JPS6254309B2 - - Google Patents
Info
- Publication number
- JPS6254309B2 JPS6254309B2 JP934880A JP934880A JPS6254309B2 JP S6254309 B2 JPS6254309 B2 JP S6254309B2 JP 934880 A JP934880 A JP 934880A JP 934880 A JP934880 A JP 934880A JP S6254309 B2 JPS6254309 B2 JP S6254309B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- picolylthio
- recrystallized
- compound
- melting point
- 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.)
- Expired
Links
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 18
- -1 chloride and bromite Chemical class 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000000921 elemental analysis Methods 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- MVQVNTPHUGQQHK-UHFFFAOYSA-N 3-pyridinemethanol Chemical compound OCC1=CC=CN=C1 MVQVNTPHUGQQHK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- DKSMCEUSSQTGBK-UHFFFAOYSA-M bromite Chemical compound [O-]Br=O DKSMCEUSSQTGBK-UHFFFAOYSA-M 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- HJRJRUMKQCMYDL-UHFFFAOYSA-N 1-chloro-2,4,6-trinitrobenzene Chemical compound [O-][N+](=O)C1=CC([N+]([O-])=O)=C(Cl)C([N+]([O-])=O)=C1 HJRJRUMKQCMYDL-UHFFFAOYSA-N 0.000 description 1
- NJWIMFZLESWFIM-UHFFFAOYSA-N 2-(chloromethyl)pyridine Chemical compound ClCC1=CC=CC=N1 NJWIMFZLESWFIM-UHFFFAOYSA-N 0.000 description 1
- HKUYJDRVSFQORH-UHFFFAOYSA-N 2-(pyridin-2-ylmethylsulfanyl)acetic acid Chemical compound OC(=O)CSCC1=CC=CC=N1 HKUYJDRVSFQORH-UHFFFAOYSA-N 0.000 description 1
- GLVYLTSKTCWWJR-UHFFFAOYSA-N 2-carbonoperoxoylbenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1C(O)=O GLVYLTSKTCWWJR-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- REGFWZVTTFGQOJ-UHFFFAOYSA-N 4,5-dihydro-1,3-thiazol-2-amine Chemical compound NC1=NCCS1 REGFWZVTTFGQOJ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000006268 Sarcoma 180 Diseases 0.000 description 1
- 206010040914 Skin reaction Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- HBFXVTVOSLPOEY-UHFFFAOYSA-N ethoxyethane;2-propan-2-yloxypropane Chemical compound CCOCC.CC(C)OC(C)C HBFXVTVOSLPOEY-UHFFFAOYSA-N 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- VHWJSJBTUWUEAL-UHFFFAOYSA-N propanamide;hydrochloride Chemical compound Cl.CCC(N)=O VHWJSJBTUWUEAL-UHFFFAOYSA-N 0.000 description 1
- CZPZWMPYEINMCF-UHFFFAOYSA-N propaneperoxoic acid Chemical compound CCC(=O)OO CZPZWMPYEINMCF-UHFFFAOYSA-N 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Description
本発明は次の一般式
（式中Ｘは酸素原子、硫黄原子またはそのモノ
―あるいはジオキサイドを意味し、R1は水素原
子または低級アルキル基を意味し、R2はチアゾ
リル基またはチアゾリニル基を意味し、R3は水
素原子または低級アルキル基を示す。）で表わさ
れる化合物およびその塩に関する。
上式で表わされる本発明の化合物は例えば一般
式
（式中Ｘ、R1及びR3は前記と同一のものを示
す。）
で表わされる酢酸誘導体またはそのカルボキシル
基における反応性誘導体と式
で表わされる２―アミノチアゾールまたは２―ア
ミノチアゾリンとを反応させることにより得られ
る。
反応は通常の酸アミド形成反応条件が採用され
る。例えば一般式〔〕で表わされる化合物と式
〔〕の化合物とをジシクロヘキシルカルボジイ
ミド等の助剤の存在下に不活性溶媒中で反応させ
てもよいし、また必要応じ一般式〔〕で表わさ
れる化合物の反応性誘導体例えばクロライド、ブ
ロマイト等のハロゲン化物、各種の活性エステ
ル、炭酸、ぎ酸等との混合酸無水物を水、ベンゼ
ン、トルエン、テトラヒドロフラン、塩化メチレ
ン、クロロホルム等の溶媒中、アルカリ金属もし
くはアルカリ土類金属水酸化物、炭酸塩・酢酸塩
等の無機塩基あるいはピリジン、トリエチルアミ
ン等の有機塩基の存在下に化合物〔〕と反応さ
せることにより収率よく目的物を得ることができ
る。
一般式〔〕におけるＸがSOまたはSO2であ
る化合物は対応するＸが硫黄原子である化合物を
水、酢酸、クロロホルム、ベンゼン、ぎ酸、塩化
メチレン等の溶媒中、過酢酸、過プロピオン酸、
過安息香酸、過フタル酸、過夭素酸ナトリウム、
過酸化水素等の過酸または過酸化物と反応させる
ことにより容易に得ることができる。尚、これら
の過酸あるいは過酸化物が液体である場合はそれ
らが溶媒を兼ねることもできる。
これらの化合物のうち、光学活性なものはＤ―
カンフアスルホン酸と塩を形成するｄ体と、塩を
形成しないｌ体とに光学分割することができる。
本発明に用いられる一方原料化合物〔〕は例
えば次の方法により製造される。
一般式〔〕においてＸが酸素原子である化合
物は例えばピリジルメタノールとα―ハロゲノ脂
肪酸とジメチルホルムアミド、ジメチルスルホキ
サイド等の不活性溶媒中反応させることにより得
られる。
またたＸが硫黄原子である化合物の場合は、ピ
コリルハライドとα―メルカブト脂肪酸とをアル
コール、ジメチルホルムアミド、ジメチルスルホ
キサイド、水等の溶媒中で反応させることにより
容易に得ることができる。
このようにして得られる本発明の化合物は優れ
た抗炎症作用、免疫賦活作用および抗腫瘍作用を
有し、医薬として用いられる。
例えば、カラゲニンによるラツトの急性後肢足
蹠浮腫に対する経口投与試験において第１表の通
り、優れた浮腫抑制率を示した。
尚、表中の化合物番号は実施例番号に対応す
る。
The present invention is based on the following general formula ( wherein , (atom or lower alkyl group) and salts thereof. The compound of the present invention represented by the above formula is, for example, represented by the general formula (In the formula, X, R 1 and R 3 are the same as above.) An acetic acid derivative represented by or a reactive derivative in its carboxyl group and the formula It can be obtained by reacting with 2-aminothiazole or 2-aminothiazoline represented by: For the reaction, usual acid amide formation reaction conditions are employed. For example, the compound represented by the general formula [] and the compound represented by the formula [] may be reacted in an inert solvent in the presence of an auxiliary agent such as dicyclohexylcarbodiimide, or if necessary, the compound represented by the general formula [] may be reacted with the compound represented by the formula []. Reactive derivatives such as halides such as chloride and bromite, various active esters, mixed acid anhydrides with carbonic acid, formic acid, etc. are mixed with alkali metals or The desired product can be obtained in good yield by reacting with the compound [ ] in the presence of an inorganic base such as an alkaline earth metal hydroxide, carbonate or acetate, or an organic base such as pyridine or triethylamine. Compounds in which X in the general formula [] is SO or SO 2 are prepared by preparing the corresponding compound in which X is a sulfur atom in a solvent such as water, acetic acid, chloroform, benzene, formic acid, methylene chloride, etc., in peracetic acid, perpropionic acid,
perbenzoic acid, perphthalic acid, sodium peroxide,
It can be easily obtained by reacting with a peracid or peroxide such as hydrogen peroxide. In addition, when these peracids or peroxides are liquids, they can also serve as a solvent. Among these compounds, optically active ones are D-
It can be optically resolved into the d-form, which forms a salt with camphorsulfonic acid, and the l-form, which does not form a salt. One raw material compound [ ] used in the present invention is produced, for example, by the following method. A compound in which X is an oxygen atom in the general formula [] can be obtained, for example, by reacting pyridylmethanol with an α-halogeno fatty acid in an inert solvent such as dimethylformamide or dimethylsulfoxide. In addition, in the case of a compound in which X is a sulfur atom, it can be easily obtained by reacting picolyl halide and α-mercabuto fatty acid in a solvent such as alcohol, dimethylformamide, dimethyl sulfoxide, water, or the like. The compounds of the present invention thus obtained have excellent anti-inflammatory, immunostimulatory and antitumor effects and are used as medicines. For example, in an oral administration test of carrageenan for acute hind paw edema in rats, it showed an excellent edema suppression rate as shown in Table 1. Note that the compound numbers in the table correspond to the example numbers.
【表】
また、ラツトのアジユバント関節炎に対して
も、例えば実施例１で得られた化合物を２週間、
５mg／Kg／日、経口投与することにより、対照群
に比較して顕著な治療効果を発現した。
このように本発明の化合物は優れた抗炎症作用
を有するほか、塩化ピクリルによるマウスの遅延
型皮膚反応に対して細胞性免疫能の増強作用を示
した。
更に、マウスの皮下に移植したザルコーマ180
結節型腫瘍に対しても、例えば実施例１で得られ
た化合物は第２表の通り優れた増殖阻止作用を示
した。[Table] In addition, for example, the compound obtained in Example 1 was administered for 2 weeks to treat adjuvant arthritis in rats.
Oral administration of 5 mg/Kg/day produced a significant therapeutic effect compared to the control group. As described above, the compound of the present invention not only has an excellent anti-inflammatory effect, but also exhibits an enhancing effect on cell-mediated immunity against the delayed skin reaction of picryl chloride in mice. Furthermore, Sarcoma 180 implanted subcutaneously into mice.
As shown in Table 2, the compound obtained in Example 1, for example, also exhibited excellent growth-inhibiting activity against nodular tumors.
【表】
実施例 １
(1) α―メルカプトロピオン酸94ｇとピコリルク
ロライド127.5ｇとを１のエタノール中炭酸
カリウム200ｇと共に２時間加熱還流し、冷後
沈澱物を去し、液を減圧濃縮して、残留物
に水300mlを加え、酢酸エチルにて一度洗つ後
希塩酸にてPH３〜４として酢酸エチルで抽出す
る。抽出液を無水硫酸マグネシウムにて脱水後
減圧濃縮して残さをエーテル―イソプロピルエ
ーテルにて再結晶して２―（２―ピコリルチ
オ）プロピオン酸100ｇを得る。
(2) 上記で得た２―（２―ピコリルチオ）プロピ
オン酸20ｇ及び１―ヒドロキシベンゾトリアゾ
ール13.5ｇをテトラヒドロフラン溶解し、０〜
５℃にて、水溶性カルボジイミド15.5mlを加え
１時間撹拌後、２―アミノチアゾール10ｇのテ
トラヒドロフラン30ml溶液を滴下し、更に１〜
２時間５〜10℃で撹拌する。
次いで反応液を減圧濃縮し、残さを酢酸エチ
ルに溶解し、数回水洗後、脱水、減圧濃縮し残
さをエタノールより再結晶して、Ｎ―（２―チ
アゾリル）―２―（２―ピコリルチオ）プロピ
オナミド18ｇを得る。融点131.4℃
元素分析値 分子式C12H13N3OS2として
Ｃ Ｈ Ｎ
理論値（％） 51.59 4.69 15.04
実測値（％） 51.29 4.82 14.93
実施例 ２
実施例１で得たＮ―（２―チアゾリル）―２―
（２―ピコリルチオ）プロピオナミドを塩化メチ
レンに溶解し、白濁が生じなくなるまで塩酸ガス
を導入した後、減圧濃縮し、残さをエタノールよ
り再結晶して、定量的にＮ―（２―チアゾリル）
―２―（２―ピコリルチオ）プロピオナミドの塩
酸塩を得る。融点211℃（分解）
元素分析値 分子式C12H14N3OS2Clとして
Ｃ Ｈ Ｎ
理論値（％） 45.63 4.46 13.30
実測値（％） 45.47 4.58 13.24
実施例 ３
(1) Ｄ―カンフアスルホン酸4.64ｇを熱時酢酸エ
チル300mlに溶解し、これにＮ―（２―チアゾ
リル）―２―（２―ピコリルチオ）プロピオナ
ミド11.2ｇを加える。冷後析出物を取し、塩
化メチレンに溶解し、重曹水次いで水で洗つた
後無水硫酸マグネシウムで乾燥し、30℃にて減
圧濃縮する。残さを塩化メチレン―イソプロピ
ルエーテルより再結晶してＮ―（２―チアゾリ
ル）―２―（２―ピコリルチオ）プロピオナミ
ドのｄ体３ｇを得る。融点121.6℃
〔α〕２５ Ｄ＝＋502.0゜（Ｃ＝１、クロロホルム）
元素分析値 分子式C12H13N3OS2として
Ｃ Ｈ Ｎ
理論値（％） 51.59 4.69 15.04
実測値（％） 51.69 4.80 15.20
(2) (1)において、前段で析出物を取した際に得
られる液を水洗後無水硫酸マグネシウムで乾
燥し、以後同様に濃縮、再結晶してｌ体３ｇを
得る。融点122.7℃
〔α〕２５ Ｄ＝＋540.5゜（Ｃ＝１、クロロホルム）
元素分析値 分子式C12H13N3OS2として
Ｃ Ｈ Ｎ
理論値（％） 51.59 4.69 15.04
実測値（％） 51.69 4.80 15.20
実施例 ４
Ｎ―（２―チアゾリル）―２―（２―ピコリル
チオ）プロピオナミド1.4ｇのクロロホルム50ml
溶液ｍ―クロル過安息香酸1.8ｇを加えて室温で
撹拌したのち、反応液を飽和重曹水、次いで水で
洗浄する。無水硫酸マグネシウムで乾燥後減圧濃
縮し、残さをシリカゲルカラムクロマトグラフイ
ーに付して、初めの流出画分よりＮ―（２―チア
ゾリル）―２―（２―ピコリルスルホニル）プロ
ピオナミド（Ａ）を１ｇ、次の流出画分よりＮ―
（２―チアゾリル）―２―（２―ピコリルスルフ
イニル）プロピオナミド（Ｂ）を0.2ｇ得た。
(A)：融点167.6℃（イソプロピルエーテルより再
結晶
元素分析値 分子式C12H13N3O3S2として
Ｃ Ｈ Ｎ
理論値（％） 46.29 4.21 13.50
実測値（％） 46.34 4.35 13.65
(B)：融点144.6℃（分解）（イソプロピルエーテル
より再結晶）
元素分析値 分子式C12H13N3O2S2として
Ｃ Ｈ Ｎ
理論値（％） 48.80 4.44 14.23
実測値（％） 48.80 4.49 14.46
実施例 ５
２―（２―ピコリルチオ）プロピオン酸に代え
て、２―（２―ピコリルチオ）酢酸を用いて実施
例１と同様にしてＮ―（２―チアゾリン）―２―
（２―ピコリルチオ）アセタミドを得た。収率75
％、融点131.3℃（イソプロピルエーテルより再
結晶）
元素分析値 分子式C11H11N3OS2として
Ｃ Ｈ Ｎ
理論値（％） 49.79 4.18 15.84
実測値（％） 49.50 4.27 15.95
実施例 ６
２―アミノチアゾールに代えて２―アミノチア
ゾリンを用い、実施例１と同様にして、Ｎ―（２
―チアゾリニル）―２―（２―ピコリルチオ）プ
ロピオナミドを得た。収率50％、融点84.4℃（ｎ
―ヘキサンより再結晶）
元素分析値 分子式C12H15N3OS2として
Ｃ Ｈ Ｎ
理論値（％） 51.22 5.37 14.93
実測値（％） 51.31 5.44 15.18
実施例 ７
３―ピリジンメタノールとα―クロロプロピオ
ン酸とを水素化ナトリウムと共にジメチルホルム
アミド中で加熱することにより得られる２―（３
―ピコリルオキシ）プロピオン酸と２―アミノチ
アゾールとを用い実施例１(2)と同様処理してＮ―
（２―チアゾリル）―２―（３―ピコリルオキ
シ）プロピオナミドを64％の収率で得た。融点
112.1℃（イソプロピルエーテルより再結晶）
元素分析値 分子式C12H13N3O2Sとして
Ｃ Ｈ Ｎ
理論値（％） 54.75 4.98 15.96
実測値（％） 54.49 4.99 15.89
実施例 ８
実施例７と同様にして次の化合物を得た。
(1) Ｎ―（２―チアゾリル）―２―（２―ピコリ
ルオキシ）カプロナミド、収率60％、融点76.2
℃（ｎ―ヘキサンより再結晶）
元素分析値 分子式C15H19N3O2Sとして
Ｃ Ｈ Ｎ
理論値（％） 58.99 6.27 13.76
実測値（％） 59.19 6.35 13.89
(2) Ｎ―（２―チアゾリン）―２―（３―ピコリ
ルオキシ）ブチラミド、収率58％、融点95.2℃
（イソプロピルエーテル）
元素分析値 分子式C13H15N3O2Sとして
Ｃ Ｈ Ｎ
理論値（％） 56.29 5.45 15.15
実測値（％） 56.43 5.50 15.26
(3) Ｎ―（２―チアゾリル）―２―（３―メチル
―２―ピコリルチオ）プロピオナミド、収率62
％、融点162.3℃（エタノールより再結晶）
元素分析値 分子式C13H15N3OS2として
Ｃ Ｈ Ｎ
理論値（％） 53.22 5.15 14.32
実測値（％） 53.08 5.17 14.38[Table] Example 1 (1) 94 g of α-mercaptropionic acid and 127.5 g of picolyl chloride were heated under reflux with 200 g of potassium carbonate in ethanol for 2 hours, and after cooling, the precipitate was removed and the liquid was concentrated under reduced pressure. Add 300 ml of water to the residue, wash once with ethyl acetate, adjust the pH to 3-4 with diluted hydrochloric acid, and extract with ethyl acetate. The extract was dehydrated over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was recrystallized from ether-isopropyl ether to obtain 100 g of 2-(2-picolylthio)propionic acid. (2) Dissolve 20 g of 2-(2-picolylthio)propionic acid and 13.5 g of 1-hydroxybenzotriazole obtained above in tetrahydrofuran, and
At 5°C, 15.5 ml of water-soluble carbodiimide was added, and after stirring for 1 hour, a solution of 10 g of 2-aminothiazole in 30 ml of tetrahydrofuran was added dropwise.
Stir for 2 hours at 5-10°C. The reaction solution was then concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water several times, dehydrated, concentrated under reduced pressure, and the residue was recrystallized from ethanol to give N-(2-thiazolyl)-2-(2-picolylthio). Obtain 18 g of propionamide. Melting point 131.4℃ Elemental analysis Molecular formula C 12 H 13 N 3 As OS 2 C H N Theoretical value (%) 51.59 4.69 15.04 Actual value (%) 51.29 4.82 14.93 Example 2 N-(2-thiazolyl obtained in Example 1) )-2-
Dissolve (2-picolylthio)propionamide in methylene chloride, introduce hydrochloric acid gas until no cloudiness occurs, and then concentrate under reduced pressure. The residue is recrystallized from ethanol to quantitatively quantify N-(2-thiazolyl).
-2-(2-picolylthio)propionamide hydrochloride is obtained. Melting point 211℃ (decomposition) Elemental analysis value Molecular formula C 12 H 14 N 3 OS 2 As Cl C H N Theoretical value (%) 45.63 4.46 13.30 Actual value (%) 45.47 4.58 13.24 Example 3 (1) D-camphorsulfone Dissolve 4.64 g of acid in 300 ml of hot ethyl acetate, and add 11.2 g of N-(2-thiazolyl)-2-(2-picolylthio)propionamide. After cooling, the precipitate is collected, dissolved in methylene chloride, washed with aqueous sodium bicarbonate and then with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure at 30°C. The residue was recrystallized from methylene chloride-isopropyl ether to obtain 3 g of the d-isomer of N-(2-thiazolyl)-2-(2-picolylthio)propionamide. Melting point 121.6℃ [α] 25 D = +502.0゜ (C = 1, chloroform) Elemental analysis value Molecular formula C 12 H 13 N 3 As OS 2 C H N Theoretical value (%) 51.59 4.69 15.04 Actual value (%) 51.69 4.80 15.20 (2) In (1), the liquid obtained when the precipitate was collected in the first step is washed with water and dried over anhydrous magnesium sulfate, then concentrated and recrystallized in the same manner to obtain 3 g of the l-isomer. Melting point 122.7℃ [α] 25 D = +540.5゜ (C = 1, chloroform) Elemental analysis value Molecular formula C 12 H 13 N 3 As OS 2 C H N Theoretical value (%) 51.59 4.69 15.04 Actual value (%) 51.69 4.80 15.20 Example 4 1.4 g of N-(2-thiazolyl)-2-(2-picolylthio)propionamide in 50 ml of chloroform
After adding 1.8 g of m-chloroperbenzoic acid solution and stirring at room temperature, the reaction solution was washed with saturated aqueous sodium bicarbonate solution and then with water. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the residue was subjected to silica gel column chromatography to obtain N-(2-thiazolyl)-2-(2-picolylsulfonyl)propionamide (A) from the first effluent fraction. 1 g, N- from the next effluent fraction
0.2 g of (2-thiazolyl)-2-(2-picolylsulfinyl)propionamide (B) was obtained. (A): Melting point 167.6℃ (recrystallized from isopropyl ether) Elemental analysis value Molecular formula C 12 H 13 N 3 O 3 S 2 C H N Theoretical value (%) 46.29 4.21 13.50 Actual value (%) 46.34 4.35 13.65 (B) : Melting point 144.6℃ (decomposed) (recrystallized from isopropyl ether) Elemental analysis value Molecular formula C 12 H 13 N 3 O 2 S 2 C H N Theoretical value (%) 48.80 4.44 14.23 Actual value (%) 48.80 4.49 14.46 Example 5 N-(2-thiazoline)-2- in the same manner as in Example 1 using 2-(2-picolylthio)acetic acid instead of 2-(2-picolylthio)propionic acid.
(2-picolylthio)acetamide was obtained. Yield 75
%, melting point 131.3℃ (recrystallized from isopropyl ether) Elemental analysis value Molecular formula C 11 H 11 N 3 OS 2 C H N Theoretical value (%) 49.79 4.18 15.84 Actual value (%) 49.50 4.27 15.95 Example 6 2-Amino N-(2
-Thiazolinyl)-2-(2-picolylthio)propionamide was obtained. Yield 50%, melting point 84.4℃ (n
- Recrystallized from hexane) Elemental analysis value Molecular formula C 12 H 15 N 3 As OS 2 C H N Theoretical value (%) 51.22 5.37 14.93 Actual value (%) 51.31 5.44 15.18 Example 7 3-Pyridinemethanol and α-chloropropion 2-(3) obtained by heating the acid with sodium hydride in dimethylformamide
-N-
(2-Thiazolyl)-2-(3-picolyloxy)propionamide was obtained in a yield of 64%. melting point
112.1℃ (recrystallized from isopropyl ether) Elemental analysis value As molecular formula C 12 H 13 N 3 O 2 S C H N Theoretical value (%) 54.75 4.98 15.96 Actual value (%) 54.49 4.99 15.89 Example 8 Same as Example 7 The following compound was obtained. (1) N-(2-thiazolyl)-2-(2-picolyloxy)capronamide, yield 60%, melting point 76.2
°C (recrystallized from n-hexane) Elemental analysis value Molecular formula C 15 H 19 N 3 O 2 S As C H N Theoretical value (%) 58.99 6.27 13.76 Actual value (%) 59.19 6.35 13.89 (2) N- (2- Thiazoline)-2-(3-picolyloxy)butyramide, yield 58%, melting point 95.2℃
(Isopropyl ether) Elemental analysis value Molecular formula C 13 H 15 N 3 O 2 S C H N Theoretical value (%) 56.29 5.45 15.15 Actual value (%) 56.43 5.50 15.26 (3) N-(2-thiazolyl)-2- (3-methyl-2-picolylthio)propionamide, yield 62
%, melting point 162.3℃ (recrystallized from ethanol) Elemental analysis value Molecular formula C 13 H 15 N 3 OS 2 as C H N Theoretical value (%) 53.22 5.15 14.32 Actual value (%) 53.08 5.17 14.38
Claims (1)
―あるいはジオキサイドを意味し、R1は水素原
子または低級アルキル基を意味し、R2はチアゾ
リル基またはチアゾリニル基を意味し、R3は水
素原子または低級アルキル基を示す。） で表わされる化合物およびその塩。[Claims] 1. General formula ( wherein , atom or lower alkyl group) and its salts.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP934880A JPS56108786A (en) | 1980-01-31 | 1980-01-31 | Acetamide derivative and its salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP934880A JPS56108786A (en) | 1980-01-31 | 1980-01-31 | Acetamide derivative and its salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS56108786A JPS56108786A (en) | 1981-08-28 |
| JPS6254309B2 true JPS6254309B2 (en) | 1987-11-13 |
Family
ID=11717960
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP934880A Granted JPS56108786A (en) | 1980-01-31 | 1980-01-31 | Acetamide derivative and its salt |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS56108786A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2007300295A1 (en) * | 2006-09-25 | 2008-04-03 | Boehringer Ingelheim International Gmbh | Compounds which modulate the CB2 receptor |
-
1980
- 1980-01-31 JP JP934880A patent/JPS56108786A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS56108786A (en) | 1981-08-28 |
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