JPH0434553B2 - - Google Patents
Info
- Publication number
- JPH0434553B2 JPH0434553B2 JP8078383A JP8078383A JPH0434553B2 JP H0434553 B2 JPH0434553 B2 JP H0434553B2 JP 8078383 A JP8078383 A JP 8078383A JP 8078383 A JP8078383 A JP 8078383A JP H0434553 B2 JPH0434553 B2 JP H0434553B2
- Authority
- JP
- Japan
- Prior art keywords
- ketone
- benzofuranyl
- bis
- bisbenzofuranyl
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- -1 7-methoxy-2-benzofuranyl Chemical group 0.000 claims description 47
- 150000002576 ketones Chemical class 0.000 claims description 46
- ZLYFWIZGRHGKMM-UHFFFAOYSA-N bis(1-benzofuran-2-yl)methanone Chemical class C1=CC=C2OC(C(C=3OC4=CC=CC=C4C=3)=O)=CC2=C1 ZLYFWIZGRHGKMM-UHFFFAOYSA-N 0.000 claims description 26
- 238000004519 manufacturing process Methods 0.000 claims description 25
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- RMZPEAFTFQMIEY-UHFFFAOYSA-N bis(6-hydroxy-1-benzofuran-2-yl)methanone Chemical compound C1=C(O)C=C2OC(C(=O)C3=CC4=CC=C(C=C4O3)O)=CC2=C1 RMZPEAFTFQMIEY-UHFFFAOYSA-N 0.000 claims description 9
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 60
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 238000000921 elemental analysis Methods 0.000 description 24
- 238000000862 absorption spectrum Methods 0.000 description 23
- 125000003118 aryl group Chemical group 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000002844 melting Methods 0.000 description 15
- 230000008018 melting Effects 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000010992 reflux Methods 0.000 description 13
- 239000002244 precipitate Substances 0.000 description 12
- 239000013078 crystal Substances 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 10
- NJKZFKQLDOVFGO-UHFFFAOYSA-N bis(7-methoxy-1-benzofuran-2-yl)methanone Chemical compound C1=CC(OC)=C2OC(C(=O)C3=CC=4C=CC=C(C=4O3)OC)=CC2=C1 NJKZFKQLDOVFGO-UHFFFAOYSA-N 0.000 description 10
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 8
- YJWAGWZPHAIDKY-UHFFFAOYSA-N bis(7-hydroxy-1-benzofuran-2-yl)methanone Chemical compound C1=CC(O)=C2OC(C(=O)C3=CC=4C=CC=C(C=4O3)O)=CC2=C1 YJWAGWZPHAIDKY-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- GLWSZUBTLXLVPC-UHFFFAOYSA-N bis(6-methoxy-1-benzofuran-2-yl)methanone Chemical compound C1=C(OC)C=C2OC(C(=O)C3=CC4=CC=C(C=C4O3)OC)=CC2=C1 GLWSZUBTLXLVPC-UHFFFAOYSA-N 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- SUNMBRGCANLOEG-UHFFFAOYSA-N 1,3-dichloroacetone Chemical compound ClCC(=O)CCl SUNMBRGCANLOEG-UHFFFAOYSA-N 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000287828 Gallus gallus Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000006900 dealkylation reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- JJVNINGBHGBWJH-UHFFFAOYSA-N ortho-vanillin Chemical compound COC1=CC=CC(C=O)=C1O JJVNINGBHGBWJH-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- YMDNODNLFSHHCV-UHFFFAOYSA-N 2-chloro-n,n-diethylethanamine Chemical compound CCN(CC)CCCl YMDNODNLFSHHCV-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- 239000003377 acid catalyst Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- OTXHZHQQWQTQMW-UHFFFAOYSA-N (diaminomethylideneamino)azanium;hydrogen carbonate Chemical compound OC([O-])=O.N[NH2+]C(N)=N OTXHZHQQWQTQMW-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- ONAOBFWXMNPKEQ-UHFFFAOYSA-N 2-methylperoxybenzaldehyde Chemical compound COOC1=CC=CC=C1C=O ONAOBFWXMNPKEQ-UHFFFAOYSA-N 0.000 description 1
- SOCNCJJCXYBPRJ-UHFFFAOYSA-N 4-hydroxy-3-(3-oxo-1h-2-benzofuran-1-yl)chromen-2-one Chemical compound C1=CC=CC2=C1OC(=O)C(C1C3=CC=CC=C3C(=O)O1)=C2O SOCNCJJCXYBPRJ-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 230000020335 dealkylation Effects 0.000 description 1
- 229940117389 dichlorobenzene Drugs 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
- 235000013601 eggs Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- VYSYZMNJHYOXGN-UHFFFAOYSA-N ethyl n-aminocarbamate Chemical compound CCOC(=O)NN VYSYZMNJHYOXGN-UHFFFAOYSA-N 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 230000035931 haemagglutination Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 208000037797 influenza A Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 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
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
Landscapes
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は新規なビスベンゾフラニルケトン誘導
体、さらに詳しくは一般式()
〔式中、Rは−NHC(NH)NH2、−
NHCOOCH2CH3、−OH基または−NHCSNH2、
R1は水素または−SO3H、R2は水素、炭素数1〜
3個の低級アルキル基、または式
(式中、mは1〜3の整数、R3およびR4はそれ
ぞれ炭素数1〜3個の低級アルキル基を表わす)
で示される置換アミノアルキル基を表わし、R1
基およびOR2基はベンゾブラン環の4、5、6ま
たは7位の任意の位置に置換している〕で示され
るビスベンゾフラニルケトン誘導体およびその塩
ならびにそれらの製法に関する。
本発明の化合物はそれ自身抗ウイルス作用を有
し、医薬として有用である。すぐれた抗ウイルス
作用を有する点で、ビス(6−ヒドロキシ−2−
ベンゾフラニル)ケトングアニルヒドラゾン、ビ
ス(7−メトキシ−2−ベンゾフラニル)ケトン
グアニルヒドラゾン、ビス(6−メトキシ−2−
ベンゾフラニル)ケトングアニルヒドラゾン、ビ
ス(6−ヒドロキシ−2−ベンゾフラニル)ケト
ンチオセミカルバゾン、ビス(7−β−ジエチル
アミノエトキシ−2−ベンゾフラニル)ケトング
アニルヒドラゾン、ビス(6−β−ジエチルアミ
ノエトキシ−2−ベンゾフラニル)ケトングアニ
ルヒドラゾンなどのビスベンゾフラニルケトン誘
導体およびそれらの塩が好ましい。
本発明のビスベンゾフラニルケトン誘導体
()は一般式()
〔式中、R1は水素または−SO3H、R2は水素、炭
素数1〜3個の低級アルキル基または式
(式中、mは1〜3の整数、R3およびR4はそれ
ぞれ炭素数1〜3個の低級アルキル基を表わす)
で示される置換アミノアルキル基を表わし、R1
基およびOR2基はベンゾフラン環の4、5、6ま
たは7位の任意の位置に置換している〕で示され
るビスベンゾフラニルケトン化合物を一般式
()
R−NH2 ()
〔式中、Rは−NHC(NH)NH2、−
NHCOOCH2CH3、−OHまたは−NHCSNH2を
表わす)で示されるアミノ化合物と脱水反応させ
ることにより容易に製造される。
前記脱水反応における溶媒としてはエタノー
ル、メタノール、水あるいはこれらの混合溶液等
が用いられ、触媒としては必要に応じて濃塩酸、
濃硫酸、濃硫酸等の無機酸あるいは水酸化ナトリ
ウム、水酸化カリウム、炭酸水素ナトリウム、炭
酸ナトリウム、炭酸カリウム、酢酸ナトリウム、
酢酸カリウム、ピリジン等のアルカリが、1滴な
いし10当量の範囲で適宜用いられる。また反応温
度としては、25℃〜還流温度の範囲の温度が、反
応時間としては30分〜15時間の範囲の時間が適宜
作用される。
出発物質であるビスベンゾフラニルケトン化合
物()において、R2で示される炭素数1〜3
個の低級アルキル基としてはメチル基、エチル
基、n−プロピル基およびイソプロピル基があげ
られ、なかでもメチル基が好ましい。またR2で
示される置換アミノエチルアルキル基としては、
β−ジメチルアルキル基、β−ジエチルアミノエ
チル基がとくに好ましい。
本発明においてはビズベンゾフラニルケトン誘
導体()は所望により塩に変えられるが、かか
る塩としては、塩酸、臭化水素酸、硫酸、硝酸、
リン酸などの無機酸またはコハク酸、メタンスル
ホン酸などの有機酸の付加塩あるいはナトリウム
塩、カリウム塩などのアルカリ塩があげられる。
これらの塩は常法にしたがつて、たとえばビスベ
ンゾフラニルケトン誘導体()にエチルエーテ
ル、メタノール、エタノールなどの適当な有機溶
媒中で相当する酸を作用させるか、あるいは水酸
化ナトリウム、水酸化カリウムなどのアルカリ水
溶液を作用させることによつて容易にえられる。
本発明における出発物質であるビスベンゾフラ
ニルケトン化合物()はいずれも新規な化合物
であるが、そのうちR1が水素、R2が低級アルキ
ル基であるものはたとえば一般式()
(式中、R5は低級アルキル基を表わす)で示さ
れるサリチルアルデヒド()と1,3−ジクロ
ロアセトンとを適当な溶媒、たとえばジオキサ
ン、アセトン、水などの溶媒中で適当な脱酸剤、
たとえば水酸化ナトリウム、水酸化カリウム、炭
酸カリウムなどの存在下で反応させることにより
容易にえられる。また、ビスベンゾフラニルケト
ン化合物()のうち、R1、R2がともに水素で
あるものは上記の反応で得られた一般式()
(式中、R5は前記と同じものを表わし、OR5基
はベンゾフラン環の4、5、6または7位の任意
の位置に置換している)で示されるビスベンゾフ
ラニルケトン化合物()を脱アルキル化するこ
とにより容易にえられる。
前記脱アルキル化反応は、ビスベンゾフラニル
ケトン化合物()をベンゼン、クロロベンゼ
ン、ジクロロベンゼン、酢酸、メタノール、エタ
ノールなどの適当な溶媒中で酸触媒の存在下に室
温ないし還流下に数時間加熱することによつて好
適に実施される。用いる酸触媒としては、無水塩
化アルミニウム、無水塩化スズ()、三フツ化
ホウ素などのルイス酸、塩酸、臭化水素酸などの
鉱酸、ピリジン塩酸塩などが好ましいものとして
あげられる。
またビスベンゾフラニルケトン化合物()の
うち、R1が−SO3Hであるものは前記の反応でえ
られた一般式()で示されるビスベンゾフラニ
ルケトン化合物()と濃硫酸を反応させること
により容易にえられる。
またビスベンゾフラニルケトン化合物()の
うち、R1が置換アミノアルキル基であるものは
前記の脱アルキル反応で得られた一般式()
(式中、−OH基はベンゾフラン環の4、5、6
または7位の任意の位置を表わす)で示されるビ
スベンゾフラニルケトン化合物()を一般式
()
(式中、Xはハロゲン、m、R2およびR3は前記
と同じものを意味する)で示される置換アミノア
ルキルハライト()またはその塩酸塩と反応さ
せることにより容易にえられる。
本発明のビスベンゾフラニルケトン誘導体
()およびその塩はすべて新規化合物であつて
それ自身すぐれた抗ウイルス作用を有し、医薬と
して有用である。たとえばビスベンゾフラニルケ
トン誘導体()およびその塩は各種ウイルスに
よつてひきおこされる感冒、咽頭炎、プール熱、
インフルエンザ、肺炎などの呼吸器感染症、帯状
包疹、角膜炎などの各種疾患の予防および治療に
有効である。
つぎに参考例および実施例をあげて本発明を説
明する。
参考例 1
〔ビス(7−メトキシ−2−ベンゾフラニル)
ケトンの製造〕
3−メトキシサリチルアルデヒド3.4g(0.022
モル)をジオキサン15mlに溶解し、これに室温、
撹拌下に水酸化ナトリウム1g(0.025モル)を
加え、徐々に加温して75℃で20〜30分間反応し、
ついで1,3−ジクロロアセトン1.3g(0.010モ
ル)を少量づつ加えさらに80℃で30分間反応し
た。反応液を冷却したのち水200mlを加え、生じ
た沈殿を濾取、乾燥し、ついでエタノール100ml
から再結晶して融点143〜144℃の黄褐色針状晶の
ビス(7−メトキシ−2−ベンゾフラニル)ケト
ン1.0gをえた。
元素分析値:C19H14O5として
計算値:C 70.80 H 4.38
実測値:C 71.09 H 4.09
赤外線吸収スペクトル(KBr錠;cm-1)
3150〜2900 (νCH)
1640 (νC=O)
1560、1490(νC=O、aromatic)
1170 (νC−O)
参考例 2
〔ビス(6−メトキシ−2−ベンゾフラニル)
ケトンの製造〕
3−メトキシサルチルアルデヒドに代えて4−
メトキシサリチルアルデヒドを用いたほかは参考
例1と同様にして融点191〜193℃の黄褐色結晶状
のビス(6−メトキシ−2−ベンゾフラニル)ケ
トンをえた。
元素分析値:C19H14O5として
計算値:C 70.80 H 4.38
実測値:C 70.89 H 4.41
赤外線吸収スペクトル(KBr錠;cm-1)
3150〜2900 (νCH)
1615 (νC=O)
1550、1490(νC=O、aromatic)
1160 (νC−O)
参考例 3
〔ビス(7−ヒドロキシ−2−ベンゾフラニ
ル)ケトンの製造〕
参考例1でえられたビス(7−メトキシ−2−
ベンゾフラニル)ケトン7.5g(0.023モル)とク
ロロベンゼン60mlを混合し、これに室温、撹拌下
に無水塩化アルミニウム9.3g(0.069モル)を少
量づつ加えた。反応液はただちに赤色の粘稠な液
となつた。ついで徐々に加温し100℃で1時間反
応すると赤褐色の沈殿が析出した。反応終了後反
応物を水中に注ぎ析出した沈殿を濾取、乾燥し、
ついでエタノールから再結晶すると分解点268〜
269℃の黄色結晶状のビス(7−ヒドロキシ−2
−ベンゾフラニル)ケトン5.7gがえられた。
元素分析値:C17H10O5・H2Oとして
計算値:C 65.39 H 3.89
実測値:C 65.17 H 3.94
元素分析値:C17H10O5として(110℃で7時間乾
燥)
計算値:C 69.39 H 3.43
実測値:C 65.51 H 3.21
赤外線吸収スペクトル(KBr錠;cm-1)
3400〜3050 (νOH)
3000〜2950 (νCH)
1620(νC=O)
1550、1490 (νC=C、aromatic)
参考例 4
〔ビス(6−ヒドロキシ−2−ベンゾフラニ
ル)ケトンの製造〕
ビス(7−メトキシ−2−ベンゾフラニル)ケ
トンに代えて参考例2でえたビス(6−メトキシ
−2−ベンゾフラニル)ケトンを用いたほかは参
考例3と同様にして分解点256〜258℃の黄色結晶
状のビス(6−ヒドロキシ−2−ベンゾフラニ
ル)ケトンをえた。
元素分析値:C17H10O5・1/2H2Oとして
計算値:C 67.55 H 3.33
実測値:C 67.36 H 3.56
赤外線吸収スペクトル(KBr錠;cm-1)
3400〜3250 (νOH)
3100〜2950 (νCH)
1625(νC=O)
1550〜1495 (νC=O、aromatic)
1170 (νC−O)
参考例 5
〔ビス(7−β−ジエチルアミノエトキシ−2
−ベンゾフラニル)ケトンおよびその2塩酸塩
の製造〕
参考例3でえたビス(7−ヒドロキシ−2−ベ
ンゾフラニル)ケトン4.4g(0.15モル)、無水炭
酸カリウム12.4g(0.090モル)およびアセトン
75mlを混合し30分間還流したのち、これにβ−ジ
エチルアミノエチルクロライド4.5g(0.033モ
ル)を加えさらに3時間還流した。反応液を冷却
後濾過し、濾液を濃縮してえられた油状物質を石
油ベンジンで抽出すると残渣が結晶化し融点75〜
77℃の黄色プリズム状のビス(7−β−ジエチル
アミノエトキシ−2−ベンゾフラニル)ケトンを
えた。
えられた結晶を塩酸ガス飽和エタノールに溶解
し、エタノールを大部分留去すると結晶が析出し
た。この結晶をエタノールから再結晶すると融点
260〜262℃(分解)の淡黄色結晶状のビス(7−
β−ジエチルアミノエトキシ−2−ベンゾフラニ
ル)ケトン2塩酸塩4.3g(収率50.0%)をえた。
元素分析値:C29H36O5N2・2HCl・H2Oとして
計算値:C 59.69 H 6.91 N 4.80
実測値:C 59.50 H 6.86 N4.80
赤外線吸収スペクトル(KBr錠;cm-1)
3100〜2900 (νCH)
2700〜2400 (νNH+)
1625 (νC=O)
1560、1495 (νC=C、aromatic)
参考例 6
〔ビス(6−β−ジエチルアミノエトキシ−2
−ベンゾフラニル)ケトンおよびその2塩酸塩
の製造〕
参考例4でえたビス(6−ヒドロキシ−2−ベ
ンゾフラニル)ケトン1.0g(0.035モル)、無水
炭酸カリウム3.0g(0.022モル)およびジメチル
ホルムアミド15mlを混合し80℃で30分間加熱した
のち、β−ジエチルアミノエチルクロライド1.0
g(0.008モル)を加えさらに80℃で1時間加熱
した。反応液を冷却後水中に注ぎ、析出した沈殿
を濾取、乾燥して融点93〜95℃の黄土色結晶状の
ビス(6−β−ジエチルアミノエトキシ−2−ベ
ンゾフラニル)ケトンをえた。
えられた結晶をエタノールに溶解し希塩酸を少
量加え、ついでエタノールを少し濃縮してえられ
た結晶をさらにエタノール・エーテル混液(1:
4容量比)から再結晶して融点234〜236℃の黄色
結晶状のビス(6−β−ジエチルアミノエトキシ
−2−ベンゾフラニル)ケトン2塩酸塩1.0g
(収率50.0%)をえた。
元素分析値:C29H36O5N2・2HCl・H2Oとして
計算値:C 59.69 H 6.91 N 4.80
実測値:C 59.74 H 6.75 N4.99
赤外線吸収スペクトル(KBr錠;cm-1)
3000〜2900 (νCH)
2700〜2450 (νNH+)
1620 (νC=O)
1560、1495 (νC=C、aromatic)
参考例 7
〔ビス(7−メトキシ−4−スルホ−2−ベン
ゾフラニル)ケトン・ジナトリウム塩の製造〕
参考例1でえたビス(7−メトキシ−2−ベン
ゾフラニル)ケトン0.6g(0.002モル)および濃
硫酸0.6gを混合し、100℃で1時間反応したの
ち、反応液を冷却後エタノールに溶解し、水酸化
ナトリウム水溶液でアルカリ性にし、析出した沈
殿物を濾過し、水から再結晶すると融点280℃以
上の黄色結晶状のビス(7−メトキシ−4−スル
ホ−2−ベンゾフラニル)ケトン・ジナトリウム
塩0.6gがえられた。
元素分析値:C19H12O11S2Na2、3H2Oとして
計算値:C 39.32 H 3.13
実測値:C 39.20 H 3.12
赤外線吸収スペクトル(KBr錠;cm-1)
3150〜2900 (νCH)
1625 (νC=O)
1590、1490 (νC=C、aromatic)
1160、1050 (νSO)
実施例 1
〔ビス(7−ヒドロキシ−2−ベンゾフラニ
ル)ケトングアニルヒドラゾン塩酸塩の製造〕
参考例3でえられたビス(7−ヒドロキシ−2
−ベンゾフラニル)ケトン0.6g(0.002モル)、
アミノグアニジン重炭酸塩0.27g(0.002モル)
およびエタノール20mlを混合し、これに濃塩酸2
〜2.5mlを加え、30分間加熱還流したのち反応液
を冷却後減圧下に濃縮し析出した沈殿物をエタノ
ールから再結晶すると融点136〜138.5℃の黄色結
晶状のビス(7−ヒドロキシ−2−ベンゾフラニ
ル)ケトングアニルヒドラゾン塩酸塩0.52gがえ
られた。
元素分析値:C18H14O4N4・2H2Oとして
計算値:C 51.13 H 4.53 N 13.25
実測値:C 50.95 H 4.52 N 13.38
赤外線吸収スペクトル(cm-1;KBr錠)
3400〜3100 (νOH、νNH)
3000〜2900 (νCH)
2500〜2300 (νNH+)
1685 (νC=N)
1640、1580 (νN−C)
1560、1490 (νc=c、aromatic)
1150 (νc−o)
実施例 2
〔ビス(6−ヒドロキシ−2−ベンゾフラニ
ル)ケトングアニルヒドラゾン塩酸塩の製造〕
ビス(7−ヒドロキシ−2−ベンゾフラニル)
ケトンに代えて参考例4でえたビス(6−ヒドロ
キシ−2−ベンゾフラニル)ケトンを用い、加熱
還流下に8時間反応したほかは実施例1と同様に
して融点146〜148℃の黄色結晶状のビス(6−ヒ
ドロキシ−2−ベンゾフラニル)ケトングアニル
ヒドラゾン塩酸塩0.8gをえた。
元素分析値:C18H14O4N4・HCl・2H2Oとして
計算値:C 51.13 H 4.53 N 13.25
実施値:C 51.01 H 4.44 N 13.35
赤外線吸収スペクトル(cm-1;KBr錠)
3400〜3100 (νOH、νNH)
3000〜2900 (νCH)
2500〜2300 (νNH+)
1690 (νC=N)
1660、1620 (νN−C)
1560、1440 (νC=C、aromatic)
1150 (νC−O)
実施例 3
〔ビス(7−メトキシ−2−ベンゾフラニル)
ケトングアニルヒドラゾン塩酸塩の製造〕
参考例1でえたビス(7−メトキシ−2−ベン
ゾフラニル)ケトン0.6g(0.002モル)、アミノ
グアニル炭酸塩0.27g(0.002モル)およびエタ
ノール20mlを混合し、これに濃塩酸2〜2.5mlを
加え、4時間加熱還流したのち、反応液を冷却
後、減圧下に濃縮し、析出した沈殿物を濾過し、
濃塩酸を含むエタノールから再結晶すると融点
228〜230℃の淡黄土色結晶状のビス(7−メトキ
シ−2−ベンゾフラニル)ケトングアニルヒドラ
ゾン塩酸塩0.8gがえられた。
元素分析値:C20H18O4N4・HCl・3.5H2Oとして
計算値:C 50.27 H 5.48 N 11.72
実施値:C 50.45 H 5.20 N 12.00
赤外線吸収スペクトル(cm-1;KBr錠)
3400〜3300 (νNH)
3000〜2900 (νCH)
2550〜2300 (νNH+)
1680 (νC=N)
1620、1590 (νN−C)
15801、1490 (νC=C、aromatic)
実施例 4
〔ビス(6−メトキシ−2−ベンゾフラニル)
ケトングアニルヒドラゾン塩酸塩の製造〕
ビス(7−メトキシ−2−ベンゾフラニル)ケ
トンに代えて参考例2でえたビス(6−メトキシ
−2−ベンゾフラニル)ケトンを用い、加熱還流
下に14時間反応したほかは実施例3と同様にし
て、融点124〜126℃の淡茶色結晶状のビス(6−
メトキシ−2−ベンゾフラニル)ケトングアニル
ヒドラゾン塩酸塩0.5gをえた。
元素分析値:C20H18O4N4・HCl・2H2Oとして
計算値:C 53.28 H 4.92 N 12.43
実施値:C 53.00 H 5.00 N 12.63
赤外線吸収スペクトル(cm-1;KBr錠)
3400〜3300 (νNH)
3000〜2900 (νCH)
2650〜2300 (νNH+)
1685〜1665 (νC=N)
1625、1590 (νN−C)
1560、1490 (νC=C、aromatic)
実施例 5
〔ビス(7−ヒドロキシ−2−ベンゾフラニ
ル)ケトンエトキシカルボニルヒドラゾンの製
造〕
参考例3でえたビス(7−ヒドロキシ−2−ベ
ンゾフラニル)ケトン0.7g(0.0025モル)、カル
バジン酸エチル0.26g(0.0025モル)、95%エタ
ノール6mlおよび濃塩酸1滴を混合し、約5時間
加熱還流したのち、反応液を冷却後、水中に注ぎ
析出した沈殿物を濾過し、アセトンと水の混液か
ら再結晶すると融点158〜160℃(分解)の白色粉
末状のビス(7−ヒドロキシ−2−ベンゾフラニ
ル)ケトンエトキシカルボニルヒドラゾン0.6g
がえられた。
元素分析値:C20H16O6N2・H2Oとして
計算値:C 60.30 H 4.55 N 7.03
実施値:C 90.53 H 4.37 N 7.08
赤外線吸収スペクトル(cm-1;KBr錠)
3400〜3200 (νOH)
3350 (νNH)
3100〜2900 (νCH)
1730 (νCOO)
1620 (νC=N)
1550、1485 (νC=C、aromatic)
1160 (νC−O)
実施例 6
〔ビス(7−メトキシ−2−ベンゾフラニル)
ケトンエトキシカルボニルヒドラゾンの製造〕
ビス(7−ヒドロキシ−2−ベンゾフラニル)
ケトンに代えて参考例1でえたビス(7−メトキ
シ−2−ベンゾフラニル)ケトンを用い、加熱還
流下に8時間反応したほかは、実施例5と同様に
して、ベンゼンと石油ベンジンの混液から再結晶
すると融点134〜136℃(分解)の白色粉末状のビ
ス(7−メトキシ−2−ベンゾフラニル)ケトン
エトキシカルボニルヒドラゾン0.6gをえた。
元素分析値:C22H20O6N2として
計算値:C 64.70 H 4.94 N 6.86
実施値:C 64.91 H 5.03 N 6.58
赤外線吸収スペクトル(cm-1;KBr錠)
3200 (νNH)
3000〜2900 (νCH)
1710 (νCOO)
1620 (νC=N)
1550、1480 (νC=C、aromatic)
実施例 7
〔ビス(6−ヒドロキシ−2−ベンゾフラニ
ル)ケトオキシムの製造〕
参考例4でえたビス(6−ヒドロキシ−2−ベ
ンゾフラニル)ケトン0.8g(0.00275モル)、ヒ
ドロキシルアミン塩酸塩0.3g(0.0043モル)、エ
タノール10mlおよび水0.5mlを混合し、これに水
酸化ナトリウム0.77g(0.001375モル)を加え、
4時間還流したのち、反応液を冷却後水中に注
ぎ、希塩酸で酸性し析出した沈殿物をエタノール
と水の混液から再結晶すると融点247〜248℃(分
解)の淡黄色粉末状のビス(6−ヒドロキシ−2
−ベンゾフラニル)ケトオキシム0.5gがえられ
た。
元素分析値:C17H11O5N・H2Oとして
計算値:C 62.39 H 4.00 N 4.28
実測値:C 62.18 H 3.98 N 4.30
赤外線吸収スペクトル(cm-1;KBr錠)
3400〜3200 (νOH)
3100〜2950 (νCH)
1630 (νC=N)
1570、1490 (νC=C、aromatic)
1150 (νC−O)
実施例 8
〔ビス(7−ヒドロキシ−2−ベンゾフラニ
ル)ケトオキシムの製造〕
ビス(6−ヒドロキシ−2−ベンゾフラニル)
ケトンに代えて参考例3でえたビス(7−ヒドロ
キシ−2−ベンゾフラニル)ケトンを用い、加熱
還流下に2時間反応したほかは実施例7と同様に
して、融点243〜244℃(分解)の白色粉末状のビ
ス(7−ヒドロキシ−2−ベンゾフラニル)ケト
オキシム0.55gをえた。
元素分析値:C17H11O5N・H2Oとして
計算値:C 62.39 H 4.00 N 4.28
実測値:C 62.60 H 3.86 N 4.39
赤外線吸収スペクトル(cm-1;KBr錠)
3400〜3200 (νOH)
3050〜2950 (νCH)
1600 (νC=N)
1550、1495 (νC=C、aromatic)
1175 (νC−O)
実施例 9
〔ビス(7−メトキシ−2−ベンゾフラニル)
ケトオキシムの製造〕
ビス(6−ヒドロキシ−2−ベンゾフラニル)
ケトンに代えて参考例1でえたビス(7−メトキ
シ−2−ベンゾフラニル)ケトンを用いたほかは
実施例7と同様にしてエタノールから再結晶する
と融点210〜212℃の白色針状晶のビス(7−メト
キシ−2−ベンゾフラニル)ケトオキシム0.7g
をえた。
元素分析値:C19H15O5Nとして
計算値:C 67.65 H 4.48 N 4.15
実測値:C 67.90 H 4.54 N 4.07
赤外線吸収スペクトル(cm-1;KBr錠)
3000〜2900 (νCH)
1610 (νC=N)
1550、1490 (νC=C、aromatic)
実施例 10
〔ビス(7−ヒドロキシ−2−ベンゾフラニ
ル)ケトンチオセミカルバゾンの製造〕
参考例3でえたビス(7−ヒドロキシ−2−ベ
ンゾフラニル)ケトン0.6g(0.002モル)、チオ
セミカルバジド0.3g(0.003モル)および95%エ
タノール40mlを混合し、これに濃硫酸4〜5滴を
加え、4時間加熱還流したのち、反応液を冷却
後、減圧下に濃縮し、水中に注ぎ希アルカリ水溶
液で弱アルカリ性にし析出した沈殿物をエタノー
ルと水の混液から再結晶すると融点202〜204℃の
黄色結晶状のビス(7−ヒドロキシ−2−ベンゾ
フラニル)ケトンチオセミカルバゾン0.5gがえ
られた。
元素分析値:C18H13O4N3S・1/2H2Oとして
計算値:C 57.44 H 4.02 N 11.16
実測値:C 57.70 H 4.30 N 11.40
赤外線吸収スペクトル(cm-1;KBr錠)
3500〜3300 (νOH)
3150 (νNH)
3100〜3000 (νCH)
1620 (νC=N)
1580、1490 (νC=C、aromatic)
1290 (νC=S)
1180 (νC−O)
実施例 11
〔ビス(6−ヒドロキシ−2−ベンゾフラニ
ル)ケトンチオセミカルバゾンの製造〕
ビス(7−ヒドロキシ−2−ベンゾフラニル)
ケトンに代えて参考例4でえたビス(6−ヒドロ
キシ−2−ベンゾフラニル)ケトンを用いたほか
は実施例10と同様にして、融点172〜174℃の黄色
結晶状のビス(6−ヒドロキシ−2−ベンゾフラ
ニル)ケトンチオセミカルバゾン0.5gをえた。
元素分析値:C18H13O4N3Sとして
計算値:C 58.85 H 3.57 N 11.44
実測値:C 58.90 H 3.83 N 11.23
赤外線吸収スペクトル(cm-1;KBr錠)
3450〜3250 (νOH、νNH2)
3150 (νNH)
3100〜2950 (νCH)
1625 (νC=N)
1560、1480 (νC=C、aromatic)
1270 (νC=S)
1155 (νC−O)
実施例 12
〔ビス(7−ヒドロキシ−2−ベンゾフラニ
ル)ケトンチオセミカルバゾンの製造〕
ビス(7−ヒドロキシ−2−ベンゾフラニル)
ケトンに代えて参考例1でえたビス(7−メトキ
シ−2−ベンゾフラニル)ケトンを用いたほかは
実施例10と同様にして、エタノールから再結晶す
ると融点203〜205℃の黄色針状結晶のビス(7−
メトキシ−2−ベンゾフラニル)ケトンチオセミ
カルバゾン0.5gをえた。
元素分析値:C20H17O4N3Sとして
計算値:C 60.75 H 4.33 N 10.63
実測値:C 60.93 H 4.37 N 10.36
赤外線吸収スペクトル(cm-1;KBr錠)
3400、3350 (νNH2)
3250 (νNH)
3100〜3000 (νCH)
1610 (νC=N)
1590、1470 (νC=C、aromatic)
1290 (νC=S)
実施例 13
〔ビス(6−メトキシ−2−ベンゾフラニル)
ケトンチオセミカルバゾンの製造〕
ビス(7−ヒドロキシ−2−ベンゾフラニル)
ケトンに代えて参考例2でえたビス(6−メトキ
シ−2−ベンゾフラニル)ケトンを用いたほかは
実施例10と同様にして、エタノールから再結晶す
ると融点202〜204℃の黄色結晶状のビス(6−メ
トキシ−2−ベンゾフラニル)ケトンチオセミカ
ルバゾン0.4gをえた。
元素分析値:C20H17O4N3Sとして
計算値:C 60.75 H 4.33 N 10.63
実測値:C 60.49 H 4.35 N 10.55
赤外線吸収スペクトル(cm-1;KBr錠)
3450、3350 (νNH2)
3250 (νNH)
3100〜2900 (νCH)
1620 (νC=N)
1600、1480 (νC=C、aromatic)
1270 (νC=S)
実施例 14
〔ビス(7−β−ジエチルアミノエトキシ−2
−ベンゾフラニル)ケトングアニルヒドラゾン
3塩酸塩の製造〕
参考例5でえたビス(7−β−ジエチルアミノ
エトキシ−2−ベンゾフラニル)ケトン1.14g
(0.002モル)、アミノグアニル重炭酸塩0.28g
(0.002モル)およびエタノール20mlを混合し、こ
れに濃硫酸2〜2.5mlを加え、2.5時間加熱還流し
たのち、反応液を冷却後、減圧下に濃縮し析出し
た沈殿物をメタノールとエーテルの混液から再結
晶すると融点265〜267℃(分解)の黄色結晶状の
ビス(7−β−ジエチルアミノエトキシ−2−ベ
ンゾフラニル)ケトングアニルヒドラゾン3塩酸
塩0.9gがえられた。
元素分析値:C30H40N6O4・3HClとして
計算値:C 54.76 H 6.59 N 12.77
実測値:C 54.99 H 6.73 N 12.70
赤外線吸収スペクトル(cm-1;KBr錠)
3300〜3150 (νNH2、νNH)
3100〜2900 (νCH)
2650〜2400 (νNH+)
1680 (νC=N)
1590、1490 (νC=C、aromatic)
実施例 15
〔ビス(6−β−ジエチルアミノエトキシ−2
−ベンゾフラニル)ケトングアニルヒドラゾン
3塩酸塩の製造〕
ビス(7−β−ジエチルアミノエトキシ−2−
ベンゾフラニル)ケトンに代えて、参考例6でえ
たビス(6−β−ジエチルアミノエトキシ−2−
ベンゾフラニル)ケトンを用い、加熱還流下に
6.5時間反応したほかは実施例14と同様にして、
エタノールとエーテルの混液から再結晶すると融
点144〜146℃の黄色粉末状結晶のビス(6−β−
ジエチルアミノエトキシ−2−ベンゾフラニル)
ケトングアニルヒドラゾン3塩酸塩0.6gをえた。
元素分析値:C30H40N6O4・3HClとして
計算値:C 54.76 H 6.59 N 12.77
実測値:C 54.51 H 6.70 N 12.56
赤外線吸収スペクトル(cm-1;KBr錠)
3400〜3200 (νNH2、νNH)
3100〜2900 (νCH)
2650〜2450 (νNH+)
1675 (νC=N)
1580、1490 (νC=C、aromatic)
実施例 16
〔ビス(7−メトキシ−4−スルホ−2−ベン
ゾフラニル)ケトングアニルヒドラゾンの製
造〕
ビス(7−β−ジエチルアミノエトキシ−2−
ベンゾフラニル)ケトンに代えて、参考例7でえ
たビス(7−メトキシ−4−スルホ−2−ベンゾ
フラニル)ケトン・ジナトリウム塩を用いたほか
は実施例14と同様にして、含水メタノールとエー
テルの混液から再結晶すると融点280℃以上の白
色粉末状のビス(7−メトキシ−4−スルホ−2
−ベンゾフラニル)ケトングアニルヒドラゾン
0.8gをえた。
元素分析値:C20H18O10N4S2として
計算値:C 44.61 H 3.37 N 10.40
実測値:C 44.83 H 3.58 N 10.53
赤外線吸収スペクトル(cm-1;KBr錠)
3550〜3250 (νNH2、νNH)
3150〜2900 (νCH)
1690 (νC=N)
1580、1490 (νC=C、aromatic)
1160、1040 (νSO3H)
実施例 17
〔鶏胎児線維芽細胞における抗ウイルス試験〕
10〜11日令の発育鶏卵の胎児を常法により組織
培養し、20〜24時間培養の初代鶏胎児線維芽細胞
にメタノールまたは水に溶解したビスベンゾフラ
ニルケトン化合物の各種濃度液と培養液で希釈し
たインフルエンザA−PR8をほぼ同時にチヤレン
ジした(最後チヤレンジm・o・i=0.1〜0.2)。
その後37℃にてインキユベートし、48時間後培養
液中のウイルス量をHA(赤血球凝集反応)テス
トによつて、また細胞内ウイルス量をヘムアドソ
ープシヨンによつて定量して被検化合物のウイル
ス活性発現最小濃度を求めた。被検化合物の細胞
毒性はウイルスチヤレンジしていない前記と同じ
ような実験系で検討し、有効係数は次式より求め
た。
有効係数=細胞毒性発現最小濃度/抗ウイルス活性
発現最小濃度
比較のために抗ウイルス剤として従来より使用
されているアマンタジン(Amantadine)につい
て前記と同様な試験をした。
これらの結果を第1表に示す。
The present invention relates to novel bisbenzofuranyl ketone derivatives, more specifically, the general formula () [In the formula, R is -NHC(NH) NH2 , -
NHCOOCH 2 CH 3 , -OH group or -NHCSNH 2 ,
R 1 is hydrogen or −SO 3 H, R 2 is hydrogen, carbon number 1-
3 lower alkyl groups or formula (In the formula, m is an integer of 1 to 3, R 3 and R 4 each represent a lower alkyl group having 1 to 3 carbon atoms)
represents a substituted aminoalkyl group represented by R 1
and OR2 group is substituted at any position of the 4, 5, 6, or 7 position of the benzobran ring], salts thereof, and methods for producing them. The compound of the present invention itself has antiviral activity and is useful as a medicine. Bis(6-hydroxy-2-
benzofuranyl) ketone guanyl hydrazone, bis(7-methoxy-2-benzofuranyl) ketone guanyl hydrazone, bis(6-methoxy-2-
benzofuranyl) ketone guanyl hydrazone, bis(6-hydroxy-2-benzofuranyl) ketone thiosemicarbazone, bis(7-β-diethylaminoethoxy-2-benzofuranyl) ketone guanylhydrazone, bis(6-β-diethylaminoethoxy-2- Bisbenzofuranyl ketone derivatives and salts thereof, such as benzofuranyl) ketone guanyl hydrazone, are preferred. The bisbenzofuranyl ketone derivative () of the present invention has the general formula () [In the formula, R 1 is hydrogen or -SO 3 H, R 2 is hydrogen, a lower alkyl group having 1 to 3 carbon atoms, or the formula (In the formula, m is an integer of 1 to 3, R 3 and R 4 each represent a lower alkyl group having 1 to 3 carbon atoms)
represents a substituted aminoalkyl group represented by R 1
group and OR2 group is substituted at any position of the 4 , 5, 6, or 7 position of the benzofuran ring]. , R is -NHC(NH) NH2 , -
It is easily produced by dehydration reaction with an amino compound represented by NHCOOCH 2 CH 3 , -OH or -NHCSNH 2 . Ethanol, methanol, water, or a mixed solution of these is used as a solvent in the dehydration reaction, and as a catalyst, concentrated hydrochloric acid,
Concentrated sulfuric acid, inorganic acids such as concentrated sulfuric acid, or sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium acetate,
An alkali such as potassium acetate or pyridine is appropriately used in the range of 1 drop to 10 equivalents. Further, the reaction temperature is suitably set at a temperature in the range of 25° C. to the reflux temperature, and the reaction time is suitably set at a time in the range of 30 minutes to 15 hours. In the starting material bisbenzofuranyl ketone compound (), carbon number 1 to 3 represented by R 2
Examples of the lower alkyl group include a methyl group, an ethyl group, an n-propyl group and an isopropyl group, with a methyl group being preferred. The substituted aminoethyl alkyl group represented by R 2 is
A β-dimethylalkyl group and a β-diethylaminoethyl group are particularly preferred. In the present invention, the bisbenzofuranyl ketone derivative () can be converted into a salt if desired, and such salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
Examples include addition salts of inorganic acids such as phosphoric acid, organic acids such as succinic acid and methanesulfonic acid, and alkali salts such as sodium salts and potassium salts.
These salts can be prepared by a conventional method, for example, by reacting a bisbenzofuranyl ketone derivative () with a corresponding acid in a suitable organic solvent such as ethyl ether, methanol, or ethanol, or by reacting a bisbenzofuranyl ketone derivative () with a corresponding acid in a suitable organic solvent such as ethyl ether, methanol, or ethanol, or by reacting a bisbenzofuranyl ketone derivative (2) with a corresponding acid in a suitable organic solvent such as ethyl ether, methanol, or ethanol; It can be easily obtained by reacting with an aqueous alkali solution such as potassium. All of the bisbenzofuranyl ketone compounds () that are the starting materials in the present invention are new compounds, but among them, those in which R 1 is hydrogen and R 2 is a lower alkyl group have the general formula () (In the formula, R 5 represents a lower alkyl group) salicylaldehyde () and 1,3-dichloroacetone are mixed in a suitable solvent such as dioxane, acetone, water, etc. with a suitable deoxidizing agent.
For example, it can be easily obtained by reaction in the presence of sodium hydroxide, potassium hydroxide, potassium carbonate, etc. In addition, among bisbenzofuranyl ketone compounds (), those in which R 1 and R 2 are both hydrogen have the general formula () obtained by the above reaction. (In the formula, R 5 represents the same as above, and the OR 5 group is substituted at any position of the 4, 5, 6, or 7 position of the benzofuran ring.) can be easily obtained by dealkylation of In the dealkylation reaction, the bisbenzofuranyl ketone compound () is heated at room temperature to reflux for several hours in the presence of an acid catalyst in a suitable solvent such as benzene, chlorobenzene, dichlorobenzene, acetic acid, methanol, or ethanol. This is preferably carried out by: Preferred examples of the acid catalyst used include anhydrous aluminum chloride, anhydrous tin chloride, Lewis acids such as boron trifluoride, mineral acids such as hydrochloric acid and hydrobromic acid, and pyridine hydrochloride. Among bisbenzofuranyl ketone compounds (), those in which R 1 is -SO 3 H are obtained by reacting concentrated sulfuric acid with the bisbenzofuranyl ketone compound () obtained by the above reaction and represented by the general formula (). It can be easily obtained by Among bisbenzofuranyl ketone compounds (), those in which R 1 is a substituted aminoalkyl group have the general formula () obtained by the above dealkylation reaction. (In the formula, -OH groups are 4, 5, 6 of the benzofuran ring.
or any position of the 7th position) is represented by the general formula (). (In the formula, X is halogen, m, R 2 and R 3 have the same meanings as above) or a hydrochloride thereof. The bisbenzofuranyl ketone derivatives () and salts thereof of the present invention are all new compounds that themselves have excellent antiviral activity and are useful as pharmaceuticals. For example, bisbenzofuranyl ketone derivatives () and their salts can be used to treat colds, pharyngitis, pool fever, etc. caused by various viruses.
It is effective in preventing and treating various diseases such as influenza, respiratory infections such as pneumonia, cystitis zoster, and keratitis. Next, the present invention will be explained with reference to reference examples and examples. Reference example 1 [bis(7-methoxy-2-benzofuranyl)
Production of ketone] 3-methoxysalicylaldehyde 3.4g (0.022
mol) in 15 ml of dioxane, add to this at room temperature,
Add 1 g (0.025 mol) of sodium hydroxide while stirring, gradually warm and react at 75°C for 20 to 30 minutes.
Then, 1.3 g (0.010 mol) of 1,3-dichloroacetone was added little by little, and the reaction was further carried out at 80°C for 30 minutes. After cooling the reaction solution, add 200 ml of water, collect the resulting precipitate by filtration, dry it, and then add 100 ml of ethanol.
Recrystallization from the solution gave 1.0 g of bis(7-methoxy-2-benzofuranyl) ketone in the form of yellowish brown needles with a melting point of 143-144°C. Elemental analysis value: C 19 H 14 O 5 Calculated value: C 70.80 H 4.38 Actual value: C 71.09 H 4.09 Infrared absorption spectrum (KBr tablet; cm -1 ) 3150-2900 (νCH) 1640 (νC=O) 1560, 1490 (νC=O, aromatic) 1170 (νC-O) Reference example 2 [Bis(6-methoxy-2-benzofuranyl)
Production of ketone] 4- instead of 3-methoxysaltyraldehyde
A yellowish brown crystalline bis(6-methoxy-2-benzofuranyl)ketone having a melting point of 191 to 193°C was obtained in the same manner as in Reference Example 1 except that methoxysalicylaldehyde was used. Elemental analysis value: C 19 H 14 O 5 Calculated value: C 70.80 H 4.38 Actual value: C 70.89 H 4.41 Infrared absorption spectrum (KBr tablet; cm -1 ) 3150-2900 (νCH) 1615 (νC=O) 1550, 1490 (νC=O, aromatic) 1160 (νC-O) Reference Example 3 [Production of bis(7-hydroxy-2-benzofuranyl)ketone] Bis(7-methoxy-2- obtained in Reference Example 1)
7.5 g (0.023 mol) of benzofuranyl)ketone and 60 ml of chlorobenzene were mixed, and 9.3 g (0.069 mol) of anhydrous aluminum chloride was added little by little at room temperature while stirring. The reaction solution immediately turned into a red viscous liquid. Then, the mixture was gradually heated and reacted at 100°C for 1 hour, and a reddish brown precipitate was deposited. After the reaction is complete, the reaction product is poured into water and the precipitate is collected by filtration and dried.
Then, when recrystallized from ethanol, the decomposition point is 268 ~
Yellow crystalline bis(7-hydroxy-2
-Benzofuranyl)ketone 5.7 g were obtained. Elemental analysis value: As C 17 H 10 O 5 · H 2 O Calculated value: C 65.39 H 3.89 Actual value: C 65.17 H 3.94 Elemental analysis value: As C 17 H 10 O 5 (dried at 110°C for 7 hours) Calculated value :C 69.39 H 3.43 Actual value: C 65.51 H 3.21 Infrared absorption spectrum (KBr tablet; cm -1 ) 3400-3050 (νOH) 3000-2950 (νCH) 1620 (νC=O) 1550, 1490 (νC=C, aromatic ) Reference Example 4 [Production of bis(6-hydroxy-2-benzofuranyl) ketone] Bis(6-methoxy-2-benzofuranyl) ketone obtained in Reference Example 2 was used instead of bis(7-methoxy-2-benzofuranyl) ketone. A yellow crystalline bis(6-hydroxy-2-benzofuranyl)ketone having a decomposition point of 256 to 258°C was obtained in the same manner as in Reference Example 3, except that the following procedure was used. Elemental analysis value: C17H10O5・1/ 2H2O Calculated value: C67.55H3.33 Actual value: C67.36H3.56 Infrared absorption spectrum (KBr tablet; cm -1 ) 3400~3250 ( νOH ) 3100~ 2950 (νCH) 1625 (νC=O) 1550-1495 (νC=O, aromatic) 1170 (νC-O) Reference example 5 [Bis(7-β-diethylaminoethoxy-2
-Production of benzofuranyl) ketone and its dihydrochloride] 4.4 g (0.15 mol) of bis(7-hydroxy-2-benzofuranyl) ketone obtained in Reference Example 3, 12.4 g (0.090 mol) of anhydrous potassium carbonate, and acetone.
After 75 ml of the mixture was mixed and refluxed for 30 minutes, 4.5 g (0.033 mol) of β-diethylaminoethyl chloride was added thereto and the mixture was further refluxed for 3 hours. The reaction solution is cooled and then filtered, and the filtrate is concentrated and the resulting oily substance is extracted with petroleum benzene.The residue crystallizes and has a melting point of 75~
Yellow prismatic bis(7-β-diethylaminoethoxy-2-benzofuranyl)ketone was obtained at 77°C. The obtained crystals were dissolved in ethanol saturated with hydrochloric acid gas, and most of the ethanol was distilled off to precipitate crystals. When this crystal is recrystallized from ethanol, the melting point is
Pale yellow crystalline bis(7-
4.3 g (yield 50.0%) of β-diethylaminoethoxy-2-benzofuranyl) ketone dihydrochloride was obtained. Elemental analysis value: C 29 H 36 O 5 N 2・2HCl・H 2 O Calculated value: C 59.69 H 6.91 N 4.80 Actual value: C 59.50 H 6.86 N4.80 Infrared absorption spectrum (KBr tablet; cm -1 ) 3100 ~2900 (νCH) 2700~2400 (νNH + ) 1625 (νC=O) 1560, 1495 (νC=C, aromatic) Reference example 6 [Bis(6-β-diethylaminoethoxy-2
-Production of benzofuranyl) ketone and its dihydrochloride] 1.0 g (0.035 mol) of bis(6-hydroxy-2-benzofuranyl) ketone obtained in Reference Example 4, 3.0 g (0.022 mol) of anhydrous potassium carbonate, and 15 ml of dimethylformamide were mixed. After heating at 80℃ for 30 minutes, β-diethylaminoethyl chloride 1.0
g (0.008 mol) and further heated at 80°C for 1 hour. After cooling the reaction solution, it was poured into water, and the precipitate precipitated was collected by filtration and dried to obtain bis(6-β-diethylaminoethoxy-2-benzofuranyl) ketone in the form of ocher crystals with a melting point of 93-95°C. The obtained crystals were dissolved in ethanol, a small amount of diluted hydrochloric acid was added, and then the ethanol was slightly concentrated, and the obtained crystals were further dissolved in an ethanol/ether mixture (1:
1.0 g of bis(6-β-diethylaminoethoxy-2-benzofuranyl)ketone dihydrochloride as yellow crystals with a melting point of 234-236°C after recrystallization from 4 volume ratio)
(yield 50.0%). Elemental analysis value: C 29 H 36 O 5 N 2・2HCl・H 2 O Calculated value: C 59.69 H 6.91 N 4.80 Actual value: C 59.74 H 6.75 N 4.99 Infrared absorption spectrum (KBr tablet; cm -1 ) 3000 ~2900 (νCH) 2700~2450 (νNH + ) 1620 (νC=O) 1560, 1495 (νC=C, aromatic) Reference example 7 [Bis(7-methoxy-4-sulfo-2-benzofuranyl) ketone disodium Production of salt] 0.6 g (0.002 mol) of bis(7-methoxy-2-benzofuranyl) ketone obtained in Reference Example 1 and 0.6 g of concentrated sulfuric acid were mixed and reacted at 100°C for 1 hour. After cooling the reaction solution, ethanol was added. The precipitate is dissolved in water, made alkaline with an aqueous sodium hydroxide solution, filtered, and recrystallized from water to produce bis(7-methoxy-4-sulfo-2-benzofuranyl) ketone in the form of yellow crystals with a melting point of 280°C or higher. 0.6 g of disodium salt was obtained. Elemental analysis value: C 19 H 12 O 11 S 2 Na 2 , as 3H 2 O Calculated value: C 39.32 H 3.13 Actual value: C 39.20 H 3.12 Infrared absorption spectrum (KBr tablet; cm -1 ) 3150 to 2900 (νCH) 1625 (νC=O) 1590, 1490 (νC=C, aromatic) 1160, 1050 (νSO) Example 1 [Production of bis(7-hydroxy-2-benzofuranyl)ketone guanyl hydrazone hydrochloride] Obtained in Reference Example 3 Bis(7-hydroxy-2
-benzofuranyl)ketone 0.6 g (0.002 mol),
Aminoguanidine bicarbonate 0.27g (0.002mol)
Mix 20 ml of ethanol and 20 ml of concentrated hydrochloric acid.
~2.5 ml was added, heated under reflux for 30 minutes, and the reaction solution was cooled and concentrated under reduced pressure. The precipitate deposited was recrystallized from ethanol to yield yellow crystalline bis(7-hydroxy-2- 0.52 g of benzofuranyl) ketone guanyl hydrazone hydrochloride was obtained. Elemental analysis value: C 18 H 14 O 4 N 4・2H 2 O Calculated value: C 51.13 H 4.53 N 13.25 Actual value: C 50.95 H 4.52 N 13.38 Infrared absorption spectrum (cm -1 ; KBr tablet) 3400-3100 ( νOH, νNH) 3000 to 2900 (νCH) 2500 to 2300 (νNH + ) 1685 (νC=N) 1640, 1580 (νN−C) 1560, 1490 (νc=c, aromatic) 1150 (νc−o) Example 2 [Production of bis(6-hydroxy-2-benzofuranyl) ketone guanyl hydrazone hydrochloride] Bis(7-hydroxy-2-benzofuranyl)
A yellow crystalline product with a melting point of 146 to 148°C was prepared in the same manner as in Example 1, except that the bis(6-hydroxy-2-benzofuranyl) ketone obtained in Reference Example 4 was used instead of the ketone and the reaction was carried out under heating and reflux for 8 hours. 0.8 g of bis(6-hydroxy-2-benzofuranyl) ketone guanyl hydrazone hydrochloride was obtained. Elemental analysis value: C 18 H 14 O 4 N 4・HCl・2H 2 O Calculated value: C 51.13 H 4.53 N 13.25 Actual value: C 51.01 H 4.44 N 13.35 Infrared absorption spectrum (cm -1 ; KBr tablet) 3400 ~ 3100 (νOH, νNH) 3000~2900 (νCH) 2500~2300 (νNH + ) 1690 (νC=N) 1660, 1620 (νN−C) 1560, 1440 (νC=C, aromatic) 1150 (νC−O) Implementation Example 3 [Bis(7-methoxy-2-benzofuranyl)
Production of ketone guanyl hydrazone hydrochloride] 0.6 g (0.002 mol) of bis(7-methoxy-2-benzofuranyl) ketone obtained in Reference Example 1, 0.27 g (0.002 mol) of aminoguanyl carbonate and 20 ml of ethanol were mixed, and mixed with this. After adding 2 to 2.5 ml of concentrated hydrochloric acid and heating under reflux for 4 hours, the reaction solution was cooled and concentrated under reduced pressure, and the precipitate deposited was filtered.
When recrystallized from ethanol containing concentrated hydrochloric acid, the melting point
0.8 g of bis(7-methoxy-2-benzofuranyl)ketone guanyl hydrazone hydrochloride was obtained in the form of pale ocher crystals with a temperature of 228-230°C. Elemental analysis value: C 20 H 18 O 4 N 4・HCl・3.5H 2 O Calculated value: C 50.27 H 5.48 N 11.72 Actual value: C 50.45 H 5.20 N 12.00 Infrared absorption spectrum (cm -1 ; KBr tablet) 3400 〜3300 (νNH) 3000〜2900 (νCH) 2550〜2300 (νNH + ) 1680 (νC=N) 1620, 1590 (νN−C) 1580 1 , 1490 (νC=C, aromatic) Example 4 [Bis (6 -methoxy-2-benzofuranyl)
Production of ketone guanylhydrazone hydrochloride] Bis(6-methoxy-2-benzofuranyl) ketone obtained in Reference Example 2 was used in place of bis(7-methoxy-2-benzofuranyl) ketone, and the reaction was conducted under heating under reflux for 14 hours. In the same manner as in Example 3, light brown crystalline bis(6-
0.5 g of methoxy-2-benzofuranyl) ketone guanyl hydrazone hydrochloride was obtained. Elemental analysis value: C 20 H 18 O 4 N 4・HCl・2H 2 O Calculated value: C 53.28 H 4.92 N 12.43 Actual value: C 53.00 H 5.00 N 12.63 Infrared absorption spectrum (cm -1 ; KBr tablet) 3400~ 3300 (νNH) 3000~2900 (νCH) 2650~2300 (νNH + ) 1685~1665 (νC=N) 1625, 1590 (νN−C) 1560, 1490 (νC=C, aromatic) Example 5 [Bis (7 -Production of hydroxy-2-benzofuranyl)ketone ethoxycarbonylhydrazone] 0.7 g (0.0025 mol) of bis(7-hydroxy-2-benzofuranyl) ketone obtained in Reference Example 3, 0.26 g (0.0025 mol) of ethyl carbazate, 95% ethanol After mixing 6 ml and 1 drop of concentrated hydrochloric acid and heating under reflux for about 5 hours, the reaction solution was cooled, poured into water, filtered the precipitate, and recrystallized from a mixture of acetone and water. 0.6 g of white powder bis(7-hydroxy-2-benzofuranyl) ketone ethoxycarbonyl hydrazone (decomposition)
It was raised. Elemental analysis value: C 20 H 16 O 6 N 2・H 2 O Calculated value: C 60.30 H 4.55 N 7.03 Actual value: C 90.53 H 4.37 N 7.08 Infrared absorption spectrum (cm -1 ; KBr tablet) 3400-3200 ( νOH) 3350 (νNH) 3100-2900 (νCH) 1730 (νCOO) 1620 (νC=N) 1550, 1485 (νC=C, aromatic) 1160 (νC-O) Example 6 [Bis(7-methoxy-2- benzofuranyl)
Production of ketone ethoxycarbonyl hydrazone] Bis(7-hydroxy-2-benzofuranyl)
A mixture of benzene and petroleum benzine was regenerated in the same manner as in Example 5, except that the bis(7-methoxy-2-benzofuranyl) ketone obtained in Reference Example 1 was used instead of the ketone and the reaction was carried out under heating and reflux for 8 hours. Upon crystallization, 0.6 g of bis(7-methoxy-2-benzofuranyl)ketone ethoxycarbonylhydrazone was obtained as a white powder with a melting point of 134-136°C (decomposed). Elemental analysis value: C 22 H 20 O 6 N 2 Calculated value: C 64.70 H 4.94 N 6.86 Actual value: C 64.91 H 5.03 N 6.58 Infrared absorption spectrum (cm -1 ; KBr tablet) 3200 (νNH) 3000-2900 ( νCH) 1710 (νCOO) 1620 (νC=N) 1550, 1480 (νC=C, aromatic) Example 7 [Production of bis(6-hydroxy-2-benzofuranyl)ketoxime] Bis(6-hydroxy obtained in Reference Example 4) -2-Benzofuranyl)ketone 0.8 g (0.00275 mol), hydroxylamine hydrochloride 0.3 g (0.0043 mol), ethanol 10 ml and water 0.5 ml were mixed, and sodium hydroxide 0.77 g (0.001375 mol) was added thereto.
After refluxing for 4 hours, the reaction solution was cooled, poured into water, acidified with dilute hydrochloric acid, and the precipitate precipitated was recrystallized from a mixture of ethanol and water to give bis(6 -Hydroxy-2
-Benzofuranyl)ketoxime 0.5 g was obtained. Elemental analysis value: C 17 H 11 O 5 N・H 2 O Calculated value: C 62.39 H 4.00 N 4.28 Actual value: C 62.18 H 3.98 N 4.30 Infrared absorption spectrum (cm -1 ; KBr tablet) 3400-3200 (νOH ) 3100-2950 (νCH) 1630 (νC=N) 1570, 1490 (νC=C, aromatic) 1150 (νC-O) Example 8 [Production of bis(7-hydroxy-2-benzofuranyl) ketoxime] Bis(6 -hydroxy-2-benzofuranyl)
A mixture with a melting point of 243 to 244°C (decomposition) was prepared in the same manner as in Example 7, except that the bis(7-hydroxy-2-benzofuranyl) ketone obtained in Reference Example 3 was used instead of the ketone and the reaction was carried out under heating and reflux for 2 hours. 0.55 g of bis(7-hydroxy-2-benzofuranyl) ketoxime in the form of a white powder was obtained. Elemental analysis value: C 17 H 11 O 5 N・H 2 O Calculated value: C 62.39 H 4.00 N 4.28 Actual value: C 62.60 H 3.86 N 4.39 Infrared absorption spectrum (cm -1 ; KBr tablet) 3400-3200 (νOH ) 3050-2950 (νCH) 1600 (νC=N) 1550, 1495 (νC=C, aromatic) 1175 (νC-O) Example 9 [Bis(7-methoxy-2-benzofuranyl)
Production of ketoxime] Bis(6-hydroxy-2-benzofuranyl)
Recrystallization from ethanol was performed in the same manner as in Example 7, except that the bis(7-methoxy-2-benzofuranyl) ketone obtained in Reference Example 1 was used instead of the ketone. 7-methoxy-2-benzofuranyl) ketoxime 0.7g
I got it. Elemental analysis value: C 19 H 15 O 5 N Calculated value: C 67.65 H 4.48 N 4.15 Actual value: C 67.90 H 4.54 N 4.07 Infrared absorption spectrum (cm -1 ; KBr tablet) 3000-2900 (νCH) 1610 (νC =N) 1550, 1490 (νC=C, aromatic) Example 10 [Production of bis(7-hydroxy-2-benzofuranyl) ketone thiosemicarbazone] Bis(7-hydroxy-2-benzofuranyl) obtained in Reference Example 3 Mix 0.6 g (0.002 mol) of ketone, 0.3 g (0.003 mol) of thiosemicarbazide, and 40 ml of 95% ethanol, add 4 to 5 drops of concentrated sulfuric acid, heat under reflux for 4 hours, cool the reaction solution, and reduce pressure. When the precipitate is recrystallized from a mixture of ethanol and water, yellow crystalline bis(7-hydroxy-2-benzofuranyl) ketone with a melting point of 202-204°C is obtained. 0.5 g of thiosemicarbazone was obtained. Elemental analysis value: C 18 H 13 O 4 N 3 S・1/2H 2 O Calculated value: C 57.44 H 4.02 N 11.16 Actual value: C 57.70 H 4.30 N 11.40 Infrared absorption spectrum (cm -1 ; KBr tablet) 3500 〜3300 (νOH) 3150 (νNH) 3100〜3000 (νCH) 1620 (νC=N) 1580, 1490 (νC=C, aromatic) 1290 (νC=S) 1180 (νC−O) Example 11 [Bis (6 -Production of hydroxy-2-benzofuranyl) ketone thiosemicarbazone] Bis(7-hydroxy-2-benzofuranyl)
A yellow crystalline bis(6-hydroxy-2-benzofuranyl) ketone with a melting point of 172 to 174°C was prepared in the same manner as in Example 10, except that the bis(6-hydroxy-2-benzofuranyl) ketone obtained in Reference Example 4 was used instead of the ketone. -Benzofuranyl) ketone thiosemicarbazone 0.5g was obtained. Elemental analysis value: C 18 H 13 O 4 N 3 S Calculated value: C 58.85 H 3.57 N 11.44 Actual value: C 58.90 H 3.83 N 11.23 Infrared absorption spectrum (cm -1 ; KBr tablet) 3450-3250 (νOH, νNH 2 ) 3150 (νNH) 3100-2950 (νCH) 1625 (νC=N) 1560, 1480 (νC=C, aromatic) 1270 (νC=S) 1155 (νC-O) Example 12 [Bis(7-hydroxy- Production of 2-benzofuranyl) ketone thiosemicarbazone] Bis(7-hydroxy-2-benzofuranyl)
In the same manner as in Example 10 except that the bis(7-methoxy-2-benzofuranyl) ketone obtained in Reference Example 1 was used instead of the ketone, recrystallization from ethanol yielded bis as yellow needle crystals with a melting point of 203 to 205°C. (7-
0.5 g of methoxy-2-benzofuranyl) ketone thiosemicarbazone was obtained. Elemental analysis value: C 20 H 17 O 4 N 3 S Calculated value: C 60.75 H 4.33 N 10.63 Actual value: C 60.93 H 4.37 N 10.36 Infrared absorption spectrum (cm -1 ; KBr tablet) 3400, 3350 (νNH 2 ) 3250 (νNH) 3100-3000 (νCH) 1610 (νC=N) 1590, 1470 (νC=C, aromatic) 1290 (νC=S) Example 13 [Bis(6-methoxy-2-benzofuranyl)
Production of ketone thiosemicarbazone] Bis(7-hydroxy-2-benzofuranyl)
Recrystallization from ethanol was repeated in the same manner as in Example 10, except that bis(6-methoxy-2-benzofuranyl) ketone obtained in Reference Example 2 was used in place of the ketone. 0.4 g of 6-methoxy-2-benzofuranyl)ketone thiosemicarbazone was obtained. Elemental analysis value: C 20 H 17 O 4 N 3 S Calculated value: C 60.75 H 4.33 N 10.63 Actual value: C 60.49 H 4.35 N 10.55 Infrared absorption spectrum (cm -1 ; KBr tablet) 3450, 3350 (νNH 2 ) 3250 (νNH) 3100-2900 (νCH) 1620 (νC=N) 1600, 1480 (νC=C, aromatic) 1270 (νC=S) Example 14 [Bis(7-β-diethylaminoethoxy-2
-Production of benzofuranyl)ketone guanylhydrazone trihydrochloride] 1.14 g of bis(7-β-diethylaminoethoxy-2-benzofuranyl)ketone obtained in Reference Example 5
(0.002 mol), aminoguanyl bicarbonate 0.28 g
(0.002 mol) and 20 ml of ethanol were mixed, 2 to 2.5 ml of concentrated sulfuric acid was added, and the mixture was heated under reflux for 2.5 hours. After cooling the reaction solution, the precipitate was concentrated under reduced pressure and the precipitate was mixed with a mixture of methanol and ether. 0.9 g of bis(7-β-diethylaminoethoxy-2-benzofuranyl)ketone guanylhydrazone trihydrochloride was obtained as yellow crystals with a melting point of 265-267°C (decomposition). Elemental analysis value: C 30 H 40 N 6 O 4・3HCl Calculated value: C 54.76 H 6.59 N 12.77 Actual value: C 54.99 H 6.73 N 12.70 Infrared absorption spectrum (cm -1 ; KBr tablet) 3300-3150 (νNH 2 , νNH) 3100-2900 (νCH) 2650-2400 (νNH + ) 1680 (νC=N) 1590, 1490 (νC=C, aromatic) Example 15 [Bis(6-β-diethylaminoethoxy-2
-Production of benzofuranyl)ketone guanylhydrazone trihydrochloride] Bis(7-β-diethylaminoethoxy-2-
Instead of benzofuranyl) ketone, bis(6-β-diethylaminoethoxy-2-
benzofuranyl) ketone under heating to reflux.
The same procedure as in Example 14 was carried out except that the reaction was carried out for 6.5 hours.
When recrystallized from a mixture of ethanol and ether, bis(6-β-
diethylaminoethoxy-2-benzofuranyl)
0.6 g of ketone guanyl hydrazone trihydrochloride was obtained. Elemental analysis value: C 30 H 40 N 6 O 4・3HCl Calculated value: C 54.76 H 6.59 N 12.77 Actual value: C 54.51 H 6.70 N 12.56 Infrared absorption spectrum (cm -1 ; KBr tablet) 3400-3200 (νNH 2 , νNH) 3100-2900 (νCH) 2650-2450 (νNH + ) 1675 (νC=N) 1580, 1490 (νC=C, aromatic) Example 16 [Bis(7-methoxy-4-sulfo-2-benzofuranyl) Production of ketone guanyl hydrazone] Bis(7-β-diethylaminoethoxy-2-
A mixture of aqueous methanol and ether was prepared in the same manner as in Example 14, except that the bis(7-methoxy-4-sulfo-2-benzofuranyl) ketone disodium salt obtained in Reference Example 7 was used in place of the benzofuranyl) ketone. When recrystallized from bis(7-methoxy-4-sulfo-2
-Benzofuranyl)ketoneguanylhydrazone
I got 0.8g. Elemental analysis value: C 20 H 18 O 10 N 4 S 2 Calculated value: C 44.61 H 3.37 N 10.40 Actual value: C 44.83 H 3.58 N 10.53 Infrared absorption spectrum (cm -1 ; KBr tablet) 3550-3250 (νNH 2 , νNH) 3150-2900 (νCH) 1690 (νC=N) 1580, 1490 (νC=C, aromatic) 1160, 1040 ( νSO3H ) Example 17 [Antiviral test in chicken fetal fibroblasts] 10-11 Fetuses from day-old embryonated chicken eggs were cultured in a conventional manner, and primary chicken fetal fibroblasts cultured for 20 to 24 hours were diluted with various concentrations of bisbenzofuranyl ketone compounds dissolved in methanol or water and culture medium. Influenza A-PR8 was challenged almost simultaneously (last challenge m.o.i = 0.1 to 0.2).
After that, the cells were incubated at 37°C, and after 48 hours, the amount of virus in the culture medium was determined by HA (hemagglutination) test, and the amount of virus in the cells was determined by heme adsorption. The minimum concentration for expression of activity was determined. The cytotoxicity of the test compound was examined in the same experimental system as above without virus challenge, and the effectiveness coefficient was determined from the following formula. Effectiveness coefficient=minimum concentration for cytotoxicity/minimum concentration for antiviral activity For comparison, the same test as above was conducted on Amantadine, which has been conventionally used as an antiviral agent. These results are shown in Table 1.
【表】【table】
Claims (1)
NHCOOCH2CH3、−OHまたは−NHCSNH2、
R1は水素または−SO3H、R2は水素、炭素数1〜
3個の低級アルキル基、または式 (式中、mは1〜3の整数、R3およびR4はそれ
ぞれ炭素数1〜3個の低級アルキル基を表わす)
で示される置換アミノアルキル基を表わし、R1
基およびOR2基はベンゾフラン環の4、5、6ま
たは7位の任意の位置に置換している〕で示され
るビスベンゾフラニルケトン誘導体およびその
塩。 2 ビス(6−ヒドロキシ−2−ベンゾフラニ
ル)ケトングアニルヒドラゾンである特許請求の
範囲第1項記載のビスベンゾフラニルケトン誘導
体およびその塩。 3 ビス(7−メトキシ−2−ベンゾフラニル)
ケトングアニルヒドラゾンである特許請求の範囲
第1項記載のビスベンゾフラニルケトン誘導体お
よびその塩。 4 ビス(6−メトキシ−2−ベンゾフラニル)
ケトングアニルヒドラゾンである特許請求の範囲
第1項記載のビスベンゾフラニルケトン誘導体お
よびその塩。 5 ビス(6−ヒドロキシ−2−ベンゾフラニ
ル)ケトンチオセミカルバゾンである特許請求の
範囲第1項記載のビスベンゾフラニルケトン誘導
体およびその塩。 6 ビス(7−β−ジエチルアミノエトキシ−2
−ベンゾフラニル)ケトングアニルヒドラゾンで
ある特許請求の範囲第1項記載のビスベンゾフラ
ニルケトン誘導体およびその塩。 7 ビス(6−β−ジエチルアミノエトキシ−2
−ベンゾフラニル)ケトングアニルヒドラゾンで
ある特許請求の範囲第1項記載のビスベンゾフラ
ニルケトン誘導体およびその塩。 8 一般式 〔式中、R1は水素または−SO3H、R2は水素、炭
素数1〜3個の低級アルキル基、または式 (式中、mは1〜3の整数、R3およびR4はそれ
ぞれ炭素数1〜3個の低級アルキル基を表わす)
で示される置換アミノアルキル基を表わし、R1
基およびOR2基はベンゾブラン環の4、5、6ま
たは7位の任意の位置に置換している〕で示され
るビスベンゾフラニルケトン化合物を一般式 R−NH2 () (式中、Rは−NHC(NH)NH2、−
NHCOOCH2CH3、−OH基または−NHCSNH2
を表わす)で示されるアミノ化合物と反応させる
ことを特徴とする一般式 (式中、R、R1およびR2基は前記と同じものを
意味し、R1基およびOR2基はベンゾフラン環の
4、5、6または7位の任意の位置に置換してい
る)で示されるビスベンゾフラニルケトン誘導体
およびその塩の製法。 9 一般式()においてR2が水素である特許
請求の範囲第8項記載の製法。[Claims] 1. General formula [In the formula, R is -NHC(NH) NH2 , -
NHCOOCH2CH3 , -OH or -NHCSNH2 ,
R 1 is hydrogen or −SO 3 H, R 2 is hydrogen, carbon number 1-
3 lower alkyl groups, or formula (In the formula, m is an integer of 1 to 3, R 3 and R 4 each represent a lower alkyl group having 1 to 3 carbon atoms)
represents a substituted aminoalkyl group represented by R 1
and OR2 group are substituted at any position of the 4, 5, 6 or 7 position of the benzofuran ring] and salts thereof. 2. The bisbenzofuranyl ketone derivative and its salt according to claim 1, which is bis(6-hydroxy-2-benzofuranyl) ketone guanyl hydrazone. 3 Bis(7-methoxy-2-benzofuranyl)
The bisbenzofuranyl ketone derivative and its salt according to claim 1, which is a ketone guanyl hydrazone. 4 Bis(6-methoxy-2-benzofuranyl)
The bisbenzofuranyl ketone derivative and its salt according to claim 1, which is a ketone guanyl hydrazone. 5. The bisbenzofuranyl ketone derivative and its salt according to claim 1, which is bis(6-hydroxy-2-benzofuranyl) ketone thiosemicarbazone. 6 Bis(7-β-diethylaminoethoxy-2
The bisbenzofuranyl ketone derivative and its salt according to claim 1, which is guanyl hydrazone (benzofuranyl)ketone. 7 Bis(6-β-diethylaminoethoxy-2
The bisbenzofuranyl ketone derivative and its salt according to claim 1, which is guanyl hydrazone (benzofuranyl)ketone. 8 General formula [In the formula, R 1 is hydrogen or -SO 3 H, R 2 is hydrogen, a lower alkyl group having 1 to 3 carbon atoms, or the formula (In the formula, m is an integer of 1 to 3, R 3 and R 4 each represent a lower alkyl group having 1 to 3 carbon atoms)
represents a substituted aminoalkyl group represented by R 1
group and OR2 group are substituted at any position of the 4 , 5, 6, or 7 position of the benzobran ring]. is −NHC(NH)NH 2 , −
NHCOOCH 2 CH 3 , -OH group or -NHCSNH 2
A general formula characterized by reacting with an amino compound represented by (In the formula, R, R 1 and R 2 groups have the same meanings as above, and R 1 group and OR 2 group are substituted at any position of the 4, 5, 6 or 7 position of the benzofuran ring) A method for producing a bisbenzofuranyl ketone derivative and a salt thereof. 9. The manufacturing method according to claim 8, wherein in the general formula (), R 2 is hydrogen.
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JP8078383A JPS59206378A (en) | 1983-05-11 | 1983-05-11 | Bisbenzofuranyl ketone derivative and its preparation |
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JP8078383A JPS59206378A (en) | 1983-05-11 | 1983-05-11 | Bisbenzofuranyl ketone derivative and its preparation |
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JPS59206378A JPS59206378A (en) | 1984-11-22 |
JPH0434553B2 true JPH0434553B2 (en) | 1992-06-08 |
Family
ID=13728037
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JP (1) | JPS59206378A (en) |
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DE19547263C2 (en) * | 1995-12-07 | 1999-04-29 | Cardiotec Inc | Amidinohydrazones of ketones derived from benzo [b] furan, processes for their preparation and medicaments containing these compounds |
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1983
- 1983-05-11 JP JP8078383A patent/JPS59206378A/en active Granted
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