JPS6160065B2 - - Google Patents
Info
- Publication number
- JPS6160065B2 JPS6160065B2 JP14477877A JP14477877A JPS6160065B2 JP S6160065 B2 JPS6160065 B2 JP S6160065B2 JP 14477877 A JP14477877 A JP 14477877A JP 14477877 A JP14477877 A JP 14477877A JP S6160065 B2 JPS6160065 B2 JP S6160065B2
- Authority
- JP
- Japan
- Prior art keywords
- pyrrole
- methyl
- acid
- guanidinopyrrole
- group
- 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
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- 150000003233 pyrroles Chemical class 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 11
- -1 2-(2-acetylaminophenyl)-5-methyl-1-guanidinopyrrole Chemical compound 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- OJVAMHKKJGICOG-UHFFFAOYSA-N 2,5-hexanedione Chemical compound CC(=O)CCC(C)=O OJVAMHKKJGICOG-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical class NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- ANFZRGMDGDYNGA-UHFFFAOYSA-N ethyl acetate;propan-2-ol Chemical compound CC(C)O.CCOC(C)=O ANFZRGMDGDYNGA-UHFFFAOYSA-N 0.000 description 2
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- OTXHZHQQWQTQMW-UHFFFAOYSA-N (diaminomethylideneamino)azanium;hydrogen carbonate Chemical compound OC([O-])=O.N[NH2+]C(N)=N OTXHZHQQWQTQMW-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OQOKBKZRXOPPTJ-UHFFFAOYSA-N 1-amino-2,3-dimethylguanidine;hydroiodide Chemical compound I.CNC(NN)=NC OQOKBKZRXOPPTJ-UHFFFAOYSA-N 0.000 description 1
- RBLXWIPBPPVLPU-UHFFFAOYSA-N 1-phenylpentane-1,4-dione Chemical compound CC(=O)CCC(=O)C1=CC=CC=C1 RBLXWIPBPPVLPU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus 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
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は新規なピロール誘導体及びその酸付加
塩に関する。
本発明のピロール誘導体は下記一般式〔〕で
表わされる。
〔式中R1は低級アルキル基、フエニル基また
はピリジル基、R2は水素原子またはフエニル
基、R3は水素原子、R4は低級アルキル基、フエ
ニル基またはピリジル基、R5は水素原子または
低級アルキル基、R6は水素原子、低級アルキル
基またはフエニル基、R7は水素原子、低級アル
キル基、フエニル基またはニトロ基を示す。但し
R1及びR4は同時にピリジル基であつてはならな
い。〕
上記一般式〔〕で表わされるピロール誘導体
及びその酸付加塩は、胃酸分泌抑制作用及び降圧
作用を有し、抗潰瘍剤及び降圧剤として有用であ
る。
上記一般式〔〕中R1及びR4の低級アルキル
基には、炭素数１〜４の直鎖状もしくは分岐状の
アルキル基例えばメチル、エチル、プロピル、イ
ソプロピル、ブチル、tert−ブチル基等が包含さ
れる。
本発明のピロール誘導体を具体的に示せば次の
通りである。
Γ２，５−ジメチル−１−グアニジノピロール
Γ２，５−ジメチル−１−グアニジノピロール
Γ２，５−ジプロピル−１−グアニジノピロール
Γ２−エチル−５−メチル−１−グアニジノピロ
ール
Γ２−プロピル−５−メチル−１−グアニジノピ
ロール
Γ２−フエニル−５−メチル−１−グアニジノピ
ロール
Γ２−（２−ピリジル）−５−メチル−１−グアニ
ジノピロール
Γ２−（３−ピリジル）−５−メチル−１−グアニ
ジノピロール
Γ２−（４−ピリジル）−５−メチル−１−グアニ
ジノピロール
Γ２，５−ジフエニル−１−グアニジノピロール
Γ２，３，５−トリフエニル−１−グアニジノピ
ロール
Γ２，３−ジフエニル−５−メチル−１−グアニ
ジノピロール
Γ２，５−ジフエニル−３−メチル−１−グアニ
ジノピロール
Γ２，３，４，５−テトラメチル−１−グアニジ
ノピロール
Γ２−フエニル−３−（２−ピリジル）−５−メチ
ル−１−グアニジノピロール
Γ２−（２−クロロフエニル）−５−メチル−１−
グアニジノピロール
Γ２−（４−ブロモフエニル）−５−メチル−１−
グアニジノピロール
Γ２−（２，６−ジメチルフエニル）−５−メチル
−１−グアニジノピロール
Γ２−（３，４−ジメトキシフエニル）−５−メチ
ル−１−グアニジノピロール
Γ２−（３，４−ジエトキシフエニル）−５−メチ
ル−１−グアニジノピロール
Γ２−（２−アセチルアミノフエニル）−５−メチ
ル−１−グアニジノピロール
Γ２，５−ジメチル−１−（１−メチルグアニジ
ン−１−イル）ピロール
Γ２，５−ジメチル−１−（１，３−ジメチルグ
アニジン−１−イル）ピロール
Γ２，５−ジメチル−１−（３−メチルグアニジ
ン−１−イル）ピロール
Γ２，５−ジメチル−１−（２，３−ジメチルグ
アニジン−１−イル）ピロール
Γ２，５−ジメチル−１−（１，２，３−トリエ
チルグアニジン−１−イル）ピロール
Γ２，５−ジメチル−１−（３−フエニルグアニ
ジン−１−イル）ピロール
Γ２，５−ジメチル−１−（２，３−ジフエニル
グアニジン−１−イル）ピロール
Γ２，５−ジメチル−１−（２，３−ジエチルグ
アニジン−１−イル）ピロール
Γ２，５−ジメチル−１−（２，３−ジエチル−
１−メチルグアニジン−１−イル）ピロール
Γ２−フエニル−５−メチル−１−（３−メチル
グアニジン−１−イル）ピロール
Γ２−フエニル−５−メチル−１−（２，３−ジ
メチルグアニジン−１−イル）ピロール
Γ２−フエニル−５−メチル−（１，３−ジメチ
ルグアニジン−１−イル）ピロール
Γ２−（２−ピリジル）−５−メチル−１−（３−
メチルグアニジン−１−イル）ピロール
Γ２−（３−ピリジル）−５−メチル−１−（３−
プロピルグアニジン−１−イル）ピロール
Γ２，３−ジフエニル−５−メチル−１−（３−
エチルグアニジン−１−イル）ピロール
Γ２，３−ジフエニル−５−メチル−１−（１−
メチルグアニジン−１−イル）ピロール
Γ２，３，５−トリフエニル−１−（２，３−ジ
エチルグアニジン−１−イル）ピロール
Γ２，３，５−トリフエニル−１−（３−フエニ
ルグアニジン−１−イル）ピロール
Γ２，５−ジメチル−１−（３−ニトログアニジ
ン−１−イル）ピロール
Γ２，５−ジメチル−１−（３−エチル−２−ニ
トログアニジン−１−イル）ピロール
Γ２−フエニル−５−メチル−１−（３−メチル
−１−ニトログアニジン−１−イル）ピロール
Γ１−グアニジンピロール
Γ１−（３−フエニルグアニジン−１−イル）ピ
ロール
Γ１−（２，３−ジメチルグアニジン−１−イ
ル）ピロール
Γ１−（１，２，３−トリプロピルグアニジン−
１−イル）ピロール
Γ２−イソプロピル−５−メチル−１−グアニジ
ンピロール
Γ２，３−ジフエニル−５−ブチル−１−（２，
３−ジメチルグアニジン−１−イル）ピロール
Γ２，５−ジメチル−１−（３−tert−ブチルグ
アニジン−１−イル）ピロール
本発明のピロール誘導体は種々の方法により製
造できる。例えば一般式
〔式中R5〜R7は上記に同じ〕
で表わされるアミノグアニジン誘導体又はその酸
付加塩と一般式
〔式中R1〜R4は上記に同じ〕
で表わされる１，４−ジケトン誘導体を反応させ
る方法により製造できる。
上記一般式〔〕及び〔〕で表わされる各化
合物はいずれも公知の化合物である。
上記反応は無溶媒で又は適当な溶媒を用いて行
なわれる。溶媒としてはベンゼン、トルエン、キ
シレン等の芳香族炭化水素類、ジエチルエーテ
ル、テトラヒドロフラン、ジオキサン、ジグライ
ム等のエーテル類、蟻酸、酢酸、プロピオン酸等
のカルボン酸類、メタノール、エタノール、イソ
プロパノール等のアルコール類、ジメチルスルホ
キシド、Ｎ，Ｎ−ジメチルホルムアミド、ヘキサ
メチルリン酸トリアミド等を例示できる。上記反
応における原料化合物の使用割合は特に制限はな
いが一般式〔〕で表わされるアミノグアニジン
誘導体１モルに対し一般式〔〕で表わされるジ
ケトン類を１〜５モル好ましくは１〜1.2モル程
度用いるのがよい。また反応温度は通常０〜200
℃好ましくは室温〜120℃程度とするのがよく、
この温度で約30分〜30時間通常２〜10時間程度で
反応は完結する。
かくして得られる本発明の一般式〔〕で表わ
されるピロール誘導体は、その薬理的に許容され
る酸付加塩とすることができ、本発明はこの酸付
加塩をも包含する。酸付加塩の形成に用いられる
酸は薬理的に許容される各種の有機酸又は無機酸
でよく、これには例えば塩酸、硫酸、臭化水素
酸、沃化水素酸、リン酸等の無機酸及び酢酸、乳
酸、蓚酸、マロン酸、コハク酸、マレイン酸、フ
マール酸、リンゴ酸、マンデル酸、メタンスルホ
ン酸、ｐ−トシル酸、安息香酸等の有機酸を例示
できる。
かくして得られる本発明の一般式〔〕で表わ
されるピロール誘導体及びその酸付加塩は、上記
した反応行程の終了後に慣用の分離手段により容
易に単離精製できる。分離手段としては例えば溶
媒抽出法、希釈法、沈殿法、再結晶法、カラムク
ロマトグラフイー、プレパラテイブ薄層クロマト
グラフイー等を例示できる。
以下本発明化合物の製造例を挙げる。
製造例 １
アミノグアニジン重炭酸塩５ｇを酢酸25mlに懸
濁させ加温溶解後、２，５−ヘキサンジオン4.2
ｇを加えて油浴上100〜110℃で加熱撹拌する。２
時間後減圧下に酢酸を留去し残渣を水に溶解し活
性炭処理する。水を留去し残渣にイソプロパノー
ル−酢酸エチルを加え結晶化させる。之を再度イ
ソプロパノール−酢酸エチルで再結晶して、黄色
プリズム状晶の２，５−ジメチル−１−グアニジ
ノピロール酢酸塩5.6ｇを得る。融点163〜166
℃。
上記で得た酢酸塩4.7ｇをエタノール15mlに加
温溶解し、濃塩酸５mlを加え60〜70℃で５分加温
する。反応液を冷却しエーテルを加えて析出する
黄色沈殿を取し、イソプロパノールより再結晶
して黄色プリズム状晶の２，５−ジメチル−１−
グアニジノピロール塩酸塩３ｇを得る。融点214
〜220℃。
得られた塩酸塩は之を核磁気共鳴スペクトル
（NMR）分析の結果、次のδDMSO-d 6を示した。
2.06ppm（6H，ｓ，２位及び５位のCH3）、
5.79ppm（2H，ｓ，３位及び４位の水素）、7.50
〜8.20ppm（5H，br.s，グアニジノ基の水素）
製造例 ２
１−フエニル−１，４−ペンタンジオン1.8ｇ
と１−アミノ−２，３−ジメチルグアニジン沃化
水素酸塩2.3ｇとを酢酸20mlに溶解し、90〜95℃
で３時間加熱する。酢酸を減圧下に留去し、残渣
をシリカゲルカラムクロマトグラフイ−（「ワコー
ゲル」60ｇ、クロロホルム：メタノール＝20：１
で溶出）で精製する。目的物画分を集め飽和重曹
水及び飽和食塩水で洗浄し、硫酸ナトリウムで乾
燥する。クロロホルムを留去し、残留物をクロロ
ホルム−エーテルから再結晶して、黄色粉末状晶
の２−フエニル−５−メチル−１−（２，３−ジ
メチルグアニジン−１−イル）ピロール1.1ｇを
得る。融点141〜144℃。
NMR分析結果（δＣＤＣｌ ３ｐｐｎ）
2.12ppm（3H，ｓ，５位のCH3）
2.50ppm（3H，ｄ，Ｊ＝５Hz，Ｎ−CH3）
2.93ppm（3H，br.s，Ｎ−CH3）
3.50〜4.00ppm（2H，br.s，グアニジノ基の水
素）
5.73ppm（1H，ｄ，Ｊ＝４Hz，４位の水素）
6.08ppm（1H，ｄ，Ｊ＝４Hz，３位の水素）
6.90〜7.60ppm（5H，ｍ，フエニル基の水素）
製造例 ３〜15
適当な出発原料を用い上記製造例と同様にして
下記第１表記載の各化合物を得る。第１表におい
て各化合物は下記一般式に示す各記号で示す。ま
た上記第１表に示す各化合物の遊離塩基又はHA
で示される酸付加塩の形態の化合物につき、その
結晶形態及び融点（℃）を第２表に示す。
The present invention relates to novel pyrrole derivatives and acid addition salts thereof. The pyrrole derivative of the present invention is represented by the following general formula []. [In the formula, R 1 is a lower alkyl group, phenyl group or pyridyl group, R 2 is a hydrogen atom or phenyl group, R 3 is a hydrogen atom, R 4 is a lower alkyl group, phenyl group or pyridyl group, R 5 is a hydrogen atom or A lower alkyl group, R 6 represents a hydrogen atom, a lower alkyl group or a phenyl group, and R 7 represents a hydrogen atom, a lower alkyl group, a phenyl group or a nitro group. however
R 1 and R 4 must not be simultaneously pyridyl groups. ] Pyrrole derivatives represented by the above general formula [ ] and acid addition salts thereof have gastric acid secretion suppressing effects and hypotensive effects, and are useful as antiulcer agents and antihypertensive agents. The lower alkyl groups of R 1 and R 4 in the above general formula [] include linear or branched alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl groups, etc. Included. Specific examples of the pyrrole derivatives of the present invention are as follows. Γ2,5-dimethyl-1-guanidinopyrrole Γ2,5-dimethyl-1-guanidinopyrrole Γ2,5-dipropyl-1-guanidinopyrrole Γ2-ethyl-5-methyl-1-guanidinopyrrole Γ2-propyl-5-methyl- 1-Guanidinopyrrole Γ2-Phenyl-5-methyl-1-guanidinopyrrole Γ2-(2-pyridyl)-5-methyl-1-guanidinopyrrole Γ2-(3-pyridyl)-5-methyl-1-guanidinopyrrole Γ2- (4-pyridyl)-5-methyl-1-guanidinopyrrole Γ2,5-diphenyl-1-guanidinopyrrole Γ2,3,5-triphenyl-1-guanidinopyrrole Γ2,3-diphenyl-5-methyl-1-guanidinopyrrole Γ2,5-diphenyl-3-methyl-1-guanidinopyrrole Γ2,3,4,5-tetramethyl-1-guanidinopyrrole Γ2-phenyl-3-(2-pyridyl)-5-methyl-1-guanidinopyrrole Γ2 -(2-chlorophenyl)-5-methyl-1-
Guanidinopyrrole Γ2-(4-bromophenyl)-5-methyl-1-
Guanidinopyrrole Γ2-(2,6-dimethylphenyl)-5-methyl-1-guanidinopyrrole Γ2-(3,4-dimethoxyphenyl)-5-methyl-1-guanidinopyrrole Γ2-(3,4-dimethylphenyl) 2-(2-acetylaminophenyl)-5-methyl-1-guanidinopyrrole Γ2,5-dimethyl-1-(1-methylguanidin-1-yl) Pyrrole Γ2,5-dimethyl-1-(1,3-dimethylguanidin-1-yl)pyrrole Γ2,5-dimethyl-1-(3-methylguanidin-1-yl)pyrrole Γ2,5-dimethyl-1-( 2,3-dimethylguanidin-1-yl)pyrrole Γ2,5-dimethyl-1-(1,2,3-triethylguanidin-1-yl)pyrrole Γ2,5-dimethyl-1-(3-phenylguanidine- 2,5-dimethyl-1-(2,3-diphenylguanidin-1-yl)pyrrole Γ2,5-dimethyl-1-(2,3-diethylguanidin-1-yl)pyrrole Γ2, 5-dimethyl-1-(2,3-diethyl-
1-methylguanidin-1-yl)pyrrole Γ2-phenyl-5-methyl-1-(3-methylguanidin-1-yl)pyrrole Γ2-phenyl-5-methyl-1-(2,3-dimethylguanidine-1 -yl)pyrrole Γ2-phenyl-5-methyl-(1,3-dimethylguanidin-1-yl)pyrrole Γ2-(2-pyridyl)-5-methyl-1-(3-
Methylguanidin-1-yl)pyrrole Γ2-(3-pyridyl)-5-methyl-1-(3-
propylguanidin-1-yl)pyrrole Γ2,3-diphenyl-5-methyl-1-(3-
ethylguanidin-1-yl)pyrrole Γ2,3-diphenyl-5-methyl-1-(1-
Methylguanidin-1-yl)pyrrole Γ2,3,5-triphenyl-1-(2,3-diethylguanidin-1-yl)pyrrole Γ2,3,5-triphenyl-1-(3-phenylguanidin-1- yl)pyrrole Γ2,5-dimethyl-1-(3-nitroguanidin-1-yl)pyrrole Γ2,5-dimethyl-1-(3-ethyl-2-nitroguanidin-1-yl)pyrrole Γ2-phenyl-5 -Methyl-1-(3-methyl-1-nitroguanidin-1-yl)pyrrole Γ1-guanidinepyrrole Γ1-(3-phenylguanidin-1-yl)pyrrole Γ1-(2,3-dimethylguanidine-1- yl)pyrrole Γ1-(1,2,3-tripropylguanidine-
1-yl)pyrrole Γ2-isopropyl-5-methyl-1-guanidinepyrrole Γ2,3-diphenyl-5-butyl-1-(2,
3-dimethylguanidin-1-yl)pyrrole Γ2,5-dimethyl-1-(3-tert-butylguanidin-1-yl)pyrrole The pyrrole derivative of the present invention can be produced by various methods. For example, general formula [In the formula, R 5 to R 7 are the same as above] An aminoguanidine derivative or its acid addition salt represented by the general formula [In the formula, R 1 to R 4 are the same as above] It can be produced by a method of reacting a 1,4-diketone derivative represented by the following formula. The compounds represented by the above general formulas [] and [] are all known compounds. The above reaction is carried out without a solvent or using a suitable solvent. Examples of solvents include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and diglyme; carboxylic acids such as formic acid, acetic acid, and propionic acid; alcohols such as methanol, ethanol, and isopropanol; Examples include dimethyl sulfoxide, N,N-dimethylformamide, hexamethylphosphoric triamide, and the like. There is no particular restriction on the ratio of the raw material compounds used in the above reaction, but 1 to 5 moles of diketones represented by the general formula [] are used, preferably about 1 to 1.2 moles, per 1 mole of the aminoguanidine derivative represented by the general formula []. It is better. Also, the reaction temperature is usually 0 to 200
℃ preferably from room temperature to about 120℃,
The reaction is completed at this temperature in about 30 minutes to 30 hours, usually about 2 to 10 hours. The pyrrole derivative represented by the general formula [] of the present invention thus obtained can be made into a pharmacologically acceptable acid addition salt thereof, and the present invention also includes this acid addition salt. The acid used to form the acid addition salt may be any pharmacologically acceptable organic or inorganic acid, including, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc. Examples include organic acids such as acetic acid, lactic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, mandelic acid, methanesulfonic acid, p-tosylic acid, and benzoic acid. The pyrrole derivative represented by the general formula [] and its acid addition salt of the present invention thus obtained can be easily isolated and purified by conventional separation means after the above-mentioned reaction steps are completed. Examples of the separation means include solvent extraction, dilution, precipitation, recrystallization, column chromatography, and preparative thin layer chromatography. Examples of manufacturing the compounds of the present invention are given below. Production Example 1 5 g of aminoguanidine bicarbonate was suspended in 25 ml of acetic acid, dissolved by heating, and 4.2 g of 2,5-hexanedione was added.
g and heat and stir on an oil bath at 100-110°C. 2
After a period of time, acetic acid was distilled off under reduced pressure, and the residue was dissolved in water and treated with activated carbon. Water is distilled off, and isopropanol-ethyl acetate is added to the residue for crystallization. This was recrystallized again from isopropanol-ethyl acetate to obtain 5.6 g of 2,5-dimethyl-1-guanidinopyrrole acetate in the form of yellow prisms. Melting point 163-166
℃. 4.7 g of the acetate obtained above was dissolved in 15 ml of ethanol under heating, 5 ml of concentrated hydrochloric acid was added, and the mixture was heated at 60 to 70°C for 5 minutes. The reaction solution was cooled and ether was added to collect the precipitated yellow precipitate, which was recrystallized from isopropanol to give yellow prismatic crystals of 2,5-dimethyl-1-
3 g of guanidinopyrrole hydrochloride are obtained. melting point 214
~220℃. As a result of nuclear magnetic resonance spectroscopy (NMR) analysis of the obtained hydrochloride, it showed the following δ DMSO-d 6 . 2.06ppm (6H, s, CH 3 in 2nd and 5th positions),
5.79ppm (2H, s, hydrogen at 3rd and 4th positions), 7.50
~8.20ppm (5H, br.s, hydrogen of guanidino group) Production example 2 1-phenyl-1,4-pentanedione 1.8g
and 2.3 g of 1-amino-2,3-dimethylguanidine hydroiodide were dissolved in 20 ml of acetic acid and heated to 90-95℃.
Heat for 3 hours. Acetic acid was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (60 g of "Wako gel", chloroform:methanol = 20:1).
(elution). The target product fractions are collected, washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over sodium sulfate. Chloroform is distilled off and the residue is recrystallized from chloroform-ether to obtain 1.1 g of 2-phenyl-5-methyl-1-(2,3-dimethylguanidin-1-yl)pyrrole as yellow powder crystals. . Melting point 141-144℃. NMR analysis results (δ CDCl 3ppn ) 2.12ppm (3H, s, 5th-position CH 3 ) 2.50ppm (3H, d, J=5Hz, N-CH 3 ) 2.93ppm (3H, br.s, N-CH 3 ) 3.50 to 4.00ppm (2H, br.s, hydrogen of guanidino group) 5.73ppm (1H, d, J = 4Hz, hydrogen at position 4) 6.08ppm (1H, d, J = 4Hz, hydrogen at position 3) 6.90 ~7.60 ppm (5H, m, hydrogen of phenyl group) Production Examples 3 to 15 Each compound listed in Table 1 below is obtained in the same manner as in the above Production Examples using appropriate starting materials. In Table 1, each compound is represented by each symbol shown in the following general formula. In addition, the free base or HA of each compound shown in Table 1 above
Table 2 shows the crystal form and melting point (° C.) of the compound in the form of an acid addition salt.
【表】【table】
【表】【table】
【表】
＜薬理試験＞
下記化合物の薬理活性を、胃液分泌抑制作用を
検定する最も一般的な試験法であるシエイ・ラツ
トの幽門結紮法に従つて試験した。この試験には
体重170ｇ前後のウイスター系雄性ラツトを使用
した。該ラツトを24時間絶食させ、幽門結紮30分
前に試験されるべき化合物を（500mg／Kg）皮下
投与し、結紮４時間後に胃液量を測定した。生理
食塩水投与群を０として抑制率を％で求めた。そ
の結果を下記第１表に示す。
なお、表中における抑制率（％）の評価は下記
のとおりである。
＋ ：10〜50％未満
＋＋：50％以上
供試化合物
No.１ ２，５−ジメチル−１−グアニジノピロー
ル塩酸塩
No.２ ２−フエニル−５−メチル−１−（２，３
−ジメチルグアニジン−１−イル）ピロール
No.３ ２−ピリジル−５−メチル−１−グアニジ
ノピロール[Table] <Pharmacological test> The pharmacological activity of the following compounds was tested according to the pylorus ligation method of Schei Ratt, which is the most common test method for testing gastric juice secretion suppressive effects. Male Wistar rats weighing approximately 170 g were used in this test. The rats were fasted for 24 hours, the compound to be tested (500 mg/Kg) was administered subcutaneously 30 minutes before pyloric ligation, and the gastric fluid volume was measured 4 hours after ligation. The inhibition rate was determined in %, setting the physiological saline administration group as 0. The results are shown in Table 1 below. In addition, the evaluation of the inhibition rate (%) in the table is as follows. +: 10 to less than 50% ++: 50% or more Test compound No. 1 2,5-dimethyl-1-guanidinopyrrole hydrochloride No. 2 2-phenyl-5-methyl-1-(2,3
-dimethylguanidin-1-yl)pyrrole No. 3 2-pyridyl-5-methyl-1-guanidinopyrrole
Claims (1)
はピリジル基、R2は水素原子またはフエニル
基、R3は水素原子、R4は低級アルキル基、フエ
ニル基またはピリジル基、R5は水素原子または
低級アルキル基、R6は水素原子、低級アルキル
基またはフエニル基、R7は水素原子、低級アル
キル基、フエニル基またはニトロ基を示す。但し
R1及びR4は同時にピリジル基であつてはならな
い。〕 で表わされるピロール誘導体及びその酸付加塩。[Claims] 1. General formula [In the formula, R 1 is a lower alkyl group, phenyl group or pyridyl group, R 2 is a hydrogen atom or phenyl group, R 3 is a hydrogen atom, R 4 is a lower alkyl group, phenyl group or pyridyl group, R 5 is a hydrogen atom or A lower alkyl group, R 6 represents a hydrogen atom, a lower alkyl group or a phenyl group, and R 7 represents a hydrogen atom, a lower alkyl group, a phenyl group or a nitro group. however
R 1 and R 4 must not be simultaneously pyridyl groups. ] A pyrrole derivative represented by these and its acid addition salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14477877A JPS5479271A (en) | 1977-12-01 | 1977-12-01 | Pyrrole derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14477877A JPS5479271A (en) | 1977-12-01 | 1977-12-01 | Pyrrole derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5479271A JPS5479271A (en) | 1979-06-25 |
| JPS6160065B2 true JPS6160065B2 (en) | 1986-12-19 |
Family
ID=15370203
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14477877A Granted JPS5479271A (en) | 1977-12-01 | 1977-12-01 | Pyrrole derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5479271A (en) |
-
1977
- 1977-12-01 JP JP14477877A patent/JPS5479271A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5479271A (en) | 1979-06-25 |
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