JPS6362495B2 - - Google Patents
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- Publication number
- JPS6362495B2 JPS6362495B2 JP58012959A JP1295983A JPS6362495B2 JP S6362495 B2 JPS6362495 B2 JP S6362495B2 JP 58012959 A JP58012959 A JP 58012959A JP 1295983 A JP1295983 A JP 1295983A JP S6362495 B2 JPS6362495 B2 JP S6362495B2
- Authority
- JP
- Japan
- Prior art keywords
- peak
- compound
- relatively large
- formula
- around
- 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
- 229920000642 polymer Polymers 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 19
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 claims description 16
- 238000010521 absorption reaction Methods 0.000 claims description 15
- 229910052732 germanium Inorganic materials 0.000 claims description 15
- 238000001228 spectrum Methods 0.000 claims description 10
- 241000700605 Viruses Species 0.000 claims description 8
- 238000004455 differential thermal analysis Methods 0.000 claims description 8
- 238000001237 Raman spectrum Methods 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 6
- 230000003595 spectral effect Effects 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- YBMRDBCBODYGJE-UHFFFAOYSA-N germanium dioxide Chemical compound O=[Ge]=O YBMRDBCBODYGJE-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 230000000704 physical effect Effects 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 229940119177 germanium dioxide Drugs 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000002075 main ingredient Substances 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 210000004072 lung Anatomy 0.000 description 9
- 239000013078 crystal Substances 0.000 description 8
- 150000002291 germanium compounds Chemical class 0.000 description 8
- 230000003902 lesion Effects 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000000862 absorption spectrum Methods 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000003612 virological effect Effects 0.000 description 6
- 201000010099 disease Diseases 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 208000012544 Viral Skin disease Diseases 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 125000000082 organogermanium group Chemical class 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 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
- 241000287828 Gallus gallus Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 235000013330 chicken meat Nutrition 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 206010022000 influenza Diseases 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- NLIJOIUVZBYQRS-UHFFFAOYSA-N 3-trichlorogermylpropanoic acid Chemical compound OC(=O)CC[Ge](Cl)(Cl)Cl NLIJOIUVZBYQRS-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 238000011887 Necropsy Methods 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000000315 cryotherapy Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 208000037797 influenza A Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- PGSADBUBUOPOJS-UHFFFAOYSA-N neutral red Chemical compound Cl.C1=C(C)C(N)=CC2=NC3=CC(N(C)C)=CC=C3N=C21 PGSADBUBUOPOJS-UHFFFAOYSA-N 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000005723 virus inoculator Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、有機ゲルマニウム化合物を主剤とす
るウイルス病用薬剤に関する。
従来、有機ゲルマニウム化合物は薬理活性の面
で近年著るしく注目されて来て居り、特公昭49−
2964号、特開昭48−61431号、特公昭46−21855
号、特公昭46−2498号等の特許公報に開示されて
いるが、これらの特許公報にその製法が開示され
ている有機ゲルマニウム化合物は、
(GeCH2CH2CO2H)2O3で示される低分子化合物
である。
これに対し、本発明者は、有機ゲルマニウム化
合物の薬理活性に注目し、上記式(GeCH2CH2
−CO2H)2O3で示される低分子化合物以外の有機
ゲルマニウム化合物の合成に鋭意研究を重ねた結
果ここに新規有機ゲルマニウム化合物を見い出し
有機ゲルマニウム重合体を完成するに至り、これ
を特願昭53−21992号(特公昭57−53800号)に開
示した。
更に本発明者は、この有機ゲルマニウム化合物
がウイルス病に特に優れた薬効を示すことを見出
した。
この有機ゲルマニウム重合体は、毒性が極めて
低く、急性毒性は経口投与でラツトについての
LD50が10000mg/Kg以上−これ以上の量を投与す
ることは、物理的に、即ちラツトの胃容積によつ
て制限され不可能である−である。
この重合体は、経口投与または注射によつてあ
るいはウイルス性皮膚疾患の場合には、各種の一
般的基材を用いて軟膏等の応用形式で適用でき
る。
この重合体を成人の治療に用いる場合の有効投
与量は10mg〜1000mg/日である。
注射液および錠剤への製剤化は、この重合体が
水溶性である為に、一般的な注射液あるいは賦形
剤および/または滑沢剤を用いることによつて通
例の如く行なうことができる。
この重合体は、ウイルス性皮膚疾患を始めとす
る各種ウイルス疾患に於て治療的に奏効する(実
施例参照)。
以上の如き優れた効果を示す有機ゲルマニウム
重合体は、一般式()または()
(≡GeCH2−CH2−COOH)oO1.5o ()
又は
〔式中、nは3以上の整数である。〕
で表わされそして以下の如き特徴的な物性:
(a) 赤外線吸収スペクトル・バンド
大きい吸収バンド;800cm-1、900cm-1および
1700cm-1の各付近
比較的大きい吸収バンド;560cm-1、705cm-1、
760cm-1、780cm-1、1250cm-1、1350cm-1およ
び1400cm-1の各付近(但し、1400cm1付近の
吸収バンドはダブレツトである)
(b) ラマンスペクトル・バンド
大きい吸収バンド;456cm-1
比較的大きい吸収バンド;382cm-1、618cm-1、
720cm-1、901cm-1、1170cm-1、1276cm-1およ
び1425cm-1
(c) 粉末X線回析スペクトル・バンド
大きい回析ピーク;650゜
比較的大きな回析ピーク;11.63゜、13.82゜、
18.36゜、21.18゜および22.41゜
(d) 示差熱分析値
ピーク開始点237℃、ピーク頂点256℃そして
ピーク終了点276℃;熱量△H=59.4mcal/mg
を示す水溶性の重合体である(この重合体は、本
発明と同一の出願人の先願の特公昭57−53800号
に詳細に開示されている。)。
本発明に従つて用いる水溶性有機ゲルマニウム
重合体の製造例を反応式により示すと以下の如く
になる:
(Mは、金属又はアンモニウムイオンでありそし
てXはハロゲン原子である)
以下上記の反応式(1)、(2)及び(3)に基づいて本発
明の化合物の製造例を詳説する。
二酸化ゲルマニウムは、ハロゲン化水素酸中で
次亜リン酸又はその塩(金属塩又はアンモニウム
塩であるのが好ましい。)で還元されて、ゲルマ
ニウム原子は、2価になり、二ハロゲン化ゲルマ
ニウムを生ずるが、このものは、ゲルマニウム原
子が4価である三ハロゲン化水素ゲルマニウムと
ハロゲン化水素酸中で平衡にある。そして、この
三ハロゲン化水素ゲルマニウムも水溶液中で反応
式(1)の右末端に示した解離型と平衡にあると考え
られている(反応式(1)参照)。この反応液は、水
で希釈することにより、ハロゲルマニウム−リン
酸コンプレツクスを単離することができるので、
この平衡系にリン酸の寄与も考えられる。
この様にして生成されたゲルマニウム試薬に分
極したアクリル酸
CH2=CH−COOH ()
を加えると、白色結晶の一般式
X3GeCH2−CH2COOH ()
(Xは、上記に記載の通り。)
で表わされる化合物が高収率で生じる(反応式(2)
参照)。
本発明の化合物は、前述の如き特徴的な物性
(赤外線吸収スペクトル・バンド、ラマンスペク
トル・バンド、粉末X線スペクトル・バンドおよ
び示差熱分析)を示す。これらは、後記の通り、
従来より公知の(GeCH2CH2COOH)2O3−例え
ば、特公昭53−7960号の実施例1の化合物−と別
異な新規化合物であることを明らかにしている。
次に本有機ゲルマニウム重合体の前述の如き薬
理効果を具体的に説明する。この為に使用した有
機ゲルマニウム重合体は次の如く合成法で作られ
る。
3−オキシゲルミルプロピオン酸低分子重合体の
製造例
水と混じ合う溶媒であるアセトン1.3に252g
(1モル)の3−トリクロロゲルミルプロピオン
酸を溶解させ、この溶液に水1.3を撹拌しなが
ら加える。白色の毛状結晶が析出するが反応液は
一昼夜放置して後、吸引して結晶を取する。得
られた結晶はアセトンの溶媒でよく洗滌し、減圧
下乾燥する。白色針状晶の低分子重合体が144g
(85%収率)得られた。又、アセトンの代りに他
の水と混じ合う溶媒(例えば、エタノール、メタ
ノール、セロソルブ、アセトニトリル、テトラヒ
ドロフラン、ジオキサン、ジメトキシエタン、ジ
グライム、ジメチルスルホキシド、ジメチルホル
ムアミド等)を用いても同様に低分子重合体(A)が
高収率で得られている。更に、水と混じり合わな
い溶媒(例えば、クロロホルム、メチレンクロリ
ド、四塩化炭素、ベンゼン、エーテル等)を溶媒
として用いて低分子重合体を得ることもでき、こ
の場合には、3−トリクロロゲルミルプロピオン
酸の溶液を水と良く振盪すると、低分子重合体が
析出した。この低分子重合体の結晶は、320℃以
下では分解も溶融もしない。
この生成物の元素分析値は以下の通りである:
理論値(%):炭素(C);21.24、水素(H);2.97
ゲルマニウム(Ge);42.79
測定値(%):炭素(C);21.10、水素(H);3.02
ゲルマニウム(Ge);42.5。
この様にして製造された本発明の低分子重合体
の粉末X線回析スペクトル、赤外線吸収スペクト
ル、ラマンスペクトル、示差熱分析をそれぞれ第
1図、第3図、第6図および第8図に示す。低分
子重合体は、水に比較的に良く溶け、水に対する
溶解度は約1g/100ml(25℃)であつた。
低分子重合体が公知化合物と構造上相違するも
のであることを説明する為に、特公昭53−7960号
の実施例1の(GeCH2CH2COOH)2O3なる公知
化合物の粉末X線回析スペクトル(第2図)、赤
外吸収スペクトル(第4図)、ラマンスペクトル
(第7図)および示差熱分析(第9図)並びにこ
の公知化合物と本発明の重合体との差スペクトル
(第5図)を測定し、そして以下の通り本発明の
重合体と公知化合物との差異を確認した:
(イ) 赤外吸収スペクトル
第3図と第4図との比較および第5図から、
両化合物の構造上の相異が明らかである。
950cm-1以下の吸収は主にGe−O−Geに基づ
く吸収で、その大きな相異は重合体構造の相異
を示している。
(ロ) ラマンスペクトル
第6図と第7図とを比較すると、前者は456
cm-1に最大吸収ピークを示し、後者は449cm-1
にそれを示している。両者は、明らかに構造
上、相異している。
(ハ) 粉末X線回析スペクトル
第1図と第2図とを比較してみると、両者ス
ペクトルは回析角度の異なる位置にピークを示
し全く異なる結晶構造をとつていることを示し
ている。
(ニ) 示差熱分析
第8図と第9図とを比較してみると、前者
は、後記の如く、1つだけ吸熱ピークを示すの
に対し後者は2つの吸熱ピークを示し又この温
度も異なるところから両物質の結晶構造は異な
ることが判る。
以下の実施例にて、上記製造例で得られた有機
ゲルマニウム化合物を使用してウイルス疾患に対
する薬理効果を実証し、本発明を更に詳細に説明
する。
ウイルス疾患に対する効果:
(1) DNA型ウイルスに対する効果:
実験群A:
製造例で得られた有機ゲルマニウム低分子
重合体が、ウイルス性皮膚疾患に奏効するこ
とを確認した。投与量は以下の通りである:
乳幼児 :10mg 1日2回に分服
学童以上:20mg 1日2回に分服
成 人 :30mg 1日3回に分服
使用した各種ウイルス性皮膚疾患に対する
効果を、以下の第1、2および3表に示す。
The present invention relates to a drug for viral diseases containing an organic germanium compound as a main ingredient. In recent years, organic germanium compounds have received considerable attention in terms of their pharmacological activity, and were
No. 2964, JP-A-48-61431, JP-A-46-21855
The organic germanium compounds whose manufacturing methods are disclosed in these patent publications are as follows:
It is a low molecular compound represented by (GeCH 2 CH 2 CO 2 H) 2 O 3 . On the other hand, the present inventor focused on the pharmacological activity of organic germanium compounds, and the above formula (GeCH 2 CH 2
As a result of intensive research into the synthesis of organic germanium compounds other than the low-molecular-weight compound represented by −CO 2 H) 2 O 3 , we discovered a new organic germanium compound, completed an organic germanium polymer, and filed a patent application for this. It was disclosed in No. 53-21992 (Special Publication No. 57-53800). Furthermore, the present inventors have discovered that this organic germanium compound exhibits particularly excellent medicinal efficacy against viral diseases. This organogermanium polymer has extremely low toxicity, with acute toxicity in rats after oral administration.
The LD 50 is 10000 mg/Kg or more - it is physically impossible to administer a larger amount, ie, limited by the stomach capacity of the rat. The polymers can be applied in application formats such as ointments by oral administration or injection or, in the case of viral skin diseases, using a variety of common bases. Effective doses of this polymer for adult treatment range from 10 mg to 1000 mg/day. Since this polymer is water-soluble, formulation into injection solutions and tablets can be carried out in a conventional manner by using common injection solutions or excipients and/or lubricants. This polymer is therapeutically effective in various viral diseases including viral skin diseases (see Examples). Organogermanium polymers exhibiting the above-mentioned excellent effects have the general formula () or () (≡GeCH 2 −CH 2 −COOH) o O 1.5o () or [In the formula, n is an integer of 3 or more. ] and have the following characteristic physical properties: (a) Infrared absorption spectral bands Large absorption bands; 800 cm -1 , 900 cm -1 and
Relatively large absorption bands around 1700cm -1 ; 560cm -1 , 705cm -1 ,
Around 760cm -1 , 780cm -1 , 1250cm -1 , 1350cm -1 and 1400cm -1 (however, the absorption band around 1400cm 1 is a doublet) (b) Raman spectrum band Large absorption band; 456cm -1 Relatively large absorption bands; 382cm -1 , 618cm -1 ,
720cm -1 , 901cm -1 , 1170cm -1 , 1276cm -1 and 1425cm -1 (c) Powder X-ray diffraction spectrum bands Large diffraction peak; 650° Relatively large diffraction peak; 11.63°, 13.82°,
18.36゜, 21.18゜ and 22.41゜(d) Differential thermal analysis values Peak start point 237℃, peak peak 256℃ and peak end point 276℃; It is a water-soluble polymer showing a calorific value △H = 59.4 mcal/mg ( This polymer is disclosed in detail in Japanese Patent Publication No. 57-53800 filed by the same applicant as the present invention.) An example of the production of the water-soluble organic germanium polymer used according to the present invention is shown below using a reaction formula: (M is a metal or ammonium ion and X is a halogen atom) Production examples of the compounds of the present invention will be explained in detail below based on the above reaction formulas (1), (2), and (3). Germanium dioxide is reduced with hypophosphorous acid or a salt thereof (preferably a metal salt or an ammonium salt) in hydrohalic acid, and the germanium atoms become divalent, yielding germanium dihalide. However, this material is in equilibrium with trihydrogengermanium halide, in which the germanium atom is tetravalent, in hydrohalic acid. This hydrogen trihalide germanium is also thought to be in equilibrium with the dissociated form shown at the right end of reaction formula (1) in an aqueous solution (see reaction formula (1)). By diluting this reaction solution with water, the halogermanium-phosphate complex can be isolated.
The contribution of phosphoric acid to this equilibrium system is also considered. When polarized acrylic acid CH 2 =CH-COOH () is added to the germanium reagent thus produced, the general formula of white crystals is X 3 GeCH 2 -CH 2 COOH (), where X is as described above. ) is produced in high yield (reaction formula (2)
reference). The compounds of the present invention exhibit characteristic physical properties (infrared absorption spectral bands, Raman spectral bands, powder X-ray spectral bands and differential thermal analysis) as described above. These are as described below.
It has been revealed that this is a new compound different from the conventionally known (GeCH 2 CH 2 COOH) 2 O 3 -for example, the compound of Example 1 of Japanese Patent Publication No. 53-7960. Next, the above-mentioned pharmacological effects of the present organic germanium polymer will be specifically explained. The organic germanium polymer used for this purpose is produced by the following synthetic method. Production example of 3-oxygermylpropionic acid low-molecular polymer 252 g in 1.3 acetone, a solvent that mixes with water
(1 mol) of 3-trichlorogermylpropionic acid is dissolved and 1.3 of water is added to this solution with stirring. White hair-like crystals precipitate out, but the reaction solution is allowed to stand for a day and night, and then the crystals are removed by suction. The obtained crystals are thoroughly washed with acetone as a solvent and dried under reduced pressure. 144g of white needle crystal low molecular weight polymer
(85% yield) was obtained. Also, if other water-miscible solvents (e.g., ethanol, methanol, cellosolve, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane, diglyme, dimethyl sulfoxide, dimethylformamide, etc.) are used instead of acetone, low-molecular polymers can be produced in the same way. (A) is obtained in high yield. Furthermore, it is also possible to obtain a low molecular weight polymer by using a solvent that is immiscible with water (for example, chloroform, methylene chloride, carbon tetrachloride, benzene, ether, etc.); in this case, 3-trichlorogermyl When the propionic acid solution was thoroughly shaken with water, a low molecular weight polymer was precipitated. The crystals of this low-molecular polymer do not decompose or melt at temperatures below 320°C. The elemental analysis values of this product are as follows: Theoretical value (%): Carbon (C); 21.24, Hydrogen (H); 2.97 Germanium (Ge); 42.79 Measured value (%): Carbon (C); 21.10, hydrogen (H); 3.02 germanium (Ge); 42.5. The powder X-ray diffraction spectrum, infrared absorption spectrum, Raman spectrum, and differential thermal analysis of the low molecular weight polymer of the present invention produced in this way are shown in Figures 1, 3, 6, and 8, respectively. show. The low molecular weight polymer was relatively well soluble in water, and its solubility in water was about 1 g/100 ml (25°C). In order to explain that low - molecular polymers are structurally different from known compounds, powder Diffraction spectrum (Figure 2), infrared absorption spectrum (Figure 4), Raman spectrum (Figure 7), differential thermal analysis (Figure 9), and difference spectrum between this known compound and the polymer of the present invention ( Figure 5) was measured, and the differences between the polymer of the present invention and known compounds were confirmed as follows: (a) Infrared absorption spectrum From the comparison between Figures 3 and 4 and Figure 5,
The structural differences between both compounds are clear. The absorption below 950 cm -1 is mainly due to Ge-O-Ge, and the large difference therein indicates a difference in the polymer structure. (b) Raman spectrum Comparing Figure 6 and Figure 7, the former is 456
It shows the maximum absorption peak at cm -1 , the latter at 449 cm -1
It shows that. The two are clearly structurally different. (c) Powder X-ray diffraction spectra Comparing Figures 1 and 2, both spectra show peaks at different diffraction angles, indicating that they have completely different crystal structures. . (d) Differential thermal analysis Comparing Figures 8 and 9, the former shows only one endothermic peak as described below, while the latter shows two endothermic peaks, and this temperature also It can be seen that the crystal structures of both substances are different from each other. In the following Examples, the present invention will be explained in more detail by demonstrating the pharmacological effects against viral diseases using the organic germanium compounds obtained in the above production examples. Effects on viral diseases: (1) Effects on DNA-type viruses: Experimental group A: It was confirmed that the organic germanium low molecular weight polymer obtained in the production example is effective against viral skin diseases. The dosage is as follows: Infants: 10mg divided twice a day School children and older: 20mg divided twice a day Adults: 30mg divided three times a day Effects on various viral skin diseases used are shown in Tables 1, 2 and 3 below.
【表】【table】
【表】
有効例数6例は、一部の疣贅が消失して来
たが、中止のため完全治瘉まで観察出来なか
つた。[Table] In 6 effective cases, some of the warts disappeared, but due to discontinuation, it was not possible to observe the warts until they were completely healed.
【表】
有効例は21日間服薬して中止したが一部に
消失を示したもの
実験群B:
実験群Aとは異つた施設において、上記製
造例に基づく有機ゲルマニウム低分子重合体
がDNA型ウイルスに非常に有効であること
を確認した。投与量は実験群Aと同じであ
り、投与効果は3ケ月で判定した(但し、4
ケ月間投与したものもある)。
患者は、再燃例〔“プレオマイシン
(Bleomycin)”の使用による治療または凍結
療法での治療を行なつたが、完治しないか又
は再発した例を意味する〕を選択した。[Table] Effective cases were those who stopped taking the drug for 21 days but showed some disappearance. Experimental group B: In a facility different from experimental group A, the organic germanium low molecular weight polymer based on the above manufacturing example was found to have DNA type. It has been confirmed that it is highly effective against viruses. The dose was the same as in experimental group A, and the administration effect was determined after 3 months (however, after 4 months)
(Some were administered for months). Patients were selected as cases of relapse (meaning cases that were treated with the use of "Bleomycin" or cryotherapy but were not completely cured or relapsed).
【表】【table】
【表】
副作用なし
(2) RNA型ウイルスに対する効果
次にRNAウイルスの一つであるマウスのイ
ンフルエンザ症に対する有機ゲルマニウム低分
子重合体の効果を検討した。
用いたウイルスはインフルエンザA2/
Adachi株で、体重10〜12gのd.d.Yマウスに経
鼻的に感染せしめた。接種量はこのウイルスの
10×LD50量である。ウイルスの接種後24時間
後より有機ゲルマニウム低分子重合体の100
mg/Kgと300mg/Kgを経口投与し始め、5日間
連続投与した。一群の実験に25匹のマウスを使
用した。14日目に剖検し、(1)死亡率、(2)肉眼的
肺の病変、(3)肺の中のウイルス量を測定した。
肺の病変は点数評価で示した。即ち、0は全く
病変なし、1は肺の1/4に病変をみとめる、2
は肺の1/2程度に病変をみとめる、3は肺の2/3
程度に病変をみとめる、4は全肺領域に変化を
みとめるもので、各マウスの病変の和を20で割
つた。14日以内に死亡し明かな充血肺をみとめ
たものは4点とした。次の肺のウイルス量は25
匹中の5匹を無作為にとり出し、ホモジネート
し、ニワトリの線維芽細胞単層の出来たペトリ
ーシヤーレに接種し37℃で培養し、3日後、ノ
イトーラルロート(中性赤)で生じた病変をそ
めて、数えそしてそれによりウイルス含量を調
べた。
実験の結果を第4表に示す。[Table] No side effects
(2) Effect on RNA-type viruses Next, we investigated the effect of organic germanium low-molecular-weight polymers on influenza disease in mice, which is an RNA virus. The virus used was influenza A 2 /
ddY mice weighing 10-12 g were intranasally infected with the Adachi strain. The dose of this virus is
The amount is 10 x LD 50 . 100% of organogermanium low molecular weight polymer 24 hours after virus inoculation.
Oral administration of mg/Kg and 300 mg/Kg was started and continued for 5 days. Twenty-five mice were used in one group of experiments. Necropsy was performed on the 14th day to measure (1) mortality, (2) gross lung lesions, and (3) the amount of virus in the lungs.
Lung lesions were indicated by scoring. That is, 0 means no lesions at all, 1 means lesions are seen in 1/4 of the lungs, and 2.
3 shows lesions in about 1/2 of the lungs, 3 shows lesions in 2/3 of the lungs
Level 4 indicates that changes are observed in the entire lung area, and the sum of lesions in each mouse was divided by 20. Those who died within 14 days and had clearly congested lungs were given a score of 4. The next lung viral load is 25
Five of the chickens were randomly taken out, homogenized, and inoculated into a Petri strain containing a monolayer of chicken fibroblasts, and cultured at 37°C. After 3 days, the lesions that appeared in the neutral funnel (neutral red) were collected, counted and thereby determined for virus content. The results of the experiment are shown in Table 4.
【表】
この結果よりみると有機ゲルマニウム低分子
重合体はインフルエンザ症にも有効であること
が判る。[Table] From the results, it can be seen that the organic germanium low molecular weight polymer is effective against influenza symptoms.
第1図は、本発明の化合物である水溶性低分子
重合体の粉末X線回析スペクトルを示すものであ
る。第2図は特公昭53−7960号の実施例1の
(GeCH2CH2COOH)2O3(以下、公知化合物と略
す)の粉末X線回析スペクトルを示すものであ
る。第3図は、本発明の化合物である水溶性低分
子重合体の赤外線吸収スペクトルを示すものであ
る。第4図は公知化合物の赤外線吸収スペクトル
を示すものである。第5図は、第3図と第4図の
赤外吸収スペクトル相互の差スペクトルを示すも
のである。第6図は、本発明の化合物である水溶
性低分子重合体のラマンスペクトルを示すもので
ある。第7図は公知化合物のラマンスペクトルを
示すものである。第8図は、本発明の化合物であ
る水溶性低分子重合体の示差熱分析チヤートを示
すものである。第9図は公知化合物の示差熱分析
チヤートを示すものである。
FIG. 1 shows a powder X-ray diffraction spectrum of a water-soluble low molecular weight polymer which is a compound of the present invention. FIG. 2 shows the powder X-ray diffraction spectrum of (GeCH 2 CH 2 COOH) 2 O 3 (hereinafter abbreviated as known compound) of Example 1 of Japanese Patent Publication No. 53-7960. FIG. 3 shows an infrared absorption spectrum of a water-soluble low molecular weight polymer which is a compound of the present invention. FIG. 4 shows infrared absorption spectra of known compounds. FIG. 5 shows a difference spectrum between the infrared absorption spectra of FIGS. 3 and 4. FIG. FIG. 6 shows a Raman spectrum of a water-soluble low molecular weight polymer which is a compound of the present invention. FIG. 7 shows a Raman spectrum of a known compound. FIG. 8 shows a differential thermal analysis chart of a water-soluble low molecular weight polymer which is a compound of the present invention. FIG. 9 shows a differential thermal analysis chart of a known compound.
Claims (1)
次亜リン酸又はその塩で処理して得られたハロゲ
ルマニウムリン酸コンプレツクスをアクリル酸と
反応させて、一般式() X3GeCH2−CH2COOH () 〔式中、Xはハロゲン原子である。〕 で示される化合物、()を得、さらに化合物
()をアセトン又は水と混合する他の有機溶媒
に溶解しそしてこの溶液に水を添加することによ
つて製造され、一般式 (≡GeCH2−CH2−COOH)oO1.5o () 又は 〔式中、nは3以上の整数である。〕 で表わされそして以下の如き特徴的な物性: (a) 赤外線吸収スペクトル・バンド 大きい吸収バンド;800cm-1、900cm-1および
1700cm-1の各付近、 比較的大きい吸収バンド;560cm-1、705cm-1、
760cm-1、780cm-1、1250cm-1、1350cm-1およ
び1400cm-1の各付近(但し、1400cm-1付近の
吸収バンドはダブレツトである)、 (b) ラマンスペクトル・バンド 大きい吸収バンド;456cm-1、 比較的大きい吸収バンド;382cm-1、618cm-1、
720cm-1、901cm-1、1170cm-1、1276cm-1およ
び1425cm-1、 (c) 粉末X線回析スペクトル・バンド 大きい回析ピーク;650゜ 比較的大きな回析ピーク;11.63゜、13.82゜、
18.36゜、21.18゜および22.41゜ (d) 示差熱分析値 ピーク開始点237℃、ピーク頂点256℃そして
ピーク終了点276℃;熱量△H=59.4mcal/mg を示す水溶性有機ゲルマニウム重合体を主剤とす
るウイルス用薬剤。[Claims] 1. A halogermanium phosphate complex obtained by treating germanium dioxide with hypophosphorous acid or its salt in hydrohalic acid is reacted with acrylic acid to form a compound of the general formula ( ) GeCH 2 -CH 2 COOH () [In the formula, X is a halogen atom. ] A compound of the general formula (≡GeCH 2 −CH 2 −COOH) o O 1.5o () or [In the formula, n is an integer of 3 or more. ] and have the following characteristic physical properties: (a) Infrared absorption spectral bands Large absorption bands; 800 cm -1 , 900 cm -1 and
Relatively large absorption bands around 1700 cm -1 ; 560 cm -1 , 705 cm -1 ,
around 760cm -1 , 780cm -1 , 1250cm -1 , 1350cm -1 and 1400cm -1 (however, the absorption band around 1400cm -1 is a doublet), (b) Raman spectrum band Large absorption band; 456cm -1 , relatively large absorption band; 382cm -1 , 618cm -1 ,
720cm -1 , 901cm -1 , 1170cm -1 , 1276cm -1 and 1425cm -1 , (c) Powder X-ray diffraction spectrum band Large diffraction peak; 650° Relatively large diffraction peak; 11.63°, 13.82° ,
18.36゜, 21.18゜ and 22.41゜(d) Differential thermal analysis values Peak start point 237℃, peak peak 256℃ and peak end point 276℃; Main ingredient is water-soluble organic germanium polymer showing calorific value △H = 59.4mcal/mg A drug for viruses.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1295983A JPS5916829A (en) | 1983-01-31 | 1983-01-31 | Antiviral drug containing organic germanium polymer as principal component |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1295983A JPS5916829A (en) | 1983-01-31 | 1983-01-31 | Antiviral drug containing organic germanium polymer as principal component |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP7517779A Division JPS55167222A (en) | 1979-06-16 | 1979-06-16 | Drug for warm-blooded animal comprising organogermanium polymer as main constituent |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5916829A JPS5916829A (en) | 1984-01-28 |
JPS6362495B2 true JPS6362495B2 (en) | 1988-12-02 |
Family
ID=11819795
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP1295983A Granted JPS5916829A (en) | 1983-01-31 | 1983-01-31 | Antiviral drug containing organic germanium polymer as principal component |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5916829A (en) |
Families Citing this family (1)
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---|---|---|---|---|
JP7110538B2 (en) * | 2018-09-20 | 2022-08-02 | エルジー・ケム・リミテッド | High refractive composition, high refractive film, and method for producing high refractive film |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5512217A (en) * | 1978-07-12 | 1980-01-28 | Hitachi Ltd | Energy saving drive method for compressor |
-
1983
- 1983-01-31 JP JP1295983A patent/JPS5916829A/en active Granted
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5512217A (en) * | 1978-07-12 | 1980-01-28 | Hitachi Ltd | Energy saving drive method for compressor |
Also Published As
Publication number | Publication date |
---|---|
JPS5916829A (en) | 1984-01-28 |
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