JPH0124767B2 - - Google Patents
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- Publication number
- JPH0124767B2 JPH0124767B2 JP7517779A JP7517779A JPH0124767B2 JP H0124767 B2 JPH0124767 B2 JP H0124767B2 JP 7517779 A JP7517779 A JP 7517779A JP 7517779 A JP7517779 A JP 7517779A JP H0124767 B2 JPH0124767 B2 JP H0124767B2
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- 229920000642 polymer Polymers 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 21
- 238000010521 absorption reaction Methods 0.000 claims description 15
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 claims description 10
- 238000001228 spectrum Methods 0.000 claims description 10
- 229910052732 germanium Inorganic materials 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 238000004455 differential thermal analysis Methods 0.000 claims description 8
- 206010020772 Hypertension Diseases 0.000 claims description 7
- 238000001237 Raman spectrum Methods 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 230000003595 spectral effect Effects 0.000 claims description 5
- YBMRDBCBODYGJE-UHFFFAOYSA-N germanium dioxide Chemical compound O=[Ge]=O YBMRDBCBODYGJE-UHFFFAOYSA-N 0.000 claims description 4
- 230000001631 hypertensive effect Effects 0.000 claims description 4
- 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
- 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
- 239000003960 organic solvent Substances 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 208000019553 vascular disease Diseases 0.000 claims 1
- 230000036772 blood pressure Effects 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 150000002291 germanium compounds Chemical class 0.000 description 7
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 7
- 238000000862 absorption spectrum Methods 0.000 description 6
- 206010003119 arrhythmia Diseases 0.000 description 6
- 230000006793 arrhythmia Effects 0.000 description 6
- 206010002383 Angina Pectoris Diseases 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 241000282414 Homo sapiens Species 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
- 208000024172 Cardiovascular disease Diseases 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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 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
- 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
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 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
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 208000006011 Stroke Diseases 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
- 230000017531 blood circulation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 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
- 208000005053 encephalomalacia Diseases 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- -1 organogermanium compound Chemical class 0.000 description 1
- 125000000082 organogermanium group Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Landscapes
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- 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
高血圧心臓血管疾患用薬剤に関する。
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号等の特許公報が開示されて
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
(GeCH2CH2CO2H)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
が高血圧心臓血管疾患に特に優れた薬効を示すこ
とを見出した。
即ち、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: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−)、経口投与(ま
たは注射)で高血圧自然発症ラツト(SHR)に
も(実施例、第1表および第1図参照)人の高血
圧症(第2図参照)にも適応し血圧を降下させる
作用があり、しかも正常値以下には降下しない特
色がある。また人の不整脈(第3図参照)、狭心
症(第4図参照)、心筋硬塞、脳軟化症、脳卒中
などを含む心臓血管障害を回復せしめる作用を示
す。
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 ()
及び
〔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線回折スペクトル・バンド
大きい回折ピーク;658゜
比較的大きな回折ピーク;11.63゜、
13.82゜18.36゜、21.18゜および22.41゜
(d) 示差熱分析
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ΔH=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
に更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
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を考えられる。
この様にして生成されたゲルマウム試薬に分極
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てる(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き合成法で作られ
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
乾操する。白色針状晶の低分子重合体が144g(85
%収率)得られた。又、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)を溶媒とし用
いて低分子重合体を得ることもでき、この場合
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線回折スペクトル、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
5図、第7図、第10図および第12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線回折スペクトル(第6図)、赤
外吸収スペクトル(第8図)、ラマンスペクトル
(第11図)および示差熱分析(第13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9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7図と第8図との比較および第9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10図と第11図とを比較すると、前者は
456cm-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線回折スペクトル
第5図と第6図とを比較してみると、両者ス
ペクトルは回折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12図と第13図とを比較してみると、前
者は、後記の如く、1つだけの吸熱ピークを示
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。
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列の如く行なうことが
できる。
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薬理効果を実証
し、本発明を更に詳細に説明する。
実施例 1
自然発症高血圧ラツトに対する効果
自然高血圧ラツトに4ヶ月に亘り1日100mg/
Kgを経口投与し、7ヶ月間後血圧を測定し、次い
で殺して心重量を測定すると第1表および第1図
に示す如き明かな結果をえた。
The present invention relates to a drug for hypertensive cardiovascular 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 . In response, the present inventor focused on the pharmacological activity of organic germanium compounds and conducted intensive research into the synthesis of organic germanium compounds other than the low-molecular compound represented by the above formula (GeCH 2 CH 2 CO 2 H) 2 O 3 . As a result of repeated efforts, a new organic germanium compound was discovered and an organic germanium polymer was completed.
No. 53800). Furthermore, the present inventors have discovered that this organogermanium compound exhibits particularly excellent medicinal efficacy against hypertensive cardiovascular diseases. That is, this organogermanium polymer has extremely low toxicity (acute toxicity: LD 50 for rats when administered orally is 10,000 mg/Kg or more - administering a larger amount is physically difficult, i.e., due to the gastric volume of the rat). Oral administration (or injection) to spontaneously hypertensive rats (SHR) (see Examples, Table 1 and Figure 1) and human hypertension (see Figure 2) ), it has the effect of lowering blood pressure, but it also has the characteristic that it does not drop below normal levels. It also shows the effect of curing cardiovascular disorders including arrhythmia (see Figure 3), angina pectoris (see Figure 4), myocardial infarction, encephalomalacia, and stroke in humans. Organic germanium polymers exhibiting the above excellent effects have the general formula () or () (≡GeCH 2 −CH 2 −COOH) o O 1.5o () and [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; 382 cm -1 , 618 cm -1 ,
720cm -1 , 901cm -1 , 1170cm -1 , 1276cm -1 and 1425cm -1 (c) Powder X-ray diffraction spectrum bands Large diffraction peak; 658° Relatively large diffraction peak; 11.63°,
13.82゜18.36゜, 21.18゜and 22.41゜(d) Differential thermal analysis Peak start point 237℃, peak peak 256℃ and peak end point 276℃; It is a water-soluble polymer showing a calorific value ΔH = 59.4mcal/mg ( This polymer is disclosed in more 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 by the following 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.
It is possible that phosphoric acid contributes to this equilibrium system. When polarized acrylic acid CH 2 =CH-COOH () is added to the germium 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
(See (2)). 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 synthesis 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 (85g) of white needle-like low molecular weight polymer
% yield) was obtained. Also, low-molecular polymers can be produced in the same way by using other water-miscible solvents (e.g., ethanol, methanol, cellosolve, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane, diglyme, dimethyl sulfoxide, dimethylformamide, etc.) instead of setone. was obtained in high yield. Furthermore, it is also possible to obtain a low-molecular polymer by using a solvent that is immiscible with water (for example, chloroform, methylene chloride, carbon tetrachloride, benzene, ether, etc.); in this case, 3-trichlorogermylpropion When the 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 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 5, 7, 10, and 12, respectively. .
The low molecular weight polymer was relatively well soluble in water, and its solubility in water was approximately 1 g/100 ml (25°C). In order to explain that low - molecular polymers are structurally different from known compounds, powder Diffraction spectrum (Figure 6), infrared absorption spectrum (Figure 8), Raman spectrum (Figure 11), differential thermal analysis (Figure 13), and difference spectrum (Figure 1) between this known compound and the polymer of the present invention. Figure 9) 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 7 and 8 and Figure 9,
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 spectra Comparing Figures 10 and 11, the former is
The maximum absorption peak is at 456 cm -1 , the latter at 449 cm
-1 shows it. The two are clearly structurally different. (c) Powder X-ray diffraction spectra Comparing Figures 5 and 6, both spectra show peaks at different diffraction angles, indicating that they have completely different crystal structures. (d) Differential thermal analysis Comparing Figures 12 and 13, the former shows only one endothermic peak, as described below, while the latter shows two endothermic peaks, and the temperature It can be seen that the crystal structures of the two substances are different from the fact that they are also different. Since this polymer is water-soluble, it can be formulated in a conventional manner using common injection solutions or excipients and/or lubricants. In the following examples, the present invention will be explained in more detail by demonstrating the pharmacological effects using the organic germanium compounds obtained in the above production examples. Example 1 Effect on spontaneously hypertensive rats 100mg/day for 4 months in spontaneously hypertensive rats
Kg was orally administered, blood pressure was measured after 7 months, and the animals were sacrificed and heart weights were measured. Clear results were obtained as shown in Table 1 and Figure 1.
【表】
但し、第1図は、自然発生高血圧ラツトの血圧
と心重量との開係を示したものである。
第1表および第1図から以下のことが判る。
(1) 実験開始前の血圧は対照群と実験群で差はな
い。
(2) 126日投与の血圧をみると実験群のそれは明
かに対照群より低い。しかも正常血圧値よりは
下らない。
(3) 126日目の心重量を比らべると実験群のそれ
は明かに対照群のものより低い。
実施例 2
心、血管系に対する薬効の人体応用例
1日量10mg〜90mg/成人(体重50Kg)の量でま
たは症状によりそれ以上の投与量で高血圧に対す
る降圧作用が認められた。第2図に具体例を示し
た。この図は、高血圧症の52才の男性に1日40
mg/成人(体重50Kg)の量で40日間投与した場合
の最高血圧の改善過程を示したものである。
狭心症、心不全および不整脈に対しても、1日
量10mg〜90mg/成人(体重50Kg)の投与量または
症状次第のそれ以上の投与量で、心電図所見より
見て明らかな改善が認められた。不整脈について
は第3図に、狭心症については第4図に具体的所
見を示した。第3図は、60才の不整脈のある男性
の投与前(a)と1日30mg/成人(体重50Kg)の量で
10日間投与した後(b)との心電図所見を示したもの
である。この図から判る様に、不整脈の改善が明
らかに達成されている。第4図は、63才の狭心症
のある女性の投与前(a)と1日40mg/成人(体重50
Kg)投与15分後(b)とのST波所見を示したもので
あり、脈膊数の正常化を示している。
抗出血作用、血液循環に対する促進作用、神経
循環衰弱症の改善および肺水腫の改善も、1日に
10mg〜90mg/成人(体重50Kg)の量でまたは症状
によりそれ以上の投与量で、最も短期間で1ヶ月
そして最も長くて6ヶ月以上で認められた。[Table] However, Figure 1 shows the relationship between blood pressure and heart weight in spontaneously hypertensive rats. The following can be seen from Table 1 and Figure 1. (1) There was no difference in blood pressure between the control group and the experimental group before the start of the experiment. (2) Looking at the blood pressure after 126 days of administration, it was clearly lower in the experimental group than in the control group. Moreover, the blood pressure does not fall below normal blood pressure. (3) Comparing the heart weight on day 126, it was clearly lower in the experimental group than in the control group. Example 2 Example of human application of medicinal effects on the heart and vascular system A hypotensive effect on hypertension was observed at a daily dose of 10 mg to 90 mg/adult (body weight 50 kg) or at a higher dose depending on the symptoms. A specific example is shown in Figure 2. This figure shows a 52-year-old man with hypertension having 40
This figure shows the improvement process in systolic blood pressure when administered for 40 days at a dose of mg/adult (body weight 50 kg). Clear improvement was also observed in electrocardiogram findings for angina pectoris, heart failure, and arrhythmia at a daily dose of 10 mg to 90 mg/adult (body weight 50 kg) or at a higher dose depending on the symptoms. . Specific findings for arrhythmia are shown in Figure 3, and for angina pectoris in Figure 4. Figure 3 shows the dose before administration (a) and 30 mg/day for an adult (weight 50 kg) in a 60-year-old man with arrhythmia.
The electrocardiogram findings shown in (b) after administration for 10 days are shown. As can be seen from this figure, improvement in arrhythmia was clearly achieved. Figure 4 shows before administration (a) and 40 mg/day for an adult (body weight 50 mg/day) in a 63-year-old woman with angina pectoris.
(b) ST wave findings 15 minutes after administration (Kg), showing normalization of the number of pulses. Anti-bleeding effect, promotion effect on blood circulation, improvement of neurocirculatory weakness, and improvement of pulmonary edema also occur in one day.
The shortest term was 1 month and the longest was over 6 months, in doses of 10 mg to 90 mg/adult (50 kg body weight) or higher depending on symptoms.
第1図は自然発生高血圧ラツトの血圧および心
重量と本発明の薬物投与との関係を図示したもの
である。第2図は本薬物投与による高血圧患者の
血圧降下の時間的経過を示すものである。第3図
は不整脈患者の心電図を本薬物投与前および後に
ついている。第4図は狭心症患者の心電図を本薬
物投与前および後について示している。第4図
は、本発明の化合物の自然高血圧ラツトに対する
効果を示すものである。第5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線回折スペ
クトルを示すものである。第6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線回折スペクト
ルを示すものである。第7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8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9図は、
第7図と第8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10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11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12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13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 illustrates the relationship between blood pressure and heart weight of spontaneously hypertensive rats and administration of the drug of the present invention. FIG. 2 shows the time course of blood pressure reduction in hypertensive patients by administration of this drug. Figure 3 shows the electrocardiogram of an arrhythmia patient before and after administration of this drug. FIG. 4 shows the electrocardiogram of a patient with angina before and after administration of this drug. FIG. 4 shows the effects of the compounds of the present invention on spontaneously hypertensive rats. FIG. 5 shows a powder X-ray diffraction spectrum of a water-soluble low molecular weight polymer which is a compound of the present invention. Figure 6 is the special public service issued in 1973.
7960 shows the powder X-ray diffraction spectrum of (GeCH 2 CH 2 COOH) 2 O 3 (hereinafter abbreviated as known compound) of Example 1. FIG. 7 shows an infrared absorption spectrum of a water-soluble low molecular weight polymer which is a compound of the present invention. FIG. 8 shows infrared absorption spectra of known compounds. Figure 9 shows
This shows a difference spectrum between the infrared absorption spectra of FIG. 7 and FIG. 8. FIG. 10 shows a Raman spectrum of a water-soluble low molecular weight polymer which is a compound of the present invention. FIG. 11 shows a Raman spectrum of a known compound. FIG. 12 shows a differential thermal analysis chart of the water-soluble low molecular weight polymer which is the compound of the present invention. FIG. 13 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 () および [式中、nは3以上の整数である。] で表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;382cm-1、618cm-1、720cm
-1、901cm-1、1170cm-1、1276cm-1および
1425cm-1、 (c) 粉末X−線回折スペクトル・バンド 大きい回折ピーク;650゜ 比較的大きい回折;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ΔH=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
る高血圧心臓血管疾患用薬剤。[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 () [wherein, X is a halogen atom]. ] and further prepared by dissolving the compound () in acetone or other organic solvent mixed with water and adding water to this solution, and having the general formula (≡GeCH 2 − CH 2 −COOH) o O 1.5o () and [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; 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; 11.63°, 13.82°, 18.36°,
21.18° and 22.41°(d) Differential thermal analysis values Peak start point 237°C, peak apex 256°C and peak end point 276°C; hypertensive heart based on water-soluble organic germanium polymer showing calorific value ΔH = 59.4 mcal/mg Drugs for vascular diseases.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7517779A JPS55167222A (en) | 1979-06-16 | 1979-06-16 | Drug for warm-blooded animal comprising organogermanium polymer as main constituent |
AU59304/80A AU533001B2 (en) | 1979-06-16 | 1980-06-13 | Germanium-containing organic polymers and pharmaceutical preparation containing same |
CA000354057A CA1162546A (en) | 1979-06-16 | 1980-06-16 | Medicine effective for warmblooded animals comprising, as an essential ingredient, a germanium- containing organic polymer |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7517779A JPS55167222A (en) | 1979-06-16 | 1979-06-16 | Drug for warm-blooded animal comprising organogermanium polymer as main constituent |
Related Child Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP1296183A Division JPS5916825A (en) | 1983-01-31 | 1983-01-31 | Drug for cancer consisting of organogernmanium polymer as main agent |
JP1295983A Division JPS5916829A (en) | 1983-01-31 | 1983-01-31 | Antiviral drug containing organic germanium polymer as principal component |
JP1296283A Division JPS5916826A (en) | 1983-01-31 | 1983-01-31 | Drug for c.r.d. complex consisting of organogermanium polymer as main agent |
JP1296083A Division JPS5916824A (en) | 1983-01-31 | 1983-01-31 | Drug for cataract consisting of organogermanium polymer as main agent |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS55167222A JPS55167222A (en) | 1980-12-26 |
JPH0124767B2 true JPH0124767B2 (en) | 1989-05-15 |
Family
ID=13568655
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP7517779A Granted JPS55167222A (en) | 1979-06-16 | 1979-06-16 | Drug for warm-blooded animal comprising organogermanium polymer as main constituent |
Country Status (3)
Country | Link |
---|---|
JP (1) | JPS55167222A (en) |
AU (1) | AU533001B2 (en) |
CA (1) | CA1162546A (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5260056A (en) * | 1988-11-15 | 1993-11-09 | Sanwa Kagaku Kenkyusho Co. Ltd. | Composition for enhancing biosynthesis of interferon |
AU635045B2 (en) * | 1989-07-20 | 1993-03-11 | Asai Germanium Research Institute Co., Ltd | Agent for preventing and treating opacity of lens |
JP4620169B1 (en) | 2010-01-28 | 2011-01-26 | 株式会社三和化学研究所 | A preventive or therapeutic agent for Crohn's disease comprising an organic acid polymer as an active ingredient |
CN105530945A (en) | 2013-08-06 | 2016-04-27 | 国立大学法人九州大学 | Medicine for preventing or suppressing survival of cancer cells and having organic acid polymer as active ingredient |
-
1979
- 1979-06-16 JP JP7517779A patent/JPS55167222A/en active Granted
-
1980
- 1980-06-13 AU AU59304/80A patent/AU533001B2/en not_active Ceased
- 1980-06-16 CA CA000354057A patent/CA1162546A/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
JPS55167222A (en) | 1980-12-26 |
AU533001B2 (en) | 1983-10-27 |
CA1162546A (en) | 1984-02-21 |
AU5930480A (en) | 1981-01-08 |
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