JP802H - Aminophenyltetrazole derivative and its salt - Google Patents
Aminophenyltetrazole derivative and its saltInfo
- Publication number
- JP802H JP802H JP802H JP 802 H JP802 H JP 802H JP 802 H JP802 H JP 802H
- Authority
- JP
- Japan
- Prior art keywords
- tetrazole
- compound
- general formula
- aminophenyl
- salt
- 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.)
- Active
Links
- 150000003839 salts Chemical class 0.000 title claims description 7
- 239000011780 sodium chloride Substances 0.000 title claims description 7
- GUCGQKSPWMDAEX-UHFFFAOYSA-N 2-(2H-tetrazol-5-yl)aniline Chemical class NC1=CC=CC=C1C1=NNN=N1 GUCGQKSPWMDAEX-UHFFFAOYSA-N 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 23
- 150000003536 tetrazoles Chemical class 0.000 claims description 16
- 150000001768 cations Chemical class 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000002844 melting Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- -1 Na and K Chemical class 0.000 description 11
- 238000003756 stirring Methods 0.000 description 10
- 238000001816 cooling Methods 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- JRMAQQQTXDJDNC-UHFFFAOYSA-M 2-ethoxy-2-oxoacetate Chemical compound CCOC(=O)C([O-])=O JRMAQQQTXDJDNC-UHFFFAOYSA-M 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- FLGISLVJQPPAMV-UHFFFAOYSA-N 3-(2H-tetrazol-5-yl)aniline Chemical compound NC1=CC=CC(C2=NNN=N2)=C1 FLGISLVJQPPAMV-UHFFFAOYSA-N 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000038129 antigens Human genes 0.000 description 3
- 108091007172 antigens Proteins 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- QFMJGOBQEYOAPB-UHFFFAOYSA-N 5-methoxy-2-(2H-tetrazol-5-yl)aniline Chemical compound NC1=CC(OC)=CC=C1C1=NN=NN1 QFMJGOBQEYOAPB-UHFFFAOYSA-N 0.000 description 2
- RRIXKCUWIAEILY-UHFFFAOYSA-N 5-methyl-2-(2H-tetrazol-5-yl)aniline Chemical compound NC1=CC(C)=CC=C1C1=NN=NN1 RRIXKCUWIAEILY-UHFFFAOYSA-N 0.000 description 2
- MXZUDRZKSUUQRR-UHFFFAOYSA-N Ammonium azide Chemical compound N.N=[N+]=[N-] MXZUDRZKSUUQRR-UHFFFAOYSA-N 0.000 description 2
- KBNIFDASRCWYGC-GXNXWABVSA-J Evans blue Chemical compound [Na+].[Na+].[Na+].[Na+].C\1=CC2=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C(N)=C2C(=O)C/1=N/NC(C(C)=C1)=CC=C1C1=CC=C(N\N=C/2C(C3=C(N)C(=CC(=C3C=C\2)S([O-])(=O)=O)S([O-])(=O)=O)=O)C(C)=C1 KBNIFDASRCWYGC-GXNXWABVSA-J 0.000 description 2
- 229960003699 Evans blue Drugs 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 210000003491 Skin Anatomy 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- OERKZOSLSXFLMY-UHFFFAOYSA-N 2-amino-4,5-dichlorobenzonitrile Chemical compound NC1=CC(Cl)=C(Cl)C=C1C#N OERKZOSLSXFLMY-UHFFFAOYSA-N 0.000 description 1
- UZHALXIAWJOLLR-UHFFFAOYSA-N 2-amino-4-chlorobenzonitrile Chemical compound NC1=CC(Cl)=CC=C1C#N UZHALXIAWJOLLR-UHFFFAOYSA-N 0.000 description 1
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical compound NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 description 1
- SWBDKCMOLSUXRH-UHFFFAOYSA-N 2-nitrobenzonitrile Chemical compound [O-][N+](=O)C1=CC=CC=C1C#N SWBDKCMOLSUXRH-UHFFFAOYSA-N 0.000 description 1
- VORQZLYWSQPYQI-UHFFFAOYSA-N 4,5-dichloro-2-(2H-tetrazol-5-yl)aniline Chemical compound NC1=CC(Cl)=C(Cl)C=C1C1=NN=NN1 VORQZLYWSQPYQI-UHFFFAOYSA-N 0.000 description 1
- KTPONJJKCBOJCQ-UHFFFAOYSA-N 4-(2H-tetrazol-5-yl)aniline Chemical compound C1=CC(N)=CC=C1C1=NNN=N1 KTPONJJKCBOJCQ-UHFFFAOYSA-N 0.000 description 1
- BUSUUPIMJLVUGH-UHFFFAOYSA-N 4-chloro-2-(2H-tetrazol-5-yl)aniline Chemical compound NC1=CC=C(Cl)C=C1C1=NN=NN1 BUSUUPIMJLVUGH-UHFFFAOYSA-N 0.000 description 1
- HENCYJMPEDACFZ-UHFFFAOYSA-N 5-(2-nitrophenyl)-2H-tetrazole Chemical compound [O-][N+](=O)C1=CC=CC=C1C1=NNN=N1 HENCYJMPEDACFZ-UHFFFAOYSA-N 0.000 description 1
- KKTZHFZXGZLTLZ-UHFFFAOYSA-N 5-chloro-2-(2H-tetrazol-5-yl)aniline Chemical compound NC1=CC(Cl)=CC=C1C1=NNN=N1 KKTZHFZXGZLTLZ-UHFFFAOYSA-N 0.000 description 1
- 241000244188 Ascaris suum Species 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- JKRZOJADNVOXPM-UHFFFAOYSA-N Oxalic acid dibutyl ester Chemical compound CCCCOC(=O)C(=O)OCCCC JKRZOJADNVOXPM-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J Tin(IV) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N Trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000002052 anaphylactic Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003266 anti-allergic Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N ethanolamine Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- JMHRGKDWGWORNU-UHFFFAOYSA-M sodium;2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetate Chemical compound [Na+].CC1=C(CC([O-])=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 JMHRGKDWGWORNU-UHFFFAOYSA-M 0.000 description 1
- POECFFCNUXZPJT-UHFFFAOYSA-M sodium;carbonic acid;hydrogen carbonate Chemical compound [Na+].OC(O)=O.OC([O-])=O POECFFCNUXZPJT-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Description
【発明の詳細な説明】
本発明は、一般式（Ｉ）
（但し、式中Ｒ１は低級アルキル基を示し、Ｒ２及びＲ
３は水素原子、低級アルキル基、低級アルコキシ基又は
ハロゲン原子を示す。）で示されるアミノフェニルテト
ラゾール誘導体及びその薬学上適当なカチオンとの塩に
関する。
但し、上記一般式（Ｉ）の化合物中、５−（２−アルキ
ルオキサリルアミノフェニル）テトラゾール、即ちアル
キルオキサリルアミノ基（R1O-CO-CO-NH-）がフェニル
環上、テトラゾール環との結合位置に対して２−位置に
結合しており、Ｒ２及びＲ３が共に水素原子である化合
物及びその薬学上適当なカチオンとの塩は、特願昭５４
−１１５１８１号（特開昭５６−４０６７３号、特公昭
５９−１７０４号）に開示されており、本発明から除か
れる。
本発明に係る一般式（Ｉ）で示される化合物はいずれも
優れた抗アレルギー作用を有し、且つ低毒性であること
から医薬品として有用である。
この化合物（Ｉ）を医薬品として製剤化する場合使用目
的により、又は溶解性を調節するため薬学上適当なカチ
オンとの塩にすることが出来る。
この場合、カチオンはテトラゾール環のＨ＋が離脱した
アニオンに付加した形の塩を形成する。
本発明で利用する薬学上適当なカチオンは、通常利用さ
れているＮａ、Ｋ等のアルカリ金属、Ｃａ、Ｍｇ等のア
ルカリ土類金属、Ａｌ等その他適当な金属あるいは、ア
ンモニア、トリメチルアミン、トリエチルアミン、トリ
ス（ヒドロキシメチル）アミノメタン等のカチオンを適
宜選択することが出来る。
本発明の化合物は下記の反応式で示される方法により製
造することが出来る。（但し、式中Ｒ１、Ｒ２及びＲ３は前記と同じ意義を示
し、Ａはハロゲン原子又は低級アルコキシ基を示す。）
即ち、一般式（II）で示されるアミノフェニルテトラゾ
ール系化合物と一般式（III）で示されるオキサリル誘
導体とを適当な溶媒中で、必要に応じ塩基の共存下、反
応させることにより一般式（Ｉ）の目的化合物を製造す
ることが出来る。
本発明に於て使用する溶媒は特に限定されるものでな
く、通常の有機合成反応に使用される不活性有機溶媒例
えば、クロロホルム、メチレンクロライド、ベンゼン、
トルエン、キシレン、メタノール、エタノール、アセト
ン、テトラヒドロフラン、ピリジン、ジメチルホルムア
ミド等が使用出来る。
一般式（III）の化合物のＡがハロゲンの場合は、通常
塩基の共存下、化合物（II）に対し1.2〜２倍モルの割
合で滴下撹拌すれば室温で容易に反応し、目的化合物
（Ｉ）を得ることが出来る。
塩基としては、有機塩基のみならず炭酸ナトリウム、炭
酸カリウム等の無機塩基を使用することが出来る。
反応混合物中の目的化合物（Ｉ）は、反応終了後、溶媒
を留去し、残留物をアルカリで溶解し、酸を加えて結晶
を析出させて分離することが出来る。
一般式（III）の化合物のＡがアルコキシ基の場合は、
この出発原料を有機溶媒で使用せずそのまま、（II）の
化合物に対して５〜１０倍量使用して反応させることが
出来る。この場合反応は１００〜１８０℃に加熱して行
なうのが好ましい。反応終了後、反応混合物を冷却すれ
ば目的化合物は結晶として析出するので濾過により分離
し、これを再結晶して高純度品を得ることが出来る。
本発明の目的化合物（Ｉ）を製造するために使用する式
（II）のアミノフェニルテトラゾール類化合物は、反応
するニトロフェニルテトラゾールを塩酸と錫、あるいは
塩酸と塩化錫で還元するか、又は対応するアミノベンゾ
ニトリルをナトリウムアジド、アンモニウムアジド等と
ジメチルスルホキサイド等の溶媒中で加熱下に反応させ
て製造することが出来る。
これらの化合物のうち文献未記載のものとしては５−
（４−メチル−２−アミノフェニル）テトラゾール（融
点163.5〜165.5℃）、５−（４−メトキシ−２−アミノ
フェニル）テトラゾール（融点188.5〜189.3℃）、５−
（４−クロロ−２−アミノフェニル）テトラゾール（融
点２０６〜２０７℃）、５−（５−クロロ−２−アミノ
フェニル）テトラゾール（融点２０５〜２０６℃）、５
−（４，５−ジクロロ−２−アミノフェニル）テトラゾ
ール（融点２５１〜２５２℃）等を挙げることが出来
る。
ニトロフェニルテトラゾール類化合物は対応するニトロ
ベンゾニトリルをナトリウムアジド、アンモニウムアジ
ド等とジメチルスルホキサイド、ジメチルホルムアミド
等の溶媒中で加熱下に反応させて製造することが出来
る。
これらの化合物のうち文献未記載のものとしては、５−
（４−メチル−２−ニトロフェニル）テトラゾール（融
点１８２〜１８３℃）、５−（４−メトキシ−２−ニト
ロフェニル）テトラゾール（融点１７２〜１７５℃）、
５−（５−クロロ−２−ニトロフェニル）テトラゾール
（融点１６５〜１６７℃）等を挙げることが出来る。
出発原料であるアミノベンゾニトリル類化合物は、次に
反応式をもって示す方法により製造することが出来る。これらの化合物としては、４，５−ジクロロ−２−アミ
ノベンゾニトリル（融点１６６℃）、４−クロロ−２−
アミノベンゾニトリル等を挙げることが出来る。
以下本発明を実施例により説明する。
実施例１
５−（３−アミノフェニル）テトラゾール１ｇ、ピリジ
ン１５mlの混合物に氷冷、撹拌下にエチルオキサリルク
ロライド1.27ｇを３０分間で滴下する。滴下終了後、徐
々に温度を上げ、室温で２時間反応させる。反応混合物
を減圧下に濃縮し、残留物に炭酸ナトリウム溶液を加え
て溶解後、希塩酸で弱酸性として析出する沈殿を濾過
し、５−（３−エチルオキサリルアミノフェニル）テト
ラゾールを得る。
収量0.70ｇ、メタノールより再結晶を行なったものの融
点１９３〜１９５℃
核磁気共鳴スペクトル（ＤＭＳＯ−ｄ６、６０MHz）
1.43ppm（ｔ、３Ｈ）、4.50ppm（ｑ、２Ｈ）、7.57〜8.
97ppm（ｍ、４Ｈ）、11.15ppm（ｓ、１Ｈ）、14.87ppm
（ブロードｓ、１Ｈ）
実施例２
５−（３−アミノフェニル）テトラゾール1.65ｇにエチ
ルオキサレート１５mlを加え浴温１５０℃で撹拌しなが
ら３時間反応する。冷却後析出した結晶を濾過し、メタ
ノールより再結晶して５−（３−エチルオキサリルアミ
ノフェニル）テトラゾールを得る。
収量1.75ｇ実施例１で得たものと混融しても融点降下を
示さず。
実施例３
５−（３−アミノフェニル）テトラゾール1.7ｇにｎ−
ブチルオキサレート１２mlを加え浴温１６５〜１７５℃
で撹拌しながら１1/2時間反応する。冷却後析出した結
晶を濾過し、５−（３−ｎ−ブチルオキサリルアミノフ
ェニル）テトラゾールを得る。
収量2.3ｇ、アセトン−ｎ−ヘキサンより再結晶したも
のの融点１５７〜１５８℃
核磁気共鳴スペクトル（ＤＭＳＯ−ｄ６、６０MHz）
1.03ppm（ｍ、３Ｈ）、1.23〜2.17ppm（ｍ、４Ｈ）、4.
40ppm（ｔ、２Ｈ）、7.57〜8.77ppm（ｍ、４Ｈ）、11.2
0ppm（ｓ、１Ｈ）、11.90ppm（ブロードｓ、１Ｈ）
実施例４
５−（４−アミノフェニル）テトラゾール1.8ｇにエチ
ルオキサレート１８mlを加え浴温１５０℃で撹拌しなが
ら３時間反応する。冷却後析出した結晶を濾過し、５−
（４−エチルオキサリルアミノフェニル）テトラゾール
を得る。
収量2.69ｇメタノールより再結晶したものの融点228.5
〜230.5℃
核磁気共鳴スペクトル（ＤＭＳＯ−ｄ６、６０MHz）
1.43ppm（ｔ、３Ｈ）、4.48ppm（ｑ、２Ｈ）、8.19ppm
（ｓ、４Ｈ）、11.15ppm（ｓ、１Ｈ）、14.37ppm（ブロ
ードｓ、１Ｈ）
実施例５
５−（４−メチル−２−アミノフェニル）テトラゾール
2.1ｇにエチルオキサレート２０mlを加え浴温１５０℃
で撹拌しながら２時間反応する。冷却後析出した結晶を
濾過し、５−（４−メチル−２−エチルオキサリルアミ
ノフェニル）テトラゾールを得る。
収量1.7ｇ、アセトン−ｎ−ヘキサンより再結晶したも
のの融点222.〜223.5℃
核磁気共鳴スペクトル（ＤＭＳＯ−ｄ６、６０MHz）
1.45ppm（ｔ、３Ｈ）、2.43ppm（ｓ、３Ｈ）、4.46ppm
（ｑ、２Ｈ）、7.08〜8.06ppm（ｍ、３Ｈ）、12.42ppm
（ｓ、１Ｈ）、13.67ppm（ブロードｓ、１Ｈ）
実施例６
５−（４−メトキシ−２−アミノフェニル）テトラゾー
ル1.18ｇにエチルオキサレート１０mlを加え浴温１５０
℃で撹拌しながら２時間反応する。冷却後析出した結晶
を濾過し、５−（４−メトキシ−２−エチルオキサリル
アミノフェニル）テトラゾールを得る。
収量1.52ｇ、メタノールより再結晶したものの融点２２
４〜２２５℃
核磁気共鳴スペクトル（ＤＭＳＯ−ｄ６、６０MHz）
1.43ppm（ｔ、３Ｈ）、3.88ppm（ｓ、３Ｈ）、4.44ppm
（ｑ、２Ｈ）、6.95ppm（dd、Ｊ＝4.5、１Hz、１Ｈ）、
7.98ppm（ｄ、Ｊ＝4.5Hz、１Ｈ）、8.28ppm（ｄ、Ｊ＝
１Hz、１Ｈ）、13.92ppm(s)
実施例７
５−（４−クロロ−２−アミノフェニル）テトラゾール
0.7ｇにエチルオキサレート７mlを加え浴温１５０℃で
撹拌しながら２1/2時間反応する。冷却後析出した結晶
を濾過し、５−（４−クロロ−２−エチルオキサリルア
ミノフェニル）テトラゾールを得る。
収量0.69ｇ、メタノールより再結晶したものの融点２１
５℃
核磁気共鳴スペクトル（ＤＭＳＯ−ｄ６、６０MHz）
1.45ppm（ｔ、３Ｈ）、4.43ppm（ｑ、２Ｈ）、7.42ppm
（dd、Ｊ＝4.5、１Hz、１Ｈ）、8.07ppm（ｄ、Ｊ＝4.5H
z、１Ｈ）、8.62ppm（ｄ、Ｊ＝１Hz、１Ｈ）、12.53ppm
（ｓ、１Ｈ）、13.88ppm（ブロードｓ、１Ｈ）
実施例８
５−（５−クロロ−２−アミノフェニル）テトラゾール
0.70ｇにエチルオキサレート７mlを加え浴温１５０℃で
撹拌しながら２1/2時間反応する。冷却後析出した結晶
を濾別し、５−（５−クロロ−２−エチルオキサリルア
ミノフェニル）テトラゾールを得る。
収量0.81ｇ、アセトン−ｎ−ヘキサンより再結晶したも
のの融点208.5〜209.5℃
実施例９
５−（４，５−ジクロロ−２−アミノフェニル）テトラ
ゾール0.66ｇにエチルオキサレート0.7mlを加え浴温１
５０〜１６０℃で撹拌しながら３1/2時間反応する。冷
却後析出した結晶を濾過し、５−（４，５−ジクロロ−
２−エチルオキサリルアミノフェニル）テトラゾールを
得る。
収量0.70ｇ、メタノールより再結晶したものの融点204.
5〜205.5℃
核磁気共鳴スペクトル（ＤＭＳＯ−ｄ６、６０MHz）
1.47ppm（ｔ、３Ｈ）、4.35ppm（ｑ、２Ｈ）、8.30ppm
（ｓ、１Ｈ）、8.87ppm（ｓ、１Ｈ）、13.57ppm（ブロ
ードｓ、２Ｈ）
参考例
ラット受身皮膚アナフイラキシー検定（ＰＣＡ）を次の
ように行なった。
ウイスター系雄性ラットの背部皮内に希釈した抗血清
（青色斑の面積が１００mm2前後となる様適宜希釈、0.1
ml/site）を注射して受身的に感作し、４８時間経過後
に抗原ＤＮＰ−ＡＳ（ブタ回虫より精製した蛋白質との
結合物）２mgを含む1.0％エバンスブルー0.5mlを静脈内
に注入する。抗原及びエバンスブルー注射３０分後に放
血致死、青色斑の径を測定する。被験薬はＮａ塩水溶液
を使用し、抗原投与前に経口投与または静脈内投与を行
なった
５−（３−エチルオキサリルアミノフェニル）テトラゾ
ールの５０％抑制投与量は
経口投与では39.1mg/kg
静脈投与では0.54mg/kgである。
なお、この化合物の急性毒性試験はddy系マウス４週
令、群１０匹のマウスを使用し、Litchfield-Wilcoxon
法により行なった。
腹腔内注射の場合ＬＤ50（ｉＰ）＝１６００mg/kg。DETAILED DESCRIPTION OF THE INVENTION The present invention has the general formula (I) (However, in the formula, R 1 represents a lower alkyl group, and R 2 and R
3 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom. And an aminophenyltetrazole derivative represented by the formula (4) and a salt thereof with a pharmaceutically suitable cation. However, in the compound of the above general formula (I), 5- (2-alkyloxalylaminophenyl) tetrazole, that is, an alkyloxalylamino group (R 1 O-CO-CO-NH-) has a tetrazole ring on the phenyl ring. A compound which is bonded at the 2-position with respect to the bonding position and in which R 2 and R 3 are both hydrogen atoms and a salt thereof with a pharmaceutically suitable cation are disclosed in Japanese Patent Application No.
-115181 (JP-A-56-40673, JP-B-59-1704), which is excluded from the present invention. All of the compounds represented by the general formula (I) according to the present invention have excellent antiallergic activity and low toxicity, and are therefore useful as pharmaceuticals. When this compound (I) is formulated as a medicine, it can be converted into a salt with a pharmaceutically suitable cation depending on the purpose of use or to adjust the solubility. In this case, the cation forms a salt in which H + of the tetrazole ring is added to the released anion. The pharmaceutically suitable cations used in the present invention include commonly used alkali metals such as Na and K, alkaline earth metals such as Ca and Mg, other suitable metals such as Al, or ammonia, trimethylamine, triethylamine, tris. A cation such as (hydroxymethyl) aminomethane can be appropriately selected. The compound of the present invention can be produced by the method represented by the following reaction formula. (However, in the formula, R 1 , R 2 and R 3 have the same meanings as described above, and A represents a halogen atom or a lower alkoxy group.) That is, the aminophenyltetrazole compound represented by the general formula (II) and the general formula The target compound of the general formula (I) can be produced by reacting the oxalyl derivative represented by the formula (III) with a suitable solvent in the presence of a base, if necessary. The solvent used in the present invention is not particularly limited, inert organic solvents used in ordinary organic synthesis reactions, for example, chloroform, methylene chloride, benzene,
Toluene, xylene, methanol, ethanol, acetone, tetrahydrofuran, pyridine, dimethylformamide and the like can be used. When A of the compound of the general formula (III) is halogen, it is easily reacted at room temperature by dropping and stirring 1.2 to 2 times the molar amount of the compound (II) in the coexistence of a base to easily react with the target compound (I ) Can be obtained. As the base, not only an organic base but also an inorganic base such as sodium carbonate or potassium carbonate can be used. After completion of the reaction, the target compound (I) in the reaction mixture can be separated by distilling off the solvent, dissolving the residue with an alkali, and adding an acid to precipitate crystals. When A of the compound of the general formula (III) is an alkoxy group,
This starting material can be reacted in the amount of 5 to 10 times the amount of the compound of (II) without using it as an organic solvent. In this case, the reaction is preferably carried out by heating at 100 to 180 ° C. After completion of the reaction, if the reaction mixture is cooled, the target compound precipitates as crystals, which can be separated by filtration and recrystallized to obtain a high-purity product. The aminophenyltetrazole compound of formula (II) used for producing the object compound (I) of the present invention is obtained by reducing the reacting nitrophenyltetrazole with hydrochloric acid and tin, or hydrochloric acid and tin chloride, or the corresponding compound. It can be produced by reacting aminobenzonitrile with sodium azide, ammonium azide or the like in a solvent such as dimethyl sulfoxide under heating. Among these compounds, those not described in the literature are 5-
(4-Methyl-2-aminophenyl) tetrazole (melting point 163.5-165.5 ° C), 5- (4-methoxy-2-aminophenyl) tetrazole (melting point 188.5-189.3 ° C), 5-
(4-chloro-2-aminophenyl) tetrazole (melting point 206-207 ° C), 5- (5-chloro-2-aminophenyl) tetrazole (melting point 205-206 ° C), 5
Examples include-(4,5-dichloro-2-aminophenyl) tetrazole (melting point 251 to 252 ° C). The nitrophenyltetrazole compound can be produced by reacting the corresponding nitrobenzonitrile with sodium azide, ammonium azide or the like in a solvent such as dimethyl sulfoxide or dimethylformamide under heating. Among these compounds, those not described in the literature include 5-
(4-methyl-2-nitrophenyl) tetrazole (melting point 182 to 183 ° C), 5- (4-methoxy-2-nitrophenyl) tetrazole (melting point 172 to 175 ° C),
Examples include 5- (5-chloro-2-nitrophenyl) tetrazole (melting point: 165 to 167 ° C). The aminobenzonitrile compound as a starting material can be produced by the method shown by the following reaction formula. These compounds include 4,5-dichloro-2-aminobenzonitrile (melting point 166 ° C.), 4-chloro-2-
Aminobenzonitrile etc. can be mentioned. The present invention will be described below with reference to examples. Example 1 To a mixture of 1 g of 5- (3-aminophenyl) tetrazole and 15 ml of pyridine, 1.27 g of ethyloxalyl chloride was added dropwise over 30 minutes with ice cooling and stirring. After completion of the dropping, the temperature is gradually raised and the reaction is allowed to proceed at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, a sodium carbonate solution is added to the residue to dissolve it, and the precipitate that is weakly acidic with dilute hydrochloric acid is filtered to obtain 5- (3-ethyloxalylaminophenyl) tetrazole. Yield 0.70 g, melting point of recrystallized from methanol 193-195 ° C. Nuclear magnetic resonance spectrum (DMSO-d 6 , 60 MHz) 1.43 ppm (t, 3H), 4.50 ppm (q, 2H), 7.57-8.
97ppm (m, 4H), 11.15ppm (s, 1H), 14.87ppm
(Broads, 1H) Example 2 15 ml of ethyl oxalate was added to 1.65 g of 5- (3-aminophenyl) tetrazole, and the mixture was reacted at a bath temperature of 150 ° C. for 3 hours with stirring. After cooling, the precipitated crystals are filtered and recrystallized from methanol to give 5- (3-ethyloxalylaminophenyl) tetrazole. Yield 1.75 g No melting point drop when mixed with the product obtained in Example 1. Example 3 n-into 1.7 g of 5- (3-aminophenyl) tetrazole
Add 12 ml of butyl oxalate and bath temperature 165-175 ° C
React for 11/2 hours with stirring. The crystals precipitated after cooling were filtered to obtain 5- (3-n-butyloxalylaminophenyl) tetrazole. Yield 2.3 g, melting point of recrystallized product from acetone-n-hexane 157-158 ° C Nuclear magnetic resonance spectrum (DMSO-d 6 , 60 MHz) 1.03 ppm (m, 3H), 1.23-2.17 ppm (m, 4H), 4 .
40ppm (t, 2H), 7.57-8.77ppm (m, 4H), 11.2
0 ppm (s, 1H), 11.90 ppm (broad s, 1H) Example 4 18 g of ethyl oxalate was added to 1.8 g of 5- (4-aminophenyl) tetrazole, and the mixture was reacted at a bath temperature of 150 ° C. for 3 hours while stirring. After cooling, the precipitated crystals were filtered,
(4-Ethyloxalylaminophenyl) tetrazole is obtained. Yield 2.69g, recrystallized from methanol, mp 228.5
-230.5 ° C Nuclear magnetic resonance spectrum (DMSO-d 6 , 60MHz) 1.43ppm (t, 3H), 4.48ppm (q, 2H), 8.19ppm
(S, 4H), 11.15ppm (s, 1H), 14.37ppm (broad s, 1H) Example 5 5- (4-methyl-2-aminophenyl) tetrazole
20 ml of ethyl oxalate was added to 2.1 g, and the bath temperature was 150 ° C.
React for 2 hours with stirring. The crystals precipitated after cooling were filtered to obtain 5- (4-methyl-2-ethyloxalylaminophenyl) tetrazole. Yield 1.7 g, although recrystallized from acetone -n- hexane mp 222.～223.5 ° C. Nuclear magnetic resonance spectrum (DMSO-d 6, 60MHz) 1.45ppm (t, 3H), 2.43ppm (s, 3H), 4.46ppm
(Q, 2H), 7.08 ~ 8.06ppm (m, 3H), 12.42ppm
(S, 1H), 13.67 ppm (broad s, 1H) Example 6 To 1.18 g of 5- (4-methoxy-2-aminophenyl) tetrazole, 10 ml of ethyl oxalate was added and the bath temperature was 150.
React for 2 hours with stirring at ℃. The crystals precipitated after cooling were filtered to obtain 5- (4-methoxy-2-ethyloxalylaminophenyl) tetrazole. Yield 1.52g, melting point 22 after recrystallization from methanol
4-225 ° C Nuclear magnetic resonance spectrum (DMSO-d 6 , 60MHz) 1.43ppm (t, 3H), 3.88ppm (s, 3H), 4.44ppm
(Q, 2H), 6.95ppm (dd, J = 4.5, 1Hz, 1H),
7.98ppm (d, J = 4.5Hz, 1H), 8.28ppm (d, J =
1Hz, 1H), 13.92ppm (s) Example 7 5- (4-chloro-2-aminophenyl) tetrazole
Ethyl oxalate (7 ml) was added to 0.7 g, and the mixture was reacted at a bath temperature of 150 ° C for 21/2 hours with stirring. After cooling, the precipitated crystals are filtered to give 5- (4-chloro-2-ethyloxalylaminophenyl) tetrazole. Yield 0.69g, melting point 21 after recrystallization from methanol
5 ° C Nuclear magnetic resonance spectrum (DMSO-d 6 , 60MHz) 1.45ppm (t, 3H), 4.43ppm (q, 2H), 7.42ppm
(Dd, J = 4.5, 1Hz, 1H), 8.07ppm (d, J = 4.5H
z, 1H), 8.62ppm (d, J = 1Hz, 1H), 12.53ppm
(S, 1H), 13.88 ppm (broad s, 1H) Example 8 5- (5-chloro-2-aminophenyl) tetrazole
Ethyl oxalate (7 ml) was added to 0.70 g, and the mixture was reacted at a bath temperature of 150 ° C for 21/2 hours with stirring. After cooling, the precipitated crystals are filtered off to obtain 5- (5-chloro-2-ethyloxalylaminophenyl) tetrazole. Yield 0.81 g, melting point of the product recrystallized from acetone-n-hexane 208.5 to 209.5 ° C. Example 9 0.76 ml of ethyl oxalate was added to 0.66 g of 5- (4,5-dichloro-2-aminophenyl) tetrazole, and the bath temperature 1
The mixture is reacted at 50 to 160 ° C. for 31/2 hours while stirring. After cooling, the precipitated crystals were filtered, and 5- (4,5-dichloro-
2-Ethyloxalylaminophenyl) tetrazole is obtained. Yield 0.70g, melting point 204 after recrystallization from methanol.
From 5 to 205.5 ° C. Nuclear magnetic resonance spectrum (DMSO-d 6, 60MHz) 1.47ppm (t, 3H), 4.35ppm (q, 2H), 8.30ppm
(S, 1H), 8.87ppm (s, 1H), 13.57ppm (broad s, 2H) Reference Example Rat passive skin anaphylactic test (PCA) was performed as follows. Antiserum diluted in the dorsal skin of Wistar male rats (appropriately diluted so that the area of blue spots is around 100 mm 2 ; 0.1
ml / site) to passively sensitize, and after 48 hours, 0.5 ml of 1.0% Evans blue containing 2 mg of antigen DNP-AS (a conjugate with a protein purified from Ascaris suum) is intravenously injected. . 30 minutes after the injection of the antigen and Evans blue, exsanguination was performed, and the diameter of blue plaque was measured. The test drug was an aqueous solution of Na salt, and was orally or intravenously administered before the antigen administration. The 50% inhibitory dose of 5- (3-ethyloxalylaminophenyl) tetrazole is 39.1 mg / kg orally and 0.54 mg / kg intravenously. For the acute toxicity test of this compound, 4-week-old ddy mice, 10 mice in each group were used, and Litchfield-Wilcoxon was used.
Method. LD 50 (iP) = 1600 mg / kg for intraperitoneal injection.
Claims (1)
３は水素原子、低級アルキル基、低級アルコキシ基又は
ハロゲン原子を示す。）で示されるアミノフェニルテト
ラゾール誘導体及びその薬学上適当なカチオンとの塩
（但し、一般式（Ｉ）の化合物中、５−（２−アルキル
オキサリルアミノフェニル）テトラゾールであるものを
除く。）。 【請求項２】一般式（II） （但し、式中Ｒ２及びＲ３は水素原子、低級アルキル
基、低級アルコキシ基又はハロゲン原子を示す。）で示
される化合物と、 一般式（III） （但し、式中Ａはハロゲン原子又は低級アルコキシ基を
示し、Ｒ１は低級アルキル基を示す。）で示される化合
物とを反応させ、所望により、薬学上適当なカチオンと
造塩させることを特徴とする、一般式（Ｉ）（式中、Ｒ１、Ｒ２及びＲ３は前記と同じ意味を有する
が、一般式（Ｉ）の化合物中、５−（２−アルキルオキ
サリルアミノフェニル）テトラゾールであるものを除
く。）で示されるアミノフェニルテトラゾール誘導体及
びその薬学上適当なカチオンとの塩の製造法。[Correction specification] [Claims] [Claim 1] General formula (I) (However, in the formula, R 1 represents a lower alkyl group, and R 2 and R
3 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom. ) Aminophenyl tetrazole derivative and a salt thereof with a pharmaceutically suitable cation (provided that the compound of the general formula (I) is not 5- (2-alkyloxalylaminophenyl) tetrazole). 2. General formula (II) (Wherein R 2 and R 3 represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom), and a compound represented by the general formula (III) (Wherein A represents a halogen atom or a lower alkoxy group, and R 1 represents a lower alkyl group), and the compound is optionally salted with a pharmaceutically suitable cation. With general formula (I) (In the formula, R 1 , R 2 and R 3 have the same meanings as described above, except for the compound of general formula (I) which is 5- (2-alkyloxalylaminophenyl) tetrazole). A method for producing an aminophenyl tetrazole derivative and a salt thereof with a pharmaceutically suitable cation.
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5827407B2 (en) | Process for producing 4- [5- (pyridin-4-yl) -1H-1,2,4-triazol-3-yl] pyridine-2-carbonitrile and intermediate | |
| JP2556722B2 (en) | Novel sulfonamide compound | |
| JPWO2004024694A1 (en) | 4-substituted aryl-5-hydroxyisoquinolinone derivatives | |
| JPH013173A (en) | Method for producing oxophthalazinyl acetic acids having a heterocyclic side chain such as benzothiazole | |
| Takahashi et al. | Synthesis of 2-aryl-3-arylsulfonylindoles and 2-anilino-3-arylsulfonylindoles from 2-(arylsulfonyl) methylanilines using the aza-Wittig reaction of iminophosphoranes | |
| JP802H (en) | Aminophenyltetrazole derivative and its salt | |
| JP2668259B2 (en) | Heterocyclic compounds and anti-ulcer agents | |
| US2701252A (en) | Isoindolenine compounds | |
| EP0165628B1 (en) | Cycloalkane-indene-carboximidamide derivatives | |
| KR102090155B1 (en) | Process for preparing 5-substituted-1h-tetrazoles in aqueous betaine solution | |
| US4421919A (en) | 4-Oximino-1,2,3,4-tetrahydroquinoline derivatives | |
| CN113185521A (en) | Method for preparing tetrahydropyrrolo [1,2-a ]1,3, 5-triazine-4-ketone compound by cyclopropyl ring opening | |
| JPH0231075B2 (en) | ||
| KR100302346B1 (en) | A method of preparing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline | |
| JPS591705B2 (en) | Aminophenyl tetrazole derivatives and their salts | |
| KR880001715B1 (en) | Process for preparing 1-furyl-3,4-dihydro-isoquinolines | |
| JPH06184074A (en) | 1-alkoxynaphthalene-2-carboxamide derivative, its preparation and medicinal composition containing said derivative | |
| JPH061776A (en) | Production of substituted pyrazinecarbonitrile | |
| GB2092130A (en) | 4-Oximino-1,2,3,4- tetrahydroquinoline Derivatives | |
| HU198023B (en) | Process for production of new derivatives of benzamid and medical preparatives containing these compounds as active substance | |
| JP4425558B2 (en) | Mixture of cyclic lactic acid oligomers | |
| JPS591704B2 (en) | Aminophenyl tetrazole derivatives and their salts | |
| JPH06340623A (en) | Production of benzylsuccinic acid derivative and intermediate for its synthesis | |
| JPS5834465B2 (en) | Trifluorotoluanilides and their production method | |
| KR100594568B1 (en) | New synthetic process of aminolevlunic acid derivatives |