JPH0217553B2 - - Google Patents
Info
- Publication number
- JPH0217553B2 JPH0217553B2 JP56113416A JP11341681A JPH0217553B2 JP H0217553 B2 JPH0217553 B2 JP H0217553B2 JP 56113416 A JP56113416 A JP 56113416A JP 11341681 A JP11341681 A JP 11341681A JP H0217553 B2 JPH0217553 B2 JP H0217553B2
- Authority
- JP
- Japan
- Prior art keywords
- lower alkyl
- alkyl group
- formula
- optionally substituted
- carbon atoms
- 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 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 235000002639 sodium chloride Nutrition 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 10
- 239000003826 tablet Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000002904 solvent Substances 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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000006793 arrhythmia Effects 0.000 description 4
- 206010003119 arrhythmia Diseases 0.000 description 4
- 229960005139 epinephrine Drugs 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- -1 2-(dimethylamino)-ethyl Chemical group 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-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
- 239000003416 antiarrhythmic agent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 235000019441 ethanol Nutrition 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
- 239000000843 powder Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 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
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229940057838 polyethylene glycol 4000 Drugs 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
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 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
- 206010002091 Anaesthesia Diseases 0.000 description 1
- PBXZXAILLGHMAZ-UHFFFAOYSA-N CCC[NH3+].CCC[NH3+].[I-].[I-] Chemical compound CCC[NH3+].CCC[NH3+].[I-].[I-] PBXZXAILLGHMAZ-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 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
- 239000002253 acid Substances 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
- 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
- 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
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 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
- 238000010438 heat treatment Methods 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
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 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
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000002245 particle 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
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 239000011541 reaction mixture Substances 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
- 239000013076 target substance Substances 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ニウム第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
発明のレセルピリニウム第４級塩誘導体は次の一
般式
（式中ｎは１または２の整数を示し、Ｘはハロ
ゲン原子を示し、R1は水素原子または低級アル
キル基を示し、R2はトリ低級アルキルアミノア
ンモニウム基で置換されていてもよい低級アルキ
ル基を示し、そしてR3は低級アルキル基を示す
が、R2の置換されていてもよい低級アルキル基
の炭素数（場合により存在する置換部分は除く）
とR3の低級アルキル基の炭素数との和は少なく
とも３以上である）で表わされる。
本発明の前記一般式〔〕で表わされるレセル
ピリニウム第４級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、式
で表わされる４−メチルレセルピリニウムヨーダ
イドが知られている（「J.Am.Chem.Soc.」第85
巻第2507頁（1963）および「Fitoterapia」第43
(3)巻第67頁（1973）参照）。しかしながら、この
化合物が抗不整脈作用を有するか否かについては
何等の報告もない。
本発明者らは種々研究を重ねた結果、新規なレ
セルピリニウム第４級塩を得ることに成功し、し
かもそれらが意外にも抗不整脈作用を有すること
を見出した。
本発明に係るレセルピリニウム第４級塩誘導体
は、一般式
（式中R4は水素原子または低級アルキル基を
示し、R5はジ低級アルキルアミノ基で置換され
ていてもよい低級アルキル基を示す）で表わされ
るレセルピリン誘導体を例えば、ニトロメタン、
ジメチルスルホキシドまたはジメチルホルムアミ
ド等の極性溶媒中に溶解させ、低級アルキルハラ
イドを等モルないし大過剰の量で添加して窒素気
流中60〜90℃の範囲の温度で５〜60時間加熱下に
反応させることにより製造される。反応溶液から
目的物質を単離精製する方法としては例えば、反
応後、冷却し、エーテルまたはベンゼン等の比較
的非極性の溶媒を添加して、合成された本発明の
第４級塩を沈殿させ、溶媒と沈殿とをデカンテー
シヨンにより分離する。得られた沈殿を再び少量
のメタノール、エタノール、ニトロメタン、ジメ
チルスルホキシドまたはジメチルホルムアミド等
の比較的極性の高い溶媒に溶解させ、次いで再度
エーテルまたはベンゼン等の溶媒を添加して第４
級塩を析出させる。別等によつて分離される第
４級塩をさらにアセトン等の溶媒により再結晶さ
せることによりさらに精製することができる。
本発明のレセルピリニウム第４級塩誘導体の効
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秒〜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、30分
後にあらかじめ設定された量のアドレナリンを急
速に注入する。５分後、10分後、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。
アドレナリン不整脈に対する効果
The present invention relates to a novel reserpirinium quaternary salt derivative and an antiarrhythmic agent containing the same. The reserpirinium quaternary salt derivative of the present invention has the following general formula: (In the formula, n represents an integer of 1 or 2, X represents a halogen atom, R 1 represents a hydrogen atom or a lower alkyl group, and R 2 represents a lower alkyl group which may be substituted with a tri-lower alkylamino ammonium group. and R 3 represents a lower alkyl group, but the number of carbon atoms in the optionally substituted lower alkyl group of R 2 (excluding optionally substituted moieties)
and the number of carbon atoms in the lower alkyl group of R 3 is at least 3). The reserpirinium quaternary salt derivative of the present invention represented by the general formula [] is a compound useful as an antiarrhythmic agent. Traditionally, this type of compound has the formula 4-methylreserpyrinium iodide represented by
Volume No. 2507 (1963) and “Fitoterapia” No. 43
(3), p. 67 (1973)). However, there are no reports on whether this compound has antiarrhythmic effects. As a result of various studies, the present inventors succeeded in obtaining novel quaternary salts of reserpirinium, and surprisingly discovered that they have antiarrhythmic effects. The reserpirinium quaternary salt derivative according to the present invention has the general formula (In the formula, R 4 represents a hydrogen atom or a lower alkyl group, and R 5 represents a lower alkyl group which may be substituted with a di-lower alkylamino group), for example, nitromethane,
Dissolve in a polar solvent such as dimethyl sulfoxide or dimethyl formamide, add lower alkyl halide in an equimolar to large excess amount, and react under heating at a temperature in the range of 60 to 90°C for 5 to 60 hours in a nitrogen stream. Manufactured by As a method for isolating and purifying the target substance from the reaction solution, for example, after the reaction, the synthesized quaternary salt of the present invention is precipitated by cooling and adding a relatively non-polar solvent such as ether or benzene. , the solvent and precipitate are separated by decantation. The obtained precipitate is again dissolved in a small amount of a relatively polar solvent such as methanol, ethanol, nitromethane, dimethyl sulfoxide or dimethyl formamide, and then a solvent such as ether or benzene is added again to form a fourth solution.
precipitates grade salts. The quaternary salt separated by separation or the like can be further purified by recrystallizing it from a solvent such as acetone. The effectiveness of the reserpirinium quaternary salt derivative of the present invention was tested by determining whether it inhibits arrhythmia induced by adrenaline administration to guinea pigs. i.e. weight 400~
A 600 g male guinea pig is 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. Anesthesia 30-60
After minutes, epinephrine is rapidly injected through the cannula and the amount of epinephrine is determined so that the resulting arrhythmia lasts 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. The amount of the test compound that completely inhibits adrenaline-induced arrhythmia once or more after 5 minutes, 10 minutes, and 15 minutes is defined as the minimum effective dose for complete inhibition (LED). The measurement results are as follows. Effect on adrenaline arrhythmia
【表】
エステルジヨーダイド
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す。[Table] Ester diiodide The above test compounds are shown below in relation to the general formula [].
【表】
エチルエステルジヨーダ
イド
急性毒性（LD50）は体重約20〜25ｇの雄ddY
マウス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ニ
ウム第４級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わか
る。
製造例 １
１−メチル−４−ｎ−プロピルレセルピリニウ
ムヨーダイド
Ｎ−メチルレセルピリン５ｇをニトロメタン15
c.c.に溶解し、沃化ｎ−プロピル12c.c.を添加して窒
素下80℃で一夜反応させる。反応液を冷却した
後、攬拌しながらエーテル60c.c.を少量ずつ添加
し、析出した粉末状沈殿物を集し、エタノール
から再結晶する。収量60ｇ（85.8％）。
IR：1710、1630、1100
NMR：7.75（[Table] Acute toxicity (LD 50 ) of ethyl ester diiodide is ddY in males weighing approximately 20 to 25 g.
The test compound dissolved in a solvent was injected into the tail vein of a mouse and measured by the Litchfield-Wilcoxon method.
The above results show that the novel reserpirinium quaternary salt derivative according to the present invention is a compound that has antiarrhythmia effects that are superior to known compounds. Production example 1 1-Methyl-4-n-propyl reserpyrinium iodide 5 g of N-methyl reserpyrine was dissolved in nitromethane 15
cc., add 12 c.c. of n-propyl iodide, and react overnight at 80° C. under nitrogen. After cooling the reaction solution, 60 c.c. of ether is added little by little while stirring, and the precipitated powder is collected and recrystallized from ethanol. Yield 60g (85.8%). IR: 1710, 1630, 1100 NMR: 7.75 (
【式】1H） 3.6（Na−
CH33H）
7.1（芳香族2H） 3.4（−COOCH3 3H）
3.8（−OCH3 6H） 0.85
（[Formula] 1H) 3.6 (N a − CH 3 3H) 7.1 (Aromatic 2H) 3.4 (−COOCH 3 3H) 3.8 (−OCH 3 6H) 0.85
(
【式】3H）
m.p.：225.0〜226.8℃
元素分析値：
Ｃ％ Ｈ％ Ｎ％
計算値： 53.60 6.06 4.82
実測値： 53.37 6.35 4.72
製造例 ２
４−ｎ−プロピル−レセルピリニウム２−（ジ
メチル−ｎ−プロピルアンモニウム）−エチル
エステルジヨーダイド
12.5ｇ（0.027モル）の２−（ジメチルアミノ）
−エチルレセルピリネートを60mlのニトロメタン
に溶解し、30mlの沃化ｎ−プロピルを添加して窒
素下に80℃で17時間加熱する。冷却後、反応混合
物を150mlのエーテルで希釈し、溶媒をデカンテ
ーシヨンにより除去する。残渣を少量のメタノー
ルに溶解し、攬拌しながら100mlのエーテルを添
加する。生成した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19ｇ（収率88.2％）。
IR：3200、1720、1620、1110
NMR：10.95（Na−Ｈ） 3.8（−OCH3 6H）
7.75（[Formula] 3H) mp: 225.0-226.8℃ Elemental analysis value: C% H% N% Calculated value: 53.60 6.06 4.82 Actual value: 53.37 6.35 4.72 Production example 2 4-n-propyl-reserpyrinium 2-(dimethyl-n- 12.5 g (0.027 mol) of 2-(dimethylamino)-ethyl ester diiodide (propylammonium)
- Ethyl reserpirinate is dissolved in 60 ml of nitromethane, 30 ml of n-propyl iodide is added and heated at 80 DEG C. for 17 hours under nitrogen. After cooling, the reaction mixture is diluted with 150 ml of ether and the solvent is removed by decantation. Dissolve the residue in a small amount of methanol and add 100 ml of ether while stirring. The resulting powdery precipitate is filtered, washed with ether, and then dried in vacuum. Yield: 19g (yield: 88.2%). IR: 3200, 1720, 1620, 1110 NMR: 10.95 (N a −H) 3.8 (−OCH 3 6H) 7.75 (
【式】1H） 0.9 （[Formula] 1H) 0.9 (
【式】6H）
7.0（芳香族 2H）
m.p.：193.3〜195.1℃
前記各製造例に従つて次の化合物が合成され
た。
４−ｎ−プロピル−レセルピリニウムヨーダイ
ド
IR：3400、1720、1640、1100
NMR：11.0（Na−Ｈ） 3.75（−OCH3 6H）
7.55（[Formula] 6H) 7.0 (aromatic 2H) mp: 193.3-195.1°C The following compounds were synthesized according to each of the above production examples. 4-n-propyl-reserpyrinium iodide IR: 3400, 1720, 1640, 1100 NMR: 11.0 (N a -H) 3.75 (-OCH 3 6H) 7.55 (
【式】1H） 3.35（−COOCH3
3H）
6.95（芳香族 2H） 0.85
（[Formula] 1H) 3.35 (−COOCH 3 3H) 6.95 (Aromatic 2H) 0.85
(
【式】3H）
m.p.：195.7〜199.7℃
１−メチル−４−イソプロピル−レセルピリニ
ウムヨーダイド
IR：1700、1620、1100
NMR：7.7（[Formula] 3H) mp: 195.7-199.7℃ 1-Methyl-4-isopropyl-reserpyrinium iodide IR: 1700, 1620, 1100 NMR: 7.7 (
【式】1H） 3.6（Na−CH3 3H） 7.15（芳香族 2H） 3.45（−COOCH3 3H） 3.8（−OCH3 6H）1.35（[Formula] 1H) 3.6 (N a −CH 3 3H) 7.15 (aromatic 2H) 3.45 (−COOCH 3 3H) 3.8 (−OCH 3 6H) 1.35 (
【式】6H）
m.p.：175.1〜177.8℃
４−メチル−レセルピリニウム２−（トリメチ
ルアンモニウム）−エチルエステル ジヨーダイ
ド
IR：3250 1720、1630、1110
NMR：11.2（Na−Ｈ） 3.8（−OCH3 6H）
7.7（[Formula] 6H) mp: 175.1-177.8℃ 4-Methyl-reserpirinium 2-(trimethylammonium)-ethyl ester diiodide IR: 3250 1720, 1630, 1110 NMR: 11.2 (N a -H) 3.8 (-OCH 3 6H) 7.7(
【式】1H） 3.35（−Nb−CH3 3H）
6.95（芳香族2H） 3.2（−Ｎ（CH3）39H）
m.p.：197.7〜199.7℃
元素分析値：
Ｃ％ Ｈ％ Ｎ％
計算値： 44.76 5.50 5.59
実測値： 44.45 5.48 5.57
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、ヒドロキシプロピル
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）
１−メチル−ｎ−４−プロピルレセルピリニウ
ムヨーダイド 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] 1H) 3.35 (-N b -CH 3 3H) 6.95 (Aromatic 2H) 3.2 (-N (CH 3 ) 3 9H) mp: 197.7-199.7℃ Elemental analysis value: C% H% N% Calculated value : 44.76 5.50 5.59 Observed value: 44.45 5.48 5.57 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, stearin are used. magnesium acid,
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) 1-Methyl-n-4-propyl reserpyrinium 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 form 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
１−メチル−４−ｎ−プロピルレセルピリニウ
ムヨーダイド） 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
１−メチル−４−ｎ−プロピルレセルピリニウ
ムヨーダイド 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 (1-methyl-4-n-propyl reserpyrinium iodide) 1 mg Sodium chloride 10 mg Distilled water Appropriate total volume 1.0 ml Sodium chloride and the active ingredient are dissolved in distilled water to make a total volume of 1.0 ml. . Formulation Example 4 Suppositories 1-Methyl-4-n-propyl reserpyrinium iodide 1 g Polyethylene glycol 4000 79 g Glycerin 20 g Total amount 100 g Glycerin is added to the active ingredient and dissolved. 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)
ゲン原子を示し、R1は水素原子または低級アル
キル基を示し、R2はトリ低級アルキルアミノア
ンモニウム基で置換されていてもよい低級アルキ
ル基を示し、そしてR3は低級アルキル基を示す
が、R2の置換されていてもよい低級アルキル基
の炭素数（場合により存在する置換部分は除く）
とR3の低級アルキル基の炭素数との和は少なく
とも３以上である）で表わされるレセルピリニウ
ム第４級塩誘導体。 ２ 一般式 （式中ｎは１または２の整数を示し、ｘはハロ
ゲン原子を示し、R1は水素原子または低級アル
キル基を示し、R2はトリ低級アルキルアミノア
ンモニウム基で置換されていてもよい低級アルキ
ル基を示し、そしてR3は低級アルキル基を示す
が、R2の置換されていてもよい低級アルキル基
の炭素数（場合により存在する置換部分は除く）
とR3の低級アルキル基の炭素数との和は少なく
とも３以上である）で表わされるレセルピリニウ
ム第４級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, n represents an integer of 1 or 2, x represents a halogen atom, R 1 represents a hydrogen atom or a lower alkyl group, and R 2 represents a lower alkyl group optionally substituted with a tri-lower alkylamino ammonium group. and R 3 represents a lower alkyl group, but the number of carbon atoms in the optionally substituted lower alkyl group of R 2 (excluding optionally substituted moieties)
and the number of carbon atoms in the lower alkyl group of R 3 is at least 3 or more). 2 General formula (In the formula, n represents an integer of 1 or 2, x represents a halogen atom, R 1 represents a hydrogen atom or a lower alkyl group, and R 2 represents a lower alkyl group optionally substituted with a tri-lower alkylamino ammonium group. and R 3 represents a lower alkyl group, but the number of carbon atoms in the optionally substituted lower alkyl group of R 2 (excluding optionally substituted moieties)
and the number of carbon atoms in the lower alkyl group of R 3 is at least 3).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11341681A JPS5813586A (en) | 1981-07-20 | 1981-07-20 | Reserpilinium quaternary salt derivative and antiarrhythmics |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11341681A JPS5813586A (en) | 1981-07-20 | 1981-07-20 | Reserpilinium quaternary salt derivative and antiarrhythmics |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5813586A JPS5813586A (en) | 1983-01-26 |
| JPH0217553B2 true JPH0217553B2 (en) | 1990-04-20 |
Family
ID=14611697
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11341681A Granted JPS5813586A (en) | 1981-07-20 | 1981-07-20 | Reserpilinium quaternary salt derivative and antiarrhythmics |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5813586A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5012551Y2 (en) * | 1972-06-30 | 1975-04-17 |
-
1981
- 1981-07-20 JP JP11341681A patent/JPS5813586A/en active Granted
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5813586A (en) | 1983-01-26 |
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