JPS6330900B2 - - Google Patents
Info
- Publication number
- JPS6330900B2 JPS6330900B2 JP6475982A JP6475982A JPS6330900B2 JP S6330900 B2 JPS6330900 B2 JP S6330900B2 JP 6475982 A JP6475982 A JP 6475982A JP 6475982 A JP6475982 A JP 6475982A JP S6330900 B2 JPS6330900 B2 JP S6330900B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- iodopropargyl
- weight
- cch
- 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
- -1 iodopropargyl compound Chemical class 0.000 claims description 22
- 150000003536 tetrazoles Chemical class 0.000 claims description 13
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 8
- 229940121375 antifungal agent Drugs 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- JHUPGXNKUPOSIE-UHFFFAOYSA-N 1-iodoprop-1-yne Chemical class CC#CI JHUPGXNKUPOSIE-UHFFFAOYSA-N 0.000 claims description 4
- 239000003429 antifungal agent Substances 0.000 claims description 4
- 150000003852 triazoles Chemical class 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000001425 triazolyl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 150000003459 sulfonic acid esters Chemical class 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 230000000843 anti-fungal effect Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- GILKVTZWTVOGJV-UHFFFAOYSA-N 1-iodoprop-2-yn-1-ol Chemical compound OC(I)C#C GILKVTZWTVOGJV-UHFFFAOYSA-N 0.000 description 4
- 241000233866 Fungi Species 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000004927 clay Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 150000001346 alkyl aryl ethers Chemical class 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 2
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000009422 growth inhibiting effect Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003973 paint Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 241000223238 Trichophyton Species 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229920005551 calcium lignosulfonate Polymers 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- RYAGRZNBULDMBW-UHFFFAOYSA-L calcium;3-(2-hydroxy-3-methoxyphenyl)-2-[2-methoxy-4-(3-sulfonatopropyl)phenoxy]propane-1-sulfonate Chemical compound [Ca+2].COC1=CC=CC(CC(CS([O-])(=O)=O)OC=2C(=CC(CCCS([O-])(=O)=O)=CC=2)OC)=C1O RYAGRZNBULDMBW-UHFFFAOYSA-L 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- BIWJNBZANLAXMG-YQELWRJZSA-N chloordaan Chemical compound ClC1=C(Cl)[C@@]2(Cl)C3CC(Cl)C(Cl)C3[C@]1(Cl)C2(Cl)Cl BIWJNBZANLAXMG-YQELWRJZSA-N 0.000 description 1
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229910052570 clay Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000002563 ionic surfactant Substances 0.000 description 1
- 239000003621 irrigation water Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- CDHAYBUDIPNGGJ-UHFFFAOYSA-N pyrrolomycin A Chemical compound [O-][N+](=O)C1=CNC(Cl)=C1Cl CDHAYBUDIPNGGJ-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 239000004563 wettable powder Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
本発明は、一般式():
IC≡CCH2X ()
〔式中、Xはピラゾリル基、トリアゾリル基、
特に1,2,4−トリアゾリル基又はテトラゾリ
ル基を表わす〕で示されるヨードプロパルギル誘
導体、その製造法及びそれらを有効成分として含
有する抗カビ剤に関するものである。
本発明者らはすでに、抗カビ抗生物質ピロロマ
イシンA(特願昭54−166926号明細書)に端を発
した抗カビ物質に関する基礎的な研究から置換ピ
ロール核を有するヨードプロパルギル化合物が有
用であることを見い出した(特願昭57−6609号明
細書)。さらに本発明者らは、これら物質の改良
を目的として種々の類似化合物を合成し、それら
の抗菌活性を検討して本発明に到達した。本発明
によつて提供される上記式()のヨードプロパ
ルギル化合物は顕著な殺菌活性、特に抗真菌活性
を示す有用物質である。
本発明のヨードプロパルギル化合物()は、
ピラゾール、トリアゾール又はテトラゾールに、
不活性溶媒中塩基の存在下で、式():
IC≡CCH2Y ()
(式中、Yはハロゲン原子もしくはスルホン酸
エステルとして活性化された水酸基を表わす)で
示されるヨードプロピン誘導体を反応させて製造
される。
本発明の製造に際し使用される原料物質のう
ち、ヨードプロピン誘導体()は公知の化合物
であり、例えばヨードプロパルギルアルコールに
塩化チオニル又は臭化チオニルのごときハロゲン
化剤を反応させてヨードプロパルギルハライドと
するか、あるいはトルエンスルホニルクロリド、
ベンゼンスルホニルクロリド又は無水メタンスル
ホン酸のようなエステル化剤を反応させてヨード
プロパルギルアルコール・スルホネートとして得
られるものである。さらに本発明の化合物の製造
に使用される他方の原料物質であるピラゾール,
トリアゾール及びテトラゾールはよく知られた化
合物で、すでに市販に供されているものであり容
易に入手可能である。
本発明によれば、式()で示されるヨードプ
ロパルギル化合物は、ピラゾール,トリアゾール
又はテトラゾールを不活性溶媒に溶解し、式
()で示されるヨードプロピン誘導体及び塩基
を添加してピラゾール,トリアゾール又はテトラ
ゾールの環窒素原子上にヨードプロパルギル基を
導入するN−アルキル化反応により製造される。
本反応に用いられる不活性溶媒の例としては、ベ
ンゼン,ジオキサン,ジクロルメタン,N,N−
ジメチルホルムアミド等があげられ、特にN,N
−ジメチルホルムアミドが好ましい。また反応に
用いられる塩基の例としては水酸化アルカリ,炭
酸アルカリ等の無機塩基の他、有機塩基、例えば
トリエチルアミン等が使用される。反応は水酸化
アルカリの使用にあたつては室温で速やかに進行
するが、副反応防止の目的で冷却下、好ましくは
0〜5℃で行なわせるか、あるいは有機塩基を使
用して40〜60℃に加温して行なうこともできる。
反応混合物からの目的物である式()で示され
るヨードプロパルギル化合物の単離は、不活性溶
媒、例えば水等の添加による晶出法又は有機溶
媒、例えばトルエン、酢酸エチル等を用いる抽出
法、あるいはそれらに必要に応じて周知の精製方
法、例えばシリカゲルを用いたクロマトグラフイ
ー又は有機溶媒による再結晶法を併用して行なわ
れる。
本発明による新規ヨードプロパルギル化合物
()の製造の実際を、以下実施例によつて説明
する。
実施例 1
1−(1′−ヨードプロピン−3′−イル)ピラゾ
ール〔化合物(1)〕
ピラゾール136mg(2ミリモル)をジメチルホ
ルムアミド5mlに溶解し、水酸化ナトリウム粉末
90mgを加え、20〜25℃でよくかきまぜたのち氷冷
した。ヨードプロパルギルアルコール・p−トル
エンスルホン酸エステル0.67g(2ミリモル)を
加え、2時間かきまぜたのち、20〜25℃で一夜放
置した。酢酸エチル及び水を加えて反応液を抽出
し、酢酸エチル層を水洗、乾燥後、減圧濃縮する
と結晶性物質が残留した。これをシリカゲルクロ
マトグラフイー(溶媒系ベンゼン/酢酸エチル=
10/1)で精製し、1−(1′−ヨードプロピン−
3′−イル)ピラゾール結晶330mgを得た。mp.94〜
95℃。元素分析値:C31.73%,H2.20%,N12.61
%;C6H5N2Iとしての計算値:C31.03%,H2.16
%,N12.60%。
実施例 2
1−(1′−ヨードプロピン−3′−イル)−1,
2,4−トリアゾール〔化合物(2)〕
1,2,4−トリアゾール160mg(2.3ミリモ
ル)にジメチルホルムアミド3ml及び水酸化ナト
リウム粉末90mgを加えて20〜25℃で1時間かきま
ぜたのち、氷冷した。反応液にヨードプロパルギ
ルアルコール・p−トルエンスルホン酸エステル
0.67g(2ミリモル)を加え、4時間かきまぜる
と共に液温を徐々に室温まで上昇させた。反応液
に水20mlを加え、酢酸エチル20mlで2回抽出し、
合併した酢酸エチル溶液を飽和食塩水で3回洗
い、乾燥した。酢酸エチル溶液を減圧下に濃縮
し、残留した結晶性物質を少量の水−メタノール
混液で洗い、1−(1′−ヨードプロピン−3′−イ
ル)−1,2,4−トリアゾール結晶を得た。収
量263mg(56%);mp・126〜128℃;元素分析
値:C25.87%,H1.73%,N18.33%;C5H4N3Iと
しての計算値:C25.77%,H1.73%,N18.03%。
実施例 3
1−(1′−ヨードプロピン−3′−イル)テトラ
ゾール〔化合物(3)〕及び2−(1′−ヨードプロ
ピン−3′−イル)テトラゾール〔化合物(4)〕
テトラゾール160mg(2ミリモル)をジメチル
ホルムアミド5mlに溶解し、水酸化ナトリウム粉
末90mgを加えてかきまぜたのち氷冷した。ヨード
プロパルギルアルコール・p−トルエンスルホン
酸エステル0.67g(2ミリモル)を加え、氷冷下
に4時間反応させ、更に20〜25℃で一夜放置し
た。反応液に水20mlを加え、酢酸エチル20mlで2
回抽出した。酢酸エチル層を合併し、水洗、乾燥
後、減圧濃縮すると無色の粗生成物が残留した。
粗生成物はシリカゲル薄層クロマトグラフイー
(溶媒系ベンゼン−酢酸エチル4:1比)でRf値
0.74及び0.34を示す二種の物質の混合物であるこ
とが示された。混合物をシリカゲル50gを用いた
カラムクロマトグラフイー(溶媒系ベンゼン−酢
酸エチル5:1比)で分離精製し、Rf値0.74を示
す分画から2−(1′−ヨードプロピン−3′−イル)
テトラゾール結晶183mgが得られた(収率39%)。
mp.92〜95℃;元素分析値:C20.27%,H1.30%,
N23.88%;C4H3N4Iとしての計算値:C20.53%,
H1.29%,N23.94%;PMRスペクトル(δ,
CDCl3)5.50ppm(−CH2−),8.45ppm(テトラゾ
ールCH)。
Rf値0.34の分画からは1−(1′−ヨードプロピ
ン−3′−イル)テトラゾール結晶258mgが得られ
た(収率55%)。mp.92〜95℃;元素分析値:
C20.62%,H1.26%,N23.96%;C4H3N4Iとして
の計算値:C20.53%,H1.29%,N23.94%;
PMRスペクトル(δ,CDCl3)5.30ppm(CH2
−),8.66ppm(テトラゾールCH)。
実施例1〜3において製造された式()で示
される化合物(1)〜(4)の抗カビ活性を表1及び表2
に示す。
The present invention is based on the general formula (): IC≡CCH 2 X () [wherein, X is a pyrazolyl group, a triazolyl group,
In particular, the present invention relates to iodopropargyl derivatives represented by 1,2,4-triazolyl group or tetrazolyl group, a method for producing the same, and an antifungal agent containing them as active ingredients. The present inventors have already discovered that iodopropargyl compounds having a substituted pyrrole nucleus are useful based on basic research on antifungal substances that began with the antifungal antibiotic pyrrolomycin A (Japanese Patent Application No. 166,926/1982). I discovered something (Japanese Patent Application No. 57-6609). Furthermore, the present inventors synthesized various similar compounds for the purpose of improving these substances, examined their antibacterial activity, and arrived at the present invention. The iodopropargyl compound of the above formula () provided by the present invention is a useful substance exhibiting remarkable bactericidal activity, particularly antifungal activity. The iodopropargyl compound () of the present invention is
to pyrazole, triazole or tetrazole,
In the presence of a base in an inert solvent, an iodopropyne derivative represented by the formula (): IC≡CCH 2 Y () (wherein Y represents a halogen atom or a hydroxyl group activated as a sulfonic acid ester) is reacted. Manufactured by Among the raw materials used in the production of the present invention, the iodopropyne derivative () is a known compound. , or toluenesulfonyl chloride,
It is obtained as iodopropargyl alcohol sulfonate by reacting it with an esterifying agent such as benzenesulfonyl chloride or methanesulfonic anhydride. Furthermore, pyrazole, which is the other raw material used in the production of the compound of the present invention,
Triazoles and tetrazoles are well-known compounds, already commercially available, and readily available. According to the present invention, the iodopropargyl compound represented by the formula () is prepared by dissolving the pyrazole, triazole or tetrazole in an inert solvent, and adding the iodopropyne derivative represented by the formula () and a base. It is produced by an N-alkylation reaction that introduces an iodopropargyl group onto the ring nitrogen atom.
Examples of inert solvents used in this reaction include benzene, dioxane, dichloromethane, N,N-
Examples include dimethylformamide, especially N,N
-dimethylformamide is preferred. Examples of bases used in the reaction include inorganic bases such as alkali hydroxides and alkali carbonates, as well as organic bases such as triethylamine. When using an alkali hydroxide, the reaction proceeds rapidly at room temperature, but in order to prevent side reactions, it may be carried out under cooling, preferably at 0 to 5°C, or by using an organic base at a temperature of 40 to 60°C. It can also be carried out by heating to ℃.
The target iodopropargyl compound represented by the formula () can be isolated from the reaction mixture by a crystallization method by adding an inert solvent, such as water, or an extraction method using an organic solvent, such as toluene, ethyl acetate, etc. Alternatively, if necessary, well-known purification methods such as chromatography using silica gel or recrystallization using an organic solvent may be used in combination. The actual production of the novel iodopropargyl compound () according to the present invention will be explained below with reference to Examples. Example 1 1-(1'-Iodopropyn-3'-yl)pyrazole [Compound (1)] 136 mg (2 mmol) of pyrazole was dissolved in 5 ml of dimethylformamide, and sodium hydroxide powder was added.
90 mg was added, stirred well at 20-25°C, and then cooled on ice. After adding 0.67 g (2 mmol) of iodopropargyl alcohol/p-toluenesulfonic acid ester and stirring for 2 hours, the mixture was left at 20 to 25°C overnight. Ethyl acetate and water were added to extract the reaction solution, and the ethyl acetate layer was washed with water, dried, and concentrated under reduced pressure, leaving a crystalline substance. This was subjected to silica gel chromatography (solvent system benzene/ethyl acetate =
10/1) and purified with 1-(1'-iodopropyne-
330 mg of 3'-yl)pyrazole crystals were obtained. mp.94~
95℃. Elemental analysis values: C31.73%, H2.20%, N12.61
%; Calculated value as C 6 H 5 N 2 I: C31.03%, H2.16
%, N12.60%. Example 2 1-(1'-iodopropyn-3'-yl)-1,
2,4-Triazole [Compound (2)] 160 mg (2.3 mmol) of 1,2,4-triazole was added with 3 ml of dimethylformamide and 90 mg of sodium hydroxide powder, stirred at 20-25°C for 1 hour, and then cooled on ice. . Iodopropargyl alcohol/p-toluenesulfonic acid ester in the reaction solution
0.67 g (2 mmol) was added and stirred for 4 hours while the temperature of the solution was gradually raised to room temperature. Add 20 ml of water to the reaction solution, extract twice with 20 ml of ethyl acetate,
The combined ethyl acetate solutions were washed three times with saturated brine and dried. The ethyl acetate solution was concentrated under reduced pressure, and the remaining crystalline material was washed with a small amount of water-methanol mixture to obtain 1-(1'-iodopropyn-3'-yl)-1,2,4-triazole crystals. . Yield 263mg (56%); mp・126-128℃; Elemental analysis values: C25.87%, H1.73%, N18.33 %; Calculated value as C5H4N3I : C25.77%, H1.73%, N18.03%. Example 3 1-(1'-iodopropyn-3'-yl)tetrazole [compound (3)] and 2-(1'-iodopropyn-3'-yl)tetrazole [compound (4)] Tetrazole 160 mg (2 mmol) was dissolved in 5 ml of dimethylformamide, 90 mg of sodium hydroxide powder was added, stirred, and cooled on ice. 0.67 g (2 mmol) of iodopropargyl alcohol/p-toluenesulfonic acid ester was added, and the mixture was allowed to react for 4 hours under ice-cooling, and then left overnight at 20 to 25°C. Add 20 ml of water to the reaction solution and dilute with 20 ml of ethyl acetate.
Extracted twice. The ethyl acetate layers were combined, washed with water, dried, and concentrated under reduced pressure to leave a colorless crude product.
The Rf value of the crude product was determined by silica gel thin layer chromatography (solvent system: benzene-ethyl acetate 4:1 ratio).
It was shown to be a mixture of two substances showing values of 0.74 and 0.34. The mixture was separated and purified by column chromatography using 50 g of silica gel (solvent system: benzene-ethyl acetate 5:1 ratio), and 2-(1'-iodopropyn-3'-yl) was extracted from the fraction showing an Rf value of 0.74.
183 mg of tetrazole crystals were obtained (yield 39%).
mp.92~95℃; Elemental analysis value: C20.27%, H1.30%,
N23.88%; Calculated value as C 4 H 3 N 4 I: C20.53%,
H1.29%, N23.94%; PMR spectrum (δ,
CDCl3 ) 5.50ppm ( -CH2- ), 8.45ppm (tetrazole CH). From the fraction with an Rf value of 0.34, 258 mg of 1-(1'-iodopropyn-3'-yl)tetrazole crystals were obtained (yield 55%). mp.92~95℃; Elemental analysis value:
C20.62%, H1.26%, N23.96%; Calculated values as C 4 H 3 N 4 I: C20.53%, H1.29%, N23.94%;
PMR spectrum (δ, CDCl 3 ) 5.30ppm (CH 2
-), 8.66ppm (tetrazole CH). Tables 1 and 2 show the antifungal activities of compounds (1) to (4) represented by formulas () produced in Examples 1 to 3.
Shown below.
【表】【table】
【表】【table】
【表】
本発明の前記式()で示される新規なヨード
プロパルギル化合物は抗カビ剤として有用であ
る。特に本発明の化合物は広範囲のカビ類に対し
て発育阻止作用を示すところから、医療を始めと
し、農業及び工業の各分野において、細菌及びカ
ビ類の生育に起因する好ましからざる諸条件の改
善に役立つものである。すなわち、医療用には例
えばキヤンデイダ属,アスペルギルス属,トリコ
フイトン属,クリプトコツカス属を始めとするカ
ビ類に起因する外部疾患の治療薬として、液剤及
び軟膏の有効成分として0.1〜5%、好ましくは
0.5〜2%の範囲で配合し、患部に塗布して治療
の目的を達することができる。更にその他、医療
用として病原菌、カビ類の生育を予防し、無菌環
境を保全する目的で、機械器具の消毒剤、その他
の有効成分として含有させることができる。
更に本発明の式()で示されるヨードプロパ
ルギル化合物は、農業及び工業用の分野について
も有用性を示すものである。特にこれら分野で
は、例えば種子,苗,木材,農園芸作物及び木工
品,紙工芸品,皮革,繊維,接着剤,塗料,合成
樹脂等の農業、工業用製品及びその製造環境、例
えば用水における腐敗菌、カビの発生は商品の価
値にとつて重大な損失を招くものである。本発明
のヨードプロパルギル化合物は、農業及び工業の
分野における有害な細菌、カビ類に対して発育阻
止作用を示すところからそれら分野における製品
の品質保持及び環境の保全の目的に供することが
できる。
農業、工業分野における本発明のヨードプロパ
ルギル化合物の使用形態としては通常用いられる
担体上に保持した製剤、即ち油溶剤、乳剤、ペー
スト剤、粉剤、水和剤、エアゾール剤、防カビ性
塗料等があげられる。用いられる担体としては、
例えばクレー,タルク,ベントナイト,カオリ
ン,無水珪酸,炭酸カルシウム等の無機性固体担
体,チロシン,リグロイン,キシレン,DMF,
DMSO等の有機溶媒系担体、ジメチルエーテル,
フロンガス等のガス担体があげられ、製剤効果を
より高めるための補助剤としては、イオン性、非
イオン性の界面活性剤、並びに酢酸ビニル,メチ
ルセルロース等の高分子化合物等があり、サイア
ベンダゾールを始めとする他の防腐、防カビ剤や
クロルデン等の殺虫剤との併用も可能である。
実際の使用に際しての本発明のヨードプロパル
ギル化合物の含量は製剤形態に従つて、広範囲に
変動し得るが、一般には0.01〜95重量%、好まし
くは0.2〜10重量%の範囲が適当である。農業及
び工業用抗カビ剤としての製剤例を以下にあげ
る。
製剤例1 水和剤
1−(1′−ヨードプロピン−3′−イル)ピラゾ
ール40重量部とポリオキシエチレンアルキルアリ
ールエーテル5重量部、リグニンスルホン酸3重
量部および珪藻土52重量部を均一に粉砕混合すれ
ば有効成分40%を含む水和剤を得る。
製剤例2 粒剤
1−(1′−ヨードプロピン−3′−イル)−1,
2,4−トリアゾール12重量部、リグニンスルホ
ン酸カルシウム1重量部、ベントナイト30重量部
およびクレー57重量部を均一に粉砕混合し、次に
適当量の水を加えて練合した後に造粒して乾燥す
れば有効成分12%を含む粒剤を得る。
製剤例3 乳剤
1−(1′−ヨードプロピン−3′−イル)テトラ
ゾール20重量部、ジメチルホルムアミド30重量
部、キシレン35重量部、ポリオキシエチレンアル
キルアリールエーテル15重量部を均一に混合すれ
ば有効成分20%を含む乳剤を得る。
製剤例4 粉剤
2−(1′−ヨードプロピン−3′−イル)テトラ
ゾール3重量部、無水珪酸微粉末0.5重量部、ス
テアリン酸カルシウム0.5重量部、クレー50重量
部およびタルク46重量部を均一に粉砕、混合すれ
ば有効成分3%を含む粉剤を得る。[Table] The novel iodopropargyl compound of the present invention represented by the above formula () is useful as an antifungal agent. In particular, the compound of the present invention exhibits a growth-inhibiting effect on a wide range of fungi, so it can be used in various fields of medicine, agriculture, and industry to improve unfavorable conditions caused by the growth of bacteria and fungi. It's useful. That is, for medical use, for example, as a therapeutic agent for external diseases caused by fungi such as Candida, Aspergillus, Trichophyton, and Cryptococcus, it is preferably 0.1 to 5% as an active ingredient in liquid preparations and ointments.
It can be mixed in a range of 0.5 to 2% and applied to the affected area to achieve the therapeutic goal. Furthermore, for medical purposes, it can be included as a disinfectant for machinery and equipment and other active ingredients for the purpose of preventing the growth of pathogenic bacteria and molds and maintaining a sterile environment. Furthermore, the iodopropargyl compound represented by formula () of the present invention also shows usefulness in the agricultural and industrial fields. In particular, in these fields, agricultural and industrial products such as seeds, seedlings, wood, agricultural and horticultural crops, woodwork products, paper crafts, leather, fibers, adhesives, paints, and synthetic resins, as well as their manufacturing environments, such as spoilage in irrigation water, are particularly important. The growth of bacteria and mold causes a serious loss in the value of products. Since the iodopropargyl compound of the present invention exhibits a growth inhibiting effect on harmful bacteria and fungi in the agricultural and industrial fields, it can be used for the purpose of maintaining the quality of products in these fields and preserving the environment. In the agricultural and industrial fields, the iodopropargyl compound of the present invention can be used in formulations supported on commonly used carriers, such as oil solvents, emulsions, pastes, powders, wettable powders, aerosols, and antifungal paints. can give. The carrier used is
For example, inorganic solid carriers such as clay, talc, bentonite, kaolin, silicic anhydride, calcium carbonate, tyrosine, ligroin, xylene, DMF,
Organic solvent carriers such as DMSO, dimethyl ether,
Examples include gas carriers such as chlorofluorocarbon gas, and auxiliary agents to further enhance formulation effects include ionic and nonionic surfactants, and polymeric compounds such as vinyl acetate and methyl cellulose. It is also possible to use it in combination with other preservatives and fungicides, and insecticides such as chlordane. The content of the iodopropargyl compound of the present invention in actual use may vary widely depending on the formulation, but is generally in the range of 0.01 to 95% by weight, preferably 0.2 to 10% by weight. Examples of formulations as agricultural and industrial antifungal agents are listed below. Formulation Example 1 Wettable powder 40 parts by weight of 1-(1'-iodopropyn-3'-yl)pyrazole, 5 parts by weight of polyoxyethylene alkylaryl ether, 3 parts by weight of lignin sulfonic acid, and 52 parts by weight of diatomaceous earth are uniformly ground and mixed. Then you will get a hydrating powder containing 40% of the active ingredient. Formulation Example 2 Granules 1-(1'-iodopropyn-3'-yl)-1,
12 parts by weight of 2,4-triazole, 1 part by weight of calcium lignosulfonate, 30 parts by weight of bentonite and 57 parts by weight of clay are uniformly ground and mixed, then an appropriate amount of water is added and kneaded, followed by granulation. When dried, granules containing 12% of the active ingredient are obtained. Formulation Example 3 Emulsion 20 parts by weight of 1-(1'-iodopropyn-3'-yl)tetrazole, 30 parts by weight of dimethylformamide, 35 parts by weight of xylene, and 15 parts by weight of polyoxyethylene alkylaryl ether are uniformly mixed to form the active ingredient. An emulsion containing 20% is obtained. Formulation Example 4 Powder 3 parts by weight of 2-(1'-iodopropyn-3'-yl)tetrazole, 0.5 parts by weight of silicic anhydride fine powder, 0.5 parts by weight of calcium stearate, 50 parts by weight of clay and 46 parts by weight of talc were uniformly ground; When mixed, a powder containing 3% of the active ingredient is obtained.
Claims (1)
はテトラゾリル基を表わす〕で示されるヨードプ
ロパルギル化合物。 2 ピラゾール、トリアゾール又はテトラゾール
に、式(): IC≡CCH2Y () (式中、Yはハロゲン原子又はスルホン酸エス
テルとして活性化された水酸基を表わす)で示さ
れるヨードプロピン誘導体を反応させることを特
徴とする式(): IC≡CCH2X () (式中、Xはピラゾリル基、トリアゾリル基又
はテトラゾリル基を表わす)で示されるヨードプ
ロパルギル化合物の製造法。 3 式(): IC≡CCH2X () (式中、Xはピラゾリル基、トリアゾリル基又
はテトラゾリル基を表わす)で示されるヨードプ
ロパルギル化合物を有効成分とする抗カビ剤。[Claims] 1. An iodopropargyl compound represented by the formula (): IC≡CCH 2 X () [wherein X represents a pyrazolyl group, a triazolyl group, or a tetrazolyl group]. 2. Reacting pyrazole, triazole or tetrazole with an iodopropyne derivative represented by the formula (): IC≡CCH 2 Y () (wherein Y represents a halogen atom or a hydroxyl group activated as a sulfonic acid ester). A method for producing an iodopropargyl compound represented by the characteristic formula (): IC≡CCH 2 X () (wherein X represents a pyrazolyl group, a triazolyl group, or a tetrazolyl group). 3. An antifungal agent containing as an active ingredient an iodopropargyl compound represented by the formula (): IC≡CCH 2
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP6475982A JPS58183672A (en) | 1982-04-20 | 1982-04-20 | Iodopropargyl compound, its preparation and antifungal agent containing said compound as active component |
DE8282109236T DE3268983D1 (en) | 1981-10-07 | 1982-10-06 | Heterocyclic compounds and antibacterial and antifungal compositions containing the same as active ingredients |
EP19820109236 EP0080051B1 (en) | 1981-10-07 | 1982-10-06 | Heterocyclic compounds and antibacterial and antifungal compositions containing the same as active ingredients |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP6475982A JPS58183672A (en) | 1982-04-20 | 1982-04-20 | Iodopropargyl compound, its preparation and antifungal agent containing said compound as active component |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS58183672A JPS58183672A (en) | 1983-10-26 |
JPS6330900B2 true JPS6330900B2 (en) | 1988-06-21 |
Family
ID=13267421
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP6475982A Granted JPS58183672A (en) | 1981-10-07 | 1982-04-20 | Iodopropargyl compound, its preparation and antifungal agent containing said compound as active component |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS58183672A (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5980667A (en) * | 1982-10-29 | 1984-05-10 | Meiji Seika Kaisha Ltd | Tetrazole compound, its preparation and antimicrobial and antifungal agent containing the same as active constituent |
DE102004037366A1 (en) * | 2004-07-30 | 2006-03-23 | Lanxess Deutschland Gmbh | 5-iodotetrazoles |
-
1982
- 1982-04-20 JP JP6475982A patent/JPS58183672A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS58183672A (en) | 1983-10-26 |
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