compounds include, for example. salts with inorganic bases such as alkali metals (such as sodium, potassium), alkaline earth metals (such as calcium), ammonium salts,
Examples include salts with organic bases such as alkylamines and pyridine. Therefore, imidazo [2゜1-b
] When converting thiazoles into various pharmacologically acceptable salts, for example, when forming acid addition salts, the compound of the present invention is mixed with a stoichiometric amount of an acid in an appropriate solvent. It can be obtained by reaction. Note that the compound obtained by the present invention may have optically active isomers such as dextrorotatory, levorotatory, or a mixture thereof, and cis-type and trans-type stereoisomers.
Any compound is included within the scope of the present invention. Some of the compounds related to the present invention show extension of survival time under hypoxic stress and potassium cyanide (KCN), and also show significant effects on cerebral ischemia, so they have been shown to improve brain function. Useful as an improving agent. In addition, some of the compounds according to the present invention show significant effects on aspirin ulcers, water immersion restraint stress ulcers, and ethanol ulcers, and also have strong effects on suppressing gastric acid secretion, so they are useful as anti-ulcer agents. . When the compound according to the present invention is used as a brain function improving agent or an antiulcer agent, it can be administered by an appropriate administration method such as oral or parenteral administration. Forms for oral administration include, for example, tablets, granules, capsules, pills, and powders, and forms for parenteral administration include, for example, injections, suppositories, and liquid preparations. When formulating these compositions for pharmaceutical administration, the compounds of the present invention (and their salts) can be prepared according to conventional methods. For example, in the case of oral preparations, excipients such as lactose, glucose, cornstarch, sucrose, etc. disintegrants such as calcium carboxymethyl cellulose and hydroxypropyl cellulose, lubricants such as calcium stearate, magnesium stearate, talc, polyethylene glycol, and hydrogenated oil, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, gelatin, A desired dosage form can be prepared by using a binder such as gum arabic, a wetting agent such as glycerin or ethylene glycol, and a surfactant, a flavoring agent, etc. as necessary. In addition, in the case of parenteral agents, water, ethanol, glycerin, propylene glycol, polyethylene glycol,
A diluent such as agar or tragalant gum may be used, and a solubilizing agent, a buffering agent, a preservative, a flavoring agent, a coloring agent, etc. may be used as necessary. When the compound of the present invention is prescribed as a brain function improving agent or an anti-ulcer agent, the dosage unit is 5 N to 800 g per adult per day per day.
, preferably 5 mg to 400 μg, in the case of parenteral administration,
1 to 300 mg per day. The dose is preferably administered in the range of 1 to 20 ON, and the desired therapeutic effect can be expected by dividing the dose into 1 to 3 doses per day. The compound of the present invention has a strong inhibitory effect on hypoxic damage and shows an effective brain function improving effect on brain damage caused by stroke and the like. In addition, the compound of the present invention has a strong gastric acid secretion suppressing effect, and also shows a strong anti-ulcer effect against aspirin ulcer, water immersion restraint stress ulcer, and ethanol ulcer. Furthermore, the compounds of the present invention have low toxicity (and are effective both orally and parenterally, so they are useful as medical drugs for human use. Describe examples and test examples,
This will be explained in more detail and concretely. However, the present invention is not limited to these Examples unless the gist thereof is exceeded. Example 1 3.6-dimethyl-2-ethoxycarbonylimidazo[
9.3 g of 2,1-bl thiazole 2-amino-5-ethoxycarbonyl-4-methylthiazole and 7.1 g of propargyl bromide were heated at 100° C. for 7 hours in n-butanol 20Wi. After cooling, 6.0 g of 2-imino-5-ethoxycarbonyl-3-propargyl-4-methylthiazole hydrobromide was precipitated.
was taken in a furnace, and this was converted into sodium ethoxide (sodium 0.
7 g and refluxed in ethanol (20 d) for 5 hours. After the reaction was completed, ethyl acetate and water were added to the residue obtained by drying to separate the layers, and 4.0 g of the title compound was obtained from the ethyl acetate phase. Melting point 128.5-129.5°C NMR δ (CDCI,) 1.37 (t, 3H. 2.36 (d, 3H. 2.71 (s, 3H. 4.32 (q, 2H. 7.06 () q, IH. CH3CO,) CH,) CH,) CH, CH,) Skeleton) Example 2 3-ethoxycarbonylimidazo[2,1-bl thiazole 2-amino-4-ethoxycarbonylthiazole 15.
4 g of chloracetaldehyde 22- was heated at 110° C. for 6.5 hours in n-butanol 140-. After the reaction was completed, the reaction solution was dried and the resulting residue was crystallized with acetone to obtain 12.2 g of the title compound. Melting point -1111- NMR (hydrochloride) δ (DMSO-d,) 1.37
(t, 3H, CH2CH,)4.41 (q, 2H,
CH2CH,) 7.77 (q, IH, skeleton) 8.20 (d, IH, skeleton) 8.39 (d, LH, skeleton) Example 3 2-ethoxycarbonyl-3-methylimidazo[2,1
-blthiazole A reaction was carried out in the same manner as in Example 2 using 2-amino-5-ethoxycarbonyl-4-methylthiazole to obtain the title compound in a yield of 83.1%. Melting point (hydrochloride) 213℃ (decomposition) NMR (hydrochloride) δ (DMSO-d, ) 2.72
(s, 3H, CH8) 4.39 (q, 2H, CH2CH,) 6.91
(d, IH, skeleton) 7.28 (d, IH, skeleton) Example 4 2-Acetyl-3,6-dimethyl-5-ethoxycarbonylimidazo[2,1-blthiazole 4-ethoxycarbonyl-5-methyl- 2-Mercaptoimidazole 4
．． 0g and 3.6g of acetone bromide to 5g of methyl ethyl ketone
It was refluxed for 2 hours at 0d. After cooling, the precipitated crystals were placed at the bottom of the furnace, and the crystals were liberated with sodium hydroxide, and acetic anhydride 3
The mixture was stirred at 100°C for 2 hours in 60w1 of pyridine. After cooling, the precipitated crystals were taken to the bottom of the furnace and recrystallized from ethanol to obtain 3.8 g of the title compound. Melting point 206.0°C to 207.0°C NMRδ (DMSO-d,) 2.30 (t, 3H, CH, CH,) 2.62
(s, 3H, CH3) 2,90 (s, 3H, CHs>3.09 (
s, 3H, C0CH,)4.30 (q, 2H, CH
, CH,) Example 5 3.6-dimethyl-5-formylimidazo[2°1-b
] Thiazole 3,6-dimethylimidazo [3.34 g of 2,1-bl thiazole hydrochloride was dissolved in phosphorus oxychloride 5II+! , dimethylformamide 20Ili! The mixture was added to the mixture prepared above and heated at 60°C for 7 hours. After the reaction was completed, the reaction solution was poured into ice water, neutralized with aqueous ammonia, and extracted with chloroform. 3.0 g of the title compound was obtained from the chloroform phase. Melting point 143.0°C to 144.0°C NMRδ (CDC13) 2.63 (s, 3H, CH8) 2.75 (d, 3H, CH,) 6.41 (q, IH, skeleton) 9.70 (s , IH, CHO) Example 6 Using 5-formylimidazo[2,1-bl thiazoleimidazo[2,1-bl thiazole, Example 5
Perform the formylation reaction in the same manner as 31.1 to convert the title compound into 31.1
% yield. Melting point -1111- NMRδ (CDCl2) 7.06 (d, IH, skeleton) 7.99 (s, IH, skeleton) 8.21 (d, IH, skeleton) 9.69 (s, IH, CHO ) Example 7 5-aminomethyl-6-methylimidazo [2°1-b]
Thiazole hydrochloride 5-hydroxyiminomethylene-6-methylimidazo [
3.6 g of 2,1-bl thiazole was suspended in 50-IN hydrochloric acid, and 3.6 g of water-cooled zinc powder was added in three portions. After stirring for 1 hour under water cooling, the mixture was made alkaline with aqueous ammonia and extracted with ethyl acetate. The crystals obtained from the ethyl acetate phase were converted into hydrochloride and recrystallized from ethanol to obtain 1.5 g of the title compound. Melting point -1111- NMRδ (CDC13) 2.53 (s, 3H, CH3) 7.56 (d, LH, skeleton) 8.42 (d, LH, skeleton) Example 8 3.6-dimethyl- 5-hydroxymethylimidazo[2
, 1-bl thiazole 3,6-dimethyl-5-formylimidazo [2゜1-b
] After suspending 1.8 g of thiazole in ethanol 40-, 1.89 g of sodium borohydride was added, and after warming at 50°C for 30 minutes, the reaction solution was dried and the resulting residue was washed with water to obtain the title compound. 1.78g was obtained. Melting point 169.0-171.0℃NMRδ(D
MSO-d,) 2.0-2.7 (b, LH, 0H) 2.22 (
s, 3H, CH,) 2.61 (d, 3H, CH3) 4.73 (s, 2H, CH2) 6.27 (q, LH, skeleton) Examples 9 to 14 In the following table, Example 8 Each example compound synthesized in accordance with the above is listed. Examples 15-20 6-methylimidazo[2,1-bl thiazole or 3,6-dimethylimidazo[2,1-bl thiazole 5
sM was dissolved in 20-mL ethanol, acetic acid solution, 6 mM of the corresponding amine, and 37% formalin 7IIM were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was dried, the residue was dissolved in water, neutralized with a base, and then extracted with chloroform. The free base of the compound was obtained from the chloroform phase and then salted with hydrochloric acid. The following table lists each example compound synthesized according to the above. Examples 21-27 5-formyl-6-methylimidazo[2,1-bl thiazole, 3,6-cymethyl-5-formylimidazo[2
, 1-bl thiazole or 2-butyl-3,6-dimethyl-5-formylimidazo[2,1-bl thiazole 20] was dissolved in 30 m of tetrahydrofuran, and the corresponding Grignard reagent was added under cooling, and stirred for 30 minutes.
Thereafter, it was heated at room temperature for 3 hours or at 50°C for 30 minutes. The mixture was cooled, neutralized with hydrochloric acid, extracted with ethyl acetate, and the compound was obtained from the ethyl acetate phase. The following table lists each example compound synthesized according to the above. Examples 28-30 3,6-dimethyl-5-formylimidazo[2°1-b
1thiazole or 5-formylimidazo[2,1-
bl thiazole 10-h is dissolved in a mixture of ethanol and pyridine, 11 aM of methylhydroxylamine hydrochloride or hydroxylamine hydrochloride is added, and after refluxing for 30 minutes, the resulting residue is converted to a hydrochloride depending on the case. The following table lists each example compound synthesized according to the above. Example 31 6-methyl-5-tetrazolylimidazo
【２゜１−ｂ】
チアゾール
５−シアノ−６−メチルイミダゾ［２，１−ｂｌチアゾ
ール８．８ｇ、塩化アンモニウム４．３ｇ、アジ化ナト
リウム５．３ｇ、塩化リチウム０．７ｇをジメチルホル
ムアミド５０ｄ中１２０℃で１８時間加熱した。反応液
を留去後、ＩＮ水酸化ナトリウムに溶かし活性炭処理後
、塩酸で中和し、析出した結晶を炉底、ＩＮ塩酸で再結
晶し表記化合物８．２ｇを得た。
融 点 ２５０．０℃以上
ＮＭＲδ（ＤＭＳＯ−ｄ、）
２．５９ （ｓ、３Ｈ，ＣＨ，）
７．３８ （ｄ、ＬＨ，骨格）
８．２０ （ｄ、ＩＨ，骨格）
実施例３２
５−（２−ジシアノメチレン）−６−メチルイミダゾ［
２，１−ｂｌチアゾール
５−ホルミル−６−メチルイミダゾ［２，１−ｂ］チア
ゾール３．３ｇ、マロンニトリル１．５ｇをメタノール
１５−１とサジ２１ｍｌ中室温で１時間撹拌後、冷却し
、析出した結晶を炉底、これを。
メタノールより再結晶し表記化合物３．６ｇを得た。
融点 １９９．０℃
ＮＭＲδ（ＣＤＣＩ３）
２．５３ （ｓ、３Ｈ，ＣＨ，）
７．０２ （ｄ、ＩＨ，骨格）
７．４５ （ｓ、ＩＨ，ＣＨ）
８．２８ （ｄ、ＩＨ，骨格）
実施例３３
エチル ３−［６−メチルイミダゾ［２，１−ｂ１チア
ゾール−５−イル］アクリレエート５−ホルミル−６−
メチルイミダゾ［２，１−ｂ］チアゾール３３．２ｇを
マロン酸３．１２ｇ、ピペラジン１．７０ｇとジメチル
ホルムアミド５０ｄ中、１２０℃で３時間加熱した。反
応終了後溶媒を留去し、残渣に水を加え３−［６−メチ
ルイミダゾ［２，１−ｂ−１チアゾール−５−イル］ア
クリル酸の結晶３．３０ｇを得た。
この結晶２．０ｇを濃硫酸２ｗｌを含むエタノール２０
ｗ１中で２時間還流した。冷浸析出した目的物の硫酸塩
結晶２．９６ｇを得た。
これを水酸化ナトリウム溶液で遊離化し、エタノールよ
り再結晶し表記化合物１．５０ｇを得た。
融 点 １３５．０〜１３６．０℃ＮＭＲδ（Ｃ
ＤＣＩ、）
１．３３ （ｔ、３Ｈ，ＣＨ，ＣＨ，）２．４８
（ｓ、３Ｈ，ＣＨ，）
４．２５ （ｑ、２Ｈ，ＣＭ２ＣＨ，）５．９６
（ｄ、ＬＨ，ＣＨ）
６．８８ （ｄ、ＩＨ，ＣＨ）
７．５９ （ｄ、ＩＨ，ＣＨ）
７．７０ （ｄ、ＩＨ，ＣＨ）
実施例３４
メチル ２−シアノ−３−【６−メチルイミダゾ［２，
１−ｂｌチアゾール−５−イル］アクリレエート
５−ホルミル−６−メチルイミダゾ［２，１−ｂ］チア
ゾール３．３２ ｇをメチルシアノアセテート２．３８
ｇとメタノール２０ｄ中で２時間還流した。冷浸析出し
た結晶を炉底し、メタノールより再結晶し、表記化合物
４．０１ｇを得た。
融 点 −一−−−−
ＮＭＲδ（ＣＤＣＩ、）
２．５５ （ｓ、３Ｈ，ＣＨ，）
３、９０ （ｓ ＝ ３ Ｈ、ＣＨｓ）６．９６
（ｄ、ＩＨ，骨格）
８．１２ （ｓ、ＩＨ，ＣＨ）
８．４１ （ｄ、ＬＨ，骨格）
実施例３５
メチル ２−シアノ−３−［３，６−シメチルイミダゾ
［２，１−ｂｌチアゾール−５−イルＪアクリレエート
５−ホルミル−３，６−シメチルイミダゾ［２゜１−ｂ
］チアゾール１．８０ｇとメチルシアノアセテート１．
５ｇをメタノール３０ｗ１中に溶かし、ピペリジン２〜
３滴加えた後、３時間還流した。
冷浸析出した結晶を炉底し、エタノールより再結晶し、
表記化合物１．７０ｇを得た。
融 点 １９５．５〜１９６．５℃実施例３６（
錠剤の調製）
本発明化合物（実施例８） ２５０ｇ乳
糖 ６２０ｇコーンスター
チ ４００ｇヒドロキシプロピルセルロ
ース ２０ｇステアリン酸マグネシウム １０
ｇ上記した本発明化合物、乳糖及びコーンスターチを均
一になるまで混合した後、ヒドロキシプロピルセルロー
スの５ｗ／ｖ％エタノール溶液を加えて練合、顆粒化す
る。１６メツシユの篩に通し整粒した後、常法により打
錠し、１錠当たりの重量１３０■、直径７ａＩＩｌ、生
薬含量２５■の錠剤とした。
実施例３７（カプセル剤の調製）
本発明化合物（実施例２２） ２５０ｇ乳
糖 ６２０ｇアビセル
６２０ｇ
ステアリン酸マグネシウム １０ｇ上記した本発
明化合物、乳糖、アビセル及びステアリン酸マグネシウ
ムを均一になるまで十分混合した後、３号カプセルに充
填し、１カプセル当たりの内容物の重量１５０ｍｇ、生
薬含量２５■のカプセル剤とした。
試験例１
低 の生 時 に る
試験方法：片部らの方法（日本薬理学雑誌８１巻、４２
１〜４２９頁、１９８３年）に準じ、排気口を有する２
０ Ｘ １０ Ｘ ３０ ｃ＋ｉの箱に９５％Ｎ２＋
５％ｏ２の混合ガスを１０ｅ／ｗｉｎの流量で通気し、
容器内空気と置換することにより低酸素状態を生じさせ
た。ｄｄｙ系雄性マウス（５週齢、対照群６匹、被験化
合物群６匹）を同時に箱内に入れ、通気を開始し、呼吸
停止に至るまでの時間を測定した。また、１０分以上生
存したマウスは、平均生存時間の算出の際には生存時間
を１ｏ分として計算した。
被験化合物は生理食塩水に溶解し、溶解不可能なものは
０．５％ツイーン８０ （Ｔｗｅｅｎ８０）で懸濁して
、１０ｄ／ｋｇの割合で実験開始３０分前に腹腔的投与
した。
なお、対照には生理食塩水を１０ｄ／ｋｇの割合で実験
開始３０分前に腹控内投与した。
試験結果：次表に示した。
対照群の平均生存時間（２２ｏ秒）を１００％として、
各被験化合物の延命率（％）を算出した。
試験例２
ＫＣＮ の生 に る
試験方法ｒｄｄｙ系雄性系中性マウス齢、−群１０匹）
ｌ：：ＫｃＮ３．Ｏｗ／ｋｇを５秒間に尾静脈内投与し
、呼吸停止までの時間（生存時間）を測定した。
被験化合物は生理食塩水に溶解し、溶解不可能なものは
０．５％ツイーン８０ （Ｔｗｅｅｎ８０）で懸濁して
、１０ｄ／ｋｇの割合で実験開始３０分前に腹腔内投与
した。
なお、対照には生理食塩水を１０−／―の割合で実験、
開始３０分前に腹腔内投与した。
試験結果：次表に示した。
対照群の平均生存時間（５０秒）を１００％として、各
被験化合物の延命率（％〉を算出した。
試験例３
抜員１皇藍Ｉ
試験方法二戸部らの方法（日本薬理学雑誌８１巻４２１
〜４２９頁、１９８３年）に準じ、ｄｄｙ系雄性マウス
（体重２４〜２７ｇ、対照群１２匹、被験化合物群８〜
１１匹）に被験化合物５０ｍｇ／蹟を腹腔内に投与し、
投与３０分後に断頭した。
断頭後、頭部のｇａｓｐｉｎｇ様呼吸が停止するまでの
時間（生存時間）を測定した。
試験結果二次表に示した。
対照群の平均生存時間（１８秒）を１００％として、各
化合物の延命率（％）を算出した。
試験例４
アスビ１ン潰 モデルに る
試験方法：２４時間絶食したＷ ｉ ｓ ｔ ａ ｒ系
中性ラット（７〜８週齢、体重１８０〜２２７ｇ；被験
化合物投与群７〜８匹、対照群１６匹）に５％アラビア
ゴム水溶液に懸濁した各被験化合物１００■１５１！／
ｋｇを経口投与し、投与３０分後に、更にアスピリン２
００■／贈を経口投与した。アスピリン投与７時間後に
エーテル麻酔下に胃を摘出し、顕微鏡下で点状及び線状
のｅｒｏｓｉｏｎ （びらん）及び潰瘍の長径を測定し
、潰瘍指数並びに抑制度を算出した。
なお、対照群には５％アラビアゴム水溶液を５ｍ／／ｂ
の用量で経口投与した。
試験結果：次表に示した。
零 Ｐ ＜ ０．０５ 本末 Ｐ＜０．０１試
験例５
拘 ストレス モデルに る抗
亙
試験方法：２４時間絶食したＷｉｓｔａｒ系雄性ラット
（７〜８週齢、体重１９１〜２３８ｇ ：被験化合物投
与群７〜８匹、対照群１６匹）に５％アラビアゴム水溶
液に懸濁した各被験化合物１００■／！Ｍ／ｋｇを経口
投与し、投与３０分後に束大薬作型ストレスケージを用
いて２２±１℃の水浴に剣状突起部までを水浸し、６時
間のストレス負荷を行った。ストレス負荷後、ラットを
頚椎脱臼により致死させ、胃を摘出し、顕微鏡下で点状
及び線状のｅｒｏｓｉｏｎ （びらん）及び潰瘍の長径
を測定し、潰瘍指数並びに抑制率を算出した。
なお、対照群には５％アラビアゴム水溶液を５ｄ／−の
用量で使用した。
試験結果二次表に示した。
水エタノール５Ｗｌ／―を経口投与した。無水エタノー
ル投与１時間後にエーテル麻酔下に胃を摘出し、顕微鏡
下で点状及び線状のｅｒｏｓｉｏｎ （びらん）及び潰
瘍の長径を測定し、潰瘍指数並びに抑制率を算出した。
なお、対照群には５％アラビアゴム水溶液を５−／贈の
用量で経口投与した。
試験結果二次表に示した。
本本 Ｐ ＜ ０．０１ 本本零 Ｐ＜０．００
１試験例６
エ ノール モデルに る
試験方法：２４時間絶食したＷ ｉ ｓ ｔ ａ ｒ系
中性ラット（７〜８週齢、体重１８０〜２５０ｇ ：被
験化合物投与群５匹、対照群４〜７匹）に５％アラビア
ゴム水溶液に懸濁した各被験化合物１００ｍｇ１５ｄ／
ｋｇを経口投与し、投与３０分後に、更に無試験例７
泌 １
試験方法：２４時間絶食したＷ ｉ ｓ ｔ ａ ｒ系
中性ラット（７〜８週齢、体重１９２〜２４１ｇ；被験
化金物投与群８〜９匹、対照群１５匹）に５％アラビア
ゴム水溶液に懸濁した各被験化合物１００■１５ｗ＆／
ｋｇを経口投与し、投与３０分後に、エーテル麻酔下に
幽門結紮を行った。４時間後にエーテル麻酔下、胃を摘
出し胃液を採取した。採取した胃液を４℃で１０分間遠
心分子ｉ（２，５００ｒｐｍ）し、上清を採取後、胃液
量及びｐＨメーターを用いて胃液ｐＨを測定した。更に
、Ｔ６ｐｆｅｒ試薬及びフェノールフタレイン試薬でそ
れぞれ遊離塩酸量及び総酸度を測定した。また、胃液の
一部を用いてＡｎｓｏｎのカイゼン（Ｃａ５ｅｉｎ）法
に準じて、胃液中のペプシン分泌量を測定した。
なお、対照群には５％アラビアゴム水溶液を５ｗ１／ｋ
ｇの用量で経口投与した。
試験結果二次表に示した。
試験例８
皇ユ皇亘
試験方法：５ＬＣ−ＩＣＲ系雄系中ウス（６〜７週齢、
体重２６．６〜３３．６ｇ、１群５匹）に５％アラビア
ゴム水溶液に懸濁した被験化合物５００及び１ 、００
０＋ａｇ／ ５＠ｌ／ｋｇを１回強制経口投与した。そ
の後７日間マウスの死亡の有無を観察した。
試験結果：次表に示した。[2゜1-b]
Thiazole 5-cyano-6-methylimidazo[2,1-bl 8.8 g of thiazole, 4.3 g of ammonium chloride, 5.3 g of sodium azide, 0.7 g of lithium chloride were heated in 50 d of dimethylformamide at 120° C. for 18 hours. . After the reaction solution was distilled off, it was dissolved in IN sodium hydroxide, treated with activated carbon, neutralized with hydrochloric acid, and the precipitated crystals were recrystallized from the bottom of the furnace with IN hydrochloric acid to obtain 8.2 g of the title compound. Melting point 250.0°C or higher NMR δ (DMSO-d,) 2.59 (s, 3H, CH,) 7.38 (d, LH, skeleton) 8.20 (d, IH, skeleton) Example 32 5- (2-dicyanomethylene)-6-methylimidazo[
3.3 g of 2,1-bl thiazole 5-formyl-6-methylimidazo[2,1-b]thiazole and 1.5 g of malonitrile were stirred at room temperature for 1 hour in methanol 15-1 and 21 ml of saline, and then cooled. Place the precipitated crystals at the bottom of the furnace. Recrystallization from methanol gave 3.6 g of the title compound. Melting point 199.0°C NMRδ (CDCI3) 2.53 (s, 3H, CH,) 7.02 (d, IH, skeleton) 7.45 (s, IH, CH) 8.28 (d, IH, skeleton) Example 33 Ethyl 3-[6-methylimidazo[2,1-b1 thiazol-5-yl]acryleate 5-formyl-6-
33.2 g of methylimidazo[2,1-b]thiazole was heated at 120° C. for 3 hours in 3.12 g of malonic acid, 1.70 g of piperazine and 50 d of dimethylformamide. After the reaction was completed, the solvent was distilled off, and water was added to the residue to obtain 3.30 g of crystals of 3-[6-methylimidazo[2,1-b-1 thiazol-5-yl]acrylic acid. 2.0g of these crystals were mixed with 20g of ethanol containing 2wl of concentrated sulfuric acid.
The mixture was refluxed in w1 for 2 hours. 2.96 g of sulfate crystals of the target product were obtained by cold leaching. This was liberated with a sodium hydroxide solution and recrystallized from ethanol to obtain 1.50 g of the title compound. Melting point 135.0-136.0℃NMRδ(C
DCI, ) 1.33 (t, 3H, CH, CH,) 2.48
(s, 3H, CH,) 4.25 (q, 2H, CM2CH,) 5.96
(d, LH, CH) 6.88 (d, IH, CH) 7.59 (d, IH, CH) 7.70 (d, IH, CH) Example 34 Methyl 2-cyano-3-[6- Methylimidazo [2,
3.32 g of 1-bl thiazol-5-yl]acryleate 5-formyl-6-methylimidazo[2,1-b]thiazole and 2.38 g of methylcyanoacetate
The mixture was refluxed for 2 hours in 20 g of methanol and 20 d of methanol. The crystals precipitated by cold leaching were taken to the bottom of the furnace and recrystallized from methanol to obtain 4.01 g of the title compound. Melting point -1--- NMRδ (CDCI,) 2.55 (s, 3H, CH,) 3,90 (s = 3H, CHs) 6.96
(d, IH, skeleton) 8.12 (s, IH, CH) 8.41 (d, LH, skeleton) Example 35 Methyl 2-cyano-3-[3,6-dimethylimidazo[2,1- bl Thiazol-5-yl J acrylate 5-formyl-3,6-dimethylimidazo [2゜1-b
] Thiazole 1.80g and methylcyanoacetate 1.
Dissolve 5g in methanol 30w1, piperidine 2~
After adding 3 drops, the mixture was refluxed for 3 hours. The crystals precipitated by cold leaching are placed at the bottom of the furnace and recrystallized from ethanol.
1.70 g of the title compound was obtained. Melting point 195.5-196.5°C Example 36 (
Preparation of tablets) Compound of the present invention (Example 8) 250g milk
Sugar 620g Cornstarch 400g Hydroxypropyl cellulose 20g Magnesium stearate 10
g After the above-mentioned compound of the present invention, lactose and cornstarch are mixed until homogeneous, a 5 w/v % ethanol solution of hydroxypropyl cellulose is added and kneaded to form granules. After passing through a 16-mesh sieve and grading, the tablets were compressed by a conventional method to obtain tablets with a weight of 130 square meters, a diameter of 7 mm, and a crude drug content of 25 square meters. Example 37 (Preparation of capsules) Compound of the present invention (Example 22) 250 g milk
Sugar 620g Avicel 620g Magnesium stearate 10g The above-mentioned compound of the present invention, lactose, Avicel, and magnesium stearate were thoroughly mixed until homogeneous, then filled into No. 3 capsules, and each capsule weighed 150 mg and contained crude drugs. It was made into a 25-inch capsule. Test Example 1 Test method for low-intensity: Katabe et al.'s method (Japanese Pharmacological Journal Vol. 81, 42
1-429, 1983), with an exhaust port.
95% N2+ in a box of 0 x 10 x 30 c+i
Aerate a mixed gas of 5% O2 at a flow rate of 10e/win,
Hypoxia was created by replacing the air inside the container. Ddy male mice (5 weeks old, 6 mice in the control group, 6 mice in the test compound group) were placed in the box at the same time, ventilation was started, and the time until respiratory arrest was measured. Furthermore, for mice that survived for 10 minutes or more, the survival time was calculated as 1 minute when calculating the average survival time. The test compounds were dissolved in physiological saline, and those that could not be dissolved were suspended in 0.5% Tween 80 and administered intraperitoneally at a rate of 10 d/kg 30 minutes before the start of the experiment. In addition, as a control, physiological saline was administered intraabdominally at a rate of 10 d/kg 30 minutes before the start of the experiment. Test results: Shown in the table below. The average survival time of the control group (22 o seconds) is set as 100%,
The survival rate (%) of each test compound was calculated. Test Example 2 Test method for KCN's birth (rddy male line neutral mice age, - group 10 mice)
l::KcN3. Ow/kg was administered into the tail vein for 5 seconds, and the time until respiratory arrest (survival time) was measured. The test compounds were dissolved in physiological saline, and those that could not be dissolved were suspended in 0.5% Tween 80 and administered intraperitoneally at a rate of 10 d/kg 30 minutes before the start of the experiment. As a control, physiological saline was used in the experiment at a ratio of 10-/-.
It was administered intraperitoneally 30 minutes before the start. Test results: Shown in the table below. The survival rate (%) of each test compound was calculated by setting the average survival time (50 seconds) of the control group as 100%.Test Example 3 Selection 1 Koai I Test Method The method of Nitobe et al. (Japanese Pharmacological Journal 81) Volume 421
~429 pages, 1983), DDY male mice (body weight 24~27g, 12 control group, 8 test compound group)
The test compound was administered intraperitoneally at 50 mg/feet to 11 animals.
The animals were decapitated 30 minutes after administration. After decapitation, the time until gasping-like breathing in the head stopped (survival time) was measured. The test results are shown in the secondary table. The survival rate (%) of each compound was calculated using the average survival time (18 seconds) of the control group as 100%. Test Example 4 Test method using Asubican crush model: Wistar neutral rats fasted for 24 hours (7 to 8 weeks old, body weight 180 to 227 g; 7 to 8 rats in test compound administration group, control group Each test compound suspended in a 5% gum arabic aqueous solution was administered to 16 animals (100 x 151!). /
kg was orally administered, and 30 minutes after administration, an additional 2 doses of aspirin were administered.
00■/gift was orally administered. Seven hours after administration of aspirin, the stomach was removed under ether anesthesia, and the long axis of punctate and linear erosions and ulcers were measured under a microscope, and the ulcer index and degree of inhibition were calculated. In addition, the control group received 5 m//b of 5% gum arabic aqueous solution.
was administered orally at a dose of Test results: Shown in the table below. Zero P < 0.05 End P < 0.01 Test Example 5 Antihypertensive test method using a stress model: Wistar male rats fasted for 24 hours (7 to 8 weeks old, body weight 191 to 238 g: test compound administration group 7) ~8 animals, control group 16 animals) each test compound suspended in 5% aqueous gum arabic solution 100 μ/! M/kg was orally administered, and 30 minutes after administration, the mice were immersed up to the xiphoid process in a water bath at 22±1°C using a stress cage of a large-scale drug type, and stress was applied for 6 hours. After the stress was applied, the rats were sacrificed by cervical dislocation, the stomach was removed, and the long axis of punctate and linear erosions and ulcers were measured under a microscope, and the ulcer index and inhibition rate were calculated. For the control group, a 5% aqueous gum arabic solution was used at a dose of 5d/-. The test results are shown in the secondary table. Water-ethanol 5Wl/- was orally administered. One hour after administration of absolute ethanol, the stomach was removed under ether anesthesia, punctate and linear erosions and the long axis of the ulcer were measured under a microscope, and the ulcer index and inhibition rate were calculated. In addition, to the control group, a 5% aqueous solution of gum arabic was orally administered at a dose of 5-/g. The test results are shown in the secondary table. Honmoto P < 0.01 Honmoto Zero P < 0.00
1 Test Example 6 Test method using enol model: 24-hour fasted Wistar neutral rats (7 to 8 weeks old, body weight 180 to 250 g: 5 in test compound administration group, 4 to 7 in control group) 100 mg of each test compound suspended in 5% gum arabic aqueous solution was administered to
kg was orally administered, and 30 minutes after administration, non-test example 7 secretion 1 Test method: Wistar neutral rats fasted for 24 hours (7 to 8 weeks old, body weight 192 to 241 g; (8 to 9 animals in the administration group and 15 animals in the control group) were given 100 x 15 w of each test compound suspended in a 5% gum arabic aqueous solution.
kg was orally administered, and 30 minutes after administration, pylorus ligation was performed under ether anesthesia. After 4 hours, the stomach was removed under ether anesthesia and gastric juice was collected. The collected gastric juice was centrifuged (2,500 rpm) at 4°C for 10 minutes, and after collecting the supernatant, the amount of gastric juice and the pH of the gastric juice were measured using a pH meter. Furthermore, the amount of free hydrochloric acid and the total acidity were measured using T6pfer reagent and phenolphthalein reagent, respectively. Furthermore, the amount of pepsin secreted in the gastric juice was measured using a portion of the gastric juice according to Anson's Ca5ein method. In addition, the control group received 5% gum arabic aqueous solution at 5w1/k.
It was administered orally at a dose of 1.5 g. The test results are shown in the secondary table. Test Example 8 Koyu Kouki Test method: 5LC-ICR male line medium mice (6-7 weeks old,
500 and 1,000 g of the test compound suspended in a 5% gum arabic aqueous solution were given to 5 animals (body weight 26.6 to 33.6 g, 5 animals per group).
0+ag/5@l/kg was orally administered once. Thereafter, the mice were observed for 7 days to see if they died. Test results: Shown in the table below.
Claims (1)
水素原子、低級アルキル基、アセチル基、ヒドロキシア
ルキル基、カルボン酸アルキルエステル基を；Ｒ＿３は
水素原子、アルデヒド基、カルボン酸アルキルエステル
基、▲数式、化学式、表等があります▼ （Ｒ＿５及びＲ＿６はそれぞれ同一又は異なり、水素原
子、低級アルキル基、ヒドロキシアルキル基、ベンジル
基あるいはＲ＿５とＲ＿６はこれらが結合している窒素
原子と一緒にモルホリノ基などの環を形成することがで
きる基を表す）、−ＣＨ（ＯＨ）−Ｒ＿７（Ｒ＿７は水
素原子、低級アルキル基、フェニル基、シクロアルキル
基を表す）、▲数式、化学式、表等があります▼（Ｒ＿
８及びＲ＿９はそれぞれ同一又は異 なり、水素原子、シアノ基、カルボン酸アルキルエステ
ル基を表す）、−ＣＨ＝Ｎ−Ｒ＿１＿０（Ｒ＿１＿０は
水酸基、低級アルコキシ基を表す）、２−シアノ−３−
ヒドロキシプロピル基、テトラゾリル基を；Ｒ＿４は水
素原子、低級アルキル基を表す］で示されるイミダゾ［
２，１−ｂ］チアゾール類又はその薬理学的に許容され
る塩。(1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 and R_2 are each the same or different,
Hydrogen atom, lower alkyl group, acetyl group, hydroxyalkyl group, carboxylic acid alkyl ester group; R_3 is a hydrogen atom, aldehyde group, carboxylic acid alkyl ester group, ▲ Numerical formula, chemical formula, table, etc. ▼ (R_5 and R_6 are (respectively the same or different, hydrogen atom, lower alkyl group, hydroxyalkyl group, benzyl group, or R_5 and R_6 represent groups capable of forming a ring such as a morpholino group together with the nitrogen atom to which they are bonded), -CH(OH)-R_7 (R_7 represents a hydrogen atom, lower alkyl group, phenyl group, cycloalkyl group), ▲Mathematical formulas, chemical formulas, tables, etc.▼(R_
8 and R_9 are the same or different and each represents a hydrogen atom, a cyano group, or a carboxylic acid alkyl ester group), -CH=N-R_1_0 (R_1_0 represents a hydroxyl group or lower alkoxy group), 2-cyano-3-
hydroxypropyl group, tetrazolyl group; R_4 represents a hydrogen atom or lower alkyl group]
2,1-b] Thiazoles or pharmacologically acceptable salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63329341A JP2804276B2 (en) | 1988-12-28 | 1988-12-28 | Imidazo [2,1-b] thiazoles |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63329341A JP2804276B2 (en) | 1988-12-28 | 1988-12-28 | Imidazo [2,1-b] thiazoles |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02178289A true JPH02178289A (en) | 1990-07-11 |
| JP2804276B2 JP2804276B2 (en) | 1998-09-24 |
Family
ID=18220371
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63329341A Expired - Fee Related JP2804276B2 (en) | 1988-12-28 | 1988-12-28 | Imidazo [2,1-b] thiazoles |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2804276B2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5851425A (en) * | 1996-04-04 | 1998-12-22 | Rolic Ag | Imidazothiazoles |
| US5919799A (en) * | 1995-03-13 | 1999-07-06 | Nikken Chemicals Co., Ltd. | Imidazothiazole compound |
| JP2015522622A (en) * | 2012-07-18 | 2015-08-06 | モラスキ，ギャレット | 5,5-heteroaromatic anti-infective compound |
-
1988
- 1988-12-28 JP JP63329341A patent/JP2804276B2/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5919799A (en) * | 1995-03-13 | 1999-07-06 | Nikken Chemicals Co., Ltd. | Imidazothiazole compound |
| US5851425A (en) * | 1996-04-04 | 1998-12-22 | Rolic Ag | Imidazothiazoles |
| CN1098854C (en) * | 1996-04-04 | 2003-01-15 | 罗利克有限公司 | Imidazothiazoles |
| JP2015522622A (en) * | 2012-07-18 | 2015-08-06 | モラスキ，ギャレット | 5,5-heteroaromatic anti-infective compound |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2804276B2 (en) | 1998-09-24 |
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| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |