JPH03287587A - Pyridylpyrrolothiazole derivative and its intermediate - Google Patents
Pyridylpyrrolothiazole derivative and its intermediateInfo
- Publication number
- JPH03287587A JPH03287587A JP2090960A JP9096090A JPH03287587A JP H03287587 A JPH03287587 A JP H03287587A JP 2090960 A JP2090960 A JP 2090960A JP 9096090 A JP9096090 A JP 9096090A JP H03287587 A JPH03287587 A JP H03287587A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- compound
- cyano
- pyridyl
- 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
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- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 1
- 125000005484 neopentoxy group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- 229950004354 phosphorylcholine Drugs 0.000 description 1
- PYJNAPOPMIJKJZ-UHFFFAOYSA-N phosphorylcholine chloride Chemical compound [Cl-].C[N+](C)(C)CCOP(O)(O)=O PYJNAPOPMIJKJZ-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 206010040560 shock Diseases 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 235000012976 tarts Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005922 tert-pentoxy group Chemical group 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、医薬殊に血小板活性化因子（ＰＡＦ）拮抗剤
として有用な新規ピリジルピロロチアゾール誘導体及び
その塩、並びに前記誘導体及びその塩の製造中間体とし
て有用で、かつそれ自体抗ＰＡＦ活性に優れた新規Ｎ−
シアノ−Ｎ′−ピリジルピロロチアゾリルインウレア誘
導体及びその塩に関する。Detailed Description of the Invention (Industrial Application Field) The present invention relates to novel pyridylpyrrolothiazole derivatives and salts thereof useful as pharmaceuticals, particularly as platelet activating factor (PAF) antagonists, and to the production of said derivatives and salts thereof. A novel N- that is useful as an intermediate and has excellent anti-PAF activity itself.
This invention relates to cyano-N'-pyridylpyrrolothiazolyl inurea derivatives and salts thereof.
（従来の技術、及び発明が解決しようとする課題）ＰＡ
Ｆは、ヒトおよび動物の細胞より放出される化学物質で
あり、下記式で示されるホスホリルコリンのアセチルグ
リセリルエーテルである。(Prior art and problems to be solved by the invention) PA
F is a chemical substance released by human and animal cells, and is acetylglyceryl ether of phosphorylcholine represented by the following formula.
（式中、ぶは１５または１７を意味する。）ＰＡＦは、
気道平滑筋の収縮、血管透過性の亢進、血小板の凝集、
血圧時下等の生理活性を有し、喘息、炎症、血栓症、シ
ョック、腎炎等の諸症状を惹き起こす因子と考えられて
いる。それ故、 ＰＡＦの生理活性に拮抗する物質の研
究が進められており、幾つかの抗ＰＡＦ薬が報告されて
いる（例えば、特開昭５９−１３４７９８号、特開昭６
１−９３１９１号、特開昭６０−１１６６７９号、特開
昭６０−１４２９３２号、特開昭５９−１３４７９８号
、＠開昭６１−８７６８４号、特開昭５１−３７７２６
号、特開昭６３−２２５８８号、特開昭６３−２２５８
９号）。(In the formula, bu means 15 or 17.) PAF is
airway smooth muscle contraction, increased vascular permeability, platelet aggregation,
It has physiological activities such as lowering blood pressure and is thought to be a factor that causes various symptoms such as asthma, inflammation, thrombosis, shock, and nephritis. Therefore, research into substances that antagonize the physiological activity of PAF is progressing, and several anti-PAF drugs have been reported (for example, JP-A-59-134798, JP-A-6
1-93191, JP 60-116679, JP 60-142932, JP 59-134798, @ JP 61-87684, JP 51-37726
No., JP-A-63-22588, JP-A-63-2258
No. 9).
本発明者は、従来の抗ＰＡＦ薬と化学構造を異ニスる新
規なピリジルピロロチアゾール誘導体及びその塩に優れ
た抗ＰＡＦ活性を認め、また。The present inventors have recognized that novel pyridylpyrrolothiazole derivatives and salts thereof, which have a different chemical structure from conventional anti-PAF drugs, have excellent anti-PAF activity.
新規なＮ−シアノ−Ｎ′−ビリジルビロロチアソ。Novel N-cyano-N'-biridylvirolothiaso.
リルイソウレア誘導体及びその塩が前記抗ＰＡＦ剤とし
て優れたピリジルピロロチアゾール誘導体及びその塩を
有利に製造するための中間体として有用であるばかりで
なく、それ自体抗ＰＡＦ活性に優れていることをつきと
め本発明を完成させるに至った。We have found that lilysourea derivatives and salts thereof are not only useful as intermediates for advantageously producing pyridylpyrrolothiazole derivatives and salts thereof which are excellent as anti-PAF agents, but also have excellent anti-PAF activity themselves. The invention was completed.
（課題を解決するための手段）
本発明のピリジルピロロチアゾール誘導体は次の一般式
（Ｉ）で示される構造な有する。(Means for Solving the Problems) The pyridylpyrrolothiazole derivative of the present invention has a structure represented by the following general formula (I).
（式中の記号は以下の意味を有する。(The symbols in the formula have the following meanings.
Ｒ１及びＲ２：同−又は異って、水素原子、低級アルキ
ル基、又は式−Ｘ、 Ｒ３で示される基。R1 and R2: the same or different, a hydrogen atom, a lower alkyl group, or a group represented by the formula -X, R3.
Ｘ：単結合又は低級アルキレン基。X: single bond or lower alkylene group.
Ｒ３：水素原子、低級アルキル基、水酸基、低級アルコ
キシ基、アラルキルオキシ基。R3: hydrogen atom, lower alkyl group, hydroxyl group, lower alkoxy group, aralkyloxy group.
アリールオキシ基、又はアシル基。）
また９本発明のＮ−シアノ−Ｎ′−ピリジルピロロチア
ゾリルイソウレア誘導体は次の一般式（ｎ）で示される
構造を有する。Aryloxy group or acyl group. ) Further, the N-cyano-N'-pyridylpyrrolothiazolyl isourea derivative of the present invention has a structure represented by the following general formula (n).
（式中の記号は以下の意味を有する。(The symbols in the formula have the following meanings.
″Ｙ：酸素原子又は硫黄原子。″Y: oxygen atom or sulfur atom.
Ｒ４：低級アルキル基、又は置換若しくは未置換のフェ
ニル基。）
本願の一つの発明は、上記−紋穴（Ｉ）で示されるピリ
ジルピロロチアゾール誘導体又はその塩を９発明の構成
とし、その提供を目的とする。R4: lower alkyl group, or substituted or unsubstituted phenyl group. ) One of the inventions of the present application constitutes a pyridylpyrrolothiazole derivative or a salt thereof represented by the above-mentioned formula (I) and aims to provide the same.
また本願の他の発明は、上記−紋穴（ｎ）で示されるＮ
−シアノ−Ｎ′−ピリジルピロロチアゾリルイソウレア
誘導体又はその塩を、その発明の構成とし、その提供を
目的とする。Further, another invention of the present application is the N indicated by the above-mentioned hole (n).
-Cyano-N'-pyridylpyrrolothiazolyl isourea derivatives or salts thereof constitute and aim to provide the invention.
以下に、これらの本発明化合物（Ｉ）及び（ＪＩ）につ
き、更に詳細に説明する。Below, these present compounds (I) and (JI) will be explained in more detail.
本明細書の一般式の定義において、特に断わらない限り
、「低級」なる用語は炭素数が１乃至６個の直鎖または
分岐状の炭素鎖を意味する。In the definition of the general formula herein, unless otherwise specified, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms.
したがって、「低級アルキル基」としては。Therefore, as a "lower alkyl group".
具体的には例えばメチル基、エチル基、プロピル基、イ
ソプロピル基、ブチル基、イソブチル基、 ５ｅｃ−
ブチル基、 ｔｅｒｔ−ブチル基、ペンチル（アミル
）基、イソペンチル基、ネオペンチル基ｌ ｔａｒｔ
−ペンチル基、１−メチルブチル基。Specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, 5ec-
Butyl group, tert-butyl group, pentyl (amyl) group, isopentyl group, neopentyl group l tart
-pentyl group, 1-methylbutyl group.
２−メチルブチル基、１，２−ジメチルプロピル基、ヘ
キシル基、イソヘキシル基、１−メチルペンチル基、２
−メチルペンチル基、３−メチルペンチル基、 １．
１−シ）ｆルフチル基、１．２−ジメチルブチル基、２
．２−ジメチルブチル基。2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2
-Methylpentyl group, 3-methylpentyl group, 1.
1-shi)f ruphthyl group, 1,2-dimethylbutyl group, 2
．． 2-dimethylbutyl group.
１．３−ジメチルブチル基、２，３−ジメチルブチル基
、３．３−ジメチルブチル基、１−エチルブチル基、２
−エチルブチル基、１．１．２−）リメチルプロビル基
、１．２．２−）リメチルプロピルＬ １−エチル−
１−メチルプロピル基、１−エチル−２−メチルプロピ
ル基等が挙げられる。1.3-dimethylbutyl group, 2,3-dimethylbutyl group, 3.3-dimethylbutyl group, 1-ethylbutyl group, 2
-ethylbutyl group, 1.1.2-)limethylpropyl group, 1.2.2-)limethylpropyl L 1-ethyl-
Examples include 1-methylpropyl group and 1-ethyl-2-methylpropyl group.
また、「低級アルコキシ基」としては、メトキシ基、エ
トキシ基、プロポキシ基、イソプロポキシ基、ブトキシ
基、イソブトキシ基、 ５ｅｅ−ブトキシ基、 ｔ
ｅｒｔ−ブトキシ基、ペンチルオキシ（アミルオキシ）
基、イソペンチルオキシ基、 ｔｅｒｔ−ペンチルオ
キシ基、ネオペンチルオキシ基、２−メチルブトキシ基
、１．２−ジメチルプロポキシ基、１−エチルプロポキ
シ基、ヘキシルオキシ基等が挙げられる。In addition, examples of the "lower alkoxy group" include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, 5ee-butoxy group, t
ert-butoxy group, pentyloxy (amyloxy)
group, isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, hexyloxy group, and the like.
「低級アルキレン基」としては、炭素数が１乃至６個の
アルキレン基が好適であり、具体的には、メチレン基、
エチレン、メチルメチレン基メチレン基、２−メチルト
リメチレン基、３−メチルトリメチレン基、１−エチル
エチレン基トラメチレン基、２−メチルテトラメチレン
基。As the "lower alkylene group", an alkylene group having 1 to 6 carbon atoms is suitable, and specifically, a methylene group,
Ethylene, methylmethylene group, methylene group, 2-methyltrimethylene group, 3-methyltrimethylene group, 1-ethylethylene group, tramethylene group, 2-methyltetramethylene group.
３−メチルテトラメチレン基、４−メチルテトラメチレ
ン基、１．１−ジメチルトリメチレン基。3-methyltetramethylene group, 4-methyltetramethylene group, 1.1-dimethyltrimethylene group.
２．２−ジメチルトリメチレン基、３．３−ジメチルト
リメチレン基、１，３−ジメチルトリメチレン基、２．
３−ジメチルトリメチレン基、１．２−ジメチルトリメ
チレン基、 １．１．２−トリメチルエチレン基、ジ
エチルメチレン基、ヘキサメチレン基、１−メチルペン
タメチレン基、 １．１−ジメチルテトラメチレン基
、２．２−ジメチルテトラメチレン基、３．３−ジメチ
ルテトラメチレン基。2.2-dimethyltrimethylene group, 3.3-dimethyltrimethylene group, 1,3-dimethyltrimethylene group, 2.
3-dimethyltrimethylene group, 1.2-dimethyltrimethylene group, 1.1.2-trimethylethylene group, diethylmethylene group, hexamethylene group, 1-methylpentamethylene group, 1.1-dimethyltetramethylene group, 2.2-dimethyltetramethylene group, 3.3-dimethyltetramethylene group.
４．４−ジメチルテトラメチレン基、１，１．３−トリ
メチルトリメチレン基、 １，１．２− トリメチル
トリメチレン基、 １，１．２．２−テトラメチルエ
チレン基、 １．１−ジメチル−２−エチルエチレン
基、１．１−ジエチルエチレン基等が挙げられる。4.4-dimethyltetramethylene group, 1,1.3-trimethyltrimethylene group, 1,1.2-trimethyltrimethylene group, 1,1.2.2-tetramethylethylene group, 1.1-dimethyl- Examples include 2-ethylethylene group and 1,1-diethylethylene group.
また、「アリールオキシ基」としては、フェノキシ基、
ナフチルオキシ基、アントリルオキシ基、フエナントリ
ルオキシ基等が挙げられる。In addition, as "aryloxy group", phenoxy group,
Examples include naphthyloxy group, anthryloxy group, and phenanthryloxy group.
また、ｒアラルキルオキシ基」は前記「低級ル基」で置
換した基を意味し１例えばアリール基トシテフェニル基
で例示すればペンシルオキシ基、フェネチルオキシ基、
１−フェニルエトキシ基、３−フェニルプロポキシ基、
２−フェニルプロポキシ基、１−フェニルプロポキシ基
。Furthermore, the term "aralkyloxy group" refers to a group substituted with the above-mentioned "lower group", such as an aryl group, a tositephenyl group, a pencyloxy group, a phenethyloxy group,
1-phenylethoxy group, 3-phenylpropoxy group,
2-phenylpropoxy group, 1-phenylpropoxy group.
１−メチル−２−フェニルエトキシ基、４−フェニルブ
トキシ基、３−フェニルブトキシ基。1-methyl-2-phenylethoxy group, 4-phenylbutoxy group, 3-phenylbutoxy group.
２−フェニルブトキシ基、１−フェニルブトキシ基、２
−メチル−３−フェニルプロポキシ基。2-phenylbutoxy group, 1-phenylbutoxy group, 2
-Methyl-3-phenylpropoxy group.
２−、Ｉｆルー２−フェニルプロポキン基、２−メチル
−１−フェニルプロポキシ基、１−メチル−３−フェニ
ルプロポキシ基、１−メチル２−フェニルプロポキシ基
、１−メチル−１−フェニルプロポキシ基、ｌ−エチル
−２−フェニルエトキシ基、 １．１−ジメチル−２
−フェニルエトキシ基、５−フェニルペンチルオキシ基
。2-, If-2-phenylpropoquine group, 2-methyl-1-phenylpropoxy group, 1-methyl-3-phenylpropoxy group, 1-methyl-2-phenylpropoxy group, 1-methyl-1-phenylpropoxy group , l-ethyl-2-phenylethoxy group, 1,1-dimethyl-2
-phenylethoxy group, 5-phenylpentyloxy group.
６−フエニルヘキジルオキ７基などが挙げら吉また。「
アシル基」としては、ホルミル基。Examples include 6-phenylhexyloxy7 groups. "
The ``acyl group'' is a formyl group.
アセチル基、プロピオニル基、ブチリル基、イツブチリ
ル基、バレリル基、インバレリル基。Acetyl group, propionyl group, butyryl group, butyryl group, valeryl group, invaleryl group.
ピバロイル基、ヘキサノイル基等の低級アルカノイル基
、ヘンシルカルボニル基、３−フェニルプロパノイル基
、２−フェニルプロパノイル基ｌ−フェニルプロパノイ
ル基、４−フェニルブタノイル基、３−フェニルブタノ
イル基、２−フェニルブタノイル基、ｌ−フェニルブタ
ノイル基、２−メチル−３−フェニルプロパノイル基、
５−フェニルペンタノイル基、４−フェニルペンタノイ
ル基、３−フェニルペンタノイル基、２−フェニルペン
タノイル基、１−−ｙエニルペンタノイルＬ ３−メ
チル−４−フェニルブタノイル基、３−メチル−２−フ
ェニルブタノイル基、６−フェニルヘキサノイル基、５
−フェニルヘキサノイル基、４−フェニルヘキサノイル
基、３−フェニルヘキサノイル基、２−フェニルヘキサ
ノイル基、ｌ−フェニルヘキサノイル基、４−メチル−
５−フェニルペンタノイル基、４−メチル−３−フェニ
ルヘキサノイル基、４−メチル−２−フェニルヘキサノ
イル基等のアラルカッイル基やベンゾイル基、ナフトイ
ル基、トルオイル基、サリチロイル基、アニンイル基、
ベラトロイル基、プロトカテクオイル基、ガロイル基な
どのアリールカルボニル基が挙げられる。Lower alkanoyl groups such as pivaloyl group and hexanoyl group, hensylcarbonyl group, 3-phenylpropanoyl group, 2-phenylpropanoyl group 1-phenylpropanoyl group, 4-phenylbutanoyl group, 3-phenylbutanoyl group, 2-phenylbutanoyl group, l-phenylbutanoyl group, 2-methyl-3-phenylpropanoyl group,
5-phenylpentanoyl group, 4-phenylpentanoyl group, 3-phenylpentanoyl group, 2-phenylpentanoyl group, 1-yenylpentanoyl L 3-methyl-4-phenylbutanoyl group, 3-methyl -2-phenylbutanoyl group, 6-phenylhexanoyl group, 5
-Phenylhexanoyl group, 4-phenylhexanoyl group, 3-phenylhexanoyl group, 2-phenylhexanoyl group, l-phenylhexanoyl group, 4-methyl-
Aralkayl groups such as 5-phenylpentanoyl group, 4-methyl-3-phenylhexanoyl group, 4-methyl-2-phenylhexanoyl group, benzoyl group, naphthoyl group, toluoyl group, salicyloyl group, aninyl group,
Examples include arylcarbonyl groups such as veratroyl group, protocatechuoyl group, and galloyl group.
また Ｑ４が示す置換フェニル基の置換基は。Also, the substituent of the substituted phenyl group represented by Q4 is:
化合物（Ｉｆ）をアミン類と反応させて化合物（Ｉ）１
とする反応において基−Ｙ−Ｒ’が基−Ｎ＜Ｒ２と置換
して脱離するものであるから、この反応に関与しない有
機基であればよい。In the reaction of compound (If) with amines to form compound (I) 1, the group -Y-R' is substituted with the group -N<R2 and is eliminated, so organic compounds that do not participate in this reaction Any base is fine.
このよう？、基としては Ｂ３が示す置換基と同一の基
の他、ハロゲン原子、アシルオキシ基。like this? In addition to the same substituent as B3, examples of the group include a halogen atom and an acyloxy group.
低級フルコキシカルボニル基、シアノ基、カルバモイル
基、 低級アルキルスルホニルＩＬ７５ルキルスルホニ
ル基、アリールスルホニル基々どが挙げられるが、これ
らの基に限定されるものではない。ここに「ハロゲン原
子」としては。Examples include, but are not limited to, lower flukoxycarbonyl groups, cyano groups, carbamoyl groups, lower alkylsulfonyl groups, and arylsulfonyl groups. Here, as a "halogen atom".
フッ素原子、塩素原子、臭素原子、ヨウ素原子であり、
アシルオキシ基やアジルア□ノ基の「アシル基」として
は前記の「アシル基」が。Fluorine atom, chlorine atom, bromine atom, iodine atom,
The "acyl group" of the acyloxy group and the azila□no group is the above-mentioned "acyl group."
低級アルコキシカルボニル基の「低級アルコキシ基Ｊと
しては前記の「低級アルコキシ基」が。The lower alkoxy group J of the lower alkoxycarbonyl group is the above-mentioned lower alkoxy group.
低級アルキルスルホニル基の「低級アルキル基」として
は前記の「低級アルキル基」がそれぞれ挙ケられる。ま
た、「アラルキルスルボニル基」や「アリールスルホニ
ル基」は、前記の「アラルキルオキシ基」やｒアリール
オキシ基」の酸素原子（−〇−）、が基−８ｏ２−で置
換された基が具体例として挙げられる。Examples of the "lower alkyl group" of the lower alkylsulfonyl group include the aforementioned "lower alkyl groups". In addition, "aralkylsulfonyl group" and "arylsulfonyl group" specifically refer to a group in which the oxygen atom (-〇-) of the above-mentioned "aralkyloxy group" or r-aryloxy group is substituted with a group -8o2-. Examples include:
本発明の化合物（Ｉ）及び化合物（ｎ）はいずれも塩を
形成する。本発明にはこれらの塩が包含される。このよ
うね塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硫
酸、硝酸、リン酸などの鉱酸や、ギ酸、酢酸、プロピオ
ン酸、シーウ酸、マロン酸、コハク酸、フマール酸、マ
レイン酸、乳酸、リンゴ酸、クエン酸、酒石酸、炭酸、
ピクリン酸、メタンスルホン酸、エタンスルホン酸等の
有機酸との酸付加塩、グルタミン酸、アスパラギン酸々
どの酸性アミノ酸との塩やアンモニウム塩が挙げられる
。Compound (I) and compound (n) of the present invention both form salts. The present invention includes these salts. Examples of such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; formic acid, acetic acid, propionic acid, sialic acid, malonic acid, succinic acid, fumaric acid, Maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid,
Examples include acid addition salts with organic acids such as picric acid, methanesulfonic acid and ethanesulfonic acid, salts with acidic amino acids such as glutamic acid and aspartic acid, and ammonium salts.
また９本発明化合物（Ｉ）及び（ＩＩ）は、いずれも不
斉炭素原子を有しており、この不斉炭素原子の存在に基
づく光学異性体が存在する。本発明は、これら異性体の
分離されたもの及び異性体の混合物を包含する。Furthermore, both of the compounds (I) and (II) of the present invention have an asymmetric carbon atom, and optical isomers exist based on the presence of this asymmetric carbon atom. The present invention includes separated versions of these isomers as well as mixtures of isomers.
法を示す。Show the law.
化合物（Ｉ）の製法
（式中、 Ｒ’、 Ｒ２，Ｒ’及びＹは前記の意味を有
する）
本発明化合物（Ｉ）は９本発明中間体化合物（ＩＩ）に
、−紋穴（ｍ）で示されるア□ン類を反応させることに
より製造できる。Method for producing compound (I) (in the formula, R', R2, R' and Y have the above-mentioned meanings) The compound (I) of the present invention is prepared by adding 9 to the intermediate compound (II) of the present invention, -Momonana (m) It can be produced by reacting the amines represented by □.
発明の反応においては以下の様にして行うのが有利であ
る。The reaction according to the invention is advantageously carried out as follows.
す？、わち９本発明の方法は、化合物（ＩＩ）と化金物
（ｍ）とを等モル々いしは一方９例えば化合物（■）、
をやや過剰量として用い、これを反応に不活性々溶媒９
例えばメタノール、エタノール、イソプロパツール等の
アルコール類、ベンゼン、トルエン、キシレン、アセト
ニトリル。vinegar? , 9 In the method of the present invention, the compound (II) and the metal compound (m) may be mixed in equimolar amounts or 9 For example, the compound (■),
was used in slightly excess amount, and this was added to the reaction with an inert solvent 9
For example, alcohols such as methanol, ethanol, isopropanol, benzene, toluene, xylene, acetonitrile.
エーテル、ジオキサン、テトラヒドロフラン等の有機溶
媒中で、室温々いしは加熱下好ましくは還流温度で反応
させることにより行うのが好適である。反応時間は種々
の反応条件を考慮して適宜設定される。The reaction is preferably carried out in an organic solvent such as ether, dioxane or tetrahydrofuran at room temperature or under heating, preferably at reflux temperature. The reaction time is appropriately set in consideration of various reaction conditions.
々お、原料化合物（ＩＦ）は、Ｙが酸素原子であるとき
はＲ４が低級アルキル基である化合物よりもＲ４が置換
又は未置換のフェノキシ基である化合物の方が、安定で
かつ緩和々条件下に高収率で化合物（Ｉ）とすることが
でき、有利である。In addition, when the starting compound (IF) is an oxygen atom, a compound in which R4 is a substituted or unsubstituted phenoxy group is more stable and meets easy conditions than a compound in which R4 is a lower alkyl group. Compound (I) can be obtained in a high yield, which is advantageous.
この原料化合物、すむわち本発明化合物（ｎ）は以下の
ようにして製造される。This raw material compound, ie, the compound (n) of the present invention, is produced as follows.
化合物（ＩＩ）の製法
（ＩＶ） （Ｖ）
（式中、Ｙ及びＲ４は前記の意味を有する）中間体とし
ても有用に本発明化合物（ｎ）は。Process for producing compound (II) (IV) (V) (wherein Y and R4 have the above-mentioned meanings) The compound (n) of the present invention is also useful as an intermediate.
−紋穴（ＴＶ）で示される７−アミノ−３−ピリジル−
ＩＨ，３Ｈ−ピロロ［１１２Ｃコチアゾ一ル誘導体と、
−紋穴（Ｖ）で示されるＮ−シアノカルボンイミド酸ジ
エステル（又はＮ−シアノカルボンジチオイミド酸ジエ
ステル）とを反応させることにより製造される。-7-amino-3-pyridyl- indicated by a pattern hole (TV)
IH,3H-pyrrolo[112C cothiazol derivative,
- Manufactured by reacting with N-cyanocarbonimidic acid diester (or N-cyanocarboxylic dithioimidic acid diester) shown by Monka (V).
この反応も、前記Ｒ，Ｌｅｅ Ｗｅｂｂらの方法を応用
したものであり１本発明化合物（ＩＩ）を製造するには
以下のように行うのが有利である。This reaction is also an application of the method of R. Lee Webb et al., and is advantageously carried out as follows in order to produce the compound (II) of the present invention.
す１．わち、この反応は１反応に不活性に溶媒。1. In other words, this reaction uses an inert solvent for one reaction.
例′えばメタノール、エタノール、インプロパツールね
どのアルコール類、ベンゼン、トルエン。For example, alcohols such as methanol, ethanol, impromptu alcohol, benzene, and toluene.
キシレン、アセトニトリル、テトラヒドロフラン、エー
テル、ジオキサン、酢酸エチル、酢酸ブチル、ジメチル
ホルムアミド、ジメチルアセトアミドやジメチルスルホ
キシド々どの有機溶媒中、化合物（ＩＶ）と化合物（Ｖ
）とをほぼ等モルあるいは一方をやや過剰量として用い
、好ましくは室温乃至加熱下（特に室温以下に設定する
必要はｋいが室温以下の反応温度で行うこともできる）
に行うのが有利である。反応時間は種々の反応条件を考
慮して適宜設定され１反応路点を確認して終了させるこ
ともできる。Compound (IV) and compound (V
) or in a slightly excess amount of one of them, preferably at room temperature or under heating (although it is not necessary to set the reaction temperature particularly below room temperature, it is also possible to conduct the reaction at a reaction temperature below room temperature).
It is advantageous to do so. The reaction time can be appropriately set in consideration of various reaction conditions, and the reaction can be terminated after confirming one reaction path point.
なお、原料化合物（ＴＶ）は９本出願人の出願に係る特
願平１−２６４７５６号に記載の方法により。The raw material compound (TV) was obtained by the method described in Japanese Patent Application No. 1-264756 filed by the present applicant.
原料化合物（■は前記Ｒ９Ｌｅｅ Ｗｅｂｂらの雑文に
記載の方法あるいはその方法に準じて、容易に入手する
ことができる。The raw material compound (■) can be easily obtained by the method described in the miscellaneous paper by R9Lee Webb et al. or according to that method.
得られた反応生成物は、遊離のままあるいはその塩とし
て単離され、精製される。塩は通常用いられる造塩反応
に付することにより製造することができる。The resulting reaction product is isolated and purified in its free form or as a salt thereof. Salts can be produced by subjecting them to commonly used salt-forming reactions.
単離精製は、抽出、濃縮、結晶化、濾過、再結晶、各種
クロマトグラフィー等通常の化学操作を適用して行われ
る。Isolation and purification is performed by applying ordinary chemical operations such as extraction, concentration, crystallization, filtration, recrystallization, and various chromatography.
（発明の効果）
本発明の化合物（Ｉ）及びその塩は、ＰＡＦ拮抗作用を
有し、ＰＡＦによって惹起される種々の疾病の治療、予
防に有用である。殊に抗喘息剤、抗炎症剤、抗腫瘍剤、
ショック症状の緩和剤、虚血性心疾患、肝疾患、血栓症
および腎炎の治療剤、臓器移植時の拒絶抑制剤等として
利用できる。(Effects of the Invention) Compound (I) of the present invention and its salts have PAF antagonistic activity and are useful for treating and preventing various diseases caused by PAF. Especially anti-asthmatic agents, anti-inflammatory agents, anti-tumor agents,
It can be used as a palliative agent for shock symptoms, a therapeutic agent for ischemic heart disease, liver disease, thrombosis and nephritis, and an agent to suppress rejection during organ transplantation.
また９本発明化合物（ＩＩ）及びその塩は、前記有用な
本発明化合物（Ｉ）及びその塩の優れた製造中間体とし
て有用である他、それ自体抗ＰＡＦ活性に優れており抗
ＰＡＦ剤としても有用である。In addition, the compound (II) of the present invention and its salts are useful as excellent intermediates for producing the above-mentioned useful compound (I) of the present invention and its salts, and also have excellent anti-PAF activity and can be used as anti-PAF agents. is also useful.
々お、中間体（ＩＩ）から最終物質に至る経路は前記の
とおりである。The route from intermediate (II) to the final substance is as described above.
本発明の化合物の抗ＰＡＦ作用はつぎの方法によって確
認されたものである。The anti-PAF effect of the compound of the present invention was confirmed by the following method.
ＰＡＦに起因する血小板凝集に対する抑制試験試験方法
：
体重的３ｋｇの雄性日本白色家兎の耳動脈より３．８％
クエン酸ナトリウム水溶液をｌ容入れたプラスチックシ
リンジに血液を９容採取した。血液を２７０ Ｘ ｇで
１０分間遠心することにより富血小板血漿（ＰＲＰ ：
ｐｌａｔｅｌｅｔ ｒｉｃｈ ｐｌａｓｍａ ）とし
、残りの血液をさらに１１００ Ｘ ｇで１５分間遠心
して乏血小板血漿（Ｐ Ｐ Ｐ ： ｐｌａｔｅｌｅｔ
ｐｏｏｒ ｐｌａｓｍａ ）を得た。ＰＲＰをＰＰＰ
で希釈して血小板数を５０万個／μｊに調製した後、Ｐ
ＡＦによる血小板凝集なボーンとクロス「ジャーナル
オプ フイジオロジー 第１６８巻、第１７８〜１９，
５頁（１９６３年）」の方法により測定した。Inhibition test on platelet aggregation caused by PAF Test method: 3.8% from the ear artery of a male Japanese white rabbit weighing 3 kg
Nine volumes of blood were collected into a plastic syringe containing one volume of sodium citrate aqueous solution. Platelet-rich plasma (PRP:
The remaining blood was further centrifuged at 1100 x g for 15 minutes to obtain platelet-poor plasma (P P P ).
(poor plasma) was obtained. PRP to PPP
After adjusting the platelet count to 500,000/μj by diluting with
Platelet aggregation bone and cross ``journal'' by AF
Op Physiology Volume 168, 178-19,
5 (1963).
すなわち、ＮＢＳヘマトレーサー（二光）くイオサイエ
ンス）を用い、ＰＡＦ（１０−’Ｍ）によるＰＲＰの光
透過度の変化を測定した。々お、化合物はＰＡＦ添加の
２分前に加え、対照におけるＰＡＦによる最大光透過度
に対する抑制率からＩＣ３ｏ値（５０％抑制濃度）を求
めた結果９例えば実施例６の化合物のＩＣ，Ｏ（Ｍ）は
４．５ Ｘ １０−’Ｍ であった。That is, the change in light transmittance of PRP due to PAF (10-'M) was measured using an NBS hematotracer (Nikko Bioscience). The compound was added 2 minutes before the addition of PAF, and the IC3o value (50% inhibitory concentration) was determined from the inhibition rate of the maximum light transmittance by PAF in the control9. M) was 4.5 x 10-'M.
本発明化合物（Ｉ）あるいは（ＩＩ）又はこれらの塩の
１種または２種以上を有効成分として含有する製剤は９
通常用いられる製剤用の担体や賦形剤、その他の添加剤
を用いて錠剤、散剤、細粒剤、カプセル剤、丸剤、液剤
、注射剤、坐剤。The preparation containing one or more of the compounds (I) or (II) of the present invention or their salts as an active ingredient is 9
Tablets, powders, fine granules, capsules, pills, liquids, injections, and suppositories are made using commonly used pharmaceutical carriers, excipients, and other additives.
軟膏、貼付剤等に調製され、経口的または非経口的に投
与される。It is prepared into ointments, patches, etc., and administered orally or parenterally.
本発明化合物の臨床的投与量は、適用される患者の症状
９体重１午令や性別等を考慮して適宜決定されるが１通
常成人１日あたり０．１〜５００■好ましくは１〜２０
０ ｆｆ１ｇであり、これを１回であるいは２〜４回に
分けて経口または非経口投与する。The clinical dosage of the compound of the present invention is appropriately determined taking into consideration the symptoms, body weight, age, gender, etc. of the patient to whom it is applied, but is usually 0.1 to 500 per day for adults, preferably 1 to 20.
0 ff1g, which is administered orally or parenterally at once or in 2 to 4 divided doses.
（実施例） 以下に実施例を掲記し９本発明を更に詳細に説明する。(Example) EXAMPLES The present invention will be described in further detail with reference to Examples below.
実施例１ ７−アミノ−３−（３−ピリジル） −１Ｈ。Example 1 7-amino-3-(3-pyridyl)-1H.
３Ｈ−ピｏｏ［ｌ、２−ｃ］チアゾール１．０９ｇ。1.09 g of 3H-pioo[l,2-c]thiazole.
Ｎ−シアノカルボンイミド酸ジフェニルエステル１．１
９ｇ、２−プロパツール１０ ｒｎｌの混液を。N-cyanocarbonimidic acid diphenyl ester 1.1
9 g, 2-Propatool 10 rnl mixture.
９０℃にて一夜攪拌した。反応液の溶媒を留去し、残留
物をシリカゲルカラムクロマトグラフィーに付し、メチ
レンクロライド−酢酸エチル（２：１）の混液で溶出し
、２−プロパツールより再結晶して、−Ｎ−シアノ−Ｏ
−フェニル−Ｎ’−［３−（３−ピリジル）−１Ｈ，３
Ｈ−ピロロ［１，２−ｃコチアゾール−７−イルコイソ
ウレアを１．４ｇ得た。Stirred at 90°C overnight. The solvent of the reaction solution was distilled off, and the residue was subjected to silica gel column chromatography, eluted with a mixture of methylene chloride and ethyl acetate (2:1), recrystallized from 2-propanol, and -N-cyano -O
-Phenyl-N'-[3-(3-pyridyl)-1H,3
1.4 g of H-pyrrolo[1,2-c cothiazole-7-ylcoisourea was obtained.
融点 １８７〜１９０’Ｃ
元素分析値 （Ｃｏｏ Ｈ＋ｓ ＮｓＯＳＣ（％）
Ｈ（％）
計算値 ６３．１４ ４．１８
実測値 ６３．１５ ４．１９
として）
Ｎ（％） Ｓ（％）
１９．３８
１９．３１
８．８７
８．８８
実施例２
Ｎ−シアノ−０−フェニル−Ｎ’−［３−（３−ピリジ
ル−ＩＨ，３）１−ビｏｏ［１，２−ｃコチアゾール−
７−イルコイソウレア０．３２ｇ。Melting point 187-190'C Elemental analysis value (Coo H+s NsOSC (%)
H (%) Calculated value 63.14 4.18 Actual value 63.15 4.19) N (%) S (%) 19.38 19.31 8.87 8.88 Example 2 N-cyano-0 -Phenyl-N'-[3-(3-pyridyl-IH,3)1-bio[1,2-c cothiazole-
0.32 g of 7-ylcoisourea.
４−フェニルブチルアミン０．１７ｍ１，２−プロパツ
ール２ ｒｎｌの混液な、９０℃にて一夜攪拌した。反
応液の溶媒を留去し、残留物をシリカゲルカラムクロマ
トグラフィーに付し、メチレンクロライド−酢酸エチル
（１：１）の混液で溶出ｌ、、 Ｎ−シアノ−Ｎ’ −
（４−フェニルブチル）−Ｎ“−［３−（３−ピリジル
）−１Ｈ，３Ｈ−ピロロ［１，２−ｃコチアゾール−７
−イル］グアニジンを０．２７ ｇ得た。A mixture of 0.17 ml of 4-phenylbutylamine and 2 rnl of 2-propanol was stirred at 90° C. overnight. The solvent of the reaction solution was distilled off, and the residue was subjected to silica gel column chromatography and eluted with a mixture of methylene chloride and ethyl acetate (1:1).
(4-phenylbutyl)-N"-[3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c cothiazole-7
0.27 g of -yl]guanidine was obtained.
元素分析値 （Ｃｔｓ Ｈｔ＊ Ｎｏ Ｓとして）Ｓ（
％）
計算値 ７．７０
実測値 ７．７２
核磁気共鳴スペクトル（ＣＤＣＪｌ、ＴＭＳ内部標準）
δ： １．３〜１．８ （４Ｈ，ｍ ）、 ２．６０
（２Ｈ。Elemental analysis value (as Cts Ht* No S) S(
%) Calculated value 7.70 Actual value 7.72 Nuclear magnetic resonance spectrum (CDCJl, TMS internal standard)
δ: 1.3-1.8 (4H, m), 2.60
(2H.
ｔ ）、３．２７（２Ｈ，ｔ ）、４．０４（ＩＨ，ｄ
）、 ４．２０ （ＩＨ，ｄ ）、 ５．１７（
ＩＨ，ｔ ）ｔ ６．０９ （ＩＨ，ｄ ）。t ), 3.27 (2H, t ), 4.04 (IH, d
), 4.20 (IH,d), 5.17(
IH,t)t 6.09 (IH,d).
６．２６ （ＩＨ，ｄ ）、 ６．３１ （ＩＨ，ｓ
）。6.26 (IH, d), 6.31 (IH, s
).
７．０〜７．７ （８Ｈ，ｍ ） 、 ８．４〜８．
７（２）１．ｍ）
実施例 ３
実施例２と同様にしてＮ−シアノ−Ｎ′−プロピビル−
Ｎ“−［３−（３−ピリジル）−１Ｈ，３Ｈ−−ピロロ
［１，２−ｃ］チアゾール−７−イルコグアニジンを得
た。7.0-7.7 (8H, m), 8.4-8.
7(2)1. m) Example 3 N-cyano-N'-propivir-
N"-[3-(3-pyridyl)-1H,3H--pyrrolo[1,2-c]thiazol-7-ylcoguanidine was obtained.
原料化合物：Ｎ−シアノ−Ｏ−フェニル−Ｎｌ−［３−
（３−ピリジル）−１Ｈ，３Ｈ−ピロロ［１，２−ｃ］
チアゾール−７−イルコイソウレア及び１−プロピルア
ミン
元素分析値（Ｃ＋ｓＨ＋ａＮｅＳとして）Ｓ（％）
理論値 ９．８２
実験値 ９．８３
核磁気共鳴スペクトル（ＣＤＣＩ、 、 ＴＭＳ内部標
準）δ： ０．８８（３Ｈ，ｔ）ｔ １．３〜１．８（
２Ｈ，ｍ）、 ３．２３（２Ｈ。Raw material compound: N-cyano-O-phenyl-Nl-[3-
(3-pyridyl)-1H,3H-pyrrolo[1,2-c]
Thiazol-7-ylkoisourea and 1-propylamine elemental analysis value (as C + sH + aNeS) S (%) Theoretical value 9.82 Experimental value 9.83 Nuclear magnetic resonance spectrum (CDCI, TMS internal standard) δ: 0.88 (3H ,t)t 1.3~1.8(
2H, m), 3.23 (2H.
ｑ）、 ４．０９（ＩＨ，ｄ）、 ４．２３（ＩＨ，ｄ
）、 ５．１８（ＩＨ。q), 4.09 (IH, d), 4.23 (IH, d
), 5.18 (IH.
ｔ）、 ６．１３（ＩＨ，ｄ）、 ６．２９（１）１．
ｄ）、 ６．３４（ＩＨ。t), 6.13 (IH, d), 6.29 (1) 1.
d), 6.34 (IH.
ｓ ）、 ７．２〜７．７ （３Ｈ，ｍ）、 ８．４〜
８．７ （２Ｈ，ｍ、重水処理により消失）
実施例４゜
実施例２と同様にしてＮ−ベンジル−Ｎ’−シアノ−Ｎ
“−［３−（３−ピリジル）−ＬＨ，３Ｈ−ピロロ［１
＋２ ｃ ］］］］チアゾールー７−イル］グアを得
た。s), 7.2~7.7 (3H, m), 8.4~
8.7 (2H,m, disappeared by heavy water treatment) Example 4゜N-benzyl-N'-cyano-N in the same manner as in Example 2
“-[3-(3-pyridyl)-LH,3H-pyrrolo[1
+2 c ]]]]thiazol-7-yl]gua was obtained.
原料化合物：Ｎ−シアノ−Ｏ−フェニル−Ｎ／−［３−
（３−ピリジル）−１Ｈ，３Ｈ−ピロロ［１，２−ｃ］
チアゾール−７−イル］インウレア及びベンジルアミン
質量分析値： ｍ／ｚ ３７４ （Ｍ”）核磁気共鳴ス
ペクトル（ＣＤＣＩ！、 ＴＭＳ内部標準）δ ：
４．０１（ＩＨ，ｄ）、 ４．１６（ＩＨ，ｄ ン、
４．４５ （２Ｈ，ｄ）。Raw material compound: N-cyano-O-phenyl-N/-[3-
(3-pyridyl)-1H,3H-pyrrolo[1,2-c]
Thiazol-7-yl]inurea and benzylamine Mass spectrometry value: m/z 374 (M”) Nuclear magnetic resonance spectrum (CDCI!, TMS internal standard) δ:
4.01 (IH, d), 4.16 (IH, d),
4.45 (2H, d).
５．５（ＩＨ，ｂｒ）、 ６．１０（ＩＨ，ｄ）、 ６
．２３（ＩＨ，ｄ）。5.5 (IH, br), 6.10 (IH, d), 6
．． 23 (IH, d).
６．２９ （ＩＨ，ａ ）、 ７．１−Ｌ７．６ （８
Ｈ，ｍ）、 ８．４〜８．６（２Ｈ，ｍ）
実施例６゜
実施例５゜
実施例２と同様にしてＮ−シアノ−Ｎ’−（２−フェニ
ルエチル） −Ｎ’−［３−（３−ピリジル）−ＩＨ，
３Ｈ−ピロロ［１，２−ｃコチアゾールー７−イルコグ
アニジンを得た。6.29 (IH,a), 7.1-L7.6 (8
H, m), 8.4-8.6 (2H, m) Example 6゜Example 5゜N-cyano-N'-(2-phenylethyl)-N'-[ 3-(3-pyridyl)-IH,
3H-pyrrolo[1,2-c cothiazole-7-ylcoguanidine was obtained.
ｉ群化合物：Ｎ−シアノ−０−フェニル−Ｎ′−［３−
（３−ピリジル）−１Ｈ，３Ｈ−ピロロ［１，２−ｅ］
チアゾール−７−イルコインウレア及びフェネチルアミ
ン
質量分析値： ｍ／ｚ ３８８（Ｍ”）核磁気共鳴スペ
クトル（ＣＤＣＩ、、 ＴＭＳ内部標準）δ： ２．８
４（２Ｈ，ｔ）、 ３．５４（２Ｈ，ｑ）、 ３．８７
（ＩＨ，ｄ）。Group i compound: N-cyano-0-phenyl-N'-[3-
(3-pyridyl)-1H,3H-pyrrolo[1,2-e]
Thiazol-7-ylcoinurea and phenethylamine Mass spectrometry value: m/z 388 (M”) Nuclear magnetic resonance spectrum (CDCI, TMS internal standard) δ: 2.8
4 (2H, t), 3.54 (2H, q), 3.87
(IH, d).
３．９９（ＩＨ，ｄ）、 ４．９４（ＩＨ，ｔ）、 ５
．９６（ＬＨ，ｄ）。3.99 (IH, d), 4.94 (IH, t), 5
．． 96 (LH, d).
６−２０ （Ｉ Ｈｔ ｄ ）＋ ６−２８ （Ｉ Ｈ
−ｓ ）−６，９７（ＩＨ２ｂｒ）−７，０〜７．８
（７Ｈ，ｍ）、 ８．４〜８．７ （２Ｈ，ｍ ）実施
例２と同様にしてＮ−シアノ−Ｎ’−（ｍ−メトキシフ
ェニル）−Ｎ”−［３−（３−ピリジル）−ＩＨ，３Ｈ
−ピロロ［１，２−ｃコチアゾール−７−イル］グアニ
ジンを得た。6-20 (I Ht d ) + 6-28 (I H
-s) -6,97 (IH2br) -7,0 to 7.8
(7H,m), 8.4-8.7 (2H,m)N-cyano-N'-(m-methoxyphenyl)-N''-[3-(3-pyridyl) -IH, 3H
-pyrrolo[1,2-c cothiazol-7-yl]guanidine was obtained.
原料化合物：Ｎ−シアノ−Ｏ−フェニル−Ｎ／−［３−
（３−ピリジル）−１Ｈ，３Ｈ−ピロロ［１，２−ｃ］
チアゾール−７−イルコイソウレア及びｍ−アニシジ／
質量分析値： ｍ／ｚ ３９０ （Ｍ ）核磁気共鳴ス
ペクトル（ＣＤＣＩｓ、 ＴＭＳ内部標準）δ： ３．
３１（３Ｈ，ｌ）、 ４．１０（ＩＨ，ｄ）、 ４．２
１ （ＩＨ，ｄ）。Raw material compound: N-cyano-O-phenyl-N/-[3-
(3-pyridyl)-1H,3H-pyrrolo[1,2-c]
Thiazol-7-ylkoisourea and m-anisidi/ Mass spectrometry value: m/z 390 (M) Nuclear magnetic resonance spectrum (CDCIs, TMS internal standard) δ: 3.
31 (3H, l), 4.10 (IH, d), 4.2
1 (IH, d).
６．１３（ＩＨ，ｄ）、 ６．４８（ＩＨ，ｄ）、 ６
．６１ （ＩＨ，ｓ）。6.13 (IH, d), 6.48 (IH, d), 6
．． 61 (IH, s).
６．６９（ＩＨ，ｄｄ）、 ６．８〜７．０ （２Ｈ，
ｍ）、 ７．２１ （ＩＨ。6.69 (IH, dd), 6.8~7.0 (2H,
m), 7.21 (IH.
ｔ）ｔ ７．３８（ＩＨ，ｄｄ）、 ７．６２（ＩＨ，
ｄ）、 ８．４〜８．６（２Ｈ，ｍ）、 ８．９０（２
Ｈ，ａ）実施例７゜
実施例８゜
実施例２と同様にしてＮ−シアノ−Ｎ’ −（ｐ −メ
トキシフェニル） −Ｎ”−［３−（３−ピリジル）Ｉ
Ｈ，３Ｈ−ピロロ［１，２−ｃ］チアゾール−７−イル
］グアニジンを得た。t) t 7.38 (IH, dd), 7.62 (IH,
d), 8.4-8.6 (2H, m), 8.90 (2
H,a) Example 7゜Example 8゜N-cyano-N'-(p-methoxyphenyl)-N''-[3-(3-pyridyl)I
H,3H-pyrrolo[1,2-c]thiazol-7-yl]guanidine was obtained.
原料化合物二Ｎ−シアノー０−フェニル−Ｎ／−［３−
（３−ピリジル）−１Ｈ，３Ｈ−ピロロ［１，２−ｃ］
チアゾール−７−イル］イソウレア及びｐ−アニンジン
質量分析値： ｍ／ｚ ３９０ （Ｍ”）核磁気共鳴ス
ペクトル（ＤＭＳＯ−ｄｏ 、ＴＭＳ内部標準）δ：
３．７４（３Ｈ，ｓ）、 ４．０９（ＩＨ，ｄ）、 ４
．１６（ＩＨ，ｄ）。Raw material compound 2N-cyano-0-phenyl-N/-[3-
(3-pyridyl)-1H,3H-pyrrolo[1,2-c]
Thiazol-7-yl] isourea and p-aningine mass spectrometry value: m/z 390 (M”) nuclear magnetic resonance spectrum (DMSO-do, TMS internal standard) δ:
3.74 (3H, s), 4.09 (IH, d), 4
．． 16 (IH, d).
６．１２（ＩＨ，ｄ）、 ６．４６（ＩＨ，ｄ）、 ６
．６０（ＩＨ，ｓ）。6.12 (IH, d), 6.46 (IH, d), 6
．． 60 (IH, s).
６．８９（２Ｂ、 ｄ）、 ７．１６（２Ｈ，ｄ）、
７．３８（ＩＨ，ｄｄ）。6.89 (2B, d), 7.16 (2H, d),
7.38 (IH, dd).
７．６３ （ＬＨ，ｄ）、 ８．４〜８．６ （２Ｈ，
ｍ）、 ８．６６ （ＩＨ。7.63 (LH, d), 8.4~8.6 (2H,
m), 8.66 (IH.
Ｓ９重水処理により消失）、 ８．６９（ＩＨ，ｓ、重
水処理により消失）
実施例２と同様にしてＮ−シアノ−Ｎ’−（ｍ−インプ
ロピルオキシフェニル）−Ｎ“−［３−（３−ピリジル
）−１Ｈ，３Ｈ−ピロロ［１，２−Ｃコチアゾール−７
−イルコグアニジンを得た。S9 disappeared by heavy water treatment), 8.69 (IH,s, disappeared by heavy water treatment) N-cyano-N'-(m-inpropyloxyphenyl)-N''-[3-( 3-pyridyl)-1H,3H-pyrrolo[1,2-C cothiazole-7
- Ircoguanidine was obtained.
原料化合物：Ｎ−シアノ−Ｏ−フェニル−Ｎ’ −［３
−（３−ピリジル）−１Ｈ，３Ｈ−ピロロ［１，２−Ｃ
］チアゾール−７−イルコイソウレア及びｍイソプロピ
ルオキシアニリン
質量分析値： ｍ／Ｚ ４１８ （Ｍ”）核磁気共鳴ス
ペクトル（ＣＤＣＩ８． ＴＭＳ内部標準）δ： １．
３３（６Ｈ，ｄ）、 ４．２０（ＩＨ，ｄ）、 ４．２
８（ＩＨ，ｄ）。Raw material compound: N-cyano-O-phenyl-N'-[3
-(3-pyridyl)-1H,3H-pyrrolo[1,2-C
] Thiazol-7-ylkoisourea and m-isopropyloxyaniline Mass spectrometry value: m/Z 418 (M”) Nuclear magnetic resonance spectrum (CDCI8. TMS internal standard) δ: 1.
33 (6H, d), 4.20 (IH, d), 4.2
8 (IH, d).
４．５４（ＩＨ，ｍ）、 ６．２２（ＩＨ，ｄ）、 ６
．３２（ＩＨ，ｄ）。4.54 (IH, m), 6.22 (IH, d), 6
．． 32 (IH, d).
６．３８（ＩＨ，＠）ｓ ６．７２（ＩＨ，ｄｄ）、
６．８６（ＬＨ，ｄｄ）。6.38 (IH, @)s 6.72 (IH, dd),
6.86 (LH, dd).
７．０２（ＩＨ，ｓ ）、 ７．１〜７．４（３Ｈ，ｍ
）、 ７．５〜７．９（２Ｈ，ｍ）、 ８．５〜８．７
（２Ｈ，ｍ）実施例９゜
実施例 １０゜
実施例２と同様にしてＮ−シアノ−Ｎ’−（ｍ−フェノ
キシフェニル） −Ｎ’−［３−（３−ピリジル）ＩＨ
，３Ｈ−ピロロ［１，２−ｃ］チアゾ−Ｎ−７−イル］
グアニジンを得た。7.02 (IH, s), 7.1-7.4 (3H, m
), 7.5-7.9 (2H, m), 8.5-8.7
(2H,m) Example 9゜Example 10゜N-cyano-N'-(m-phenoxyphenyl)-N'-[3-(3-pyridyl)IH
,3H-pyrrolo[1,2-c]thiazo-N-7-yl]
Guanidine was obtained.
原料化合物：Ｎ−シアノ−Ｏ−フェニル−Ｎ’ −［３
−（３−ピリジル） −１Ｈ，３Ｈ−ピロロ［ｌ、２−
Ｃ］チアゾール−７−イルコイソウレア及びｍ−フェノ
キシアニリン
質量分析値： ｍ／ｚ ４５２ （Ｍ”）核磁気共鳴ス
ペクトル（ＣＤＣＩｌ、 ＴＭＳ内部標準）δ： ４．
１７（ＩＩ（、ｄ）、 ４．２７（ＩＨ，ｄ）、 ６．
２１（ＩＨ，ｄ）。Raw material compound: N-cyano-O-phenyl-N'-[3
-(3-pyridyl) -1H,3H-pyrrolo[l,2-
C] Thiazol-7-ylkoisourea and m-phenoxyaniline Mass spectrometry value: m/z 452 (M”) Nuclear magnetic resonance spectrum (CDCIl, TMS internal standard) δ: 4.
17 (II (, d), 4.27 (IH, d), 6.
21 (IH, d).
６．３２（ＩＨ，ｄ）、 ６．３８（ＩＨ，ｍ）、 ６
．８０（ＩＨ，ｄ）。6.32 (IH, d), 6.38 (IH, m), 6
．． 80 (IH, d).
６−９〜７．５ （１０Ｈ−ｍ ）＊ ７．６３ （Ｉ
Ｈ−ｄｔ ）、７−８５（Ｉ Ｈｅ ｂｒ ）−＆４
〜Ｂ−７（２Ｈｅ ｍ ）実施例２と同様にして Ｎ
−（ｍ−ベンゾイルフェニル）−Ｎ′−シアノ−Ｎ”−
［３−（３−ピリジル−ＩＨ，３Ｈ−ピロロ［１，２−
ｅコチアゾール−７−イル］グアニジンを得た。6-9~7.5 (10H-m)*7.63 (I
H-dt), 7-85 (IHebr)-&4
~B-7 (2He m)N in the same manner as in Example 2
-(m-benzoylphenyl)-N'-cyano-N"-
[3-(3-pyridyl-IH,3H-pyrrolo[1,2-
e cothiazol-7-yl]guanidine was obtained.
ｉ 群化合物： Ｎ−シアノ−Ｏ−フェニル−Ｎ’ −
［３−（３−ピリジル） −１Ｈ，３Ｈ−ピロロ［１，
２−ｃ］チアゾール−７−イルコイソウレア及びｍ −
ベンゾイルアニリン
質量分析値： ｍ／ｚ ４６４ （Ｍ”）核磁気共鳴ス
ペクトル（ＣＤＣＩ、、 ＴＭＳ内部棟準）δ： ４．
２０（ＩＨ，ｄ）、 ４．３０（ＩＨ，ｄ）、 ６．２
６（ＩＨ，ｄ）。i group compound: N-cyano-O-phenyl-N'-
[3-(3-pyridyl)-1H,3H-pyrrolo[1,
2-c]thiazole-7-ylcoisourea and m-
Benzoylaniline mass spectrometry value: m/z 464 (M”) Nuclear magnetic resonance spectrum (CDCI, TMS internal building standard) δ: 4.
20 (IH, d), 4.30 (IH, d), 6.2
6 (IH, d).
６−３６ （Ｉ Ｌ ｄ ）−６，４０（１１（、ｓ
）−７，２３（Ｉ Ｈｌｂｒ）。6-36 (IL d )-6,40(11(,s
)-7,23 (I Hlbr).
Claims (1)
ルキル基、又は式▲数式、化学式、表等があります▼で
示さ れる基。 Ｘ：単結合又は低級アルキレン基。 Ｒ＾３：水素原子、低級アルキル基、水酸基、低級アル
コキシ基、アラルキルオキシ 基、アリールオキシ基、又はアシル基。） で示されるピリジルピロロチアゾール誘導体又はその塩
。 ２、一般式 ▲数式、化学式、表等があります▼ （式中の記号は以下の意味を有する。 Ｙ：酸素原子又は硫黄原子。 Ｒ＾４：低級アルキル基又は置換若しくは未置換のフェ
ニル基。） で示されるＮ−シアノ−Ｎ′−ピリジルピロロチアゾリ
ルイソウレア誘導体又はその塩。[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (Symbols in the formula have the following meanings. R^1 and R^2: Same or different, hydrogen atom, lower Alkyl group or group represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. X: Single bond or lower alkylene group. R^3: Hydrogen atom, lower alkyl group, hydroxyl group, lower alkoxy group, aralkyloxy group, aryloxy group or acyl group) or a salt thereof. 2. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (Symbols in the formula have the following meanings. Y: Oxygen atom or sulfur atom. R^4: Lower alkyl group or substituted or unsubstituted phenyl group. ) An N-cyano-N'-pyridylpyrrolothiazolyl isourea derivative or a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2090960A JPH03287587A (en) | 1990-04-04 | 1990-04-04 | Pyridylpyrrolothiazole derivative and its intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2090960A JPH03287587A (en) | 1990-04-04 | 1990-04-04 | Pyridylpyrrolothiazole derivative and its intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03287587A true JPH03287587A (en) | 1991-12-18 |
Family
ID=14013065
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2090960A Pending JPH03287587A (en) | 1990-04-04 | 1990-04-04 | Pyridylpyrrolothiazole derivative and its intermediate |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03287587A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006017406A1 (en) * | 2004-08-02 | 2006-02-16 | Abbott Laboratories | Cyanoamidine p2x7 antagonists for the treatment of pain |
-
1990
- 1990-04-04 JP JP2090960A patent/JPH03287587A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006017406A1 (en) * | 2004-08-02 | 2006-02-16 | Abbott Laboratories | Cyanoamidine p2x7 antagonists for the treatment of pain |
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