JPH0378864B2 - - Google Patents
Info
- Publication number
- JPH0378864B2 JPH0378864B2 JP29191685A JP29191685A JPH0378864B2 JP H0378864 B2 JPH0378864 B2 JP H0378864B2 JP 29191685 A JP29191685 A JP 29191685A JP 29191685 A JP29191685 A JP 29191685A JP H0378864 B2 JPH0378864 B2 JP H0378864B2
- Authority
- JP
- Japan
- Prior art keywords
- pyratine
- tetrazolyl
- carboxamide
- crystals
- melting point
- 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
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 239000013078 crystal Substances 0.000 description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
- 238000002844 melting Methods 0.000 description 32
- 230000008018 melting Effects 0.000 description 32
- 239000000243 solution Substances 0.000 description 29
- -1 1-azetinyl Chemical group 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 238000000921 elemental analysis Methods 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 24
- 238000000354 decomposition reaction Methods 0.000 description 23
- 238000001914 filtration Methods 0.000 description 23
- 239000000725 suspension Substances 0.000 description 23
- 150000001875 compounds Chemical class 0.000 description 21
- 238000010992 reflux Methods 0.000 description 20
- BUTPBERGMJVRBM-UHFFFAOYSA-N methanol;methylsulfinylmethane Chemical compound OC.CS(C)=O BUTPBERGMJVRBM-UHFFFAOYSA-N 0.000 description 18
- 235000002639 sodium chloride Nutrition 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- ULRPISSMEBPJLN-UHFFFAOYSA-N 2h-tetrazol-5-amine Chemical compound NC1=NN=NN1 ULRPISSMEBPJLN-UHFFFAOYSA-N 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000002329 infrared spectrum Methods 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 5
- QAXZWHGWYSJAEI-UHFFFAOYSA-N n,n-dimethylformamide;ethanol Chemical compound CCO.CN(C)C=O QAXZWHGWYSJAEI-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000003266 anti-allergic effect Effects 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229960001340 histamine Drugs 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000003419 expectorant effect Effects 0.000 description 3
- 239000003889 eye drop Substances 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- VBNJFJMZDMJMLS-UHFFFAOYSA-N 6-methyl-n-(5h-tetrazol-5-yl)pyridine-2-carboxamide Chemical compound CC1=CC=CC(C(=O)NC2N=NN=N2)=N1 VBNJFJMZDMJMLS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 208000030603 inherited susceptibility to asthma Diseases 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
- 239000007923 nasal drop Substances 0.000 description 2
- 229940100662 nasal drops Drugs 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 description 2
- 229960005342 tranilast Drugs 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
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 1
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 1
- FXHRAKUEZPSMLJ-UHFFFAOYSA-N 1-methyl-1,4-diazepane Chemical compound CN1CCCNCC1 FXHRAKUEZPSMLJ-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- NZHGWWWHIYHZNX-UHFFFAOYSA-N 2-((3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl)amino)benzoic acid Chemical compound C1=C(OC)C(OC)=CC=C1C=CC(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-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
- JEGMWWXJUXDNJN-UHFFFAOYSA-N 3-methylpiperidine Chemical compound CC1CCCNC1 JEGMWWXJUXDNJN-UHFFFAOYSA-N 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 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
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 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 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 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 1
- 241001465754 Metazoa Species 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 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 1
- 239000011230 binding agent Substances 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 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
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000006285 cell suspension Substances 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
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229940116364 hard fat Drugs 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 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
- 210000003630 histaminocyte Anatomy 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
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate 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
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- ACYINGGNKOBDCT-UHFFFAOYSA-N methanol;methoxymethane Chemical compound OC.COC ACYINGGNKOBDCT-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
産業上の利用分野
本発明は優れた抗アレルギー作用及び去痰作用
を有する新規なピラチン誘導体、及びその薬理学
的に許容しうる塩に関するものである。
従来の技術
本発明のピラチン誘導体に関する文献は見当た
らず、また抗アレルギー作用及び去痰作用のある
ことも全く知られていない。
発明が解決しようとする問題点
気管支喘息は、種々の要因で発症することが知
られている。そのうちの１つとして、アレルゲン
の侵入により型アレルルギー反応（アナフイラ
キシー反応）が惹起され、肥満細胞から化学伝達
物質が遊離されることによつて発症することが知
られている。このようなアレルギー性疾患の治療
薬として、化学伝達物質の遊離を阻害する薬剤が
用いられるようになつてきた。この種の薬剤とし
ては、たとえば、１，３−ビス（２−カルボキシ
クロモン−５−イルオキシ）−２−ハイドロキシ
プロパン・二ナトリウム塩［一般名：クロモグリ
ク酸ナトリウム、略名：DSCG、メルク・インデ
ツクス（The Merck Index）、10th edition
2580］及びＮ−（３，４−ジメトキシシンナモイ
ル）アントラニル酸［一般名：トラニラスト、メ
ルク・インデツクス（The Merck Index）、10th
edition9392］が臨床に供されている。また現在
研究開発されているものとして、６−メチル−Ｎ
−（1H−５−テトラゾリル）ピリジン−２−カル
ボキサミド［治験番号：TA−5707F、ジヤパニ
ーズ・ジヤーナル・オブ・フアーマコロジー
（Japanese Journal of Pharmacology）40巻、
37〜46頁（1986年）］が知られている。しかしな
がらこの種の作用を有する薬剤は数少なく、薬効
及び安全性の点において必ずしも満足すべきもの
とは言い難い。これらの事情から医療の場におい
て、新しい抗アレルギー剤の開発が強く望まれて
いる。
問題点を解決するための手段
本発明者らは、前述の事情を鑑み鋭意研究した
結果、ピラチン誘導体、及びその薬理学的に許容
しうる塩が優れた抗アレルギー作用を有すること
を見い出し、本発明を完成させた。
即ち、本発明は一般式（）
（式中、R1は水素原子又は
INDUSTRIAL APPLICATION FIELD The present invention relates to a novel piratine derivative having excellent antiallergic and expectorant effects, and a pharmacologically acceptable salt thereof. PRIOR TECHNOLOGY No literature has been found regarding the piratin derivative of the present invention, and it is not known at all that it has antiallergic and expectorant effects. Problems to be Solved by the Invention Bronchial asthma is known to be caused by various factors. As one of these, it is known that an allergy-type allergic reaction (anaphylactic reaction) is induced by the invasion of an allergen, and the disease develops when chemical mediators are released from mast cells. Drugs that inhibit the release of chemical mediators have come to be used as therapeutic agents for such allergic diseases. Examples of this type of drug include 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane disodium salt [generic name: sodium cromoglycate, abbreviation: DSCG, Merck Index ( The Merck Index), 10th edition
2580] and N-(3,4-dimethoxycinnamoyl)anthranilic acid [generic name: tranilast, The Merck Index, 10th
edition9392] is in clinical use. In addition, 6-methyl-N is currently being researched and developed.
-(1H-5-tetrazolyl)pyridine-2-carboxamide [Clinical trial number: TA-5707F, Japanese Journal of Pharmacology, Volume 40,
37-46 (1986)] is known. However, there are only a few drugs that have this type of action, and it cannot be said that they are necessarily satisfactory in terms of efficacy and safety. Under these circumstances, there is a strong desire for the development of new antiallergic agents in the medical field. Means for Solving the Problems As a result of intensive research in view of the above circumstances, the present inventors discovered that pyratine derivatives and pharmacologically acceptable salts thereof have excellent anti-allergic effects. completed the invention. That is, the present invention is based on the general formula () (In the formula, R 1 is a hydrogen atom or
【式】基を表わ
す。この時、R2及びR3は同一又は異なつて水素
原子、低級アルキル基を表わすか、又はR2及び
R3が隣接する窒素原子と共に環状アミノ基を形
成することを表わす。該環状アミノ基は環構成原
子としてヘテロ原子を含有していてもよく、又置
換基を有していてもよい。）
で示される新規なピラチン誘導体、及びその薬理
学的に許容しうる塩に関するものである。
本発明の一般式（）中、R2及びR3で示され
る低級アルキル基としては、たとえば、メチル、
エチル、ｎ−プロピル、イソプロピル、ｎ−ブチ
ル、イソブチル、sec−ブチル、tert−ブチル基
等が挙げられる。又、R2及びR3が隣接する窒素
原子と共に形成する環状アミノ基としては、たと
えば、１−アゼチニル、１−ピロリジニル、１−
ピペリジニル、３−メチル−１−ピペリジニル、
４−メチル−１−ピペリジニル、４−ヒドロキシ
−１−ピペリジニル、３−ヒドロキシ−１−ピペ
リジニル、ヘキサハイドロ−1H−１−アゼピニ
ル、１−ピペラジニル、４−メチル−１−ピペラ
ジニル、４−エチル−１−ピペラジニル、４−フ
エニル−１−ピペラジニル、４−モルホリニル、
４−チオモルホリニル、１−ホモピペラジニル、
４−メチル−１−ホモピペラジニル基等が挙げら
れる。
本発明の前記一般式（）で示される化合物
は、所望に応じて薬理学的に許容しうる塩に変換
することも、又は生成した塩から塩基を遊離させ
ることもできる。
本発明の前記一般式（）で示される化合物の
薬理学的に許容しうる塩としては、酸付加塩又は
アルカリ付加塩が挙げられ、酸付加塩としては、
たとえば、塩酸、臭化水素酸、ヨウ化水素酸、硝
酸、硫酸、燐酸等の鉱酸塩、あるいは、酢酸、マ
レイン酸、フマル酸、クエン酸、シユウ酸、酒石
酸等の有機酸塩が、アルカリ付加塩としては、た
とえば、ナトリウム、カリウム、カルシウム、ア
ルミニウム等の金属塩等、あるいは、トリエチル
アミン、トリエタノールアミン、ピロリジン、エ
チレンジアミン等の有機塩基の塩等が挙げられ
る。
本発明の前記一般式（）で示される新規なピ
ラチン誘導体は、以下の様にして製造することが
できる。
本発明に係わる化合物の製造方法の第一の様式
によれば、前記一般式（）で示される化合物
は、次の一般式（）
（式中、R1は前述と同意義を表わす。）
で示されるピラチン−２−カルボン酸誘導体をそ
の反応誘導体（酸クロリド、酸無水物、混合酸無
水物等）に変換した後、次の式（）
で示される５−アミノテトラゾールを、塩基の存
在下あるいは非存在下、不活性有機溶媒中で反応
させることにより製造することができる。
本発明の方法において使用される塩基として
は、たとえば、ピリジン、ピコリン、ルチジン、
コリジン、Ｎ−メチルピペリジン、Ｎ−メチルピ
ロリジン、Ｎ−メチルモルホリン、トリエチルア
ミン、炭酸カリウム、炭酸ナトリウム等が挙げら
れる。
又、本発明の方法において使用される不活性有
機溶媒としては、反応を阻害しない限りいかなる
ものでもよく、たとえば、エーテル、ベンゼン、
テトラヒドロフラン、ジオキサン、クロロホル
ム、塩化メチレン、ジメチルスルホキシド、Ｎ，
Ｎ−ジメチルホルムアミド等が挙げられる。
又、反応は−10°から加熱還流下において行わ
れるが、好ましくは使用される溶媒の加熱還流下
において行われることである。
なお、本発明の原料となつた前記一般式（）
で示されるピラチン−２−カルボン酸誘導体は、
ジサータチオンズ・フオーマシユテイア・フアー
マコロジカ（Dissertationes pharmaceutiae
pharmacologicae）24巻、577頁（1972）に既に
開示されている公知の物質である。
本発明に係わる化合物の製造方法の第二の様式
によれば、前記一般式（）で示される化合物
は、次の一般式（）
（式中、Ｘはハロゲン原子を表わす。）
で示される６−ハロゲノピラチン誘導体と、次の
一般式（）
（式中、R2及びR3は前述と同意義を表わす。）で
示されるアミン類とを、無溶媒下あるいは溶媒下
において反応させることにより製造することがで
きる。
本発明の方法において使用される溶媒として
は、反応を阻害しない限りいかなるものでもよ
く、たとえば、水、メタノール、エタノール、プ
ロパノール、ブタノール等のアルコール類、エチ
レングリコールジメチルエーテル（モノグライ
ム）、ジエチレングリコールジメチルエーテル
（ジグライム）、トリエチレングリコールジメチル
エーテル（トリグライム）等のエーテル類、ジメ
チルホルムアミド、ジメチルスルホキシド、ヘキ
サメチルフオスホリツクトリアミド等の非プロト
ン性溶媒、ベンゼン、トルエン等の芳香族炭化水
素系溶媒、あるいは、ピリジン、ピコリン、ルチ
ジン、コリジン、トリエチルアミン等の有機塩基
が挙げられる。
又、反応は室温から200°の範囲で行われる。
なお、ここで原料となつた一般式（）で示さ
れる化合物は次の様にして製造される。
即ち、前記一般式（）で示される化合物は、
次の一般式（）
（式中、Ｘは前述と同意義を表わす。）
で示されるピラチンカルボン酸誘導体と前記式
（）で示される５−アミノテトラゾールとを、
前記製造方法の第一の様式の如く反応することに
より製造することができる。
本発明の一般式（）で示される化合物、ある
いはその薬理学的に許容しうる塩はそのままでも
用いられるが、通常、カプセル剤、錠剤、細粒
剤、顆粒剤、シロツプ剤、散剤等の経口剤、ある
いは注射剤、坐剤、吸入剤、点眼剤、点鼻剤等の
非経口剤として製剤化されて用いられる。これら
の製剤は、薬理学的、製剤学的に許容しうる添加
物を加え、常法により製造できる。すなわち経口
剤及び坐剤にあつては、賦形剤（白糖、乳糖、Ｄ
−マンニトール、でんぷん、結晶セルロース等）、
崩壊剤（カルボキシメチルセルロース、カルボキ
シメチルセルロースカルシウム等）、結合剤（ヒ
ドロキシプロピルセルロース、ヒドロキシプロピ
ルメチルセルロース、ポリビニルピロリドン等）、
滑沢剤（ステアリン酸マグネシウム、タルク等）、
コーテイング剤（ヒドロキシプロピルメチルセル
ロース、白糖等）、基剤（ポリエチレングリコー
ル、ハードフアツト等）等の製剤用成分が、又、
注射剤、点眼剤、点鼻剤にあつては水性または用
時溶解型あるいは懸濁型製剤を構成しうる溶解剤
ないし溶解補助剤（注射用蒸留水、滅菌精製水、
生理食塩水、プロピレングリコール等）、PH調節
剤（無機酸、有機酸又は無機塩基、有機塩基）、
安定化剤、防腐剤、等張化剤（ブドウ糖、塩化ナ
トリウム、Ｄ−マンニトール、グリセリン）、懸
濁化剤（ポリソルベート80、ポリオキシエチレン
硬化ヒマシ油、ヒドロキシプロピルセルロース、
ポリビニルピロリドン）等の製剤成分が使用され
る。
本剤の治療患者への投与量は、患者の症状にも
よるが、通常成人の場合、一日量として、経口投
与で１〜1000mg、好ましくは10〜500mgを、点眼、
点鼻剤として用いる場合には１回0.1〜100mg、好
ましくは１〜50mgを投与する。
作 用
以下、本発明により見い出された優れた作用を
試験例により説明する。尚、対照化合物として、
DSCG、トラニラスト及びTA−5707Fを用いた。
試験例 １
ヒスタミン遊離抑制作用
体重約350〜400ｇのウイスター系雄性ラツトか
ら得た腹腔細胞を、ラツト抗DNP−As血清（多
田、奥村の方法［Tada、T.and Okumura、
Ｋ：J.Immunology、106、1002（1971）］に準じ
て調製）と、37°で２時間インキユベートして感
作したのちHepes Tyrode緩衝液（Heparin
10unit／ml、BSA0.3％を含む）で細胞懸濁液を
調整（１×105個／ml）し、その0.8mlずつをポリ
エチレン製チユーブにとり、37°で10分間プレイ
ンキユベーシヨン後、種々の濃度の被験化合物溶
液0.1mlを加え、１分間インキユベートした。次
いで、50μｇ／mlのDNP−As溶液0.1mlを加えて
37°で20分間インキユベートし、ヒスタミンの遊
離率を測定した。ヒスタミン量はShoreの変法で
蛍光測定した。IC50は用量反応曲線より算出し
た。結果を表１に示す。[Formula] represents a group. At this time, R 2 and R 3 are the same or different and represent a hydrogen atom, a lower alkyl group, or R 2 and
Indicates that R 3 forms a cyclic amino group together with the adjacent nitrogen atom. The cyclic amino group may contain a heteroatom as a ring-constituting atom, or may have a substituent. ) and its pharmacologically acceptable salts. In the general formula () of the present invention, the lower alkyl group represented by R 2 and R 3 includes, for example, methyl,
Examples include ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl groups. Further, examples of the cyclic amino group formed by R 2 and R 3 together with the adjacent nitrogen atom include 1-azetinyl, 1-pyrrolidinyl, 1-
piperidinyl, 3-methyl-1-piperidinyl,
4-Methyl-1-piperidinyl, 4-hydroxy-1-piperidinyl, 3-hydroxy-1-piperidinyl, hexahydro-1H-1-azepinyl, 1-piperazinyl, 4-methyl-1-piperazinyl, 4-ethyl-1 -piperazinyl, 4-phenyl-1-piperazinyl, 4-morpholinyl,
4-thiomorpholinyl, 1-homopiperazinyl,
Examples include 4-methyl-1-homopiperazinyl group. The compound represented by the general formula () of the present invention can be converted into a pharmacologically acceptable salt as desired, or the base can be liberated from the generated salt. Examples of the pharmacologically acceptable salts of the compound represented by the general formula () of the present invention include acid addition salts and alkali addition salts, and the acid addition salts include:
For example, mineral acid salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, etc., or organic acid salts such as acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, tartaric acid, etc. Examples of addition salts include metal salts such as sodium, potassium, calcium, and aluminum, and salts of organic bases such as triethylamine, triethanolamine, pyrrolidine, and ethylenediamine. The novel pyratine derivative of the present invention represented by the general formula () can be produced as follows. According to the first mode of the method for producing a compound according to the present invention, the compound represented by the general formula () is prepared by the following general formula () (In the formula, R 1 represents the same meaning as above.) After converting the pyratine-2-carboxylic acid derivative represented by the following into its reaction derivative (acid chloride, acid anhydride, mixed acid anhydride, etc.), the following formula() 5-aminotetrazole represented by can be produced by reacting in an inert organic solvent in the presence or absence of a base. Examples of the base used in the method of the present invention include pyridine, picoline, lutidine,
Examples include collidine, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, triethylamine, potassium carbonate, and sodium carbonate. Furthermore, any inert organic solvent used in the method of the present invention may be used as long as it does not inhibit the reaction, such as ether, benzene,
Tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl sulfoxide, N,
Examples include N-dimethylformamide. The reaction is carried out under heating under reflux from -10°, preferably under heating under reflux of the solvent used. Note that the general formula (), which is the raw material of the present invention,
The pyratine-2-carboxylic acid derivative represented by
Dissertationes pharmaceutiae
pharmacologicae), Vol. 24, p. 577 (1972). According to the second mode of the method for producing a compound according to the present invention, the compound represented by the general formula () has the following general formula () (In the formula, X represents a halogen atom.) A 6-halogenopyratine derivative represented by the following general formula () (In the formula, R 2 and R 3 represent the same meanings as described above.) It can be produced by reacting the amines shown in the formula without a solvent or in a solvent. The solvent used in the method of the present invention may be any solvent as long as it does not inhibit the reaction, such as water, alcohols such as methanol, ethanol, propanol, butanol, ethylene glycol dimethyl ether (monoglyme), diethylene glycol dimethyl ether (diglyme), etc. , ethers such as triethylene glycol dimethyl ether (triglyme), aprotic solvents such as dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, aromatic hydrocarbon solvents such as benzene and toluene, or pyridine and picoline. , lutidine, collidine, triethylamine, and other organic bases. Further, the reaction is carried out at a temperature ranging from room temperature to 200°. Incidentally, the compound represented by the general formula () used as a raw material here is produced in the following manner. That is, the compound represented by the general formula () is
The following general formula () (In the formula, X represents the same meaning as above.) A pyratine carboxylic acid derivative represented by the formula () and 5-aminotetrazole represented by the above formula (),
It can be produced by reacting as in the first mode of the production method. The compound represented by the general formula () of the present invention or a pharmacologically acceptable salt thereof can be used as is, but it is usually administered in the form of capsules, tablets, fine granules, granules, syrups, powders, etc. It is used in the form of parenteral preparations such as injections, suppositories, inhalants, eye drops, and nasal drops. These preparations can be manufactured by conventional methods by adding pharmacologically and pharmaceutically acceptable additives. That is, for oral preparations and suppositories, excipients (white sugar, lactose, D
- mannitol, starch, crystalline cellulose, etc.),
Disintegrants (carboxymethylcellulose, carboxymethylcellulose calcium, etc.), binders (hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.),
Lubricants (magnesium stearate, talc, etc.),
Pharmaceutical ingredients such as coating agents (hydroxypropyl methylcellulose, sucrose, etc.), bases (polyethylene glycol, hard fat, etc.),
For injections, eye drops, and nasal drops, solubilizing agents or solubilizing agents (distilled water for injection, sterile purified water,
physiological saline, propylene glycol, etc.), PH regulators (inorganic acids, organic acids or inorganic bases, organic bases),
Stabilizers, preservatives, tonicity agents (glucose, sodium chloride, D-mannitol, glycerin), suspending agents (polysorbate 80, polyoxyethylene hydrogenated castor oil, hydroxypropyl cellulose,
Formulation components such as polyvinylpyrrolidone) are used. The dosage of this drug for patients to be treated depends on the patient's symptoms, but the usual daily dose for adults is 1 to 1000 mg, preferably 10 to 500 mg, by oral administration, eye drops,
When used as a nasal spray, the dose is 0.1 to 100 mg, preferably 1 to 50 mg, per dose. Effects The excellent effects found by the present invention will be explained below using test examples. In addition, as a control compound,
DSCG, Tranilast and TA-5707F were used. Test Example 1 Histamine Release Inhibition Effect Peritoneal cells obtained from male Wistar rats weighing approximately 350 to 400 g were treated with rat anti-DNP-As serum (Tada, T. and Okumura's method [Tada, T. and Okumura's method]).
K: J. Immunology, 106 , 1002 (1971)] and sensitized by incubating at 37° for 2 hours, followed by Hepes Tyrode buffer (Heparin
Prepare a cell suspension (1 x 10 5 cells/ml) (10 units/ml, containing 0.3% BSA), place 0.8 ml of each into a polyethylene tube, and pre-incubate at 37° for 10 minutes. 0.1 ml of test compound solutions of various concentrations were added and incubated for 1 minute. Next, add 0.1 ml of 50 μg/ml DNP-As solution.
After incubation at 37° for 20 minutes, the release rate of histamine was measured. The amount of histamine was determined by fluorescence measurement using a modified Shore method. IC 50 was calculated from the dose-response curve. The results are shown in Table 1.
【表】
試験例 ２
急性毒性試験
生後５週齢のICR系雄性マウスを１群５匹とし
て用い、被験化合物の各用量を経口投与した。
LD50値は１週間内に死亡した動物数からProbit
法を用いて算出した。結果を表２に示す。[Table] Test Example 2 Acute Toxicity Test Each dose of the test compound was orally administered to 5-week-old ICR male mice in groups of 5 mice.
The LD 50 value is calculated from the number of animals that died within one week.
Calculated using the method. The results are shown in Table 2.
【表】
本発明化合物は対照化合物に比べて優れたヒス
タミン遊離抑制作用を示し、又、毒性も弱いこと
から新しい抗アレルギー剤として有用性が期待さ
れる。
実施例
以下、本発明を実施例及び参考例によつて説明
するが、本発明はこれらの例の特定の細部に限定
されるものではない。
参考例 １
６−クロロ−Ｎ−（1H−５−テトラゾリル）ピ
ラチン−２−カルボキサミド
６−クロロピラチン−２−カルボン酸1.59ｇの
テトラヒドロフラン30ml懸濁液中に、氷冷攪拌
下、トリエチルアミン1.54ml及びピバロイルクロ
ライド1.36mlを加え１時間攪拌後、1H−５−テ
トラゾリルアミン0.94ｇを加え18時間加熱還流す
る。反応後水50mlを加え結晶をろ取し、ジメチル
スルホキシド−メタノールより再結晶して、融点
261〜264°（分解）の淡赤色粉末晶0.78ｇを得る。
元素分析値 C6H4ClN7O
理論値 Ｃ、31.94；Ｈ、1.79；Ｎ、43.16
実験値 Ｃ、32.03；Ｈ、1.70；Ｎ、43.68
実施例 １
Ｎ−（1H−５−テトラゾリル）ピラチン−２−
カルボキサミド
ピラチン−２−カルボン酸1.50ｇのテトラヒド
ロフラン50ml懸濁液中に、氷冷攪拌下、トリエチ
ルアミン1.85ml及びクロル炭酸エチル1.27mlを加
え30分間攪拌後、1H−５−テトラゾリルアミン
1.37ｇを加え、室温にて28.5時間攪拌する。反応
後析出結晶をろ取し塩酸水溶液にて洗浄して、無
色結晶2.05ｇを得る。ジメチルスルホキシドより
再結晶して、融点291〜296°（分解）の無色結晶を
得る。
元素分析値 C6H5N7O
理論値 Ｃ、37.70：Ｈ、2.64；Ｎ、54.29
実験値 Ｃ、37.43；Ｈ、2.97；Ｎ、51.74
実施例 ２
６−（ジメチルアミノ）−Ｎ−（1H−５−テトラ
ゾリル）ピラチン−２−カルボキサミド
(a) ６−ジメチルピラチン−２−カルボン酸580
mgのテトラヒドロフラン10ml懸濁液中に、氷冷
攪拌下、トリエチルアミン0.53ml及びピバロイ
ルクロライド0.47mlを加え１時間攪拌後、1H
−５−テトラゾリルアミン330mgを加え、室温
で１時間攪拌し、さらに６時間加熱還流する。
反応後水70mlを加え結晶をろ取し、ジメチルス
ルホキシド−メタノールより再結晶して、融点
267〜269°（分解）の黄色針状晶360mgを得る。
元素分析値 C8H10N8O
理論値 Ｃ、41.02；Ｈ、4.30；Ｎ、47.84
実験値 Ｃ、40.95；Ｈ、4.63；Ｎ、47.83
(b) ６−クロロ−Ｎ−（1H−５−テトラゾリル）
ピラチン−２−カルボキサミド30ｇのエタノー
ル260ml懸濁液に50％ジメチルアミン水溶液60
mlを加え、封管中80〜90°で９時間加熱する。
反応液に濃塩酸を加えてPH２とする。析出結晶
をろ取し、ジメチルホキシド−メタノールより
再結晶して、融点267〜269°（分解）の黄色針状
晶23.1ｇを得る。このものは、先に得た化合物
のNMRスペクトル、マススペクトル、IRスペ
クトルで完全に一致する。
実施例 ３
６−（１−ピロリジニル）−Ｎ−（1H−５−テト
ラゾリル）ピラチン−２−カルボキシサミド
(a) ６−（１−ピロリジニル）ピラチン−２−カ
ルボン酸2.90ｇのテトラヒドロフラン45ml懸濁
液中に、氷冷攪拌下、トリエチルアミン2.30ml
及びピバロイルクロライド2.00mlを加え１時間
攪拌後、1H−５−テトラゾリルアミン1.40ｇ
を加え、室温で１時間攪拌し、さらに12時間加
熱還流する。反応液を減圧下留去し、残渣に水
を加えて結晶をろ取し、ジメチルスルホキシド
より再結晶して、融点273〜275°（分解）の黄色
針状晶1.63ｇを得る。
元素分析値 C10H12N8O
理論値 Ｃ、46.15；Ｈ、4.65；Ｎ、43.05
実験値 Ｃ、46.14；Ｈ、4.91；Ｎ、43.43
(b) ６−クロロ−Ｎ−（1H−５−テトラゾリル）
ピラチン−２−カルボキサミド200ｇのエタノ
ール1800ml懸濁液にピロリジン220mlを加え、
22時間加熱還流する。反応液に濃塩酸を加えて
PH２とする。析出結晶をろ取し、ジメチルスル
ホキシド−メタノールより再結晶して、融点
273〜275°（分解）の黄色針状晶193ｇを得る。
このものは、先に得た化合物とNMRスペクト
ル、マススペクトル、IRスペクトルで完全に
一致する。
(c) ６−クロロ−Ｎ−（1H−５−テトラゾリル）
ピラチン−２−カルボキサミド33.8ｇのエタノ
ール102ml懸濁液にピロリジン37.2mlを加え、
室温で30分間攪拌後、３時間加熱還流する。冷
後析出結晶をろ取し、メタノールより再結晶し
て、融点281〜283°（分解）の６−（１−ピロリ
ジニル）−Ｎ−（1H−５−テトラゾリル）ピラ
チン−２−カルボキサミド・ピロリジン塩の黄
色結晶33.0ｇを得る。
元素分析値 C10H12N8O・C4H9N
理論値 Ｃ、50.74；Ｈ、6.39；Ｎ、38.04
実験値 Ｃ、50.73；Ｈ、6.27；Ｎ、38.32
６−（１−ピロリジニル）−Ｎ−（1H−５−テ
トラゾリル）ピラチン−２−カルボキサミド・
ピロリジン塩30ｇを水300mlに溶解し、ろ過後、
10％塩酸を加えてPH３とする。析出結晶をろ取
して、融点273〜275°（分解）の黄色結晶24.4ｇ
を得る。このものは先に得た化合物とNMRス
ペクトル、マススペクトル、IRスペクトルで
完全に一致する。
(d) ６−（１−ピロリジニル）−Ｎ−（1H−５−テ
トラゾリル）ピラチン−２−カルボキサミド・
ナトリウム塩
上記で得た化合物21.9ｇの水110ml懸濁液に
10％水酸化ナトリウム水溶液29.8mlを加え、溶
解させる。これにエタノール465mlを加え、0°
で１時間冷却する。析出結晶をろ取し、水−エ
タノールより再結晶して、融点300°以上の黄色
柱状晶17.6ｇを得る。
元素分析値 C10H11N8O・Na
理論値 Ｃ、42.56；Ｈ、3.93；Ｎ、39.70
実験値 Ｃ、42.44；Ｈ、4.16；Ｎ、39.89
実施例 ４
６−（１−ピペリジニル）−Ｎ−（1H−５−テト
ラゾリル）ピラチン−２−カルボキサミド
(a) ６−（１−ピペリジニル）ピラチン−２−カ
ルボン酸1.28ｇのテトラヒドロフラン18ml懸濁
液中に、氷冷攪拌下、トリエチルアミン0.95ml
及びピバロイルクロライド0.84mlを加え１時間
攪拌後、1H−５−テトラゾリルアミン0.58ｇ
を加え、室温で30分間攪拌し、さらに12時間加
熱還流する。反応液を減圧下留去し、残渣に水
を加えて結晶をろ取し、ジメチルスルホキシド
−メタノールより再結晶して、融点247〜250°
（分解）の黄色柱状晶0.55ｇを得る。
元素分析値 C11H14N8O
理論値 Ｃ、48.17；Ｈ、5.14；Ｎ、40.85
実験値 Ｃ、48.12；Ｈ、5.38；Ｎ、40.93
(b) ６−クロロ−Ｎ−（1H−５−テトラゾリル）
ピラチン−２−カルボキサミド30ｇのエタノー
ル270ml懸濁液にピペリジン39.4mlを加え15時
間加熱還流する。反応液にエタノール性塩酸を
加えてPH３とする。析出結晶をろ取し、ジメチ
ルスルホキシド−メタノールより再結晶して、
融点247〜250°（分解）の黄色柱状晶26.4ｇを得
る。このものは、先に得た化合物とNMRスペ
クトル、マススペクトルで完全に一致する。
実施例 ５
６−（４−モルホリニル）−Ｎ−（1H−５−テト
ラゾリル）ピラチン−２−カルボキサミド
(a) ６−（４−モルホリニル）ピラチン−２−カ
ルボン酸2.50ｇのテトラヒドフラン50ml懸濁液
中に、氷冷攪拌下、トリエチルアミン3.60ml及
びピバロイルクロライド1.60mlを加え１時間攪
拌後、1H−５−テトラゾリルアミン1.12ｇを
加え、１時間攪拌し、さらに12時間加熱還流す
る。反応液を減圧下留去し、残渣に水を加えて
結晶をろ取し、ジメチルスルホキシド−メタノ
ールより再結晶して融点276〜278°（分解）の黄
色針状晶1.74ｇを得る。
元素分析値 C10H12N8O2
理論値 Ｃ、43.48；Ｈ、4.38；Ｎ、40.56
実験値 Ｃ、43.47；Ｈ、4.56；Ｎ、40.70
(b) ６−クロロ−Ｎ−（1H−５−テトラゾリル）
ピラチン−２−カルボキサミド2.26ｇのエタノ
ール30ml懸濁液にモルホリン4.36mlを加え、18
時間加熱還流する。反応液に濃塩酸を加えてPH
２とする。析出結晶をろ取し、ジメチルスルホ
キシド−メタノールより再結晶して、融点276
〜278°（分解）の黄色針状晶2.06ｇを得る。こ
のものは、先に得た化合物とNMRスペクト
ル、マススペクトル、IRスペクトルで完全に
一致する。
実施例 ６
６−（ジエチルアミノ）−Ｎ−（1H−５−テトラ
ゾリル）ピラチン−２−カルボキサミド
６−クロロ−Ｎ−（1H−５−テトラゾリル）ピ
ラチン−２−カルボキサミド1.13ｇのベンゼン20
ml懸濁液にジエチルアミン20mlを加え、封管中80
〜90°で24時間加熱する。反応液を減圧下留去し、
残渣に水を加え、次いで希塩酸を加えてPH３に調
製する。析出結晶をろ取し、ジメチルスルホキシ
ド−メタノールより再結晶して、融点217〜218°
の黄色板状晶0.75ｇを得る。
元素分析値 C10H14N8O
理論値 Ｃ、45.80；Ｈ、5.38；Ｎ、42.72
実験値 Ｃ、45.57；Ｈ、5.67；Ｎ、42.84
実施例 ７
６−（３−メチル−１−ピペリジニル）−Ｎ−
（1H−５−テトラゾリル）ピラチン−２−カル
ボキサミド
６−クロロ−Ｎ−（1H−５−テトラゾリル）ピ
ラチン−２−カルボキサミド1.13ｇのベンゼン20
ml懸濁液に３−メチルピペリジン2.9mlを加え、
６時間加熱還流する。反応液を減圧下留去し、残
渣にエタノールを加え、次いでエタノール性塩酸
を加えてPH３とする。析出結晶をろ取し、ジメチ
ルスルホキシド−メタノールより再結晶して、融
点236.5〜238.5°の淡黄色柱状晶0.81ｇを得る。
元素分析値 C12H16N8O
理論値 Ｃ、49.99；Ｈ、5.59；Ｎ、38.87
実験値 Ｃ、49.77；Ｈ、5.77；Ｎ、38.79
以下、実施例１〜７と同様にして、実施例８〜
15の化合物を得る。
実施例 ８
６−（４−メチル−１−ピペリジニル）−Ｎ−
（1H−５−テトラゾリル）ピラチン−２−カル
ボキサミド
ジメチルスルホキシド−メタノールより再結晶
して、融点246.5〜248.5°（分解）の黄色柱状晶を
得る。
元素分析値 C12H16N8O
理論値 Ｃ、49.99；Ｈ、5.59；Ｎ、38.87
実験値 Ｃ、49.72；Ｈ、5.94；Ｎ、38.91
実施例 ９
６−（メチルアミノ）−Ｎ−（1H−５−テトラゾ
リル）ピラチン−２−カルボキサミド
ジメチルスルホキシド−メタノールより再結晶
して、融点260°（徐々に分解）の淡黄色針状晶を
得る。
元素分析値 C7H8N8O
理論値 Ｃ、38.18；Ｈ、3.66；Ｎ、50.89
実験値 Ｃ、38.16；Ｈ、3.85；Ｎ、51.14
実施例 10
６−（エチルアミノ）−Ｎ−（1H−５−テトラゾ
リル）ピラチン−２−カルボキサミド
ジメチルスルホキシド−メタノールより再結晶
して、融点272〜273.5°（分解）の淡黄色針状晶を
得る。
元素分析値 C8H10N8O
理論値 Ｃ、41.02；Ｈ、4.30；Ｎ、47.84
実験値 Ｃ、40.95；Ｈ、4.45；Ｎ、47.99
実施例 11
６−（ｎ−プロピルアミノ）−Ｎ−（1H−５−テ
トラゾリル）ピラチン−２−カルボキサミド
ジメチルスルホキシド−メタノールより再結晶
して、融点278〜279.5°（分解）の淡黄色針状晶を
得る。
元素分析値 C9H12N8O
理論値 Ｃ、43.54；Ｈ、4.87；Ｎ、45.14
実験値 Ｃ、43.42；Ｈ、5.23；Ｎ、44.91
実施例 12
６−（イソプロピルアミノ）−Ｎ−（1H−５−テ
トラゾリル）ピラチン−２−カルボキサミド
ジメチルスルホキシド−メタノールより再結晶
して、融点272〜274°（分解）の淡黄色羽毛状晶を
得る。
元素分析値 C9H12N8O
理論値 Ｃ、43.54；Ｈ、4.87；Ｎ、45.14
実験値 Ｃ、43.51；Ｈ、5.00；Ｎ、45.49
実施例 13
６−（３−ヒドロキシ−１−ピペリジニル）−Ｎ
−（1H−５−テトラゾリル）ピラチン−２−カ
ルボキサミド
ジメチルスルホキシド−メタノールより再結晶
して、融点257〜259°（分解）の黄色粉末を得る。
元素分析値 C11H14N8O2
理論値 Ｃ、45.51；Ｈ、4.86；Ｎ、38.60
実験値 Ｃ、45.41；Ｈ、5.16；Ｎ、38.42
実施例 14
６−（４−ヒドロキシ−１−ピペリジニル）−Ｎ
−（1H−５−テトラゾリル）ピラチン−２−カ
ルボキサミド
ジメチルスルホキシド−メタノールより再結晶
して、融点259.5〜261°（分解）の淡黄色粉末を得
る。
元素分析値 C11H14N8O2
理論値 Ｃ、45.51；Ｈ、4.86；Ｎ、38.60
実験値 Ｃ、45.35；Ｈ、5.15；Ｎ、38.57
実施例 15
６−（４−メチル−１−ピペラジニル）−Ｎ−
（1H−５−テトラゾリル）ピラチン−２−カル
ボキサミド・塩酸塩
ジメチルスルホキシド−メタノールより再結晶
して、融点246〜250（分解）の淡黄色粉末を得る。
元素分析値 C11H15N9O・HCl・H2O
理論値 Ｃ、38.43；H5.28；Ｎ、36.67
実験値 Ｃ、38.62；Ｈ、5.15；Ｎ、36.71
実施例 16
６−（ｎ−ブチルアミノ）−Ｎ−（1H−５−テト
ラゾリル）ピラチン−２−カルボキサミド
６−クロロ−Ｎ−（1H−５−テトラゾリル）ピ
ラチン−２−カルボキサミド2.26ｇのエタノール
30ml懸濁液にｎ−ブチルアミン4.95mlを加え、21
時間加熱還流する。反応液を減圧下濃縮し、残渣
に水及び10％塩酸を加えPH３とする。析出結果を
ろ取し、ジメチルホルムアミド−エタノールより
再結晶して、融点269〜272°（分解）の淡黄色針状
晶を2.00ｇ得る。
元素分析値 C10H14N8O
理論値 Ｃ、45.80；Ｈ、5.38；Ｎ、42.72
実験値 Ｃ、45.65；Ｈ、5.53；Ｎ、42.83
実施例 17
６−（イソブチルアミノ）−Ｎ−（1H−５−テト
ラゾリル）ピラチン−２−カルボキサミド
６−クロロ−Ｎ−（1H−５−テトラゾリル）ピ
ラチン−２−カルボキサミド2.26ｇのエタノール
30ml懸濁液にイソブチルアミン4.97mlを加え、19
時間加熱還流する。反応液を減圧下濃縮し、残渣
に水及び10％塩酸を加えPH３とする。析出結晶を
ろ取し、ジメチルホルムアミド−エタノールより
再結晶して、融点265〜275°（分解）の淡黄色プリ
ズム晶を2.10ｇ得る。
元素分析値 C10H14N8O
理論値 Ｃ、45.80；Ｈ、5.38；Ｎ、42.72
実験値 Ｃ、45.77；Ｈ、5.38；Ｎ、42.82
実施例 18
６−（sec−ブチルアミノ）−Ｎ−（1H−５−テ
トラゾリル）ピラチン−２−カルボキサミド
６−クロロ−Ｎ−（1H−５−テトラゾリル）ピ
ラチン−２−カルボキサミド2.26ｇのエタノール
30ml懸濁液にsec−ブチルアミン5.05mlを加え、
47時間加熱還流する。反応液を減圧下濃縮し、残
渣に水及び10％塩酸を加えPH３とする。析出結晶
をろ取し、ジメチルホルムアミド−エタノールよ
り再結晶して、融点265〜269°（分解）の淡黄色針
状晶を1.28ｇ得る。
元素分析値 C10H14N8O
理論値 Ｃ、45.80；Ｈ、5.38；Ｎ、42.72
実験値 Ｃ、45.54；Ｈ、5.36；Ｎ、42.49
実施例 19
６−（tert−ブチルアミノ）−Ｎ−（1H−５−テ
トラゾリル）ピラチン−２−カルボキサミド
６−クロロ−Ｎ−（1H−５−テトラゾリル）ピ
ラチン−２−カルボキサミド2.26ｇのジメチルス
ルホキシド15ml懸濁液にtert−ブチルアミン5.25
mlを加え、封管中80〜90°で41時間加熱する。反
応液に水及び10％水酸化ナトリウム水溶液を加え
アルカリ性とした後、クロロホルムで洗浄する。
水層をろ過した後、ろ液に10％塩酸を加えてPH３
とする。析出結晶をろ取し、ジメチルホルムアミ
ド−エタノールより再結晶して、融点266〜270°
（分解）の黄色粉末を1.07ｇ得る。
IRスペクトル ν（KBr）cm-1：1705
NMRスペクトル δ（DMSO−d6）ppm：1.47
（9H、一重線）、7.19（1H、一重線）、8.20（1H、
一重線）、8.31（1H、一重線）、11.01（1H、一重
線）
実施例 20
６−（１−ピペラジニル）−Ｎ−（1H−５−テト
ラゾリル）ピラチン−２−カルボキサミド
６−クロロ−Ｎ−（1H−５−テトラゾリル）ピ
ラチン−２−カルボキサミド2.26ｇのエタノール
50ml懸濁液に無水ピペラジン8.61ｇを加え、22時
間加熱還流する。反応混合物をろ過し、得られた
黄色結晶に水及び10％水酸化ナトリウム水溶液を
加え、アルカリ性とした後、クロロホルムで洗浄
する。水層を10％塩酸でPH８とする。結晶を水及
び10％水酸化ナトリウム水溶液を加えアルカリ性
とし溶解した後、10％塩酸でPH８とする。析出結
晶をろ取し、融点300°以上の淡黄色粉末を1.68ｇ
得る。
IRスペクトル ν（KBr）cm-1：1690
NMRスペクトル δ（CF3COOD）ppm：2.70−
2.95（4H、多重線）、3.35−3.54（4H、多重線）、
8.87（1H、一重線）、8.89（1H、一重線）
実施例 21
６−（４−エチル−１−ピペラジニル）−Ｎ−
（1H−５−テトラゾリル）ピラチン−２−カル
ボキサミド・塩酸塩
６−クロロ−Ｎ−（1H−５−テトラゾリル）ピ
ラチン−２−カルボキサミド2.26ｇのエタノール
30ml懸濁液にＮ−エチルピペラジン4.56ｇを加
え、24時間加熱還流する。反応液を減圧下留去
し、残渣に水及び10％水酸化ナトリウム水溶液を
加え、アルカリ性とした後、クロロホルムで洗浄
する。水層を10％塩酸でPH３とする。析出結果を
ろ取し、ジメチルスルホキシド−メタノールより
再結晶して、融点230〜243°（分解）の黄色粉末を
2.32ｇ得る。
元素分析値 C12H17N9O・HCl
理論値 Ｃ、42.42；Ｈ、5.34；Ｎ、37.10
実験値 Ｃ、42.59；Ｈ、5.55；Ｎ、36.83
実施例 22
６−（４−フエニル−１−ピペラジニル）−Ｎ−
（1H−５−テトラゾリル）ピラチン−２−カル
ボキサミド
６−クロロ−Ｎ−（1H−５−テトラゾリル）ピ
ラチン−２−カルボキサミド2.26ｇのエタノール
30ml懸濁液にＮ−フエニルピペラジン4.58mlを加
え、17時間加熱還流する。反応液にエタノール性
塩酸を加えてPH２とした後、析出結晶をろ取す
る。得られた結晶に水及び10％塩酸を加えてPH３
とする。析出結果をろ取し、ジメチルホルムアミ
ド−エタノールより再結晶して、融点250〜262°
（分解）の黄色針状晶を2.17ｇ得る。
元素分析値 C16H17N9O
理論値 Ｃ、54.69；Ｈ、4.84；Ｎ、35.88
実験値 Ｃ、54.66；Ｈ、4.92；Ｎ、36.02
実施例 23
６−（１−ホモピペラジニル）−Ｎ−（1H−５−
テトラゾリル）ピラチン−２−カルボキサミド
６−クロロ−Ｎ−（1H−５−テトラゾリル）ピ
ラチン−２−カルボキサミド2.26ｇのエタノール
50ml懸濁液にホモピペラジン10.0ｇを加え、23時
間加熱還流する。反応混合物をろ過し、得られた
黄色結晶に水及び10％水酸化ナトリウム水溶液を
加え、アルカリ性とした後、クロロホルムで洗浄
する。水層を10％塩酸でPH８とする。結晶を水及
び10％水酸化ナトリウム水溶液を加え、アルカリ
性とし溶解した後、10％塩酸でPH８とする。析出
結晶をろ取し、融点295〜300°以上（分解）の淡
黄色粉末を1.87ｇ得る。
元素分析値 C11H15N9O
理論値 Ｃ、45.67；Ｈ、5.23；Ｎ、43.57
実験値 Ｃ、45.37；Ｈ、5.42；Ｎ、43.42
実施例 24
６−（４−メチル−１−ホモピペラジニル）−Ｎ
−（1H−５−テトラゾリル）ピラチン−２−カ
ルボキサミド
６−クロロ−Ｎ−（1H−５−テトラゾリル）ピ
ラチン−２−カルボキサミド2.26ｇのエタノール
30ml懸濁液にＮ−メチルホモピペラジン4.56ｇを
加え、18時間加熱還流する。反応液をエタノール
性塩酸にてPH１とする。析出結晶をろ取し、結晶
に水及び10％水酸化ナトリウム水溶液を加え、ア
ルカリ性とした後ろ過する。ろ液を10％塩酸でPH
８とする。結晶に水及び10％水酸化ナトリウム水
溶液を加え、アルカリ性とし溶解した後、10％塩
酸でPH８とする。析出結晶をろ取し、融点300°以
上の微黄色粉末を1.30ｇ得る。
元素分析値 C12H17N9O
理論値 Ｃ、47.52；Ｈ、5.65；Ｎ、41.50
実験値 Ｃ、47.71；Ｈ、5.66；Ｎ、41.32
発明の効果
この様にして製造される前記一般式（）で示
される新規なピラチン誘導体、及びその薬理学的
に許容しうる塩は、優れた抗アレルギー作用、去
痰作用を有し、気管支喘息、アレルギー性胃腸障
害、枯草熱、じん麻疹、アレルギー性鼻炎等の治
療剤として極めて有用である。[Table] The compound of the present invention exhibits superior histamine release inhibiting action compared to the control compound, and is also less toxic, so it is expected to be useful as a new antiallergic agent. EXAMPLES The present invention will be described below with reference to Examples and Reference Examples, but the present invention is not limited to the specific details of these Examples. Reference Example 1 6-chloro-N-(1H-5-tetrazolyl)pyratine-2-carboxamide Into a suspension of 1.59 g of 6-chloropyratine-2-carboxylic acid in 30 ml of tetrahydrofuran, 1.54 ml of triethylamine and pyratine were added under ice-cooling and stirring. After adding 1.36 ml of baloyl chloride and stirring for 1 hour, 0.94 g of 1H-5-tetrazolylamine was added and heated under reflux for 18 hours. After the reaction, 50 ml of water was added, the crystals were collected by filtration, and recrystallized from dimethyl sulfoxide-methanol to determine the melting point.
0.78 g of pale red powder crystals of 261-264° (decomposition) are obtained. Elemental analysis value C 6 H 4 ClN 7 O Theoretical value C, 31.94; H, 1.79; N, 43.16 Experimental value C, 32.03; H, 1.70; N, 43.68 Example 1 N-(1H-5-tetrazolyl)pyratine- 2-
Carboxamide To a suspension of 1.50 g of pyratine-2-carboxylic acid in 50 ml of tetrahydrofuran, 1.85 ml of triethylamine and 1.27 ml of ethyl chlorocarbonate were added under ice-cooling and stirring, and after stirring for 30 minutes, 1H-5-tetrazolylamine was added.
Add 1.37g and stir at room temperature for 28.5 hours. After the reaction, the precipitated crystals were collected by filtration and washed with an aqueous hydrochloric acid solution to obtain 2.05 g of colorless crystals. Recrystallization from dimethyl sulfoxide gives colorless crystals with a melting point of 291-296° (decomposition). Elemental analysis value C 6 H 5 N 7 O Theoretical value C, 37.70: H, 2.64; N, 54.29 Experimental value C, 37.43; H, 2.97; N, 51.74 Example 2 6-(dimethylamino)-N-(1H -5-tetrazolyl)pyratine-2-carboxamide (a) 6-dimethylpyratine-2-carboxylic acid 580
0.53 ml of triethylamine and 0.47 ml of pivaloyl chloride were added to 10 ml of tetrahydrofuran suspension under ice cooling and stirring for 1 hour.
Add 330 mg of -5-tetrazolylamine, stir at room temperature for 1 hour, and further heat under reflux for 6 hours.
After the reaction, 70 ml of water was added and the crystals were collected by filtration and recrystallized from dimethyl sulfoxide-methanol to determine the melting point.
360 mg of yellow needles of 267-269° (decomposition) are obtained. Elemental analysis value C 8 H 10 N 8 O Theoretical value C, 41.02; H, 4.30; N, 47.84 Experimental value C, 40.95; H, 4.63; N, 47.83 (b) 6-chloro-N-(1H-5- Tetrazolyl)
A suspension of 30 g of pyratine-2-carboxamide in 260 ml of ethanol and a 50% dimethylamine aqueous solution 60
ml and heat in a sealed tube at 80-90° for 9 hours.
Add concentrated hydrochloric acid to the reaction solution to adjust the pH to 2. The precipitated crystals were collected by filtration and recrystallized from dimethyl oxide-methanol to obtain 23.1 g of yellow needle crystals with a melting point of 267-269° (decomposition). This spectrum completely matches the NMR spectrum, mass spectrum, and IR spectrum of the previously obtained compound. Example 3 6-(1-pyrrolidinyl)-N-(1H-5-tetrazolyl)pyratine-2-carboxamide (a) Suspension of 2.90 g of 6-(1-pyrrolidinyl)pyratine-2-carboxylic acid in 45 ml of tetrahydrofuran Add 2.30ml of triethylamine to the solution while stirring on ice.
After adding 2.00 ml of pivaloyl chloride and stirring for 1 hour, 1.40 g of 1H-5-tetrazolylamine was added.
was added, stirred at room temperature for 1 hour, and further heated under reflux for 12 hours. The reaction solution was evaporated under reduced pressure, water was added to the residue, the crystals were collected by filtration, and recrystallized from dimethyl sulfoxide to obtain 1.63 g of yellow needle crystals with a melting point of 273-275° (decomposition). Elemental analysis value C 10 H 12 N 8 O Theoretical value C, 46.15; H, 4.65; N, 43.05 Experimental value C, 46.14; H, 4.91; N, 43.43 (b) 6-chloro-N-(1H-5- Tetrazolyl)
Add 220 ml of pyrrolidine to a suspension of 200 g of pyratine-2-carboxamide in 1,800 ml of ethanol,
Heat to reflux for 22 hours. Add concentrated hydrochloric acid to the reaction solution
Set the pH to 2. The precipitated crystals were collected by filtration and recrystallized from dimethyl sulfoxide-methanol to determine the melting point.
193 g of yellow needles of 273-275° (decomposition) are obtained.
This product's NMR spectrum, mass spectrum, and IR spectrum completely match those of the previously obtained compound. (c) 6-chloro-N-(1H-5-tetrazolyl)
Add 37.2 ml of pyrrolidine to a suspension of 33.8 g of pyratine-2-carboxamide in 102 ml of ethanol,
After stirring at room temperature for 30 minutes, the mixture was heated under reflux for 3 hours. After cooling, the precipitated crystals were collected by filtration and recrystallized from methanol to obtain 6-(1-pyrrolidinyl)-N-(1H-5-tetrazolyl)pyratine-2-carboxamide pyrrolidine salt with a melting point of 281-283° (decomposition). 33.0 g of yellow crystals were obtained. Elemental analysis value C 10 H 12 N 8 O・C 4 H 9 N Theoretical value C, 50.74; H, 6.39; N, 38.04 Experimental value C, 50.73; H, 6.27; N, 38.32 6-(1-pyrrolidinyl)- N-(1H-5-tetrazolyl)pyratine-2-carboxamide.
Dissolve 30g of pyrrolidine salt in 300ml of water and filter it.
Add 10% hydrochloric acid to adjust the pH to 3. Filter the precipitated crystals to obtain 24.4 g of yellow crystals with a melting point of 273-275° (decomposition).
get. This product's NMR spectrum, mass spectrum, and IR spectrum completely match the previously obtained compound. (d) 6-(1-pyrrolidinyl)-N-(1H-5-tetrazolyl)pyratine-2-carboxamide.
Sodium salt A suspension of 21.9 g of the compound obtained above in 110 ml of water
Add 29.8ml of 10% sodium hydroxide aqueous solution and dissolve. Add 465ml of ethanol to this and
Cool for 1 hour. The precipitated crystals were collected by filtration and recrystallized from water-ethanol to obtain 17.6 g of yellow columnar crystals with a melting point of 300° or more. Elemental analysis value C 10 H 11 N 8 O・Na Theoretical value C, 42.56; H, 3.93; N, 39.70 Experimental value C, 42.44; H, 4.16; N, 39.89 Example 4 6-(1-piperidinyl)-N -(1H-5-tetrazolyl)pyratine-2-carboxamide (a) In a suspension of 1.28 g of 6-(1-piperidinyl)pyratine-2-carboxylic acid in 18 ml of tetrahydrofuran, under ice-cooling and stirring, 0.95 ml of triethylamine.
After adding 0.84 ml of pivaloyl chloride and stirring for 1 hour, 0.58 g of 1H-5-tetrazolylamine was added.
was added, stirred at room temperature for 30 minutes, and heated under reflux for an additional 12 hours. The reaction solution was distilled off under reduced pressure, water was added to the residue, the crystals were collected by filtration, and recrystallized from dimethyl sulfoxide-methanol to give a melting point of 247-250°.
Obtain 0.55 g of yellow columnar crystals (decomposition). Elemental analysis value C 11 H 14 N 8 O Theoretical value C, 48.17; H, 5.14; N, 40.85 Experimental value C, 48.12; H, 5.38; N, 40.93 (b) 6-chloro-N-(1H-5- Tetrazolyl)
39.4 ml of piperidine was added to a suspension of 30 g of pyratine-2-carboxamide in 270 ml of ethanol, and the mixture was heated under reflux for 15 hours. Add ethanolic hydrochloric acid to the reaction solution to adjust the pH to 3. The precipitated crystals were collected by filtration and recrystallized from dimethyl sulfoxide-methanol.
26.4 g of yellow columnar crystals with a melting point of 247-250° (decomposition) are obtained. This product's NMR spectrum and mass spectrum completely match those of the previously obtained compound. Example 5 6-(4-morpholinyl)-N-(1H-5-tetrazolyl)pyratine-2-carboxamide (a) Suspension of 2.50 g of 6-(4-morpholinyl)pyratine-2-carboxylic acid in 50 ml of tetrahydrofuran 3.60 ml of triethylamine and 1.60 ml of pivaloyl chloride were added to the solution under ice-cooling and stirring, and after stirring for 1 hour, 1.12 g of 1H-5-tetrazolylamine was added, stirred for 1 hour, and further heated under reflux for 12 hours. The reaction solution was distilled off under reduced pressure, water was added to the residue, the crystals were collected by filtration, and recrystallized from dimethyl sulfoxide-methanol to obtain 1.74 g of yellow needle crystals with a melting point of 276-278° (decomposed). Elemental analysis value C 10 H 12 N 8 O 2 Theoretical value C, 43.48; H, 4.38; N, 40.56 Experimental value C, 43.47; H, 4.56; N, 40.70 (b) 6-chloro-N-(1H-5 -tetrazolyl)
Add 4.36 ml of morpholine to a suspension of 2.26 g of pyratine-2-carboxamide in 30 ml of ethanol,
Heat to reflux for an hour. Add concentrated hydrochloric acid to the reaction solution to adjust the pH.
Set it to 2. The precipitated crystals were collected by filtration and recrystallized from dimethyl sulfoxide-methanol to give a melting point of 276.
2.06 g of yellow needles of ~278° (decomposition) are obtained. This product's NMR spectrum, mass spectrum, and IR spectrum completely match those of the previously obtained compound. Example 6 6-(diethylamino)-N-(1H-5-tetrazolyl)pyratine-2-carboxamide 6-chloro-N-(1H-5-tetrazolyl)pyratine-2-carboxamide 1.13 g of benzene 20
Add 20 ml of diethylamine to the 80 ml suspension in a sealed tube.
Heat at ~90° for 24 hours. The reaction solution was distilled off under reduced pressure,
Add water to the residue, then add dilute hydrochloric acid to adjust the pH to 3. The precipitated crystals were collected by filtration and recrystallized from dimethyl sulfoxide-methanol to give a melting point of 217-218°.
0.75 g of yellow plate crystals were obtained. Elemental analysis value C 10 H 14 N 8 O Theoretical value C, 45.80; H, 5.38; N, 42.72 Experimental value C, 45.57; H, 5.67; N, 42.84 Example 7 6-(3-methyl-1-piperidinyl) -N-
(1H-5-tetrazolyl)pyratine-2-carboxamide 6-chloro-N-(1H-5-tetrazolyl)pyratine-2-carboxamide 1.13 g benzene 20
ml suspension, add 2.9ml of 3-methylpiperidine,
Heat to reflux for 6 hours. The reaction solution was distilled off under reduced pressure, ethanol was added to the residue, and then ethanolic hydrochloric acid was added to adjust the pH to 3. The precipitated crystals were collected by filtration and recrystallized from dimethyl sulfoxide-methanol to obtain 0.81 g of pale yellow columnar crystals with a melting point of 236.5-238.5°. Elemental analysis value C 12 H 16 N 8 O Theoretical value C, 49.99; H, 5.59; N, 38.87 Experimental value C, 49.77; H, 5.77; N, 38.79 Hereinafter, Examples 1 to 7 were conducted. 8～
15 compounds are obtained. Example 8 6-(4-methyl-1-piperidinyl)-N-
(1H-5-tetrazolyl)pyratine-2-carboxamide Recrystallize from dimethylsulfoxide-methanol to obtain yellow columnar crystals with a melting point of 246.5-248.5° (decomposition). Elemental analysis value C 12 H 16 N 8 O Theoretical value C, 49.99; H, 5.59; N, 38.87 Experimental value C, 49.72; H, 5.94; N, 38.91 Example 9 6-(methylamino)-N-(1H -5-Tetrazolyl)pyratine-2-carboxamide Recrystallization from dimethylsulfoxide-methanol gives pale yellow needles with a melting point of 260° (gradual decomposition). Elemental analysis value C 7 H 8 N 8 O Theoretical value C, 38.18; H, 3.66; N, 50.89 Experimental value C, 38.16; H, 3.85; N, 51.14 Example 10 6-(ethylamino)-N-(1H -5-Tetrazolyl)pyratine-2-carboxamide Recrystallization from dimethylsulfoxide-methanol gives pale yellow needles with a melting point of 272-273.5° (decomposition). Elemental analysis value C 8 H 10 N 8 O Theoretical value C, 41.02; H, 4.30; N, 47.84 Experimental value C, 40.95; H, 4.45; N, 47.99 Example 11 6-(n-propylamino)-N- (1H-5-tetrazolyl)pyratine-2-carboxamide Recrystallization from dimethylsulfoxide-methanol gives pale yellow needles with a melting point of 278-279.5° (decomposition). Elemental analysis value C 9 H 12 N 8 O Theoretical value C, 43.54; H, 4.87; N, 45.14 Experimental value C, 43.42; H, 5.23; N, 44.91 Example 12 6-(isopropylamino)-N-(1H -5-Tetrazolyl)pyratine-2-carboxamide Recrystallization from dimethylsulfoxide-methanol gives pale yellow feathery crystals with a melting point of 272-274° (decomposition). Elemental analysis value C 9 H 12 N 8 O Theoretical value C, 43.54; H, 4.87; N, 45.14 Experimental value C, 43.51; H, 5.00; N, 45.49 Example 13 6-(3-hydroxy-1-piperidinyl) -N
-(1H-5-tetrazolyl)pyratine-2-carboxamide Recrystallization from dimethylsulfoxide-methanol gives a yellow powder with a melting point of 257-259° (decomposition). Elemental analysis value C 11 H 14 N 8 O 2 Theoretical value C, 45.51; H, 4.86; N, 38.60 Experimental value C, 45.41; H, 5.16; N, 38.42 Example 14 6-(4-hydroxy-1-piperidinyl )-N
-(1H-5-tetrazolyl)pyratine-2-carboxamide Recrystallization from dimethylsulfoxide-methanol gives a pale yellow powder with a melting point of 259.5-261° (decomposition). Elemental analysis value C 11 H 14 N 8 O 2 Theoretical value C, 45.51; H, 4.86; N, 38.60 Experimental value C, 45.35; H, 5.15; N, 38.57 Example 15 6-(4-Methyl-1-piperazinyl) )-N-
(1H-5-tetrazolyl)pyratine-2-carboxamide hydrochloride Recrystallized from dimethyl sulfoxide-methanol to obtain a pale yellow powder with a melting point of 246-250 (decomposed). Elemental analysis value C 11 H 15 N 9 O・HCl・H 2 O Theoretical value C, 38.43; H 5.28; N, 36.67 Experimental value C, 38.62; H, 5.15; N, 36.71 Example 16 6-(n- 2.26 g of ethanol
Add 4.95 ml of n-butylamine to 30 ml suspension,
Heat to reflux for an hour. The reaction solution was concentrated under reduced pressure, and water and 10% hydrochloric acid were added to the residue to adjust the pH to 3. The precipitate was collected by filtration and recrystallized from dimethylformamide-ethanol to obtain 2.00 g of pale yellow needle crystals with a melting point of 269-272° (decomposed). Elemental analysis value C 10 H 14 N 8 O Theoretical value C, 45.80; H, 5.38; N, 42.72 Experimental value C, 45.65; H, 5.53; N, 42.83 Example 17 6-(isobutylamino)-N-(1H -5-tetrazolyl)pyratine-2-carboxamide 6-chloro-N-(1H-5-tetrazolyl)pyratine-2-carboxamide 2.26 g of ethanol
Add 4.97 ml of isobutylamine to the 30 ml suspension and add 19
Heat to reflux for an hour. The reaction solution was concentrated under reduced pressure, and water and 10% hydrochloric acid were added to the residue to adjust the pH to 3. The precipitated crystals were collected by filtration and recrystallized from dimethylformamide-ethanol to obtain 2.10 g of pale yellow prism crystals with a melting point of 265-275° (decomposition). Elemental analysis value C 10 H 14 N 8 O Theoretical value C, 45.80; H, 5.38; N, 42.72 Experimental value C, 45.77; H, 5.38; N, 42.82 Example 18 6-(sec-butylamino)-N- (1H-5-tetrazolyl)pyratine-2-carboxamide 6-chloro-N-(1H-5-tetrazolyl)pyratine-2-carboxamide 2.26 g of ethanol
Add 5.05ml of sec-butylamine to the 30ml suspension,
Heat to reflux for 47 hours. The reaction solution was concentrated under reduced pressure, and water and 10% hydrochloric acid were added to the residue to adjust the pH to 3. The precipitated crystals were collected by filtration and recrystallized from dimethylformamide-ethanol to obtain 1.28 g of pale yellow needle crystals with a melting point of 265-269° (decomposition). Elemental analysis value C 10 H 14 N 8 O Theoretical value C, 45.80; H, 5.38; N, 42.72 Experimental value C, 45.54; H, 5.36; N, 42.49 Example 19 6-(tert-butylamino)-N- (1H-5-tetrazolyl)pyratine-2-carboxamide A suspension of 2.26 g of 6-chloro-N-(1H-5-tetrazolyl)pyratine-2-carboxamide in 15 ml of dimethyl sulfoxide contains 5.25 g of tert-butylamine.
ml and heat in a sealed tube at 80-90° for 41 hours. The reaction solution is made alkaline by adding water and a 10% aqueous sodium hydroxide solution, and then washed with chloroform.
After filtering the aqueous layer, add 10% hydrochloric acid to the filtrate to pH 3.
shall be. The precipitated crystals were collected by filtration and recrystallized from dimethylformamide-ethanol to give a melting point of 266-270°.
Obtain 1.07g of yellow powder (decomposition). IR spectrum ν (KBr) cm -1 : 1705 NMR spectrum δ (DMSO−d 6 ) ppm: 1.47
(9H, single line), 7.19 (1H, single line), 8.20 (1H,
Example 20 6-(1-piperazinyl)-N-(1H-5-tetrazolyl)pyratine-2-carboxamide 6-chloro-N- (1H-5-tetrazolyl)pyratine-2-carboxamide 2.26g ethanol
Add 8.61 g of anhydrous piperazine to the 50 ml suspension and heat under reflux for 22 hours. The reaction mixture is filtered, and the yellow crystals obtained are made alkaline by adding water and a 10% aqueous sodium hydroxide solution, and then washed with chloroform. Adjust the aqueous layer to pH 8 with 10% hydrochloric acid. Add water and a 10% aqueous sodium hydroxide solution to make the crystals alkaline and dissolve them, then adjust the pH to 8 with 10% hydrochloric acid. Filter the precipitated crystals and obtain 1.68g of pale yellow powder with a melting point of 300° or higher.
obtain. IR spectrum ν (KBr) cm -1 : 1690 NMR spectrum δ (CF 3 COOD) ppm: 2.70−
2.95 (4H, multiplet), 3.35−3.54 (4H, multiplet),
8.87 (1H, singlet), 8.89 (1H, singlet) Example 21 6-(4-ethyl-1-piperazinyl)-N-
(1H-5-tetrazolyl)pyratine-2-carboxamide hydrochloride 2.26 g of 6-chloro-N-(1H-5-tetrazolyl)pyratine-2-carboxamide in ethanol
Add 4.56 g of N-ethylpiperazine to the 30 ml suspension and heat under reflux for 24 hours. The reaction solution is evaporated under reduced pressure, water and a 10% aqueous sodium hydroxide solution are added to the residue to make it alkaline, and the residue is washed with chloroform. Adjust the aqueous layer to PH3 with 10% hydrochloric acid. The precipitation results were collected by filtration and recrystallized from dimethyl sulfoxide-methanol to yield a yellow powder with a melting point of 230-243° (decomposition).
Obtain 2.32g. Elemental analysis value C 12 H 17 N 9 O・HCl Theoretical value C, 42.42; H, 5.34; N, 37.10 Experimental value C, 42.59; H, 5.55; N, 36.83 Example 22 6-(4-phenyl-1- piperazinyl)-N-
(1H-5-tetrazolyl)pyratine-2-carboxamide 6-chloro-N-(1H-5-tetrazolyl)pyratine-2-carboxamide 2.26 g of ethanol
Add 4.58 ml of N-phenylpiperazine to the 30 ml suspension and heat under reflux for 17 hours. After adjusting the pH to 2 by adding ethanolic hydrochloric acid to the reaction solution, the precipitated crystals are collected by filtration. Add water and 10% hydrochloric acid to the obtained crystals to adjust the pH to 3.
shall be. The precipitation results were collected by filtration and recrystallized from dimethylformamide-ethanol to obtain a melting point of 250-262°.
Obtain 2.17 g of yellow needle-like crystals of (decomposition). Elemental analysis value C 16 H 17 N 9 O Theoretical value C, 54.69; H, 4.84; N, 35.88 Experimental value C, 54.66; H, 4.92; N, 36.02 Example 23 6-(1-homopiperazinyl)-N-( 1H-5-
6-chloro-N-(1H-5-tetrazolyl)pyratine-2-carboxamide 2.26 g of ethanol
Add 10.0 g of homopiperazine to the 50 ml suspension and heat under reflux for 23 hours. The reaction mixture is filtered, and the yellow crystals obtained are made alkaline by adding water and a 10% aqueous sodium hydroxide solution, and then washed with chloroform. Adjust the aqueous layer to pH 8 with 10% hydrochloric acid. Add water and a 10% aqueous sodium hydroxide solution to make the crystals alkaline and dissolve them, then adjust the pH to 8 with 10% hydrochloric acid. The precipitated crystals were collected by filtration to obtain 1.87 g of pale yellow powder with a melting point of 295-300° or higher (decomposed). Elemental analysis value C 11 H 15 N 9 O Theoretical value C, 45.67; H, 5.23; N, 43.57 Experimental value C, 45.37; H, 5.42; N, 43.42 Example 24 6-(4-methyl-1-homopiperazinyl) -N
-(1H-5-tetrazolyl)pyratine-2-carboxamide 6-chloro-N-(1H-5-tetrazolyl)pyratine-2-carboxamide 2.26 g of ethanol
Add 4.56 g of N-methylhomopiperazine to the 30 ml suspension and heat under reflux for 18 hours. The reaction solution was adjusted to pH 1 with ethanolic hydrochloric acid. Filter the precipitated crystals, add water and a 10% aqueous sodium hydroxide solution to the crystals to make them alkaline, and then filter. PH the filtrate with 10% hydrochloric acid
8. Add water and a 10% aqueous sodium hydroxide solution to the crystals to make them alkaline and dissolve them, then adjust the pH to 8 with 10% hydrochloric acid. Filter the precipitated crystals to obtain 1.30 g of a slightly yellow powder with a melting point of 300° or higher. Elemental analysis value C 12 H 17 N 9 O Theoretical value C, 47.52; H, 5.65; N, 41.50 Experimental value C, 47.71; H, 5.66; N, 41.32 Effect of the invention The above general formula produced in this way ( ) and its pharmacologically acceptable salts have excellent antiallergic and expectorant effects, and are effective against bronchial asthma, allergic gastrointestinal disorders, hay fever, hives, and allergic rhinitis. It is extremely useful as a therapeutic agent.
Claims (1)
原子、低級アルキル基を表わすか、又はR2及び
R3が隣接する窒素原子と共に環状アミノ基を形
成することを表わす。該環状アミノ基は環構成原
子としてヘテロ原子を含有していてもよく、又置
換基を有していてもよい。） で示されるピラチン誘導体、及びその薬理学的に
許容しうる塩。[Claims] 1. General formula (In the formula, R 1 represents a hydrogen atom or a [Formula] group. At this time, R 2 and R 3 are the same or different and represent a hydrogen atom, a lower alkyl group, or R 2 and
Indicates that R 3 forms a cyclic amino group together with the adjacent nitrogen atom. The cyclic amino group may contain a heteroatom as a ring-constituting atom, or may have a substituent. ) A pyratine derivative represented by: and a pharmacologically acceptable salt thereof.
Priority Applications (14)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29191685A JPS62153284A (en) | 1985-12-26 | 1985-12-26 | Pyrazine derivative |
| US06/941,918 US4792547A (en) | 1985-12-26 | 1986-12-15 | Pyrazine-2-carboxamide derivatives useful in treating allergic disease |
| AU66586/86A AU596624B2 (en) | 1985-12-26 | 1986-12-16 | N-(5-tetrazolyl) pyrazine-2-carboxamides and their use as anti-allergic agents |
| AT86117566T ATE52090T1 (en) | 1985-12-26 | 1986-12-17 | PYRAZIN DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THEREOF. |
| EP86117566A EP0227026B1 (en) | 1985-12-26 | 1986-12-17 | Pyrazine derivative, a process for preparation thereof and pharmaceutical composition therefrom |
| ES198686117566T ES2029791T3 (en) | 1985-12-26 | 1986-12-17 | A PROCEDURE FOR THE PREPARATION OF PIRAZINE DERIVATIVES. |
| DE8686117566T DE3670491D1 (en) | 1985-12-26 | 1986-12-17 | PYRAZINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS WITH THESE. |
| CA000525801A CA1293251C (en) | 1985-12-26 | 1986-12-18 | Pyrazine derivative, a process for preparation thereof and pharmaceutical composition therefrom |
| ZA869515A ZA869515B (en) | 1985-12-26 | 1986-12-18 | Pyrazine derivative,a process for preparation thereof and pharmaceutical composition therefrom |
| YU218986A YU46037B (en) | 1985-12-26 | 1986-12-19 | PROCEDURE FOR OBTAINING NEW PYRAZINE DERIVATIVES |
| KR860010990A KR870006043A (en) | 1985-12-26 | 1986-12-20 | Pyrazine derivatives manufacturing method and pharmaceutical composition |
| HU865380A HU197001B (en) | 1985-12-26 | 1986-12-22 | Process for producing new pyrazine derivatives and pharmaceuticals comprising same |
| FI865251A FI865251A (en) | 1985-12-26 | 1986-12-22 | PYRAZINDERIVAT, FOERFARANDE FOER DESS FRAMSTAELLNING OCH DESS FARMACEUTISK BLANDNING. |
| DK628086A DK628086A (en) | 1985-12-26 | 1986-12-23 | PYRAZINE DERIVATIVES AND PHARMACEUTICAL ACCEPTABLE SALTS AND PROCEDURES FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITION CONTAINING SAME |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29191685A JPS62153284A (en) | 1985-12-26 | 1985-12-26 | Pyrazine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62153284A JPS62153284A (en) | 1987-07-08 |
| JPH0378864B2 true JPH0378864B2 (en) | 1991-12-17 |
Family
ID=17775115
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP29191685A Granted JPS62153284A (en) | 1985-12-26 | 1985-12-26 | Pyrazine derivative |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS62153284A (en) |
| ZA (1) | ZA869515B (en) |
-
1985
- 1985-12-26 JP JP29191685A patent/JPS62153284A/en active Granted
-
1986
- 1986-12-18 ZA ZA869515A patent/ZA869515B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA869515B (en) | 1987-08-26 |
| JPS62153284A (en) | 1987-07-08 |
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