JPH02145572A - N-substituted amide - Google Patents
N-substituted amideInfo
- Publication number
- JPH02145572A JPH02145572A JP63294491A JP29449188A JPH02145572A JP H02145572 A JPH02145572 A JP H02145572A JP 63294491 A JP63294491 A JP 63294491A JP 29449188 A JP29449188 A JP 29449188A JP H02145572 A JPH02145572 A JP H02145572A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compd
- pyridine
- reacting
- obtd
- 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
- -1 N-substituted amide Chemical class 0.000 title claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 22
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 11
- 238000000034 method Methods 0.000 abstract description 9
- 239000000203 mixture Substances 0.000 abstract description 8
- 208000019423 liver disease Diseases 0.000 abstract description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002253 acid Substances 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 2
- 150000001340 alkali metals Chemical group 0.000 abstract description 2
- 150000001412 amines Chemical class 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract description 2
- 230000008707 rearrangement Effects 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 206010067125 Liver injury Diseases 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229960001438 immunostimulant agent Drugs 0.000 description 2
- 239000003022 immunostimulating agent Substances 0.000 description 2
- 230000003308 immunostimulating effect Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- QKGHBQJLEHAMKJ-UHFFFAOYSA-N (3,4,6-triacetyloxy-5-azidooxan-2-yl)methyl acetate Chemical compound CC(=O)OCC1OC(OC(C)=O)C(N=[N+]=[N-])C(OC(C)=O)C1OC(C)=O QKGHBQJLEHAMKJ-UHFFFAOYSA-N 0.000 description 1
- WDTSYONULAZKIE-UHFFFAOYSA-N 2-bromo-1-pyridin-3-ylethanone;hydron;bromide Chemical compound [Br-].BrCC(=O)C1=CC=C[NH+]=C1 WDTSYONULAZKIE-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- RJBWVMIFKQOFBF-UHFFFAOYSA-N N-(2-oxo-2-pyridin-3-ylethyl)acetamide Chemical compound CC(=O)NCC(=O)c1cccnc1 RJBWVMIFKQOFBF-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000009692 acute damage Effects 0.000 description 1
- 231100000439 acute liver injury Toxicity 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000009693 chronic damage Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- PKHMTIRCAFTBDS-UHFFFAOYSA-N hexanoyl hexanoate Chemical compound CCCCCC(=O)OC(=O)CCCCC PKHMTIRCAFTBDS-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 235000018343 nutrient deficiency Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- DRTZAIDVOGUYSP-UHFFFAOYSA-N pyridin-1-ium;chloride;hydrochloride Chemical compound Cl.Cl.C1=CC=NC=C1 DRTZAIDVOGUYSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 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
- 238000005406 washing Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Abstract
Description
【発明の詳細な説明】
り策上久千浬１１
本発明は、医薬の分野、特に肝臓疾患の予防および治療
に有用な新規Ｎ−置換アミド類に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel N-substituted amides useful in the field of medicine, particularly in the prevention and treatment of liver diseases.
従】１１支賓
肝ＭＩａは、ウィルス、アルコール、栄養不足、肝循環
障害などの種々の原因により急性または慢性の障害を受
け、脂肪肝、黄厄、肝硬変などの肝疾患を起こす。最近
、これらの肝疾患治療剤としてマロチレートなどが報告
された。しかし、食事療法などの対症療法、ステロイド
剤、免疫賦活剤などによる薬物療法などを含め、真に有
効な治療法および治療剤はまだ見出されていない。11. Liver MIa suffers from acute or chronic damage due to various causes such as viruses, alcohol, nutritional deficiencies, and hepatic circulation disorders, resulting in liver diseases such as fatty liver, yellow disease, and liver cirrhosis. Recently, malotylate and the like have been reported as therapeutic agents for these liver diseases. However, truly effective treatments and therapeutic agents have not yet been found, including symptomatic treatments such as dietary therapy and drug therapy using steroids, immunostimulants, and the like.
明が 決しようとする課題
上記のように肝疾患、特に遷延または慢性化したものに
対しては、未だ満足すべきものがない。Issues to be solved by the Ming Dynasty As mentioned above, there are still unsatisfactory results regarding liver diseases, especially those that are prolonged or chronic.
また、ステロイド剤、免疫賦活剤などによる薬物療法に
あっては、重篤な副作用の問題がある。Furthermore, drug therapy using steroids, immunostimulants, etc. has the problem of serious side effects.
課題を解決するための手段
本発明者らは、上記課題を解決した肝疾患治療剤を開発
すべく種々のＮ−置換アミド類を合成し、その効果を調
べた。その結果、本発明化合物が実験肝障害モデルにお
いて顕著な肝障害抑制作用を示すことを見出し、本発明
を完成した。Means for Solving the Problems The present inventors synthesized various N-substituted amides and investigated their effects in order to develop therapeutic agents for liver diseases that solved the above problems. As a result, the present inventors discovered that the compound of the present invention exhibits a remarkable hepatic damage-suppressing effect in an experimental liver damage model, and completed the present invention.
本発明は、下記式Ｉ
［式中、Ａは式
（式中、Ｒは低級アルキル基を示す、）で表わされる基
を示し、Ｒ’は水素原子または低級アルキル基を示し、
Ｒ１は炭素原子数１〜６のアルキル基を示す。）で表わ
されるＮ−置換アミド類である。The present invention represents a group represented by the following formula I [wherein A represents a formula (in the formula, R represents a lower alkyl group], R' represents a hydrogen atom or a lower alkyl group,
R1 represents an alkyl group having 1 to 6 carbon atoms. ) are N-substituted amides represented by
本発明において低級アルキル基とは、炭素原子数１〜４
のアルキル基であり、直鎖状であっても分枝鎖状であっ
てもよい。それらはたとえば、メチル基、エチル基、ノ
ルマルプロピル基、イソプロピル基、ノルマルブチル基
などである。炭素原子数１〜６のアルキル基とは、直鎖
状であっても分枝鎖状であってもよいアルキル基であり
、それらを例示すればメチル基、エチル基、ノルマルプ
ロピル基、イソプロピル基、ノルマルブチル基、ノルマ
ルペンチル基、ノルマルヘキシル基などである。In the present invention, a lower alkyl group has 1 to 4 carbon atoms.
is an alkyl group, which may be linear or branched. These include, for example, a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a normal butyl group, and the like. An alkyl group having 1 to 6 carbon atoms is an alkyl group that may be linear or branched, and examples thereof include methyl group, ethyl group, normal propyl group, and isopropyl group. , normal butyl group, normal pentyl group, normal hexyl group, etc.
本発明化合物は、たとえば、以下に示される方法によっ
て製造することができる。The compound of the present invention can be produced, for example, by the method shown below.
すなわち、ジ〜−ナルオプザケミカルソザイアテイ−（
Ｊ、Ｃｈｅｍ、Ｓｏｃ、 ） 、 １９３８年、第７５
３頁に記載の方法に準じて製造される０−ｐ−トルエン
スルホニル−３−アセチルピリジンオキシムを、式■
ＭＯＲＩｆ
（式中、Ｒは前記と同意義であり、Ｍはアルカリ金属原
子である。）で示されるアルコキサイドと反応筋せた後
、塩酸などの酸と処理することにより（ネーバー転位）
、下記式■および式■″トリエチルアミンどである。反
応温度、反応時間などは通常のアシル化方法と同様でよ
い。In other words, di~nal opza chemical society (
J, Chem, Soc, ), 1938, No. 75
0-p-toluenesulfonyl-3-acetylpyridine oxime, which is produced according to the method described on page 3, has the formula (1) MORIf (wherein, R has the same meaning as above, and M is an alkali metal atom). ) After reacting with the alkoxide shown in ), by treating with an acid such as hydrochloric acid (Never rearrangement)
, the following formulas (1) and (2), triethylamine, etc. The reaction temperature, reaction time, etc. may be the same as in a normal acylation method.
■ ■゛（式中、Ｒは
前記と同意義である。）で示されるアミノ体の混合物が
得られる。A mixture of amino compounds represented by the following formula (wherein R has the same meaning as above) is obtained.
次いで、得られた式■および■′のアミノ体の混合物を
弐■
（Ｒ’ＣＯ）、０ またｌ：ｔ： Ｒ’ＣＯＸ
Ｉ’／（式中、Ｒ１は前記と同異議であり、Ｘはハロ
ゲン原子である。）で示される酸無水物または酸ハライ
ドをアシル化剤とするアシル化方法により、Ｒ１が水素
原子である本発明化合物とすることができる。本反応で
は、ピリジン、Ｎ、Ｎ−ジメチルホルムアミド、ジメチ
ルスルホキシド、エチルエーテル、ベンゼン、トルエン
などを溶媒として用いることができる。また、本反応は
塩基存在下行うと好都合である。それらの塩基とは、炭
酸ナトリウト、炭酸カリウム、次階水素ナトリウム、酢
酸ナトリウム、水酸化ナトリウム、ピリジン、、１１
とＡか である式Ｉの化合物の混合物が得らＣ−
れるが、これらは再結晶法またはカラムクロマトグラフ
ィー法などにより容易に分離することができる。また、
本発明の他の化合物は、下記に示す方法によって製造す
ることができる。Next, the obtained mixture of amino bodies of formulas ■ and ■' is converted into 2■ (R'CO), 0 and l:t: R'COX
R1 is a hydrogen atom by an acylation method using an acid anhydride or an acid halide as an acylating agent represented by I'/ (wherein R1 is the same as above and X is a halogen atom) It can be a compound of the present invention. In this reaction, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, ethyl ether, benzene, toluene, etc. can be used as a solvent. Moreover, it is convenient to carry out this reaction in the presence of a base. These bases are sodium carbonate, potassium carbonate, sodium hydroxide, sodium acetate, sodium hydroxide, pyridine, etc. to give mixtures of compounds of formula I, which can be reused. It can be easily separated by crystallization method or column chromatography method. Also,
Other compounds of the present invention can be produced by the methods shown below.
ずなわち、３−（２−ハロゲノアセチル）ピリジンを式
Ｖ
Ｒ’ＮＨ，’ｌ／
（式中、Ｒ’は前記と同意義である。）で示されるアミ
ンと反応させ、式■
（式中、Ｒ１は前記と同意義である。）のアミノ体とす
る。本反応における溶媒は、メタノール、エタノールな
どのアルコール系溶媒、エチルエーテル、ジオキサン、
テトラヒドロフランなどのエーテル系溶媒のほか、アセ
トン、ベンゼンなどを用いることができる。反応温度は
一り０℃〜溶媒の沸点温度であり、好ましくは０°Ｃ〜
室温である。反応は瞬時に終了するが、０．５〜２時間
程度攪拌してもよい。That is, 3-(2-halogenoacetyl)pyridine is reacted with an amine represented by the formula VR'NH,'l/ (wherein, R' has the same meaning as above) to form the formula (wherein, R1 has the same meaning as above). Solvents used in this reaction include alcoholic solvents such as methanol and ethanol, ethyl ether, dioxane,
In addition to ether solvents such as tetrahydrofuran, acetone, benzene, etc. can be used. The reaction temperature is from 0°C to the boiling point temperature of the solvent, preferably from 0°C to
It is at room temperature. The reaction completes instantaneously, but may be stirred for about 0.5 to 2 hours.
次いで、得られた式■のアミノ体を、前記の方法と同様
に、弐■で示される酸無水物または酸ハライドをアシル
化剤とするアシル化反応により、本発明化合物とするこ
とができる。Next, the obtained amino compound of formula (1) can be converted into the compound of the present invention by an acylation reaction using the acid anhydride or acid halide represented by (2) as an acylating agent in the same manner as in the above-mentioned method.
の方法で得られた式■
（式中、Ｒ１およびＲ１は前記と同意義である。）の化
合物をチオセミカルバジドとともに室温〜溶媒の沸点温
度で反応いせることにより得ることができる。本反応は
無溶媒またはエタノール、ベンゼン、トルエン、クロロ
ホルム、テトラヒドロフラン、ジオキサンなどの有機溶
媒中で行う。また、本反応は、触媒なしでも進行するが
、ベンゼンスルホン酸、パラトルエンスルホン酸、オキ
シ塩化リン、三フッ化ホウ素または塩化亜鉛などを用い
ることにより効率的に反応を進行させることができる。It can be obtained by reacting the compound of formula (1) (wherein R1 and R1 have the same meanings as above) obtained by the method with thiosemicarbazide at room temperature to the boiling point temperature of the solvent. This reaction is carried out without a solvent or in an organic solvent such as ethanol, benzene, toluene, chloroform, tetrahydrofuran, or dioxane. Further, although this reaction proceeds without a catalyst, it can be made to proceed efficiently by using benzenesulfonic acid, para-toluenesulfonic acid, phosphorus oxychloride, boron trifluoride, zinc chloride, or the like.
灸馴μγ殖迷
本発明化合物は、四塩化炭素で誘発された実験的肝障害
モデル（ラット）において、血清ＧＰＴ活性を著しく抑
制し、顕著な肝障害抑制効果を示した。したがって、本
発明化合物は、肝疾患の予防または治療剤として有用で
ある。Moxibustion-adapted μγ growth The compound of the present invention significantly inhibited serum GPT activity in an experimental liver injury model (rat) induced by carbon tetrachloride, and exhibited a significant liver injury-suppressing effect. Therefore, the compounds of the present invention are useful as preventive or therapeutic agents for liver diseases.
以下、本発明化合物の有用性を試験例にて示す。The usefulness of the compounds of the present invention will be shown below in test examples.
試験例１
［Ｄ−ガラクトサミン誘発急性肝障害に対する作用］
ウィスター系雄性ラット（生後８週齢、体重的２００ｇ
）６匹を１群とし、試験に供した。実施例で得り化合物
を０．２％カルボキシメチルセルロースナトリウム水溶
液に懸濁調製し、０．２％カルボキシメチルセルロース
ナトリウム水溶液を対照群とした。被検薬２００ｍｇ／
ｋｇ体重を個別の動物に経口投与し、その３０分後に
Ｄ−ガラクトサミン３００ｍｇ／ ｋｇ体重を腹腔的投
与した。２４時間放置後乙の動物をエーテル麻酔下に採
血し遠心分離後血清ＧＰＴ値を測定した。被検薬および
対照群の血清ＧＰＴ値より抑制率（％）を算出した。Test Example 1 [Effect on D-galactosamine-induced acute liver injury] Male Wistar rats (8 weeks old, weight 200 g)
) Six animals were made into one group and used for the test. The compounds obtained in the Examples were prepared by suspending them in a 0.2% aqueous sodium carboxymethylcellulose solution, and the 0.2% aqueous sodium carboxymethylcellulose solution was used as a control group. Test drug 200mg/
kg body weight was administered orally to individual animals, followed 30 minutes later by intraperitoneal administration of D-galactosamine 300 mg/kg body weight. After leaving the animal for 24 hours, blood was collected from the animal under ether anesthesia, and after centrifugation, the serum GPT value was measured. The inhibition rate (%) was calculated from the serum GPT values of the test drug and the control group.
その結果を第１表に示した。The results are shown in Table 1.
第１表
（注）
ａ：３−（ヘキサンアミドアセチル）ピリジンｂ ：
３−（１，１−ジェトキシ−２−ヘキサンアミドエチル
）ピリジン
ｃ：３−（ヘキサンアミドアセチル）ピリジン塩酸塩
ｄ：３−（ペンタンアミドアセチル）ピリジン火」１例
次に、実施例を挙げて本発明を更に詳細に説明する。Table 1 (note) a: 3-(hexaneamide acetyl)pyridine b:
3-(1,1-jethoxy-2-hexaneamidoethyl)pyridine c: 3-(hexaneamidoacetyl)pyridine hydrochloride d: 3-(pentanamidoacetyl)pyridine 1 example Next, examples are given. The present invention will be explained in more detail.
実施例１
金属カリウム１．１７ ｇ （０，０３モル）をエタノ
ール２０ｍ１に溶解してカリウムエトキサイドを調製し
、こ（１）溶液に０−ｐ−トルエンスルホニル−３−ア
セチルピリジンオキシム７．９ｇ（０，０２７モル）を
加えて１時間攪拌した。ｐ−１−ルエンスルホン酸カリ
ウムの沈殿を濾過して除き、濾液をエーテルで希釈し、
２規定塩酸で抽出した。抽出液を減圧下３０〜４０°Ｃ
で濃縮し、３−（２−アミノアセチル）ビリジンニ塩酸
塩と３−（２−アミノ−１，１−ジエトキシエナル）ビ
リジンニ塩酸塩の混合物６．３ｇを得た。Example 1 Potassium ethoxide was prepared by dissolving 1.17 g (0.03 mol) of metallic potassium in 20 ml of ethanol, and 7.9 g of 0-p-toluenesulfonyl-3-acetylpyridine oxime was added to this (1) solution. (0,027 mol) was added and stirred for 1 hour. Filter off the precipitate of potassium p-1-luenesulfonate, dilute the filtrate with ether,
It was extracted with 2N hydrochloric acid. Heat the extract at 30-40°C under reduced pressure.
was concentrated to obtain 6.3 g of a mixture of 3-(2-aminoacetyl)pyridine dihydrochloride and 3-(2-amino-1,1-diethoxyenal)pyridine dihydrochloride.
これを氷水５０ｍ１に溶かし、無水ヘキサン酸１２．８
６ ｇ（０，０６モル）を加え、酢酸ナトリウム１１．
５９ｇ （０，１４モル）の水溶液３０ｍＱを１０℃以
下で加えた。室温に戻して４時間攪拌した後、ジクロロ
メタンで抽出し、抽出液を飽和戻酸水素ナトリウム水溶
液、水で順次洗浄し、乾燥、濃縮して残渣をシリカゲル
クロマトグラフィー（展開溶媒；酢酸エチル：メタノー
ル＝３７：３）で精製し、（ａ）２．２５ｇおよび（ｂ
）０．９３ｇを得た。Dissolve this in 50ml of ice water and add 12.8ml of hexanoic anhydride.
Add 6 g (0.06 mol) and 11.6 g (0.06 mol) of sodium acetate.
30 mQ of an aqueous solution of 59 g (0.14 mol) was added at below 10°C. After returning to room temperature and stirring for 4 hours, extraction was performed with dichloromethane. The extract was washed successively with a saturated aqueous sodium hydrogen oxide solution and water, dried and concentrated, and the residue was subjected to silica gel chromatography (developing solvent: ethyl acetate: methanol = 37:3) to give (a) 2.25 g and (b
) 0.93g was obtained.
（ａ）：
Ｎ Ｍ Ｒ（ＣＤ（Ｊ）３ ） ８ （ｐｐｍ） ；０
．８５（３Ｈ，ｔ＞ 、 １．１９（４Ｈ，ｍ） 、
１．２２（６Ｈ，ｔ） 。(a): NMR(CD(J)3)8(ppm);0
．． 85 (3H, t>, 1.19 (4H, m),
1.22 (6H, t).
１、４５（２Ｈ，ｍ） 、 ２．０４（２Ｈ，ｄｔ）
、 ３．４６（４Ｈ，ｄｑ） 。1, 45 (2H, m), 2.04 (2H, dt)
, 3.46 (4H, dq).
３、７３（２Ｈ，ｄ） 、 ５．３２（１１（、ｂｒ）
、 ７．３２（ＩＨ，ｄｑ） 。3,73(2H,d), 5.32(11(,br)
, 7.32 (IH, dq).
７、８４（ＬＨ，ｄｔ） 、 ８．５７（ＬＨ，ｄｄ）
、 ８．７７（１８，ｄｄ）ＭＳ（ｍ／ｅ）；
３０９（Ｍ”＋１）
（ｂ）：
ｍ、ｐ、 ７４〜７８．５℃
Ｎ Ｍ Ｒ（ＣＤ（Ｊ’３） Ｓ （ｐｐｍ） ；０
、９１（３Ｈ，ｔ） 、 １．３５（４Ｈ，ｍ） 、
１．７１（２Ｈ，ｍ） 。7, 84 (LH, dt), 8.57 (LH, dd)
, 8.77 (18, dd) MS (m/e); 309 (M''+1) (b): m, p, 74-78.5°C NMR (CD (J'3) S (ppm) ;0
, 91 (3H, t) , 1.35 (4H, m) ,
1.71 (2H, m).
２、３４（２Ｈ，ｔ＞ 、 ４．８２（２Ｈ，ｄ） 、
６．５５（ＩＨ，ｂｒ） 。2, 34 (2H, t>, 4.82 (2H, d),
6.55 (IH, br).
７．５０（ＩＨ，ｄｑ） 、 ８．２９（１）１．ｄｔ
） 。7.50 (IH, dq), 8.29 (1) 1. dt
).
８、８７（ＩＨ，ｄｄ） 、 ９．２４（ＩＨ，ｄｄ）
Ｍ Ｓ （ｍ／ｅ）；
２３４（Ｍ”）、７９（ｂａｓｅ）
実施例１と同様の方法で以下の化合物を得た。8, 87 (IH, dd), 9.24 (IH, dd)
M S (m/e); 234 (M''), 79 (base) The following compound was obtained in the same manner as in Example 1.
Ｈ，ｔ−ジェトキシ−２−アセタミドエチル〉ピリジン
ｍ、ｐ、 ７８〜８２℃
Ｎ Ｍ Ｒ（ＣＤＣ＆＋３）δ（ｐｐｍ） ；１．２２
（６）！、ｔ） 、 １．８３（３Ｈ，ｓ） 、 ３．
４６（４Ｈ，ｄｑ） 。H, t-jethoxy-2-acetamidoethyl>pyridine m, p, 78-82°C NMR (CDC&+3) δ (ppm); 1.22
(6)! ,t), 1.83(3H,s), 3.
46 (4H, dq).
３、７２（２１，ｄ） 、 ５．３７（ＬＨ，ｂｒ）
、 ７．３２（ＩＨ，ｄｑ） 。3,72(21,d), 5.37(LH,br)
, 7.32 (IH, dq).
７、８４（ＩＨ，ｄｊ） 、 ８．５８（ＩＨ，ｄｄ）
、 ８．７７（ＬＨ，ｄｄ）ＭＳ（ｍ／ｅ）；
２５３（Ｍ”＋１）、 １２４（ｂａｓｅ）３−（ア
セタミドアセチル）ピリジン
Ｎ Ｍ Ｒ（ＣＤＣＪ）３＞８（ｐｐｍ） ；２、１３
（３Ｈ，ｓ） 、 ４．８１（２Ｈ，ｄ） 、 ６．５
８（ＩＨ，ｂｒ） 。7, 84 (IH, dj), 8.58 (IH, dd)
, 8.77 (LH, dd) MS (m/e); 253 (M''+1), 124 (base) 3-(acetamidoacetyl)pyridine NMR (CDCJ) 3>8 (ppm); 2 , 13
(3H,s), 4.81(2H,d), 6.5
8 (IH, br).
７、５０（ＬＨ，ｄｑ） 、 ８．２８（ＩＨ，ｄｔ）
、 ８．８７（ＬＨ，ｄｄ） 。7, 50 (LH, dq), 8.28 (IH, dt)
, 8.87 (LH, dd).
９、２３（ＩＨ，ｄｄ）
Ｍ Ｓ （ｍ／ ｃ） ；
１７９（Ｍ”＋１） 、 ７９（ｂａｓｅ）Ｎ Ｍ Ｒ
（ＣＤＣ１）３） δ（ｐｐｍ） ；０、１１１３（
３Ｈ，ｔ） 、 １．１８（２Ｈ，ｍ） 、 １．２１
（６Ｈ，ｔ） 。9, 23 (IH, dd) M S (m/c); 179 (M”+1), 79 (base) N M R
(CDC1)3) δ(ppm) ;0, 1113(
3H,t), 1.18(2H,m), 1.21
(6H, t).
１、４１（２Ｈ，ｍ） 、 ２．０１（２Ｈ，ｔ） 、
３．４４（４Ｈ，ｄｑ） 。1, 41 (2H, m), 2.01 (2H, t),
3.44 (4H, dq).
３、７１（２Ｈ，ｄ） 、 ５．２５（ＬＨ，ｂｒ）
、 ７．２８（ＬＨ，ｄｑ） 。3,71(2H,d), 5.25(LH,br)
, 7.28 (LH, dq).
７、８０（ＩＨ，ｄｔ） 、 ８．５３（１８，ｄｄ）
、 ８．７３（ＩＨ，ｄｄ）ＭＳ（ｍ／ｅ）；
２９５（Ｍ”＋１） 、 １８０（ｂａｓｅ）３−（ペ
ンタンアミドアセチル）ピリジンＮ Ｍ Ｒ（ＣＤＣ＃
３ ） Ｓ （ｐＩ）ｉｔ） ；０、９４（３Ｈ，ｔ）
、 １．３９（２Ｈ，ｍ） 、 １．６８（２Ｈ，ｍ
） 。7, 80 (IH, dt), 8.53 (18, dd)
, 8.73 (IH, dd) MS (m/e); 295 (M''+1), 180 (base) 3-(pentanamidoacetyl)pyridine NMR (CDC#
3) S (pI)it) ;0,94(3H,t)
, 1.39 (2H, m) , 1.68 (2H, m
).
２、３３（２Ｈ，ｔ） 、 ４．７９（２Ｂ、ｄ） 、
６．４６（ＬＨ，ｂｒ） 。2, 33 (2H, t), 4.79 (2B, d),
6.46 (LH, br).
７．４５＜ＩＨ，ｄｑ） 、 ８．２４（ＩＨ，ｄｔ）
。7.45<IH, dq), 8.24 (IH, dt)
.
８、８３（ＬＨ，ｄｄ） 、 ９．１８（ＬＨ，ｄｄ）
ＭＳ（ｍ／ｅ）；
２２０（Ｍ”）、７９（ｂａｓｅ）
実施例２
３−（Ｎ−メチルアセタミドアセチル）ピリジンの製造
３−（２−ブロモアセチル）ピリジン臭化水素酸塩８．
４３ｇ（０，０３モル）をジオキサン７０ｍ１ｌに懸濁
し、メチルアミン（水酸化カリウム３０ｇと４０％メチ
ルアミン水溶液３０ｍ１により発生）を２５〜３０℃で
通気した。室温で４時間攪拌後、過剰のメチルアミンを
減圧下で除き、ピリジン９．４８ ｇ （０，１２モル
）と無水酢酸９．１８ｇ（０，０９モル〉を３０〜３５
℃で加え、５０〜６０°Ｃで２時間攪拌した。反応液を
氷水中に注ぎ、炭酸カリワムで中和し、ジクロロメタン
で抽出し、抽出液を水洗、乾燥、濃縮し、残渣をシリカ
ゲルクロマトグラフィーで精製し、標題化合物０、２６
ｇを得た。8, 83 (LH, dd), 9.18 (LH, dd)
MS (m/e); 220 (M”), 79 (base) Example 2 Production of 3-(N-methylacetamidoacetyl)pyridine 3-(2-bromoacetyl)pyridine hydrobromide 8.
43 g (0.03 mol) were suspended in 70 ml of dioxane and methylamine (generated from 30 g of potassium hydroxide and 30 ml of 40% aqueous methylamine solution) was bubbled through at 25-30°C. After stirring at room temperature for 4 hours, excess methylamine was removed under reduced pressure, and 9.48 g (0.12 mol) of pyridine and 9.18 g (0.09 mol) of acetic anhydride were added to 30-35 g of acetic anhydride.
The mixture was added at 50°C to 60°C and stirred for 2 hours. The reaction solution was poured into ice water, neutralized with potassium carbonate, and extracted with dichloromethane. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel chromatography to obtain the title compound 0, 26.
I got g.
ＮＭ Ｒ（ＣＤＣ＃３ ）
２．２１（３Ｈ，ｓ）
７．４５（ＬＨ，ｍ）
９．１７（ＩＨ，ｍ）
ＭＳ（ｍ／ｅ）；
１９２（Ｍ”）
Ｓ （ｐｐｍ） ；
、 ３．１３（３Ｈ，ｓ） 、 ４．８２（２Ｈ，ｓ）
。NMR (CDC#3) 2.21 (3H, s) 7.45 (LH, m) 9.17 (IH, m) MS (m/e); 192 (M") S (ppm); , 3 .13 (3H, s), 4.82 (2H, s)
.
、 ８．２５（１８，ｍ） 、 ８．８１（ＩＨ，ｍ）
。, 8.25 (18, m) , 8.81 (IH, m)
.
実施例２と同様の方法で以下の化合物を得た。The following compounds were obtained in the same manner as in Example 2.
３−（Ｎ−メチルヘキサンアミドアセチル）ピリジン
Ｎ Ｍ Ｒ（ＣＤＣ＃３） Ｓ （ｐｐｍ） ：０．
９１（３Ｈ，ｍ＞ 、 １．３５（４Ｈ，ｍ＞ 、 １
．６８（２Ｈ，ｍ） 。3-(N-methylhexaneamide acetyl)pyridine NMR (CDC#3) S (ppm): 0.
91(3H,m>, 1.35(4H,m>, 1
．． 68 (2H, m).
２、４４（２Ｈ，ｔ） 、 ３．１３（３Ｈ，ｓ） 、
４．８１（２Ｈ，ｓ） 。2,44(2H,t), 3.13(3H,s),
4.81 (2H, s).
７、４３（ＩＨ，ｍ） 、 ８．２５（ＩＨ，ｍ） 、
８．８１（ＩＨ，ｍ） 。7, 43 (IH, m), 8.25 (IH, m),
8.81 (IH, m).
９．１７（ＩＨ，ｍ）
ＭＳ（ｍ／ｅ）；
２４ＢＣＭ”＞
実施例３
３−（アセタミドアセチル）ピリジンチオセミカルバゾ
ンの製造
３−（アセタミドアセチル）ピリジン１゜１２ｇ（６，
３モル）、チオセミカルバジド０．５７４ ｇ （６，
３モル）およびパラトルエンスルホン＃ ０．０１５
ｇ ヲ９５％エタノール２５ｍＱと水４ｍＱ混合液に加
え、２０時間還流した。冷後、析出した固体を濾過し、
エタノールで洗浄して標題化合物１．４８７ｇを得た。9.17 (IH, m) MS (m/e); 24BCM''> Example 3 Production of 3-(acetamidoacetyl)pyridinethiosemicarbazone 3-(acetamidoacetyl)pyridine 1°12g (6 ，
3 mol), thiosemicarbazide 0.574 g (6,
3 mol) and paratoluenesulfone # 0.015
g It was added to a mixed solution of 25 mQ of 95% ethanol and 4 mQ of water, and the mixture was refluxed for 20 hours. After cooling, the precipitated solid was filtered,
Washing with ethanol gave 1.487 g of the title compound.
ｆｆ１．ｐ、 ２４２℃（分解）
Ｎ Ｍ Ｒ（ＤＭＳＯ−ｄａ） Ｓ （ｐｐｍ） ；１
．８６（３Ｈ，ｓ） 、 ４．３０（２Ｈ，ｄ） 、
７．４３（ＩＨ，ｄｑ） 。ff1. p, 242°C (decomposition) NMR (DMSO-da) S (ppm); 1
．． 86 (3H, s), 4.30 (2H, d),
7.43 (IH, dq).
８．１５（ＩＨ，ｓ） 、 ８．４０（ＩＨ，ｓ） 、
８．４０（ＩＨ，ｄｔ） 。8.15 (IH, s), 8.40 (IH, s),
8.40 (IH, dt).
８、５８（ＩＨ，ｄｄ） 、 ８．８０（ＩＨ，ｔ）
、 ９．１５（ＩＨ，ｄｄ）１１．１３（ＬＨ，ｓ）
ＭＳ（ｍ／ｅ）；8, 58 (IH, dd), 8.80 (IH, t)
, 9.15 (IH, dd) 11.13 (LH, s) MS (m/e);
Claims (1)
表等があります▼または▲数式、化学式、表等がありま
す▼ （式中、Ｒは低級アルキル基を示す。）で表わされる基
を示し、Ｒ＾１は水素原子または低級アルキル基を示し
、Ｒ＾２は炭素原子数１〜６のアルキル基を示す。）で
表わされるＮ−置換アミド類。(1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, A is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Numerical formulas, chemical formulas,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ^2 represents an alkyl group having 1 to 6 carbon atoms. ) N-substituted amides represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63294491A JPH02145572A (en) | 1988-11-21 | 1988-11-21 | N-substituted amide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63294491A JPH02145572A (en) | 1988-11-21 | 1988-11-21 | N-substituted amide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02145572A true JPH02145572A (en) | 1990-06-05 |
Family
ID=17808453
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63294491A Pending JPH02145572A (en) | 1988-11-21 | 1988-11-21 | N-substituted amide |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02145572A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998057929A1 (en) * | 1997-06-16 | 1998-12-23 | American Home Products Corporation | Elevation of hdl cholesterol by n-[4-[ (aminothioxomethyl) hydrazono] -4-arylbutyl]amides |
| WO1998057926A1 (en) * | 1997-06-16 | 1998-12-23 | American Home Products Corporation | Elevation of hdl cholesterol by n-[2-[ (aminothioxomethyl)hydrazono] -2-arylethyl]amides |
| JP2001247527A (en) * | 2000-03-07 | 2001-09-11 | Nippon Soda Co Ltd | Method of producing alpha-amino ketones |
| US6353108B1 (en) * | 1998-07-09 | 2002-03-05 | Aventis Pharma S.A. | Method for preparing 4-(3-pyridinyl)-1h-imidazole and the intermediates used |
-
1988
- 1988-11-21 JP JP63294491A patent/JPH02145572A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998057929A1 (en) * | 1997-06-16 | 1998-12-23 | American Home Products Corporation | Elevation of hdl cholesterol by n-[4-[ (aminothioxomethyl) hydrazono] -4-arylbutyl]amides |
| WO1998057926A1 (en) * | 1997-06-16 | 1998-12-23 | American Home Products Corporation | Elevation of hdl cholesterol by n-[2-[ (aminothioxomethyl)hydrazono] -2-arylethyl]amides |
| US6353108B1 (en) * | 1998-07-09 | 2002-03-05 | Aventis Pharma S.A. | Method for preparing 4-(3-pyridinyl)-1h-imidazole and the intermediates used |
| JP2002520325A (en) * | 1998-07-09 | 2002-07-09 | アベンティス ファルマ ソシエテ アノニム | Method for producing 4- (3-pyridinyl) -1H-imidazole and intermediate used |
| JP2001247527A (en) * | 2000-03-07 | 2001-09-11 | Nippon Soda Co Ltd | Method of producing alpha-amino ketones |
| JP4490543B2 (en) * | 2000-03-07 | 2010-06-30 | 日本曹達株式会社 | Process for producing α-amino ketones |
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