JPH0160027B2 - - Google Patents
Info
- Publication number
- JPH0160027B2 JPH0160027B2 JP8500081A JP8500081A JPH0160027B2 JP H0160027 B2 JPH0160027 B2 JP H0160027B2 JP 8500081 A JP8500081 A JP 8500081A JP 8500081 A JP8500081 A JP 8500081A JP H0160027 B2 JPH0160027 B2 JP H0160027B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- oxadiazole
- spectrum
- nitrosamino
- morpholino
- 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
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical class N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 claims description 3
- 239000003146 anticoagulant agent Substances 0.000 claims description 3
- 229960004676 antithrombotic agent Drugs 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000002075 main ingredient Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- -1 5-substituted-2-[(N-morpholinoamino)-methyl]oxadiazole Chemical class 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000002329 infrared spectrum Methods 0.000 description 12
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 12
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- MKQLBNJQQZRQJU-UHFFFAOYSA-N morpholin-4-amine Chemical compound NN1CCOCC1 MKQLBNJQQZRQJU-UHFFFAOYSA-N 0.000 description 6
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 6
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 235000010288 sodium nitrite Nutrition 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 210000004623 platelet-rich plasma Anatomy 0.000 description 3
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 2
- 238000011047 acute toxicity test Methods 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- UCGJAQHFSXERIT-UHFFFAOYSA-N 2-(chloromethyl)-5-propan-2-yl-1,3,4-oxadiazole Chemical compound CC(C)C1=NN=C(CCl)O1 UCGJAQHFSXERIT-UHFFFAOYSA-N 0.000 description 1
- WNHVLRSXJZLWNT-UHFFFAOYSA-N 2-(chloromethyl)-5-propyl-1,3,4-oxadiazole Chemical compound CCCC1=NN=C(CCl)O1 WNHVLRSXJZLWNT-UHFFFAOYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 210000001841 basilar artery Anatomy 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000002449 bone cell Anatomy 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 210000001363 mesenteric artery superior Anatomy 0.000 description 1
- XLFWDASMENKTKL-UHFFFAOYSA-N molsidomine Chemical compound O1C(N=C([O-])OCC)=C[N+](N2CCOCC2)=N1 XLFWDASMENKTKL-UHFFFAOYSA-N 0.000 description 1
- 229960004027 molsidomine Drugs 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 210000002254 renal artery Anatomy 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
本発明は新規の５―置換―２―〔（Ｎ―モルホ
リノ）―Ｎ―ニトロソアミノ―メチル〕―１，
３，４―オキサジアゾール誘導体及び該誘導体を
主成分とする血栓防止剤に係る。
本発明による化合物は一般式
（式中Ｒは炭素原子数１〜３個の直鎖又は分枝
状アルキル基又はフエニル基、パラジメチルアミ
ノフエニル基を意味する）にて示される。
これら化合物は文献未記載の新規化合物であつ
て、一般式
（式中Ｒは前記の意味を有する）にて示される
５―置換―２―〔（Ｎ―モルホリノアミノ）―メ
チル〕オキサジアゾールをニトロソ化することに
より得ることができる。
本発明による化合物は血栓防止作用を有し、従
つて血栓の発生に起因する各種疾患の予防及び治
療剤として有用であり、殊にＲがメチル基である
５―メチル―２―〔（Ｎ―モルホリノ）Ｎ―ニト
ロソアミノ―メチル〕―１，３，４―オキサジア
ゾールは特に有用である。
次に、本発明による化合物の製造例、薬効薬理
試験例に関連して本発明を更に詳細に説明する。
製造例 １
２―クロルメチル―５―メチル―１，３，４―
オキサジアゾール20.0ｇ（0.15モル）を氷冷下に
Ｎ―アミノモルホリン77.0ｇ（0.75モル）に添加
する。この混合物を室温になした後に８時間に亘
つて撹拌し、濃アンモニア水を添加し、次いで塩
化メチレンにて抽出する。抽出物を硫酸ナトリウ
ムにて乾燥し、濃縮し、シリカゲルカラムを使用
してエーテル／酢酸エチルで展開し、濃縮した後
にエーテルで結晶化すれば、融点約80℃の５―メ
チル―２―〔（Ｎ―モルホリノアミノ）メチル〕
―１，３，４―オキサジアゾール3.1ｇ（収率
10.4％）が得られる。
IRスペクトル（KBr）cm-1：3250（アミノ）
NMRスペクトル（d1クロロホルム）δ：4.20
（メチレン）
質量スペクトル（CI／DI）：199
得たる５―メチル―２―〔（Ｎ―モルホリノア
ミノ）メチル〕―１，３，４―オキサジアゾール
3.0ｇ（15.2ミリモル）を水４ml中に溶解し、36
％塩酸1.52mlを滴下し、氷冷して、これに水３ml
に溶解せしめた亜硝酸ナトリウム1.08ｇ（15.2ミ
リモル）を滴下する。混合物を１時間に亘つて撹
拌し、塩化メチレンにて抽出し、抽出物を乾燥濃
縮し、エーテルにて結晶化し、塩化メチレン／エ
ーテルにて再結晶すれば、融点58〜60℃の５―メ
チル―２―〔（Ｎ―モルホリノ）―Ｎ―ニトロソ
アミノ―メチル〕―１，３，４―オキサジアゾー
ル2.2ｇ（収率63.7％）が得られる。
IRスペクトル（KBr）cm-1：1465（ニトロソ）
NMRスペクトル（d1クロロホルム）δ：5.03
（メチレン）
元素分析：
Ｃ Ｈ Ｎ
理論値 42.29 5.77 30.82
実測値 42.59 5.83 30.72
製造例 ２
２―クロルメチル―５―エチル―１，３，４―
オキサジアゾール25.0ｇ（0.171モル）を氷冷下
にＮ―アミノモルホリン87.0ｇ（0.853モル）に
添加する。この混合物を室温になした後に８時間
に亘つて撹拌し、濃アンモニア水を添加し、次い
で塩化メチレンにて抽出する。抽出物を硫酸ナト
リウムにて乾燥し、濃縮し、シリカゲルカラムを
使用してエーテル／酢酸エチルで展開すれば、油
状物質である５―エチル―２―〔（Ｎ―モルホリ
ノアミノ）メチル〕―１，３，４―オキサジアゾ
ール4.9ｇ（収率13.5％）が得られる。
IRスペクトル（KBr）cm-1：3250（アミノ）
NMRスペクトル（d1クロロホルム）δ：4.21
（メチレン）
質量スペクトル（CI／DI）：213
得たる５―エチル―２―〔（Ｎ―モルホリノア
ミノ）メチル〕―１，３，４―オキサジアゾール
3.0ｇ（14.2ミリモル）を水５ml中に溶解し、36
％塩酸1.42mlを滴下し、氷冷して、これに水4.5
mlに溶解せしめた亜硝酸ナトリウム1.01ｇ（14.2
ミリモル）を滴下する。混合物を１時間に亘つて
撹拌し、塩化メチレンにて抽出し、乾燥濃縮し、
次いでシリカゲルカラムを使用してエーテル／酢
酸エチルにて展開すれば、油状物質である５―エ
チル―２―〔（Ｎ―モルホリノ）―Ｎ―ニトロソ
アミノ―メチル〕―１，３，４―オキサジアゾー
ル1.8ｇ（収率52.5％）が得られる。
IRスペクトル（KBr）cm-1：1460（ニトロソ）
NMRスペクトル（d1クロロホルム）δ：5.08
（メチレン）
元素分析：
Ｃ Ｈ Ｎ
理論値 44.80 6.27 29.03
実測値 44.89 6.18 28.54
製造例 ３
２―クロルメチル―５―ｎ―プロピル―１，
３，４―オキサジアゾール20.5ｇ（0.127モル）
を氷冷下にＮ―アミノモルホリン65.0ｇ（0.637
モル）に添加する。この混合物を室温になした後
に８時間に亘つて撹拌し、濃アンモニア水を添加
し、次いで塩化メチレンにて抽出する。抽出物を
硫酸ナトリウムにて乾燥し、濃縮し、シリカゲル
カラムを使用してエーテル／酢酸エチルで展開す
れば、油状物質である５―ｎ―プロピル―２―
〔（Ｎ―モルホリノアミノ）メチル〕―１，３，４
―オキサジアゾール3.6ｇ（収率12.4％）が得ら
れる。
IRスペクトル（KBr）cm-1：3250（アミノ）
NMRスペクトル（d1クロロホルム）δ：4.25
（メチレン）
質量スペクトル（CI／DI）：227
得たる５―ｎ―プロピル―２―〔（Ｎ―モルホ
リノアミノ）メチル〕―１，３，４―オキサジア
ゾール3.0ｇ（13.3ミリモル）を水10ml中に溶解
し、36％塩酸1.33mlを滴下し、氷冷して、これに
水５mlに溶解せしめた亜硝酸ナトリウム0.95ｇ
（13.3ミリモル）を滴下する。混合物を１時間に
亘つて撹拌し、塩化メチレンにて抽出し、乾燥濃
縮し、次いでシリカゲルカラムを使用してエーテ
ル／酢酸エチルにて展開すれば、油状物質である
５―ｎ―プロピル―２―〔（Ｎ―モルホリノ）―
Ｎ―ニトロソアミノ―メチル〕―１，３，４―オ
キサジアゾール2.2ｇ（収率64.8％）が得られる。
IRスペクトル（KBr）cm-1：1460（ニトロソ）
NMRスペクトル（d1クロロホルム）δ：5.06
（メチレン）
元素分析：
Ｃ Ｈ Ｎ
理論値 47.05 6.71 27.44
実測値 47.18 6.76 26.79
製造例 ４
２―クロルメチル―５―イソプロピル―１，
３，４―オキサジアゾール25.0ｇ（0.156モル）
を氷令下にＮ―アミノモルホリン79.4ｇ（0.778
モル）に添加する。混合物を室温になした後に８
時間に亘つて撹拌し、濃アンモニア水を添加し、
次いで塩化メチレンにて抽出する。抽出物を硫酸
ナトリウムにて乾燥し、濃縮し、シリカゲルカラ
ムを使用してエーテル／エタノールで展開すれ
ば、油状物質である５―イソプロピル―２―
〔（Ｎ―モルホリノアミノ）メチル〕―１，３，４
―オキサジアゾール4.2ｇ（収率14.5％）が得ら
れる。
IRスペクトル（KBr）cm-1：3250（アミノ）
NMRスペクトル（d1クロロホルム）δ：4.21
（メチレン）
質量スペクトル（CI／DI）：227
得たる５―イソプロピル―２―〔（Ｎ―モルホ
リノアミノ）メチル〕―１，３，４―オキサジア
ゾール3.0ｇ（13.3ミリモル）を水10ml中に溶解
し、36％塩酸1.33mlを滴下し、氷冷して、これに
水５mlに溶解せしめた亜硝酸ナトリウム0.95ｇ
（13.3ミリモル）を滴下する。混合物を１時間に
亘つて撹拌し、塩化メチレンにて抽出し、乾燥濃
縮し、次いでシリカゲルカラムを使用してエーテ
ル／酢酸エチルにて展開すれば、油状物質である
５―イソプロピル―２―〔（Ｎ―モルホリノ）―
Ｎ―ニトロソアミノ―メチル〕―１，３，４―オ
キサジアゾール1.7ｇ（収率50.1％）が得られる。
IRスペクトル（KBr）cm-1：1460（ニトロソ）
NMRスペクトル（d1クロロホルム）δ：5.07
（メチレン）
元素分析
Ｃ Ｈ Ｎ
理論値 47.05 6.71 27.44
実測値 46.95 6.74 26.99
製造例 ５
２―クロルメチル―５―フエニル―１，３，４
―オキサジアゾール22.9ｇ（0.118モル）を氷冷
下にＮ―アミノモルホリン60.0ｇ（0.588モル）
に添加する。この混合物を室温になした後に８時
間に亘つて撹拌し、濃アンモニア水を添加し、次
いで塩化メチレンにて抽出する。抽出物を硫酸ナ
トリウムにて乾燥し、濃縮し、シリカゲルカラム
を使用してエーテルで展開すれば、融点約97℃の
５―フエニル―２―〔（Ｎ―モルホリノアミノ）
メチル〕―１，３，４―オキサジアゾール3.3ｇ
（収率10.8％）が得られる。
IRスペクトル（KBr）cm-1：3250（アミノ）
NMRスペクトル（d1クロロホルム）δ：4.28
（メチレン）
質量スペクトル（CI／DI）：261
得たる５―フエニル―２―〔（Ｎ―モルホリノ
アミノ）メチル〕―１，３，４―オキサジアゾー
ル3.0ｇ（11.5ミリモル）を水30ml中に溶解し、
36％塩酸1.15mlを滴下し、氷冷して、これに水３
mlに溶解せしめた亜硝酸ナトリウム0.82ｇ（11.5
ミリモル）を滴下する。混合物を１時間に亘つて
撹拌し、塩化メチレンにて抽出し、乾燥濃縮し、
次いでシリカゲルカラムを使用してエーテル／エ
タノールにて展開し、クロロホルム／エーテルに
て再結晶せしめれば、融点92〜94℃の５―フエニ
ル―２―〔（Ｎ―モルホリノ）―Ｎ―ニトロソア
ミノ―メチル〕―１，３，４―オキサジアゾール
1.4ｇ（収率41.9％）が得られる。
IRスペクトル（KBr）cm-1：1445（ニトロソ）
NMRスペクトル（d1クロロホルム）δ：5.19
（メチレン）
元素分析：
Ｃ Ｈ Ｎ
理論値 53.97 5.23 24.21
実測値 53.96 5.13 23.77
製造例 ６
２―クロロメチル―５―〔（4′―Ｎ，Ｎ―ジメ
チルアミノ）フエニル〕―１，３，４―オキサジ
アゾール20.0ｇ（0.084モル）を氷冷下、Ｎ―ア
ミノモルホリン43.0ｇ（0.421モル）へ加える。
室温にもどして16時間撹拌し、塩化メチレンで抽
出する。無水硫酸ナトリウムで乾燥、濃縮してシ
リカゲルカラムにてエーテル／エタノールで展開
し、融点161℃の５―（4′―Ｎ，Ｎ―ジメチルア
ミノ）フエニル―２―〔（Ｎ―モルホリノアミノ）
メチル〕―１，３，４―オキサジアゾール2.7ｇ
（収率10.6％）が得られる。
IRスペクトル（KBr）cm-1：3250（アミノ）
NMRスペクトル（d1クロロホルム）δ：4.24
（メチレン）
質量スペクトル（CI／DI）：304
得たる５―（4′―Ｎ，Ｎ―ジメチルアミノ）フ
エニル―２―〔（Ｎ―モルホリノアミノ）メチル〕
―１，３，４―オキサジアゾール2.5ｇ（8.2ミリ
モル）を水40mlに懸濁し、36％塩酸0.82mlを滴下
する。氷冷して亜硝酸ナトリウム0.57ｇ（8.2ミ
リモル）を水15mlにとかし滴下する。2.5時間撹
拌して析出した結晶をろ取する。クロロホルム／
シクロヘキサンにて再結晶すれば、融点134℃の
５―（4′―Ｎ，Ｎ―ジメチルアミノ）フエニル―
２―〔（Ｎ―モルホリノ）―Ｎ―ニトロソアミノ
―メチル〕―１，３，４―オキサジアゾール1.89
ｇ（収率69.0％）が得られる。
IRスペクトル（KBr）cm-1：1451（ニトロソ）
NMRスペクトル（d1クロロホルム）δ：5.13
（メチレン）
元素分析：
Ｃ Ｈ Ｎ
理論値 54.21 6.07 25.29
実測値 54.07 6.11 25.17
薬効薬理試験例
本発明による化合物の血管及び血小板に対する
作用を検定し、また急性毒性試験を実施した。こ
れらの実験方法は以下のとおりであり、その実験
結果は表１〜表４に示すとおりであつた。
〔〕 血管平滑筋に対する作用
ａ 実験方法
ウサギより種々部分の血管を摘出し直ちに結合
組織と外膜を取除きルイス等の方法（Lewis，J.
H and Koessler，K.K.“Arch.Intern.Med”第39
巻第182―187頁、1927年）に従つて長軸に対し
45゜の角度で螺旋状に切り試験条片を作製する。
適当な長さのこの条片を37℃に保温されたクレブ
ス・ヘンゼライト栄養液中に95％O2―５％CO2ガ
スを通気しながら吊下し、上端を絹糸によりフオ
ルコ偏位（Forco―displacement）トランスデユ
ーサに接続し、その等尺性張力変化を記録計にて
記録する。血管条片標本については実験開始に先
立ち少なくとも１時間放置し平衡状態ならしめて
おく。この間予め一定の張力を与えておく（大動
脈２ｇ、腎動脈及び上腸間膜動脈１ｇ、脳底動脈
及び冠状動脈0.5ｇ）。
先ずKCl及びCaCl2、セロトニン、ヒスタミン、
ノルエピネコリン等を添加して条片をその最大収
縮の約40〜60％迄収縮させて張力が一定となつた
後に薬物の投与を開始する。薬物は約３倍づつの
濃度で累積的に投与する（１×10-8M、３×
10-8M、１×10-7M ３×10-7M…）。最後に
10-4Mのパパベリンを投与し、この際の弛緩を
100％としそれぞれの濃度での弛緩を％で表わす。
横軸に薬物濃度を又縦軸に弛緩度（％）をとつて
プロツトして50％弛緩濃度（ED50）を求める。
〔〕 ヒト血小板凝集に対する作用
ａ 実験方法
クエン酸加血（0.38％クエン酸トリナトリウム
対ヒト血液＝１対９）より調製した多血小板血漿
（PRP）を用い、理化電機社製のアググレゴメー
タにてボーン等の方法（Born，G.V.R.“Nature”
第194巻第927―929頁、1962年）に従つて血小板
凝集を測定した。
本発明による化合物を生理食塩水で稀釈した
種々濃度の試料液を調製し、その0.03mlを
PRP0.27mlに添加し、37℃で３分間培養した後に
各種の凝集惹起物質を適量添加し、生ずる凝集度
を光透過度で記録即ちPRP ０〜100％とした際
の光透過度に置き換えて記録する。
〔〕 急性毒性試験
室温23±１℃、湿度55±５％の恒温恒湿飼育室
にて雄性ddY系マウス（体重23〜26ｇ）を１群６
匹として用い、被検物質（製造例１の化合物）を
５％アラビアゴム溶液に懸濁せしめて経口投与後
１週間観察して死亡率から急性毒性値を求める。
これら〔〕〜〔〕の薬効薬理試験の比較に
はモルシドミン＝５―エトキシカルボニル―３―
モルホリノシドノンイミンを用いた。これは市販
製剤から抽出精製した。
実験結果
〔〕 血管弛緩に対する効果
The present invention provides novel 5-substituted-2-[(N-morpholino)-N-nitrosamino-methyl]-1,
The present invention relates to a 3,4-oxadiazole derivative and an antithrombotic agent containing the derivative as a main component. The compounds according to the invention have the general formula (In the formula, R means a straight chain or branched alkyl group having 1 to 3 carbon atoms, a phenyl group, or a paradimethylaminophenyl group). These compounds are new compounds that have not been described in any literature, and have the general formula It can be obtained by nitrosating a 5-substituted-2-[(N-morpholinoamino)-methyl]oxadiazole represented by the formula (wherein R has the above-mentioned meaning). The compound according to the present invention has an antithrombotic effect and is therefore useful as a prophylactic and therapeutic agent for various diseases caused by the occurrence of thrombus, especially 5-methyl-2-[(N- Particularly useful is morpholino)N-nitrosamino-methyl]-1,3,4-oxadiazole. Next, the present invention will be explained in more detail with reference to manufacturing examples and pharmacological test examples of compounds according to the present invention. Production example 1 2-chloromethyl-5-methyl-1,3,4-
20.0 g (0.15 mol) of oxadiazole is added to 77.0 g (0.75 mol) of N-aminomorpholine under ice cooling. After the mixture has reached room temperature, it is stirred for 8 hours, concentrated aqueous ammonia is added, and then extracted with methylene chloride. The extract is dried over sodium sulfate, concentrated, developed with ether/ethyl acetate using a silica gel column, and crystallized with ether after concentration to obtain 5-methyl-2-[( N-morpholinoamino)methyl]
-1,3,4-oxadiazole 3.1g (yield
10.4%). IR spectrum (KBr) cm -1 : 3250 (amino) NMR spectrum (d 1 chloroform) δ: 4.20
(Methylene) Mass spectrum (CI/DI): 199 Obtained 5-methyl-2-[(N-morpholinoamino)methyl]-1,3,4-oxadiazole
Dissolve 3.0 g (15.2 mmol) in 4 ml of water, 36
Add 1.52ml of % hydrochloric acid dropwise, cool on ice, and add 3ml of water to this.
1.08 g (15.2 mmol) of sodium nitrite dissolved in water is added dropwise. The mixture was stirred for 1 hour, extracted with methylene chloride, the extract was concentrated to dryness, crystallized from ether, and recrystallized from methylene chloride/ether to give 5-methyl, mp 58-60°C. 2.2 g (yield: 63.7%) of -2-[(N-morpholino)-N-nitrosamino-methyl]-1,3,4-oxadiazole is obtained. IR spectrum (KBr) cm -1 : 1465 (nitroso) NMR spectrum (d 1 chloroform) δ: 5.03
(Methylene) Elemental analysis: C H N Theoretical value 42.29 5.77 30.82 Actual value 42.59 5.83 30.72 Production example 2 2-chloromethyl-5-ethyl-1,3,4-
25.0 g (0.171 mol) of oxadiazole is added to 87.0 g (0.853 mol) of N-aminomorpholine under ice cooling. After the mixture has reached room temperature, it is stirred for 8 hours, concentrated aqueous ammonia is added, and then extracted with methylene chloride. The extract is dried over sodium sulfate, concentrated, and developed with ether/ethyl acetate using a silica gel column to obtain an oily substance, 5-ethyl-2-[(N-morpholinoamino)methyl]-1, 4.9 g (yield 13.5%) of 3,4-oxadiazole is obtained. IR spectrum (KBr) cm -1 : 3250 (amino) NMR spectrum (d 1 chloroform) δ: 4.21
(Methylene) Mass spectrum (CI/DI): 213 Obtained 5-ethyl-2-[(N-morpholinoamino)methyl]-1,3,4-oxadiazole
Dissolve 3.0 g (14.2 mmol) in 5 ml of water, 36
Drop 1.42 ml of % hydrochloric acid, cool on ice, and add 4.5 ml of water.
1.01 g of sodium nitrite dissolved in 14.2 ml
(mmol) dropwise. The mixture was stirred for 1 hour, extracted with methylene chloride, concentrated to dryness, and
Next, using a silica gel column and developing with ether/ethyl acetate, the oily substance 5-ethyl-2-[(N-morpholino)-N-nitrosamino-methyl]-1,3,4-oxadi 1.8 g of azole (yield 52.5%) is obtained. IR spectrum (KBr) cm -1 : 1460 (nitroso) NMR spectrum (d 1 chloroform) δ: 5.08
(Methylene) Elemental analysis: C H N Theoretical value 44.80 6.27 29.03 Actual value 44.89 6.18 28.54 Production example 3 2-chloromethyl-5-n-propyl-1,
3,4-oxadiazole 20.5g (0.127mol)
65.0 g (0.637 g) of N-aminomorpholine under ice-cooling.
moles). After the mixture has reached room temperature, it is stirred for 8 hours, concentrated aqueous ammonia is added, and then extracted with methylene chloride. The extract is dried with sodium sulfate, concentrated, and developed with ether/ethyl acetate using a silica gel column to obtain 5-n-propyl-2-, which is an oily substance.
[(N-morpholinoamino)methyl]-1,3,4
-3.6 g of oxadiazole (yield 12.4%) is obtained. IR spectrum (KBr) cm -1 : 3250 (amino) NMR spectrum (d 1 chloroform) δ: 4.25
(Methylene) Mass spectrum (CI/DI): 227 3.0 g (13.3 mmol) of the obtained 5-n-propyl-2-[(N-morpholinoamino)methyl]-1,3,4-oxadiazole was added to 10 ml of water. Add 1.33 ml of 36% hydrochloric acid dropwise, cool on ice, and add 0.95 g of sodium nitrite dissolved in 5 ml of water.
(13.3 mmol) dropwise. The mixture was stirred for 1 hour, extracted with methylene chloride, concentrated to dryness, and then developed on a silica gel column with ether/ethyl acetate to give an oily substance, 5-n-propyl-2- [(N-morpholino)-
2.2 g (yield 64.8%) of N-nitrosamino-methyl]-1,3,4-oxadiazole is obtained. IR spectrum (KBr) cm -1 : 1460 (nitroso) NMR spectrum (d 1 chloroform) δ: 5.06
(Methylene) Elemental analysis: C H N Theoretical value 47.05 6.71 27.44 Actual value 47.18 6.76 26.79 Production example 4 2-chloromethyl-5-isopropyl-1,
3,4-oxadiazole 25.0g (0.156mol)
N-aminomorpholine 79.4g (0.778g) under ice
moles). 8 after the mixture has come to room temperature.
Stir for hours, add concentrated aqueous ammonia,
Then, it is extracted with methylene chloride. The extract is dried with sodium sulfate, concentrated, and developed with ether/ethanol using a silica gel column to obtain 5-isopropyl-2-, which is an oily substance.
[(N-morpholinoamino)methyl]-1,3,4
-4.2 g of oxadiazole (yield 14.5%) is obtained. IR spectrum (KBr) cm -1 : 3250 (amino) NMR spectrum (d 1 chloroform) δ: 4.21
(Methylene) Mass spectrum (CI/DI): 227 3.0 g (13.3 mmol) of the obtained 5-isopropyl-2-[(N-morpholinoamino)methyl]-1,3,4-oxadiazole was added to 10 ml of water. Dissolve, drop 1.33 ml of 36% hydrochloric acid, cool on ice, and add 0.95 g of sodium nitrite dissolved in 5 ml of water.
(13.3 mmol) dropwise. The mixture was stirred for 1 hour, extracted with methylene chloride, concentrated to dryness, and then developed on a silica gel column with ether/ethyl acetate to give an oily substance, 5-isopropyl-2-[( N-morpholino)-
1.7 g (yield 50.1%) of N-nitrosamino-methyl]-1,3,4-oxadiazole is obtained. IR spectrum (KBr) cm -1 : 1460 (nitroso) NMR spectrum (d 1 chloroform) δ: 5.07
(Methylene) Elemental analysis C H N Theoretical value 47.05 6.71 27.44 Actual value 46.95 6.74 26.99 Production example 5 2-chloromethyl-5-phenyl-1,3,4
- 22.9 g (0.118 mol) of oxadiazole was added to 60.0 g (0.588 mol) of N-aminomorpholine under ice cooling.
Add to. After the mixture has reached room temperature, it is stirred for 8 hours, concentrated aqueous ammonia is added, and then extracted with methylene chloride. The extract is dried over sodium sulfate, concentrated, and developed with ether using a silica gel column to obtain 5-phenyl-2-[(N-morpholinoamino) with a melting point of about 97°C.
Methyl]-1,3,4-oxadiazole 3.3g
(Yield 10.8%) is obtained. IR spectrum (KBr) cm -1 : 3250 (amino) NMR spectrum (d 1 chloroform) δ: 4.28
(Methylene) Mass spectrum (CI/DI): 261 3.0 g (11.5 mmol) of the obtained 5-phenyl-2-[(N-morpholinoamino)methyl]-1,3,4-oxadiazole was added to 30 ml of water. dissolve,
Drop 1.15 ml of 36% hydrochloric acid, cool on ice, and add 3 ml of water.
0.82 g of sodium nitrite dissolved in 11.5 ml
(mmol) dropwise. The mixture was stirred for 1 hour, extracted with methylene chloride, concentrated to dryness, and
Next, using a silica gel column and developing with ether/ethanol and recrystallizing with chloroform/ether, 5-phenyl-2-[(N-morpholino)-N-nitrosamino- Methyl]-1,3,4-oxadiazole
1.4 g (yield 41.9%) is obtained. IR spectrum (KBr) cm -1 : 1445 (nitroso) NMR spectrum (d 1 chloroform) δ: 5.19
(Methylene) Elemental analysis: C H N Theoretical value 53.97 5.23 24.21 Actual value 53.96 5.13 23.77 Production example 6 2-Chloromethyl-5-[(4'-N,N-dimethylamino)phenyl]-1,3,4- 20.0 g (0.084 mol) of oxadiazole is added to 43.0 g (0.421 mol) of N-aminomorpholine under ice cooling.
The mixture was allowed to warm to room temperature, stirred for 16 hours, and extracted with methylene chloride. Dry over anhydrous sodium sulfate, concentrate, and develop with ether/ethanol on a silica gel column to obtain 5-(4'-N,N-dimethylamino)phenyl-2-[(N-morpholinoamino) with a melting point of 161°C.
Methyl]-1,3,4-oxadiazole 2.7g
(Yield 10.6%) is obtained. IR spectrum (KBr) cm -1 : 3250 (amino) NMR spectrum (d 1 chloroform) δ: 4.24
(Methylene) Mass spectrum (CI/DI): 304 Obtained 5-(4'-N,N-dimethylamino)phenyl-2-[(N-morpholinoamino)methyl]
2.5 g (8.2 mmol) of -1,3,4-oxadiazole is suspended in 40 ml of water, and 0.82 ml of 36% hydrochloric acid is added dropwise. Cool on ice, dissolve 0.57 g (8.2 mmol) of sodium nitrite in 15 ml of water, and add dropwise. Stir for 2.5 hours and collect the precipitated crystals by filtration. Chloroform/
If recrystallized from cyclohexane, 5-(4'-N,N-dimethylamino)phenyl-
2-[(N-morpholino)-N-nitrosamino-methyl]-1,3,4-oxadiazole 1.89
g (yield 69.0%) is obtained. IR spectrum (KBr) cm -1 : 1451 (nitroso) NMR spectrum (d 1 chloroform) δ: 5.13
(Methylene) Elemental analysis: C H N Theoretical value 54.21 6.07 25.29 Actual value 54.07 6.11 25.17 Pharmacology test example The effects of the compound according to the present invention on blood vessels and platelets were examined, and an acute toxicity test was also conducted. The experimental methods were as follows, and the experimental results were as shown in Tables 1 to 4. [] Action on vascular smooth muscle a Experimental method Blood vessels from various parts were removed from rabbits, the connective tissue and adventitia were immediately removed, and the method of Lewis et al. (Lewis, J.
H and Koessler, KK “Arch.Intern.Med” No. 39
Vol. 182-187, 1927)
A test strip is prepared by cutting it spirally at a 45° angle.
This strip of appropriate length was suspended in a Krebs-Henseleite nutrient solution kept at 37°C while aerating 95% O 2 -5% CO 2 gas, and the upper end was tied with a silk thread for forco deflection. (displacement) transducer, and record the isometric tension change with a recorder. Allow the vascular strip specimen to equilibrate for at least 1 hour before starting the experiment. During this time, a constant tension is applied in advance (2 g of the aorta, 1 g of the renal artery and superior mesenteric artery, and 0.5 g of the basilar artery and coronary artery). First, KCl and CaCl 2 , serotonin, histamine,
Norepinecoline or the like is added to contract the strip to about 40-60% of its maximum contraction, and after the tension becomes constant, administration of the drug is started. Drugs are administered cumulatively at approximately three times the concentration (1×10 -8 M, 3×
10 -8 M, 1×10 -7 M 3×10 -7 M…). lastly
Administer 10 -4 M papaverine to induce relaxation.
Relaxation at each concentration is expressed as %, assuming 100%.
The drug concentration is plotted on the horizontal axis and the degree of relaxation (%) is plotted on the vertical axis to determine the 50% relaxation concentration (ED 50 ). [] Effect on human platelet aggregation a Experimental method Platelet-rich plasma (PRP) prepared from citrated blood (0.38% trisodium citrate to human blood = 1 to 9) was used to infuse bone cells using an aggregometer manufactured by Rika Denki. (Born, GVR “Nature” method)
194, pp. 927-929, 1962), platelet aggregation was measured. Sample solutions of various concentrations were prepared by diluting the compound according to the present invention with physiological saline, and 0.03 ml of the sample solution was diluted with physiological saline.
Add to 0.27 ml of PRP, incubate at 37℃ for 3 minutes, then add an appropriate amount of various aggregation-inducing substances, and record the degree of aggregation as light transmittance. Record. [] Acute toxicity test Male ddY mice (weight 23-26 g) were placed in a group of 6 male ddY mice (body weight 23-26 g) in a constant temperature and humidity breeding room with a room temperature of 23 ± 1°C and a humidity of 55 ± 5%.
The test substance (compound of Production Example 1) is suspended in a 5% gum arabic solution and observed for one week after oral administration, and the acute toxicity value is determined from the mortality rate. Molsidomine = 5-ethoxycarbonyl-3-
Morpholinosydnonimine was used. This was extracted and purified from a commercially available preparation. Experimental results [] Effect on vascular relaxation
【表】【table】
【表】【table】
【表】【table】
【表】【table】
Claims (1)
枝状アルキル基又はフエニル基、パラジメチルア
ミノフエニル基を意味する） にて示される新規の５―置換―２―［（Ｎ―モル
ホリノ）―Ｎ―ニトロソアミノ―メチル］―１，
３，４―オキサジアゾール誘導体。 ２ 一般式 （式中Ｒは炭素原子数１―３個の直鎖または分
枝状アルキル基又はフエニル基、パラジメチルア
ミノフエニル基を意味する） にて示される新規の５―置換―２―［（Ｎ―モル
ホリノ）―Ｎ―ニトロソアミノ―メチル］―１，
３，４―オキサジアゾール誘導体を主成分とする
血栓防止剤。 ３ ５―メチル―２―［（Ｎ―モルホリノ）―Ｎ
―ニトロソアミノ―メチル］―１，３，４―オキ
サジアゾールを主成分とする、特許請求の範囲第
２項記載の血栓防止剤。[Claims] 1. General formula (In the formula, R means a straight-chain or branched alkyl group having 1 to 3 carbon atoms, a phenyl group, or a paradimethylaminophenyl group.) -morpholino)-N-nitrosamino-methyl]-1,
3,4-oxadiazole derivative. 2 General formula Novel 5-substituted-2-[(N -morpholino)-N-nitrosamino-methyl]-1,
An antithrombotic agent whose main ingredient is a 3,4-oxadiazole derivative. 3 5-methyl-2-[(N-morpholino)-N
The antithrombotic agent according to claim 2, which contains as a main component nitrosamino-methyl]-1,3,4-oxadiazole.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8500081A JPS57200372A (en) | 1981-06-04 | 1981-06-04 | Novel 5-substituted-2-((n-morpholino)-n-nitrosoamino- methyl)oxadiazole derivative and preventing agent for thrombosis containing the same as principal constituent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8500081A JPS57200372A (en) | 1981-06-04 | 1981-06-04 | Novel 5-substituted-2-((n-morpholino)-n-nitrosoamino- methyl)oxadiazole derivative and preventing agent for thrombosis containing the same as principal constituent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57200372A JPS57200372A (en) | 1982-12-08 |
| JPH0160027B2 true JPH0160027B2 (en) | 1989-12-20 |
Family
ID=13846370
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8500081A Granted JPS57200372A (en) | 1981-06-04 | 1981-06-04 | Novel 5-substituted-2-((n-morpholino)-n-nitrosoamino- methyl)oxadiazole derivative and preventing agent for thrombosis containing the same as principal constituent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS57200372A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4954526A (en) * | 1989-02-28 | 1990-09-04 | The United States Of America As Represented By The Department Of Health And Human Services | Stabilized nitric oxide - primary amine complexes useful as cardiovascular agents |
-
1981
- 1981-06-04 JP JP8500081A patent/JPS57200372A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57200372A (en) | 1982-12-08 |
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