JPH0469385A - New imidazoline derivative - Google Patents
New imidazoline derivativeInfo
- Publication number
- JPH0469385A JPH0469385A JP17832690A JP17832690A JPH0469385A JP H0469385 A JPH0469385 A JP H0469385A JP 17832690 A JP17832690 A JP 17832690A JP 17832690 A JP17832690 A JP 17832690A JP H0469385 A JPH0469385 A JP H0469385A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- thienyl
- pyridyl
- present
- 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
- 150000002462 imidazolines Chemical class 0.000 title claims 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 7
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims 1
- 229940126585 therapeutic drug Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 3
- PQJVASLIHPOECX-UHFFFAOYSA-N pyridin-2-yl(thiophen-2-yl)methanone Chemical compound C=1C=CC=NC=1C(=O)C1=CC=CS1 PQJVASLIHPOECX-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- KWMBADTWRIGGGG-UHFFFAOYSA-N 2-diethoxyphosphorylacetonitrile Chemical compound CCOP(=O)(CC#N)OCC KWMBADTWRIGGGG-UHFFFAOYSA-N 0.000 abstract 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 abstract 1
- 238000006052 Horner reaction Methods 0.000 abstract 1
- 150000007960 acetonitrile Chemical class 0.000 abstract 1
- MOOAHMCRPCTRLV-UHFFFAOYSA-N boron sodium Chemical compound [B].[Na] MOOAHMCRPCTRLV-UHFFFAOYSA-N 0.000 abstract 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 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 9
- 239000008103 glucose Substances 0.000 description 9
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 8
- 208000002249 Diabetes Complications Diseases 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000003178 anti-diabetic effect Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 230000002218 hypoglycaemic effect Effects 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 208000013016 Hypoglycemia Diseases 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- -1 cellucose Polymers 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000004310 lactic acid Substances 0.000 description 4
- 235000014655 lactic acid Nutrition 0.000 description 4
- 231100000053 low toxicity Toxicity 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 206010012655 Diabetic complications Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229940123208 Biguanide Drugs 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 229940100389 Sulfonylurea Drugs 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229940127003 anti-diabetic drug Drugs 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 150000004283 biguanides Chemical class 0.000 description 2
- SCPOPPZYKMBXRM-UHFFFAOYSA-N boric acid;2-methylaniline Chemical compound OB(O)O.CC1=CC=CC=C1N SCPOPPZYKMBXRM-UHFFFAOYSA-N 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 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
- 108010010803 Gelatin Proteins 0.000 description 1
- 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 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 238000010876 biochemical test Methods 0.000 description 1
- 229960004111 buformin Drugs 0.000 description 1
- XSEUMFJMFFMCIU-UHFFFAOYSA-N buformin Chemical compound CCCC\N=C(/N)N=C(N)N XSEUMFJMFFMCIU-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- MFFWLPUTVHVELN-UHFFFAOYSA-N dichloromethane;propan-2-yl acetate Chemical compound ClCCl.CC(C)OC(C)=O MFFWLPUTVHVELN-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000009207 exercise therapy Methods 0.000 description 1
- 239000001530 fumaric acid 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
- 229960004580 glibenclamide Drugs 0.000 description 1
- 238000007446 glucose tolerance test Methods 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 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
- 239000011976 maleic acid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
で表わされるイ
ミダプリン誘導体である本発明化
合物は、極めて優れた抗糖尿病作用を有しており、糖尿
病および糖尿病合併症などを予防あるいは治療する医薬
品として利用することができる。[Detailed Description of the Invention] The compound of the present invention, which is an imidapurine derivative expressed in the industrial field of application, has extremely excellent antidiabetic effects and can be used as a pharmaceutical for preventing or treating diabetes and diabetic complications. can do.
Ｂ 従来の技術
イノスリン非依存性糖尿病を治療するための経口糖尿病
薬は、 トルブタマイト、グリベンクラミドに代表され
るスルホニルウレア系およびブホルミン、メトホルミン
に代表されるビグアナイド系に大別される。しかしなが
ら前者は重篤な低血糖を、後者は乳酸ア／ドー／スを引
き起こす危険を有している。さらに前者は、高イノスリ
ン血症を悪化させる。従って、現在イノスリ／非依存性
糖尿病患者の治療においては、食事および運動療法に主
眼がおかれ、スルホニルウレア系経口糖尿病薬は補助的
に使用されているに過ぎない。ビグアナイド系薬剤の使
用はさらに頻度が低い。B. Prior Art Oral antidiabetic drugs for treating inosulin-independent diabetes mellitus are broadly classified into sulfonylureas represented by tolbutamite and glibenclamide, and biguanides represented by buformin and metformin. However, the former has the risk of causing severe hypoglycemia, and the latter has the risk of causing lactic acid intake/dose. Furthermore, the former worsens hyperinosulinemia. Therefore, in the current treatment of Inosuri/non-dependent diabetic patients, the main focus is on diet and exercise therapy, and oral sulfonylurea antidiabetic drugs are only used as an adjunct. Biguanides are used even less frequently.
トルブタマイトは正常実験動物において、その正常血糖
値あるいは糖負荷後の血糖値を強く低下させる。しかし
ながら遺伝的糖尿病動物、例えばｏｂ１０ｂマウス、Ｋ
Ｋマウスの血糖値にはほとんど影響を及ぼさないことが
知られている［例えば、Ｃｈｅｍ、Ｐｈａｒｍ、 Ｂ
ｕｌｌ、、３４．４１５０ （１９８６）； Ｂｉｏ
ｃｈｅｍ、 Ｐｈａｒｍａｃｏｔ、 ３２，８４
９ （１９８３）； Ａｒｚｎｅｉｍ、−Ｆｏｒｓｃ
ｈ、、３６． １７７０ （１９８６）などを参照。］
。Tolbutamite strongly lowers normal blood sugar levels or blood sugar levels after glucose loading in normal experimental animals. However, genetically diabetic animals such as ob10b mice, K
It is known that it has almost no effect on the blood sugar level of K mice [for example, Chem, Pharm, B
ull, 34.4150 (1986); Bio
chem, Pharmacot, 32,84
9 (1983); Arzneim, -Forsc.
h,,36. 1770 (1986), etc. ]
.
ある種のイミダ／ツノ誘導体、例えば２−［２−フェニ
ル−２−（２−ピリジル）エチル］−２イミダシリンが
血糖降下作用を有することが知られている［例えば、Ｃ
Ｃ１１ｅ、 Ｐｈａｒｍ、 Ｂｕｌｌ、 ２８
．１３９４（１９８０）； 特開昭５２−１５６９３２
などを参照。さらに特開昭５２−１５１１６５も参照。Certain imida/horn derivatives, such as 2-[2-phenyl-2-(2-pyridyl)ethyl]-2-imidacillin, are known to have hypoglycemic effects [e.g.
C11e, Pharm, Bull, 28
．． 1394 (1980); JP-A-52-156932
See etc. Also refer to JP-A-52-151165.
］。].
しかしながら、チエニル基を有することを特徴とする本
発明化合物およびこれらの優れた抗糖尿病作用について
の記載は全く知られていない。However, no description is known of the compounds of the present invention characterized by having a thienyl group and their excellent antidiabetic effects.
Ｃ０発明が解決しようとする問題点
前述したように、従来の糖尿病側薬は低血糖あるいは乳
酸アンドーンスなどの副作用を生じるという問題点を有
している。本発明の目的は、低血糖あるいは乳酸ア／ド
ーシスなどの副作用を生じず、しかも低毒性で安全性に
優れた薬物を提供することにある。Problems to be Solved by the C0 Invention As mentioned above, conventional antidiabetic drugs have the problem of causing side effects such as hypoglycemia and lactic acid imbalance. An object of the present invention is to provide a drug that does not cause side effects such as hypoglycemia or lactic acid adhesion, has low toxicity, and is highly safe.
Ｄ、 問題点を解決するための手段と作用本発明者ら
は、Ｉで表される２−［２−（２−ピリジル）−２−（
２−チエニル）エチルコー２イミグゾリノまたはその酸
付加塩を合成することにより、前記問題点を解決しよう
と試みた。D. Means and action for solving the problems The present inventors have discovered that 2-[2-(2-pyridyl)-2-(
An attempt was made to solve the above problems by synthesizing 2-thienyl)ethylco-2imigzolino or an acid addition salt thereof.
本発明化合物（１）は、式
ミン酸付加塩を作用させることにより、製造する事がで
きる。The compound (1) of the present invention can be produced by reacting with a minic acid addition salt of the formula.
原料となる■は、２−ピリジル２−チエニルケトン［米
国特許第３４０８３５８号（１９６８）Ｃｈｅｍ、Ａｂ
Ｓｔｒ、 ７０，４７３１３Ｑ（１９６９）： Ｊ
、Ｍｅｄ、Ｃｈｅｍ、、１２． １０９３ （１９６９
）に記載の化合物。コにノアツメチルフォスフオン酸ジ
エチルを用いたＷ ＋ ｔ ｔＩ ｇ −Ｈｏ ｒ ｎ
ｅ ｒ反応により、式で表わされる化合物を得、さら
に水素化ホウ素ナトリウムなどにより還元することによ
り、容易に合成することができる。The raw material ■ is 2-pyridyl 2-thienyl ketone [US Pat. No. 3,408,358 (1968) Chem, Ab
Str, 70, 47313Q (1969): J
,Med,Chem,, 12. 1093 (1969
). W + t tI g -Hor n using diethyl Noahs methylphosphonate
It can be easily synthesized by obtaining a compound represented by the formula by an er reaction and further reducing it with sodium borohydride or the like.
本発明化合物（＋）は、通常の方法にて酸付加塩とする
ことができる。酸付加塩としては、薬学的に許容される
塩、例えば塩酸、硫酸、フマル酸、マレイン酸、酒石酸
、メタンスルホノ酸、パラトルエンスルホン酸などの塩
が適当である。The compound (+) of the present invention can be converted into an acid addition salt by a conventional method. Suitable acid addition salts include pharmaceutically acceptable salts such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, tartaric acid, methanesulfonic acid, and paratoluenesulfonic acid.
本発明化合物（１）は極めて優れた抗糖尿病作用を示す
。この作用は、自然発症糖尿病マウスであるｏｂ１０ｂ
マウスあるいはＫＫマウスにおける糖負荷試験によって
確認することができる。すなわち、本発明化合物（＋）
の、例えば２５あるいは５０ｍｇ／ｋｇの経口投与は、
ｏｂ１０ｂマウスあるいはＫＫマウスにおいて糖負荷に
よる血糖値の上昇を強く抑制した。Compound (1) of the present invention exhibits extremely excellent antidiabetic activity. This effect was demonstrated in ob10b, a spontaneously diabetic mouse.
This can be confirmed by a glucose tolerance test in mice or KK mice. That is, the compound of the present invention (+)
For example, oral administration of 25 or 50 mg/kg of
In ob10b mice or KK mice, the increase in blood sugar level caused by glucose loading was strongly suppressed.
また、本発明化合物（＋）は極めて低毒性であった。す
なわち、ｄｄＹ系マウスに３００ Ｂ／ｋｇを２週間連
続投与した時、化合物による影響は認められなかった。Moreover, the compound (+) of the present invention had extremely low toxicity. That is, when 300 B/kg was continuously administered to ddY mice for two weeks, no effect of the compound was observed.
本発明化合物（＋）は申独で、あるいは他の組成物と共
に、例えば錠剤、トローチ剤、丸剤、顆粒剤、散剤、カ
プセル剤、ア、／プル剤、坐剤などの形態で使用するこ
とができる。他の組成物としては例えば、デ／プン、デ
キストリン、ノコ糖、ケイ酸、カルホキ／メチルセルロ
ース、セルコース、ゼラチン、ポリビニルピロリド／、
グリセリン、寒天、炭酸カル／ラム、炭酸水素ナトリウ
ム、パラフィン、セチルアルコール、ステアリン酸エス
テル、カオリベ ベットナイト、タルク、ステアリン酸
カル／ウム、ステアリン酸マグネ／ウムポリエチレング
リコール、水、エタノール、イ゛／プロパ／−ル、プロ
ビレ７グリコールなどが挙げられる。The compound (+) of the present invention can be used alone or with other compositions, for example, in the form of tablets, troches, pills, granules, powders, capsules, tablets/pulls, suppositories, etc. I can do it. Other compositions include, for example, de/pun, dextrin, saw sugar, silicic acid, calhoki/methylcellulose, cellucose, gelatin, polyvinylpyrrolid/,
Glycerin, agar, cal/rum carbonate, sodium bicarbonate, paraffin, cetyl alcohol, stearate, kaolivetonite, talc, cal/um stearate, magne/um stearate polyethylene glycol, water, ethanol, dipropylene/propanol. /-ol, probile 7 glycol, and the like.
本発明化合物（＋）は、極めて優れた抗糖尿病作用を有
しており、糖尿病および糖尿病合併症などを予防あるい
は治療する医薬品として有用である。The compound (+) of the present invention has an extremely excellent antidiabetic effect and is useful as a pharmaceutical for preventing or treating diabetes and diabetic complications.
Ｅ、 実施例
（１） ２−［２−（２−ピリジル’）−２−（２
−チエニル）エチル］−２−イミダハン３−（２−ピリ
ノル）−３−（２−チエニル）プロピオニトリル（６，
４ｇ）およびエチレンジアミノパラトルエンスルホノ酸
塩（８，４ｇ）の混合物を１８５−１９０°Ｃに２時間
加熱。冷抜水を加え、ＮａＯＨアルカリ性とした後、塩
化メチレンにて抽出。有機層を水洗、硫酸マグ不ノウム
で乾燥。溶媒留去後残さをカラムクロマトグラフィー（
シリカゲル、塩化メチレン： メタノール＝２０＝１）
にて精製。塩化メチレン−酢酸イソプロピルより再結晶
し、無色プリズム品、ｍｐ９０−９２℃、 ４．６ ｇ
を得。E, Example (1) 2-[2-(2-pyridyl')-2-(2
-thienyl)ethyl]-2-imidahane 3-(2-pyrinol)-3-(2-thienyl)propionitrile (6,
4g) and ethylene diamino para-toluenesulfonate (8.4g) was heated to 185-190°C for 2 hours. Add cold drained water to make the mixture alkaline with NaOH, and then extract with methylene chloride. Wash the organic layer with water and dry with magfunoum sulfate. After evaporation of the solvent, the residue was subjected to column chromatography (
Silica gel, methylene chloride: methanol = 20 = 1)
Refined at. Recrystallized from methylene chloride-isopropyl acetate, colorless prism product, mp90-92℃, 4.6 g
get.
ＮＭＲ（ＣＤＣＩ３）δ： ３．０４ （ＩＨ，ｄｄ
。NMR (CDCI3) δ: 3.04 (IH, dd
.
Ｊ＝１４．６． ６．８Ｈｚ）、 ３．２０ （ＩＨ
，ｄｄ。J=14.6. 6.8Hz), 3.20 (IH
, dd.
Ｊ＝１４．６． ８．６Ｈｚ）、 ３．４３ （４Ｈ
，Ｓ）。J=14.6. 8.6Hz), 3.43 (4H
,S).
４．２３ （ＩＨ，ｂｒｓ）、 ４．８１ （
ＩＨ，ｄｄ。4.23 (IH, brs), 4.81 (
IH, dd.
Ｊ＝８．６． ６．８Ｈｚ）、 ６．７８−６．
９４ （２Ｈ，ｍ）、 ６．９６−７．２８
（３Ｈ，ｍ）、 ７．５３ （ＩＨ，ｔｄ、
Ｊ＝７．４． ２．１Ｈｚ）、 ８．４４−８．
６２（ＩＨ，ｍ）。J=8.6. 6.8Hz), 6.78-6.
94 (2H, m), 6.96-7.28
(3H, m), 7.53 (IH, td,
J=7.4. 2.1Hz), 8.44-8.
62 (IH, m).
２塩酸塩、無色プリズム晶（メタノ−ルーア七トン）、
ｍｐｌｏｏ−１０３℃。Dihydrochloride, colorless prismatic crystals (methanol 7 tons),
mploo-103°C.
（２） ３−（２−ビリノル）−３−（２−チエニ
ル）アクリロニトリル
ナトリウム（４，５５ｇ）およびエタノール（２５０ｍ
ｌ）より製したナトリウムエチラートの溶液にンアノメ
チルフォスフオン酸ジエチルを加え２０分攪拌。ついで
２−ピリジル２−チエニルケトン（３２，３ｇ）を添加
した後、１時間還流。冷抜水を加え、酢酸エチルにて抽
出。有機層を水洗、硫酸マグネ／ラムで乾燥。溶媒留去
後残さをカラムクロマトグラフィー（シリカゲル、ヘキ
サン：エーテル−３：ｌ）にて精製、Ｚおよび８体１゜
６： ｌの混合物として無色油状物３３２ｇを得。(2) 3-(2-bilinol)-3-(2-thienyl)acrylonitrile sodium (4.55 g) and ethanol (250 m
Diethyl anomethylphosphonate was added to the solution of sodium ethylate prepared in step 1) and stirred for 20 minutes. Then, 2-pyridyl 2-thienyl ketone (32.3 g) was added, and the mixture was refluxed for 1 hour. Add cold drained water and extract with ethyl acetate. The organic layer was washed with water and dried with magnesium sulfate/rum. After evaporation of the solvent, the residue was purified by column chromatography (silica gel, hexane:ether-3:l) to obtain 332 g of a colorless oil as a mixture of Z and 8-isomers at 1°6:l.
ＺおよびＥ体をカラムクロマトグラフィー（シリカゲル
、エーテル： へ牛サン＝ｌ： ３）にて分離した。The Z and E forms were separated by column chromatography (silica gel, ether: 3).
２体１．無色油状物。ＮＭＲ（ＣＤＣＩ３）δ： ６１
９ （ＩＨ，ｓ）、 ６．９９−７．８９ （
６Ｈ，ｍ）８．５０−８．７８ （ＩＨ，ｍ）。2 bodies 1. Colorless oil. NMR (CDCI3) δ: 61
9 (IH,s), 6.99-7.89 (
6H, m) 8.50-8.78 (IH, m).
Ｅ体、無色油状物。ＮＭＲ（ＣＤＣ１３）６： ５８
８ （ＩＨ，ｓ）、 ６．８８−７．９６ （
６Ｈ，ｍ）８．６０−８．８４ （ＩＨ，ｍ）。E-form, colorless oil. NMR (CDC13) 6: 58
8 (IH,s), 6.88-7.96 (
6H, m) 8.60-8.84 (IH, m).
（３） ３−（２−ピリジル）−３−（２−チエニ
ル）プロピオニトリル
３−（２−ピリジル）−３−（２−チエニル）アクリロ
ニトリル（３３，２ｇ）、エタノール（１５０ｍｌ）お
よび水（７０ｍｌ）の混合物を還流しながら、数回に分
は水素化ホウ素ナトリウム（１０ｇ）を添加。さらに５
時間還流。冷抜水を加え、酢酸エチルにて抽出。有機層
を水洗、硫酸マグネシウムで乾燥。溶媒留去後残さをカ
ラムクロマトグラフィー（シリカゲル、ヘキサン： エ
ーテル＝３： ２）にて精製、無色油状物２３５ｇを
得。(3) 3-(2-pyridyl)-3-(2-thienyl)propionitrile 3-(2-pyridyl)-3-(2-thienyl)acrylonitrile (33.2 g), ethanol (150 ml) and water ( While refluxing the mixture (70 ml), sodium borohydride (10 g) was added in portions. 5 more
Time reflux. Add cold drained water and extract with ethyl acetate. The organic layer was washed with water and dried with magnesium sulfate. After evaporating the solvent, the residue was purified by column chromatography (silica gel, hexane:ether=3:2) to obtain 235 g of a colorless oil.
ＮＭＲ（ＣＤＣＩ、）δ： ３．＋ ６ （ＩＨ，ｄ
ｄ。NMR (CDCI,) δ: 3. + 6 (IH, d
d.
Ｊ＝１６．７． ６．９Ｈ１）、 ３．３４
（ＩＨ，ｄｄ。J=16.7. 6.9H1), 3.34
(IH, dd.
Ｊ＝１６．７． ６．９Ｈｚ）、 ４．７０ （
ＩＨ，ｔ。J=16.7. 6.9Hz), 4.70 (
IH,t.
Ｊ＝６．９Ｈｚ）、 ６．９０−７．３３ （５Ｈ
，ｍ）。J=6.9Hz), 6.90-7.33 (5H
, m).
７．４８−７．８０ （ＩＨ，ｍ）、 ８．４８
−８．７８（ＩＨ，ｍ）。7.48-7.80 (IH, m), 8.48
-8.78 (IH, m).
Ｆ 効果
本発明化合物（１）は、極めて優れた抗糖尿病作用を示
した。さらに極めて低毒性であった。これらは次の様な
方法で確認することができる。F Effect The compound (1) of the present invention showed extremely excellent antidiabetic activity. Furthermore, the toxicity was extremely low. These can be confirmed by the following methods.
月齢３−４ケ月のｏｂ１０ｂマウスを１８時時間音し、
検体あるいは精製水を経口投与（０，０２ｍ１／ｇ）３
０分後にグルコース（４ｇ ／’ ｋ ｇ ）を経口投
与。採血は、検体あるいは精製水投与前、グルコース投
与前、グルコース投与３０．６０．１２０分後に尾静脈
より行い、血糖値はｏ−トルイジンホウ酸性にて測定。A 3-4 month old ob10b mouse was exposed to a sound at 18:00.
Oral administration of specimen or purified water (0.02ml/g)3
Glucose (4 g/' kg) was orally administered 0 minutes later. Blood was collected from the tail vein before administering the sample or purified water, before administering glucose, and 30,60,120 minutes after administering glucose, and blood sugar levels were measured using o-toluidine boric acid.
月齢３−４ケ月のＫＫマウスを１８時時間音し、検体あ
るいは精製水を経口投与（０，０２ｍ１／ｇ）、３０分
後にグルコース（４ｇ／ｋ ｇ）を経口投与。採血は、
検体あるいは精製水投与前、グルコ−ス投与前、グルコ
ース投与３０．６０．１２０分後に尾静脈より行い、血
糖値はｏ−トルイジンホウ酸洗にて測定。KK mice aged 3 to 4 months were kept at 6:00 p.m., and the sample or purified water was orally administered (0.02 ml/g), and 30 minutes later, glucose (4 g/kg) was orally administered. Blood collection is
Measurement was performed from the tail vein before administration of the sample or purified water, before administration of glucose, and 30, 60, and 120 minutes after administration of glucose, and the blood sugar level was measured by washing with o-toluidine boric acid.
ｄｄＹ系マウスに検体を１日１回２週間経口投与。投与
期間中行動観察、生化学検査を実施。投与終了後直ちに
組織学的、病理学的検査を実施。The sample was orally administered to ddY mice once a day for 2 weeks. Behavioral observations and biochemical tests were conducted during the administration period. Histological and pathological examinations were conducted immediately after the end of administration.
本発明化合物（１）は、例えば２５あるいは５Ｑ ｍ
ｇ ／ ｋ ｇの経口投与で糖負荷による血糖値の上昇
を極めて強く抑制した。一方、トルブタマイトの５０ｍ
ｇ／ｋｇ投与は有意な作用を示さなかった。また塩酸ブ
士ルミンの５０ ｍ ｇ ／ ｋ ｇ 投与は有意な作
用を示さないかあるいは弱かった。The compound (1) of the present invention is, for example, 25 or 5Q m
Oral administration at a dose of g/kg extremely strongly suppressed the rise in blood sugar levels caused by glucose loading. On the other hand, 50m of trubutamite
g/kg administration had no significant effect. Furthermore, administration of 50 mg/kg of butylmine hydrochloride showed no significant effect or had a weak effect.
また、本発明化合物（１）は低毒性であった。Moreover, the compound (1) of the present invention had low toxicity.
すなわち、ｄｄＹ系マウスに３００ ｍ ｇ ／ ｋ
ｇを２週間連続投与した時、化合物による影響は認めら
れなかった。That is, 300 mg/k for ddY mice.
No effect of the compound was observed when g was administered continuously for two weeks.
本発明化合物（１）は、血糖値の上昇を強く抑制するに
も関わらず、低血糖を生じにくく、また乳酸ア／ドーン
スなどの副作用を生ぜず、極めて低毒性であり優れた薬
物である。Although the compound (1) of the present invention strongly suppresses the increase in blood sugar level, it is an excellent drug because it hardly causes hypoglycemia, does not cause side effects such as lactic acid addition/dose, and has extremely low toxicity.
本発明化合物（１）は、極めて優れた抗糖尿病作用を有
しており、糖尿病および糖尿病合併症などを予防あるい
は治療する医薬品として育用である。The compound (1) of the present invention has an extremely excellent anti-diabetic effect and is being used as a drug for preventing or treating diabetes and diabetic complications.
Claims (2)
付加塩を含有することを特徴とする糖尿病治療薬。(2) A therapeutic drug for diabetes characterized by containing the compound according to claim 1 or an acid addition salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17832690A JPH0469385A (en) | 1990-07-05 | 1990-07-05 | New imidazoline derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17832690A JPH0469385A (en) | 1990-07-05 | 1990-07-05 | New imidazoline derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0469385A true JPH0469385A (en) | 1992-03-04 |
Family
ID=16046533
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17832690A Pending JPH0469385A (en) | 1990-07-05 | 1990-07-05 | New imidazoline derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0469385A (en) |
-
1990
- 1990-07-05 JP JP17832690A patent/JPH0469385A/en active Pending
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