JPH0217554B2 - - Google Patents
Info
- Publication number
- JPH0217554B2 JPH0217554B2 JP56113417A JP11341781A JPH0217554B2 JP H0217554 B2 JPH0217554 B2 JP H0217554B2 JP 56113417 A JP56113417 A JP 56113417A JP 11341781 A JP11341781 A JP 11341781A JP H0217554 B2 JPH0217554 B2 JP H0217554B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- lower alkyl
- ethyl
- alkyl group
- reserpirin
- 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 - Lifetime
Links
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- -1 reserpiline quaternary ammonium salt Chemical class 0.000 claims description 6
- 239000003416 antiarrhythmic agent Substances 0.000 claims description 4
- 229950010889 reserpiline Drugs 0.000 claims description 4
- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 3
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- 239000003826 tablet Substances 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 238000009472 formulation Methods 0.000 description 7
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 4
- 229930182837 (R)-adrenaline Natural products 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 4
- 229960005139 epinephrine Drugs 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000003288 anthiarrhythmic effect Effects 0.000 description 3
- 230000006793 arrhythmia Effects 0.000 description 3
- 206010003119 arrhythmia Diseases 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- FGWJRZQNNZVCHR-BCRCDCHUSA-N reserpiline Chemical class COC1=C(OC)C=C2C(CCN3C[C@H]4[C@H](C)OC=C([C@H]4C[C@@H]33)C(=O)OC)=C3NC2=C1 FGWJRZQNNZVCHR-BCRCDCHUSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は新規なレセルピリン第4級塩誘導体お
よびそれを含有する抗不整脈剤に関する。本発明
のレセルピリン第4級塩誘導体は次の一般式
(式中Xはハロゲン原子を示し、R1は水素原
子またはトリ低級アルキルアンモニウム基で置換
された低級アルキル基を示し、そしてR2は低級
アルキル基またはトリ低級アルキルアミノアンモ
ニウム基で置換された低級アルキル基を示すが、
R1およびR2のうちの一方はトリ低級アルキルア
ンモニウム基で置換された低級アルキル基であ
る)で表わされる。
本発明のレセルピリン第4級アンモニウム塩誘
導体は抗不整脈剤として有用な化合物である。こ
の種の化合物としては従来、4級塩化されていな
い一般式
(式中R1は水素、アルキル基およびジアルキ
ルアミノアルキル基を表わし、R2はアルキル基、
モルホリノアルキル基およびジメチルアミノアル
キル基を表わす)で示されるレセルピリン誘導体
が抗不整脈作用を有することが知られている(特
開昭52−93799号公報参照)。本発明者等は種々研
究を重ねた結果、こうした従来既知のレセルピリ
ン誘導体を第4級アンモニウム塩化することによ
つて、それらが意外にも強い抗不整脈作用を有す
ることを見出した。
本発明のレセルピリン第4級アンモニウム塩誘
導体は、前記一般式〔〕で表わされるレセルピ
リン誘導体を例えばアセトン程度の極性を有する
有機溶媒に溶解し、低級アルキルハライドを等モ
ルないし大過剰の範囲の量で添加して攬拌し、0
℃ないし室温において2時間ないし24時間反応さ
せることにより製造される。こうして得られる本
発明のレセルピリン第4級アンモニウム塩誘導体
は反応液から分離してくるので、例えば溶媒をデ
カンテーシヨンによつて除去し、残渣を再びアセ
トン、エタノール等の極性溶媒に溶解させ、次い
でエーテル、ベンゼン等の比較的無極性の溶媒を
添加すれば結晶として析出させることができる。
別後、得られた結晶は前記と同様の再結晶化を
繰り返し行なうことによりさらに精製できる。
本発明のレセルピリン第4級アンモニウム塩誘
導体の効果の検定はモルモツトへのアドレナリン
投与によつて誘発される不整脈を阻止するか否か
を測定することにより行なわれた。すなわち、体
重400〜600gの雄モルモツトに1.2g/Kgのウレ
タンを腹腔内に注射した後、背位に固定し、外頚
静脈にカニユレーシヨンする。四肢にECG用電
極を固定し心電図を第2誘導により観察する。麻
酔30〜60分後にアドレナリンをカニユーレを通し
て急速に注入し、生ずる不整脈が25〜60秒間持続
するようにアドレナリン量をきめる。注入アドレ
ナリン量の設定30分後に供試化合物を徐々に静注
する。供試化合物の静注5分後、10分後、15分後
および30分後にあらかじめ設定した量のアドレナ
リンを急速に注入する。5分後、10分後および15
分後のアドレナリン誘発不整脈を一度以上完全に
阻止しえた供試化合物の量を完全阻止最少有効量
(LED)とする。その測定結果は次のとおりであ
る。
The present invention relates to a novel reserpirin quaternary salt derivative and an antiarrhythmic agent containing the same. The reserpirin quaternary salt derivative of the present invention has the following general formula: (In the formula , Indicates an alkyl group,
One of R 1 and R 2 is a lower alkyl group substituted with a tri-lower alkyl ammonium group. The reserpirin quaternary ammonium salt derivative of the present invention is a compound useful as an antiarrhythmic agent. Conventionally, this type of compound has a general formula that is not quaternary chlorinated. (In the formula, R 1 represents hydrogen, an alkyl group and a dialkylaminoalkyl group, R 2 represents an alkyl group,
It is known that reserpiline derivatives represented by morpholinoalkyl group and dimethylaminoalkyl group have antiarrhythmic effects (see JP-A-52-93799). As a result of various studies, the present inventors have discovered that by converting these conventionally known reserpirin derivatives into quaternary ammonium salts, they have unexpectedly strong antiarrhythmic effects. The reserpirin quaternary ammonium salt derivative of the present invention can be obtained by dissolving the reserpirin derivative represented by the general formula [] in an organic solvent having a polarity such as acetone, and adding lower alkyl halide in an amount ranging from equimolar to large excess. Add and stir, 0
It is produced by reacting for 2 to 24 hours at ℃ to room temperature. Since the reserpiline quaternary ammonium salt derivative of the present invention thus obtained is separated from the reaction solution, the solvent is removed, for example, by decantation, and the residue is dissolved again in a polar solvent such as acetone or ethanol. By adding a relatively non-polar solvent such as ether or benzene, it can be precipitated as crystals.
After separation, the obtained crystals can be further purified by repeating the same recrystallization as described above. The efficacy of the reserpirin quaternary ammonium salt derivative of the present invention was tested by determining whether it inhibited arrhythmia induced by adrenaline administration to guinea pigs. That is, male guinea pigs weighing 400 to 600 g are intraperitoneally injected with 1.2 g/Kg of urethane, fixed in a dorsal position, and cannulated into the external jugular vein. ECG electrodes are fixed to the limbs and the electrocardiogram is observed through the second lead. After 30 to 60 minutes of anesthesia, epinephrine is rapidly injected through the cannula, and the amount of epinephrine is determined so that the resulting arrhythmia lasts for 25 to 60 seconds. Thirty minutes after setting the amount of epinephrine to be injected, the test compound is slowly injected intravenously. A preset amount of epinephrine is rapidly injected 5, 10, 15, and 30 minutes after the intravenous injection of the test compound. After 5 minutes, 10 minutes and 15 minutes
The amount of the test compound that completely inhibits adrenaline-induced arrhythmia after one or more minutes is defined as the minimum effective dose for complete inhibition (LED). The measurement results are as follows.
【表】
ピリネートヨーダイド
1〓〓2〓(ジメチル〓n〓プロピ 3
5/5 10.0 3.3
ルアンモニウム)〓エチル〓〓
レセルピリンヨーダイド
上記の供試化合物を前記一般式〔〕との関連
において示すと次のとおりである。[Table] Pyrinate iodide
1〓〓2〓(Dimethyl〓n〓Propy 3
5/5 10.0 3.3
ammonium)〓ethyl〓〓
Reserpirin Iodide The above test compound is shown below in relation to the general formula [].
【表】
ダイド ル
急性毒性(LD50)は雄ddYマウス(体重約20
〜25g)を用いて溶剤に溶解した供試化合物を尾
静脈に注入してリツチフイールド・ウイルコキソ
ン(Litchfield−Wilcoxon)法により測定され
た。
前記の結果から本発明に係る新規なレセルピリ
ン第4級アンモニウム塩誘導体は既知の化合物よ
り一層優れた抗不整脈作用を有する化合物である
ことが判る。
製造例 1
2−(ジメチル−n−プロピルアンモニウム)−
エチルレセルピリネートヨーダイド
2−(ジメチルアミノ)−エチルレセルピリネー
ト5gを無水アセトン15mlに溶解し、ヨウ化n−
プロピル10mlを添加して窒素下に室温において17
時間放置する。黄色油状物が分離するので溶媒を
デカンテーシヨンにより除去する。残渣に再びア
セトン100c.c.を添加し、不溶物を過する。液
に攬拌下エーテルを添加し、生成する粉末状沈殿
物を過しエーテルで洗浄後真空乾燥する。収量
3.5g(収率51.4%)。
IR:3200、1710、1620、1100
NMR:10.6(Na−H) 3.75(−OCH3、6H)
7.6([Table] Daedl acute toxicity (LD 50 ) was measured in male ddY mice (body weight approx.
The test compound dissolved in a solvent was injected into the tail vein using ~25 g), and the test compound was measured by the Litchfield-Wilcoxon method. The above results show that the novel reserpirin quaternary ammonium salt derivative according to the present invention is a compound that has antiarrhythmia effects that are superior to known compounds. Production example 1 2-(dimethyl-n-propylammonium)-
Ethyl reserpirinate iodide Dissolve 5 g of 2-(dimethylamino)-ethyl reserpirinate in 15 ml of anhydrous acetone, and dissolve n-iodide.
17 at room temperature under nitrogen by adding 10 ml of propyl
Leave it for a while. A yellow oil separates and the solvent is removed by decantation. Add 100 c.c. of acetone to the residue again and filter out the insoluble matter. Ether is added to the solution while stirring, and the resulting powdery precipitate is filtered, washed with ether, and then dried in vacuum. yield
3.5g (yield 51.4%). IR: 3200, 1710, 1620, 1100 NMR: 10.6 (N a −H) 3.75 (−OCH 3 , 6H)
7.6(
【式】1H) 0.85([Formula] 1H) 0.85 (
【式】3H) 6.9(芳香族
2H)
m.p.:161.1〜164.4℃
製造例 2
1−{2−(ジメチル−n−プロピルアンモニウ
ム)−エチル}−レセルピリンヨーダイド
前記製造例1において使用された2−(ジメチ
ルアミノ)エチルレセルピリネートに代えて1−
{2−(ジメチルアミノ)−エチル}−レセルピリン
を使用する以外は製造例1の操作に従つて標記化
合物が製造された。
IR:1680、1600、1190
NMR:7.70([Formula] 3H) 6.9 (aromatic 2H) mp: 161.1-164.4°C Production Example 2 1-{2-(Dimethyl-n-propylammonium)-ethyl}-reserpiline iodide 2 used in Production Example 1 above -1- in place of (dimethylamino)ethyl reserpirinate
The title compound was prepared according to the procedure of Preparation Example 1 except that {2-(dimethylamino)-ethyl}-reserpiline was used. IR: 1680, 1600, 1190 NMR: 7.70 (
【式】1H) 3.7(−
COOCH3 3H)
7.10(芳香族 2H) 0.9
([Formula] 1H) 3.7 (- COOCH 3 3H) 7.10 (Aromatic 2H) 0.9
(
【式】3H)
3.9及び3.8(−OCH3 6H)
m.p.:212.7〜214.6℃
本発明の化合物は、通常薬学的製剤の形態で経
口的または非経口的に投与されうる。薬学的製剤
の形態としては、錠剤、カプセル剤、坐剤、トロ
ーチ剤、シロツプ剤、クリーム剤、軟膏剤、貼付
剤、ハツプ剤、顆粒剤、散剤、注射剤、懸濁剤、
吸入剤、エアゾール剤等がある。また他の薬剤と
ともに二重層錠、多層錠とすることができる。さ
らに錠剤は、必要に応じて通常の剤皮を施した錠
剤、例えば糖衣錠、腸溶被錠、フイルムコート錠
とすることもできる。
固体製剤とする場合は、添加剤、例えば、乳
糖、白糖、結晶セルロース、トウモロコシデンプ
ン、リン酸カルシウム、ソルビトール、グリシ
ン、カルボキシメチルセルロース、アラビアゴ
ム、ポリビニルピロリドン、ヒドワキシプロピル
セルロース、グリセリン、ポリエチレングリコー
ル、ステアリン酸、ステアリン酸マグネシウム、
タルク等が用いられる。
半固体製剤とする場合は、植物性または合成ロ
ウまたは脂肪等が用いられる。
液体製剤とする場合は、添加剤、例えば、塩化
ナトリウム、ソルビトール、グリセリン、オリブ
油、アーモンド油、プロピレングリコール、エチ
ルアルコール等が用いられる。
これらの製剤の有効成分の量は製剤の0.1〜100
重量%であり、適当には経口投与のための製剤の
場合には1〜50重量%であり、そして注射用製剤
の場合には0.1〜10重量%である。
本発明の抗不整脈剤の投与方法および投与量に
はとくに制限はなく、各種製剤形態、投与経路、
患者の年齢、性別、疾患の程度などにより適宜選
択されるが、有効成分の1日あたりの投与量は
0.01〜1000mgである。
製剤例1 錠剤(1錠)
2−(ジメチル−n−プロピルアンモニウム)
エチルレセルピリネートヨーダイド 1mg
乳 糖 76mg
結晶セルロース 15mg
トウモロコシデンプン 7mg
ステアリン酸マグネシウム 1mg
100mg
各成分を均一に混合し直打用粉末とする。これ
をロータリー式打錠機で直径6mm、重量100mgの
錠剤に成型する。
製剤例2 顆粒剤(1分包)[Formula] 3H) 3.9 and 3.8 (-OCH 3 6H) mp: 212.7-214.6°C The compounds of the present invention can be administered orally or parenterally, usually in the form of a pharmaceutical preparation. Forms of pharmaceutical preparations include tablets, capsules, suppositories, troches, syrups, creams, ointments, patches, poultices, granules, powders, injections, suspensions,
There are inhalants, aerosols, etc. It can also be made into double-layer tablets or multi-layer tablets together with other drugs. Furthermore, the tablets can be made into tablets with conventional coatings, such as sugar-coated tablets, enteric-coated tablets, or film-coated tablets, if necessary. When preparing a solid preparation, additives such as lactose, sucrose, crystalline cellulose, corn starch, calcium phosphate, sorbitol, glycine, carboxymethylcellulose, gum arabic, polyvinylpyrrolidone, hydroxypropylcellulose, glycerin, polyethylene glycol, stearic acid are used. ,Magnesium stearate,
Talc etc. are used. In the case of semi-solid preparations, vegetable or synthetic waxes or fats are used. When preparing a liquid preparation, additives such as sodium chloride, sorbitol, glycerin, olive oil, almond oil, propylene glycol, and ethyl alcohol are used. The amount of active ingredient in these preparations ranges from 0.1 to 100% of the preparation
% by weight, suitably from 1 to 50% by weight in the case of formulations for oral administration and from 0.1 to 10% by weight in the case of formulations for injection. There are no particular restrictions on the administration method or dosage of the antiarrhythmic agent of the present invention, and there are various formulation forms, administration routes,
The daily dose of the active ingredient is selected depending on the patient's age, gender, degree of disease, etc.
It is 0.01-1000mg. Formulation Example 1 Tablet (1 tablet) 2-(dimethyl-n-propylammonium)
Ethyl reserpirinate iodide 1 mg Lactose 76 mg Crystalline cellulose 15 mg Corn starch 7 mg Magnesium stearate 1 mg 100 mg Each component is mixed uniformly to make a powder for direct compression. This is molded into tablets with a diameter of 6 mm and a weight of 100 mg using a rotary tablet press. Formulation example 2 Granules (1 sachet)
【表】
Aの成分を均一に混合した後、Bの溶液を加え
て練合し、押出造粒法で整粒し、次いで50℃の乾
燥機で乾燥する。乾燥上がり顆粒を粒度297μm〜
1460μmにふるい分けたものを顆粒剤とする。1
分包量を200mgとする。
製剤例3 注射液
2−(ジメチル−n−プロピルアンモニウム)
エチルレセルピリネートヨーダイド 1mg
塩化ナトリウム 10mg
蒸留水 適量
全量 1.0ml
塩化ナトリウムおよび有効成分を蒸留水を加え
て溶解し、全量を1.0mlとする。
製剤例4 坐剤
2−(ジメチル−n−プロピルアンモニウム)
エチルレセルピリネートヨーダイド 1g
ポリエチレングリコール4000 79g
グリセリン 20g
全量 100g
グリセリンを有効成分に加えて溶解する。そこ
へ、ポリエチレングリコール4000を加えて加温し
溶解後、坐剤型に注入して冷却固化し、1個当た
り1.5gの坐剤を製造する。[Table] After the components of A are mixed uniformly, the solution of B is added and kneaded, the granules are sized using an extrusion granulation method, and then dried in a dryer at 50°C. Particle size of dried granules is 297 μm ~
The granules are sieved to 1460μm. 1
The sachet amount is 200mg. Formulation Example 3 Injection 2-(dimethyl-n-propylammonium)
Ethyl reserpirinate iodide 1 mg Sodium chloride 10 mg Distilled water Appropriate total volume 1.0 ml Add distilled water to dissolve sodium chloride and the active ingredient to make a total volume of 1.0 ml. Formulation example 4 Suppositories 2-(dimethyl-n-propylammonium)
Ethyl reserpyrinate iodide 1g Polyethylene glycol 4000 79g Glycerin 20g Total amount 100g Add glycerin to the active ingredients and dissolve. Polyethylene glycol 4000 is added thereto, heated and dissolved, poured into suppository molds, cooled and solidified to produce suppositories weighing 1.5 g each.
Claims (1)
子またはトリ低級アルキルアンモニウム基で置換
された低級アルキル基を示し、そしてR2は低級
アルキル基またはトリ低級アルキルアミノアンモ
ニウム基で置換された低級アルキル基を示すが、
R1およびR2のうちの一方はトリ低級アルキルア
ンモニウム基で置換された低級アルキル基であ
る)で表わされるレセルピリン第4級アンモニウ
ム塩誘導体。 2 一般式 (式中Xはハロゲン原子を示し、R1は水素原
子またはトリ低級アルキルアンモニウム基で置換
された低級アルキル基を示し、そしてR2は低級
アルキル基またはトリ低級アルキルアミノアンモ
ニウム基で置換された低級アルキル基を示すが、
R1およびR2のうちの一方はトリ低級アルキルア
ンモニウム基で置換された低級アルキル基であ
る)で表わされるレセルピリン第4級アンモニウ
ム塩誘導体を含有することを特徴とする抗不整脈
剤。[Claims] 1. General formula (In the formula , Indicates an alkyl group,
One of R 1 and R 2 is a lower alkyl group substituted with a tri-lower alkyl ammonium group). 2 General formula (In the formula , Indicates an alkyl group,
An antiarrhythmic agent characterized in that it contains a reserpiline quaternary ammonium salt derivative represented by R 1 and R 2 , in which one of R 1 and R 2 is a lower alkyl group substituted with a tri-lower alkyl ammonium group.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP11341781A JPS5815981A (en) | 1981-07-20 | 1981-07-20 | Reserpiline quaternary ammonium salt derivative and antiarrhythmic agent |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP11341781A JPS5815981A (en) | 1981-07-20 | 1981-07-20 | Reserpiline quaternary ammonium salt derivative and antiarrhythmic agent |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5815981A JPS5815981A (en) | 1983-01-29 |
JPH0217554B2 true JPH0217554B2 (en) | 1990-04-20 |
Family
ID=14611722
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP11341781A Granted JPS5815981A (en) | 1981-07-20 | 1981-07-20 | Reserpiline quaternary ammonium salt derivative and antiarrhythmic agent |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5815981A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9174856B2 (en) | 2009-07-17 | 2015-11-03 | Japan Science And Technology Agency | Floatation separation apparatus, method of floatation separation, and method of manufacturing products using the same |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS4935400A (en) * | 1972-08-06 | 1974-04-01 | ||
JPS5113799A (en) * | 1974-07-22 | 1976-02-03 | Nisshin Flour Milling Co | RESERUPIRIN JUDOTAINO SEIZOHO |
JPS5293799A (en) * | 1976-02-02 | 1977-08-06 | Nisshin Flour Milling Co Ltd | Recerpine derivatives and antiarryhythics |
JPS5510595A (en) * | 1978-06-09 | 1980-01-25 | Rolex Montres | Electronic timer for submarine use |
-
1981
- 1981-07-20 JP JP11341781A patent/JPS5815981A/en active Granted
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS4935400A (en) * | 1972-08-06 | 1974-04-01 | ||
JPS5113799A (en) * | 1974-07-22 | 1976-02-03 | Nisshin Flour Milling Co | RESERUPIRIN JUDOTAINO SEIZOHO |
JPS5293799A (en) * | 1976-02-02 | 1977-08-06 | Nisshin Flour Milling Co Ltd | Recerpine derivatives and antiarryhythics |
JPS5510595A (en) * | 1978-06-09 | 1980-01-25 | Rolex Montres | Electronic timer for submarine use |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9174856B2 (en) | 2009-07-17 | 2015-11-03 | Japan Science And Technology Agency | Floatation separation apparatus, method of floatation separation, and method of manufacturing products using the same |
Also Published As
Publication number | Publication date |
---|---|
JPS5815981A (en) | 1983-01-29 |
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