JPS62174017A - 1,4-dihydropyridine derivative - Google Patents
1,4-dihydropyridine derivativeInfo
- Publication number
- JPS62174017A JPS62174017A JP20323186A JP20323186A JPS62174017A JP S62174017 A JPS62174017 A JP S62174017A JP 20323186 A JP20323186 A JP 20323186A JP 20323186 A JP20323186 A JP 20323186A JP S62174017 A JPS62174017 A JP S62174017A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- dihydropyridine
- benzyl
- ester
- nitrophenyl
- 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.)
- Granted
Links
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 title abstract description 4
- -1 hypotensor Substances 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 201000010099 disease Diseases 0.000 claims abstract 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract 2
- TZDPJNSHSWMCPN-UHFFFAOYSA-N 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC([N+]([O-])=O)=C1 TZDPJNSHSWMCPN-UHFFFAOYSA-N 0.000 claims description 2
- 210000000056 organ Anatomy 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 27
- 238000002844 melting Methods 0.000 abstract description 5
- 230000008018 melting Effects 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 2
- 150000002148 esters Chemical class 0.000 abstract description 2
- 229940124549 vasodilator Drugs 0.000 abstract description 2
- 239000003071 vasodilator agent Substances 0.000 abstract description 2
- 150000004820 halides Chemical class 0.000 abstract 2
- 230000000304 vasodilatating effect Effects 0.000 abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract 1
- 230000026030 halogenation Effects 0.000 abstract 1
- 238000005658 halogenation reaction Methods 0.000 abstract 1
- 230000001077 hypotensive effect Effects 0.000 abstract 1
- 230000002093 peripheral effect Effects 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 230000004531 blood pressure lowering effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 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 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000314 lubricant 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
- 239000000203 mixture Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- COLPLFZHPXIFCQ-UHFFFAOYSA-N 1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=CNC=C(C(O)=O)C1 COLPLFZHPXIFCQ-UHFFFAOYSA-N 0.000 description 1
- UTTCOAGPVHRUFO-UHFFFAOYSA-N 1-benzylpiperidin-3-ol Chemical compound C1C(O)CCCN1CC1=CC=CC=C1 UTTCOAGPVHRUFO-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- GGISZLOBBISXOZ-UHFFFAOYSA-N acetic acid;chloroform Chemical compound CC(O)=O.ClC(Cl)Cl GGISZLOBBISXOZ-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 1
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 1
- OAIVIYSBZFEOIU-UHFFFAOYSA-N chloroform;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl OAIVIYSBZFEOIU-UHFFFAOYSA-N 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 235000010944 ethyl methyl cellulose Nutrition 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229920003087 methylethyl cellulose Polymers 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000000810 peripheral vasodilating agent Substances 0.000 description 1
- 229960002116 peripheral vasodilator Drugs 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 210000002254 renal artery Anatomy 0.000 description 1
- 206010038464 renal hypertension Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は塩酸塩の融点が１９６〜２０２℃である２、−
６−ジメチル−４−（３−ニトロフェニル）＝１，４−
ジヒドロピリジン−３，５−ジカルボン酸−５−（１−
ベンジル−３−ピペリジル）エステル−５−メチルエス
テルおよびその塩に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention provides 2,-
6-dimethyl-4-(3-nitrophenyl)=1,4-
Dihydropyridine-3,5-dicarboxylic acid-5-(1-
Benzyl-3-piperidyl) ester-5-methyl ester and its salt.
本化合物は血圧降下作用、冠血管拡張作用、末梢血管拡
張作用などを有し、血圧降下剤、血管拡張剤などの循環
器官用蘂として有用な化合物である。This compound has a blood pressure lowering effect, a coronary vasodilator effect, a peripheral vasodilator effect, etc., and is a compound useful as a blood pressure lowering agent, a vasodilator, and the like for cardiovascular organs.
本発明者らは、２．６−ジメチル−４−（３，’−ニト
ロフェニル）−１，４−ジヒドロピリジン−３，５−ジ
カルボン酸−５−（１−ベンジル−３−ピペリジル）エ
ステル−５−メチルエステルを包含する１、４−ジヒド
ロピリジン誘導体を出願している〔特願昭５６−５６９
３７号（特開昭５７−１７１９６８号公報）〕。The present inventors discovered that 2,6-dimethyl-4-(3,'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-5-(1-benzyl-3-piperidyl) ester-5 -A patent application has been filed for 1,4-dihydropyridine derivatives including methyl esters [Patent application No. 56-569]
No. 37 (Japanese Unexamined Patent Publication No. 57-171968)].
２．６−ジメチル−４−（３−ニトロフェニル）−１，
４−ジヒドロピリジン−３，５−ジカルボン！！−５−
（１−ベンジル−３−ピペリジル）エステル−５−メチ
ルエステルには２個の不斉炭素がある為、ジアステレオ
マーが存在する。本発明者らはこれらのジアステレオマ
ーの分離及び薬理活性について検討した。2.6-dimethyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3,5-dicarvone! ! -5-
(1-Benzyl-3-piperidyl) ester-5-methyl ester has two asymmetric carbon atoms, so diastereomers exist. The present inventors investigated the separation and pharmacological activity of these diastereomers.
以下に本発明の詳細な説明する。The present invention will be explained in detail below.
本化合物の製造工程の一例は次の通りである。An example of the manufacturing process of the present compound is as follows.
明細書の浄書（内容に変更なし）
化合物■ 化合物■化合物■は、化
合物■とハロゲン化試薬（例えば、塩化チオニル、三塩
化リン、五塩化リン、オキシ塩化リン、三臭化リン等）
との反応により得られる。Copy of specification (no change in content) Compound ■ Compound ■ Compound ■ is compound ■ and halogenating reagent (e.g., thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, etc.)
Obtained by reaction with
反応はジクロルメタン、クロロホルム、四塩化炭素、ク
ロルベンゼン等のハロゲン化炭化水明細書の浄ｔＦ（内
容に変更なし）
索類、ベジゼン、トルエン等の芳香族炭化水素類、テト
ラヒドロフラン、ジオキサン等のエーテル類、アセトニ
トリル、Ｎ、Ｎ−ジメチルホルムアミド、ヘキサメチル
ホスホリックトリアミド等の非プロ 」
トン性極性溶媒、ピリジン、トリエチルアミン等のアミ
ン類の存在下または非存在下に行われるが、特に、好ま
しくは塩化チオニルをハロゲン化試薬として用い、Ｎ、
Ｎ−ジメチルホルムアミドまたはへキサメチルホス承り
ツクトリアミドの存在下、上記の溶媒を併用または併用
せずして行われる。The reaction is performed with halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and chlorobenzene (no change in content), aromatic hydrocarbons such as hydrocarbons, bezizene, and toluene, and ethers such as tetrahydrofuran and dioxane. , acetonitrile, N,N-dimethylformamide, hexamethylphosphoric triamide, etc., in the presence or absence of amines such as pyridine, triethylamine, etc., but chloride is particularly preferred. Using thionyl as a halogenating reagent, N,
The reaction is carried out in the presence of N-dimethylformamide or hexamethylphostriamide, with or without the above-mentioned solvents.
カルボン酸と塩化チオニルのモル比は１．０：０゜８〜
１．０：２．０の範囲、好ましくは１． Ｏ：’Ｑ、９
〜１．０：１．２である。The molar ratio of carboxylic acid and thionyl chloride is 1.0:0°8~
1.0:2.0 range, preferably 1.0:2.0. O:'Q, 9
~1.0:1.2.
塩化チオニルとＮ、Ｎ−ジメチルホルムアミドまたはへ
キサメチルホスホリックトリアミドのモル比は１：１〜
１ ： １００、好ましくは１：５〜１：ぎ０である。The molar ratio of thionyl chloride and N,N-dimethylformamide or hexamethylphosphoric triamide is 1:1 to
The ratio is 1:100, preferably 1:5 to 1:0.
反応は一７０℃〜１００℃、好ましくは一２０℃〜５０
℃の温度で行われる。The reaction is carried out at -70°C to 100°C, preferably -20°C to 50°C.
It is carried out at a temperature of °C.
次いで、得られた化合物■（単離しなくともよい）と化
合物■とを反応させることにより目的化合物が得られる
。溶媒としては、化合物■から化合物■を製造する際に
使用された溶媒が用いられる。Next, the target compound is obtained by reacting the obtained compound (1) (which may not be isolated) with compound (2). As the solvent, the solvent used in producing compound (2) from compound (1) is used.
反応は、化合物■と化合物■とのモル比１．０＝０．８
〜１．０：２．０好ましくはｉ、ｏ：ｏ、９〜１．０：
１．２の範囲で、−７０℃〜１００℃好ましくは一２０
℃〜５０℃の温度で行われる。The reaction takes place at a molar ratio of compound (1) and compound (2) of 1.0 = 0.8.
~1.0:2.0 preferably i, o:o, 9-1.0:
1.2 in the range of -70°C to 100°C, preferably -20°C
It is carried out at a temperature of 50°C to 50°C.
反応液中には、２，６−ジメチル−４−（３−ニトロフ
ェニル）−１，４−ジヒドロピリジン−３゜５−ジカル
ボン酸−５−（１−ベンジル−３−ピペリジル）エステ
ル−５−メチルエステルの融点１９６〜２０２℃の化合
物（α体）と融点２３６〜２４２℃の化合物（β体）と
の混合物が存在するので、目的化合物であるα体を単離
するのには次の如く行なう。In the reaction solution, 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3°5-dicarboxylic acid-5-(1-benzyl-3-piperidyl) ester Since there is a mixture of an ester compound with a melting point of 196 to 202°C (α form) and a compound with a melting point of 236 to 242°C (β form), the target compound, the α form, can be isolated as follows. .
反応液を抽出、濃縮等の通常の操作の後、適当な単一ま
たは混合溶媒から分別結晶を行えばα体が晶出し、β体
は溶液中に残る。After conventional operations such as extraction and concentration of the reaction solution, fractional crystallization is performed from a suitable single or mixed solvent, whereby the α-isomer crystallizes and the β-isomer remains in the solution.
分別結晶に適当な単一または混合溶媒としては、エタノ
ール、クロロホルム、エタノール−アセトン、クロロホ
ルム−アセトン、クロロホルム−エーテル、クロロホル
ム−酢酸エチル等があげられ、特にエタノール−アセト
ン、クロロホルムーアセ明細書の浄書（内容に変更なし
）
「 トンの混合溶媒が好ましい。尚出発原料である化合
物■は文献既知（Ｔ、Ｓｈｉｂａｎｕｍａ ｅｔ ａｌ
、。Suitable single or mixed solvents for fractional crystallization include ethanol, chloroform, ethanol-acetone, chloroform-acetone, chloroform-ether, chloroform-ethyl acetate, etc., especially ethanol-acetone, chloroform acetate, etc. (No change in content) ``Ton mixed solvent is preferred.The starting material, Compound ■, is known from the literature (T, Shibanuma et al.
,.
Ｃｈｅｍ、Ｐｈａｒｍ、 Ｂｕｌｌｌ、 ２８．２８０
９（１９８０））の化合物であり、次に示す反応式によ
って得られる。Chem, Pharm, Bull, 28.280
9 (1980)) and is obtained by the reaction formula shown below.
１Ｉ
ＣＨ２０Ｃ２Ｈｓ
ＣＨ２０Ｃ２Ｈ５
明細書の浄′ｇ！（内容に変更なし）
■
化合物■
」
本化合物の塩としては、塩酸塩、臭化水素酸塩、りん酸
塩、硫酸塩などの無機酸塩、ぎ酸塩、酢酸塩、フマル酸
塩、マレイン酸塩、リンゴ酸塩などの有機酸塩があげら
れる。1I CH20C2Hs CH20C2H5 Specification clean'g! (No change in content) ■ Compound Examples include organic acid salts such as acid salts and malate.
次に本化合物の血圧降下作用を説明する。Next, the blood pressure lowering effect of this compound will be explained.
試験方法
雑Ｎ成犬（８−１５ｋｇ）をベンドパルビタール・ナト
リウム３０ ｍｇ／ ｋｇの静脈内投与により麻酔した
。左大腿動脈にカニユーレを挿入し、圧カドランスジュ
ーサー（日本光電）により、血圧を測定してポリグラフ
に記録した。Test Method Adult dogs (8-15 kg) were anesthetized by intravenous administration of 30 mg/kg of bendoparbital sodium. A cannula was inserted into the left femoral artery, and blood pressure was measured using a pressure cadence juicer (Nihon Kohden) and recorded on a polygraph.
薬物は、ポリエチレングリコール４００に溶解してぐ体
重１ ｋｇあたり、０．１ ｍ ｌを上腕静脈より投与
した。The drug was dissolved in polyethylene glycol 400, and 0.1 ml per 1 kg of body weight was administered through the brachial vein.
その結果を第１表に示す。The results are shown in Table 1.
第１表に示したようにα体は投与後１分から明らかな血
圧降下作用を発現し、９０分以上持続した。As shown in Table 1, the α form exerted a clear blood pressure lowering effect from 1 minute after administration and lasted for more than 90 minutes.
試験方法
雑犬（９−１８ｋｇ）をチオベンタール・ナトリウム麻
酔下方腎動脈を狭窄し、腎性高血圧犬を作成した。左頚
動脈から下行動脈内に挿入したポリエチレンカニユーレ
（頚背部に固定）を介し、無麻酔下、血圧変化を観血的
に測定した。薬物は、０．３％カルボキシメチルセルロ
ースに懸濁したものを体重１ ｋｇあたりＱ、５ｍｊ２
．経口投与用チューブを用いて経口投与した。Test method A mongrel dog (9-18 kg) was anesthetized with thiobental sodium and the inferior renal artery was constricted to create a dog with renal hypertension. Changes in blood pressure were measured invasively under anesthesia via a polyethylene cannula (fixed to the back of the neck) inserted into the descending artery from the left carotid artery. The drug was suspended in 0.3% carboxymethylcellulose at Q, 5mj2 per kg of body weight.
．． It was administered orally using an oral administration tube.
そめ結果を第２表に示す
第 ２ 表
注）使用薬物：α体
本発明化合物は、その薬理作用にかんがみて、投与目的
に対する各種の製薬形態で使用可能であり、特に、錠剤
、散剤などの経口服用形態として用いるのが好ましい。The results are shown in Table 2. Note) Drug used: α-form The compound of the present invention can be used in various pharmaceutical forms for the purpose of administration, especially in tablets, powders, etc. in view of its pharmacological action. Preferably, it is used as an oral dosage form.
錠剤の場合は一錠中に本発明化合物を５〜３０％Φ／ｗ
）含有せしめればよい。その他の成分（担体）としては
通常用いられる賦形剤、崩壊剤、滑沢剤、結合剤、剤皮
剤等が用いられる。In the case of tablets, each tablet contains 5 to 30% Φ/w of the compound of the present invention.
) may be included. Other components (carriers) include commonly used excipients, disintegrants, lubricants, binders, coating agents, and the like.
賦形剤としてはブドウ糖、乳糖等、崩壊剤としてはデン
プン、カルボキシメチルセルロース、カルシウム等、滑
沢剤としてはステアリン酸マグネシウム、タルク等、結
合剤としては単シロップ、ポリビニルアルコール、ゼラ
チン、ヒドロキシプロピルセルロース等、剤皮剤として
は分散剤と可塑剤があげられるが、分散剤としてはメチ
ルセルロース、エチルセルロース等、可塑剤としてはグ
リセリン、ポリエチレングリコール等が用いられる。ま
た結晶セルロースは崩壊、結合および賦形剤としての性
質をすべて有するものとして使用される。Excipients include glucose, lactose, etc. Disintegrants include starch, carboxymethyl cellulose, calcium, etc. Lubricants include magnesium stearate, talc, etc. Binders include simple syrup, polyvinyl alcohol, gelatin, hydroxypropyl cellulose, etc. Examples of coating agents include dispersants and plasticizers, and examples of dispersants include methyl cellulose and ethyl cellulose, and examples of plasticizers include glycerin and polyethylene glycol. Crystalline cellulose is also used as having disintegration, binding and excipient properties.
散剤の場合は本発明化合物を１〜２０％（ｗ／ｗ）含有
せしめればよい。担体としてはブドウ糖、乳糖等の賦形
剤、ヒドロキシプロピルセルロース等の結合剤等が用い
られる。本発明化合物（α体）の雄ラット経口投与にお
けるＬＤｓｏは１２７ｍｇ／Ｋｇである。投与量は成人
（約６０ｋｇ）１日あたり１−１００■の範囲が好まし
い。In the case of a powder, the compound of the present invention may be contained in an amount of 1 to 20% (w/w). As carriers, excipients such as glucose and lactose, binders such as hydroxypropyl cellulose, etc. are used. The LDso of the compound of the present invention (α form) when administered orally to male rats is 127 mg/Kg. The dosage is preferably in the range of 1-100 ml per day for an adult (approximately 60 kg).
実施例１
２．６−ジメチル−４−（３−ニトロフェニル）−１，
４−ジヒドロピリジン−３，５−ジカルボン酸モノメチ
ルエステル１０．ＯＯｇをジクロルメタンとＮ、Ｎ−ジ
メチルホルムアミドの混合溶媒（４： ｌｖ／ｖ）７０
ｍ４に懸濁し、水冷下に塩化チオニル２．４３ｍｆｆを
加えた。１時間水冷攪拌後、１−ベンジル−３−ヒドロ
キシピペリジン６．３３ｇを加え、さらに水冷攪拌した
。２．５時間反応後、該反応液を水１００ｍｌ、次いで
食塩水１００ｍβで洗浄し、ジクロルメタン層を無水硫
酸ナトリウムで乾燥後、減圧濃縮した。その後、該濃縮
液にアセトン１００ｍβとエタノール３ｍＡを加えて、
黄色の２，６−ジメチル−４−（３−ニトロフェニル）
−１，４−ジヒドロピリジン−３，５−ジカルボン酸−
５−（１−ベンジル−３−ピペリジル）エステル−５−
メチルエステル塩酸塩（α体）７．５７ｇを得た。融点
１９７−１９８℃（エタノール）。Example 1 2.6-dimethyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester 10. OOg in a mixed solvent of dichloromethane and N,N-dimethylformamide (4: lv/v) 70
2.43 mff of thionyl chloride was added while cooling with water. After stirring under water cooling for 1 hour, 6.33 g of 1-benzyl-3-hydroxypiperidine was added, and the mixture was further stirred under water cooling. After reacting for 2.5 hours, the reaction solution was washed with 100 ml of water and then with 100 mβ of brine, and the dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then, 100 mβ of acetone and 3 mA of ethanol were added to the concentrated solution,
Yellow 2,6-dimethyl-4-(3-nitrophenyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid-
5-(1-benzyl-3-piperidyl)ester-5-
7.57 g of methyl ester hydrochloride (α form) was obtained. Melting point 197-198°C (ethanol).
またその結晶母液からβ体５．２１ｇを得た。Further, 5.21 g of β-isomer was obtained from the crystal mother liquor.
融点２３９−２４０℃（エタノール−メタ、′−ル）α
体の物性値を以下に示す。Melting point 239-240℃ (ethanol-meth,'-l) α
The physical properties of the body are shown below.
ＩＲ（ＫＢｒ、ａｍ−’）：１６８０，１５２５゜ＮＭ
Ｒ（ＤＭＳＯｄｂ 、 δ） ：Ｌ、３−２．２
（４Ｈ，、ｂｒｏａｄ）、２．３３ （６Ｈ，ｓ） 、
２．７ −３゜４ （４Ｈ、ｂｒｏａｄ）、３．５７
（３Ｈ，ｓ） 、４．４０（２Ｈ，ｓ） 、４．９８
（ＬＨ，ｓ） 、５．２０（ＬＨ，ｂｒｏａｄ ）、
７．３ ８．２ （９Ｈ，ｍ）、９、４７ （Ｉ Ｈ，
ｂｒｏａｄ）
元素分析値（ＣｚＩＩＨ３□ＣＩｔ Ｎ 、ｌ○、とし
て）：ＣＨ’ Ｎ
実測値（％） ６２．１６ ６．０１ ７．７６計
算値（％）６２．０４． ５．９６ ７．７５手続
補正書 （方式）
％式％
１、事件の表示
昭和６１年特許願第２０３２３１号
２、発明の名称
１．４−ジヒドロピリジン誘導体
３、補正をする者
事件との関係 特許出願人IR (KBr, am-'): 1680, 1525゜NM
R(DMSOdb, δ): L, 3-2.2
(4H,,broad), 2.33 (6H,s),
2.7 -3°4 (4H, broad), 3.57
(3H, s) , 4.40 (2H, s) , 4.98
(LH,s), 5.20(LH,broad),
7.3 8.2 (9H, m), 9, 47 (I H,
Broad) Elemental analysis value (as CzIIH3□CIt N , l○): CH' N Actual value (%) 62.16 6.01 7.76 Calculated value (%) 62.04. 5.96 7.75 Procedural amendment (method) % formula % 1. Indication of the case 1985 Patent Application No. 203231 2. Title of the invention 1. 4-dihydropyridine derivative 3. Person making the amendment Relationship to the case Patent applicant
Claims (1)
ル−４−（３−ニトロフェニル）−１，４−ジヒドロピ
リジン−３，５−ジカルボン酸−３−（１−ベンジル−
３−ピペリジル）エステル−５−メチルエステルおよび
その塩を有効成分とする循環器官疾患治療剤。2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(1-benzyl-
A therapeutic agent for circulatory organ diseases containing 3-piperidyl) ester-5-methyl ester and its salt as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20323186A JPS62174017A (en) | 1986-08-29 | 1986-08-29 | 1,4-dihydropyridine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20323186A JPS62174017A (en) | 1986-08-29 | 1986-08-29 | 1,4-dihydropyridine derivative |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57180616A Division JPS5970667A (en) | 1982-10-15 | 1982-10-15 | 1,4-dihydropyridine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62174017A true JPS62174017A (en) | 1987-07-30 |
| JPH0251525B2 JPH0251525B2 (en) | 1990-11-07 |
Family
ID=16470620
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20323186A Granted JPS62174017A (en) | 1986-08-29 | 1986-08-29 | 1,4-dihydropyridine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62174017A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS504652A (en) * | 1972-09-13 | 1975-01-18 | ||
| JPS50123667A (en) * | 1974-03-05 | 1975-09-29 | ||
| JPS55301A (en) * | 1978-02-14 | 1980-01-05 | Yamanouchi Pharmaceut Co Ltd | 1,4-dihydropyridine-3,5-dicarboxylic ester derivative and its preparation |
-
1986
- 1986-08-29 JP JP20323186A patent/JPS62174017A/en active Granted
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS504652A (en) * | 1972-09-13 | 1975-01-18 | ||
| JPS50123667A (en) * | 1974-03-05 | 1975-09-29 | ||
| JPS55301A (en) * | 1978-02-14 | 1980-01-05 | Yamanouchi Pharmaceut Co Ltd | 1,4-dihydropyridine-3,5-dicarboxylic ester derivative and its preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0251525B2 (en) | 1990-11-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR860001946B1 (en) | Process for preparing 1,4-dihydropyridine derivatives | |
| JPH0428269B2 (en) | ||
| CA2433190C (en) | Amlodipine hemimaleate | |
| JPH07267954A (en) | New 3-phenylsulfonyl-3,7-diazabicyclo(3,3,1)nonane compound,its production, and antiarrhythmic agent | |
| JPS59225162A (en) | 1,4-dihydropyridine derivative | |
| JPS62174017A (en) | 1,4-dihydropyridine derivative | |
| JPS59137461A (en) | 1,4-dihydropyridine derivative | |
| CN114349745A (en) | Medicine for treating myocardial ischemia and preparation method thereof | |
| JPS5970667A (en) | 1,4-dihydropyridine derivative | |
| JP3748935B2 (en) | Oxindole derivatives | |
| JPS58201764A (en) | Dihydropyridine derivative | |
| JPS5970666A (en) | 1,4-dihydropyridine derivative | |
| KR860001951B1 (en) | Process for preparing 1,4-dihydropyridine derivatives | |
| JPS6216417A (en) | Treating and preventing agent for ischemic cardiopathy and arrhythmia | |
| JP3049284B2 (en) | Hydantoin derivatives and preventive and therapeutic agents for diabetic complications and cardiovascular diseases using the same as active ingredients | |
| JP2535533B2 (en) | Benzodioxole derivatives | |
| JPS63233992A (en) | Dihydropyridine-5-phosphonic acid cyclic esters | |
| JP2802778B2 (en) | Homopiperazine derivatives and cerebral protective agents containing the same | |
| JPS6339863A (en) | Anfukaen*sonoseizohoho*narabinikoreofukumuyakuzais | |
| JPH0368555A (en) | Derivative of 1, 4-dihydropyridine, its preparation and pharmaceutical agents for treating cardiovascular affection and high blood pressure containing same | |
| WO1996025932A1 (en) | Preventive/remedy for interstitial pneumonia, inflammatory intestinal diseases or vascular thickening containing quinolizinone compounds, salt thereof or hydrates therefor | |
| JPH0251526B2 (en) | ||
| JPH0753561A (en) | Tetrahydrothienopyridine derivative, its production and hematocyte coagulation inhibitor | |
| JPS606682A (en) | Dithiolane derivative and its use | |
| JPS6089420A (en) | Vasodilator |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EXPY | Cancellation because of completion of term |