JPS6158449B2 - - Google Patents
Info
- Publication number
- JPS6158449B2 JPS6158449B2 JP58125726A JP12572683A JPS6158449B2 JP S6158449 B2 JPS6158449 B2 JP S6158449B2 JP 58125726 A JP58125726 A JP 58125726A JP 12572683 A JP12572683 A JP 12572683A JP S6158449 B2 JPS6158449 B2 JP S6158449B2
- Authority
- JP
- Japan
- Prior art keywords
- present
- antitumor agent
- group
- compound
- compounds
- 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
- 239000002246 antineoplastic agent Substances 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 description 18
- 150000002291 germanium compounds Chemical class 0.000 description 11
- 238000000034 method Methods 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 239000002075 main ingredient Substances 0.000 description 5
- 201000009030 Carcinoma Diseases 0.000 description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 4
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910052732 germanium Inorganic materials 0.000 description 3
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 3
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 3
- 230000001766 physiological effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XRYJTKGEJGVBCC-UHFFFAOYSA-N 2-germylpropanoic acid Chemical class CC([GeH3])C(O)=O XRYJTKGEJGVBCC-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical class NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical class C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- -1 compound carboxyethylgermanium sesquioxide Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- MUDDKLJPADVVKF-UHFFFAOYSA-N trichlorogermane Chemical compound Cl[GeH](Cl)Cl MUDDKLJPADVVKF-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-SVYQBANQSA-N (2H8)-1,4-Dioxane Chemical compound [2H]C1([2H])OC([2H])([2H])C([2H])([2H])OC1([2H])[2H] RYHBNJHYFVUHQT-SVYQBANQSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IQULGZQMMPRBLA-UHFFFAOYSA-N 2-carboxyethylgermanium Chemical compound OC(=O)CC[Ge] IQULGZQMMPRBLA-UHFFFAOYSA-N 0.000 description 1
- ZJUHNMADISSFJZ-UHFFFAOYSA-N 2-trichlorogermylpropanoic acid Chemical class OC(=O)C(C)[Ge](Cl)(Cl)Cl ZJUHNMADISSFJZ-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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical group O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000002100 tumorsuppressive effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/30—Germanium compounds
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (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
抗腫瘍剤に関するものである。
金属の一種であるゲルマニウム(Ge)は、炭
素の同族体という点で共通するシリコン(Si)と
同様に半導体効果を有するという特殊性から、長
年に亘つてその側面からの研究の対象となつてい
たが、近年になつてその有機化合物に関する研究
が進んでその成果の発表が活発に行なわれた結
果、各方面、特に医薬学会から注目されるように
なつた。例えば、式(GeCH2CH2COOH)2O3で表
わされるカルボキシエチルゲルマニウムセスキオ
キサイドなる化合物が、極めて強力な血圧降下作
用や抗腫瘍作用等の生理活性を示す反面、全く毒
性や副作用が見られないものであるということ
は、医薬学会では周知の事実となりつつある。
一方、前記化合物に代表されるセスキオキサイ
ド型化合物のアナログ化合物についての研究も精
力的に行なわれ、前記化合物に於てゲルマニウム
原子と交互に結合して該化合物を網目状の巨大分
子としている酸素原子を、同様の結合性を持つ硫
黄原子に置換した構造のセスキスルフイド型化合
物(Ge−C−C−CO−)2S3が本発明の発明者
の一人により合成され、その製造方法と共にすで
に特許出願されている(特開昭57−203090号)
が、前記セスキオキサイド型化合物の生理活性に
ついては未だ明確に解明されていないとはいつて
も、その構造中のゲルマニウム−酸素結合に由来
するとの説が支配的である点に鑑みれば、該結合
の酸素原子をその同族体の硫黄で置換したセスキ
スルフイド型化合物も又、優れた生理活性を示す
ことは十分期待される。
本発明の発明者らは上述した事情を背景とし
て、様々な実験を精力的に行つた結果、セスキス
ルフイド型有機ゲルマニウム化合物のあるものが
極めて強い抗腫瘍性を示すことを知得して本発明
を完成させたもので、本発明の抗腫瘍剤は、一般
式
(式中、Aは水素原子又は低級アルキル基若しく
はフエニル基、Bは水素原子又は低級アルキル
基、Zは水酸基又はアミノ基をそれぞれ示す)
で表わされる有機ゲルマニウム化合物を主剤とす
ることを特徴とするものである。
次に本発明抗腫瘍剤について詳細に説明する。
本発明抗腫瘍剤は、上述したように一般式
()で表わされる有機ゲルマニウム化合物を主
剤とするので、まずこの化合物について説明する
と、これはゲルマニウム原子に、酸素官能基CO
−Zを有するプロピオン酸残基が結合したゲルミ
ルプロピオン酸誘導体を基本的構造とし、該ゲル
ミルプロピオン酸と硫黄原子とが2:3の割合で
交互に結合した分子化合物であつて、その一般式
中の置換基Aは水素原子又はメチル基、エチル
基、プロピル基やイソプロピル基等の所謂低級ア
ルキル基若しくは置換又は無置換のフエニル基で
あり、又、置換基Bは水素原子又は前記Aと同様
の低級アルキル基であつて、それらの結合位置は
置換基Aがゲルマニウム原子のα位、同Bがゲル
マニウム原子のβ位となつている。
一方、酸素官能基に関連する置換基Zは水酸基
−OH又はアミノ基−NH2のいずれかを示してい
るから、従つて本発明抗腫瘍剤の主剤たる有機ゲ
ルマニウム化合物には例えば次のようなものが含
まれる。
上記構造の有機ゲルマニウム化合物はいずれも
種々の方法により合成することができるが、その
一例を挙げれば、前記特開昭57−203090号公報に
開示されている方法に準じた下記反応式に示す方
法のように、アクリル酸誘導体()にトリクロ
ルゲルマンHGeCl3を付加せしめて得られるトリ
クロルゲルミルプロピオン酸誘導体()に対
し、無水状態で且つ塩基の存在下に硫化水素を作
用せしめてトリメルカプト体()とし、該トリ
メルカプト体()の分子間で脱硫化水素するの
である。
(A、B及びZは前述したものと同一である)
又、一般に置換アクリル酸アミド〔(〕に於
てZ=NH2のもの〕は、高価であるか又は入手が
困難であるばかりか、該置換アクリル酸アミドは
トリクロルゲルマンとの付加反応で好ましくない
副反応を伴うので、特に置換基ZがNH2のもの
は、下記反応式に示すように、置換又は無置換の
アクリル酸を出発原料とする方法による方が良い
場合もある。
尚、上記のいずれの方法による場合も、硫化水
素の作用により生成するトリメルカプト体()
は単離しても単離しなくても良い。
上記方法により得られた化合物(1)〜(7)を含め、
一般式()で表わされる有機ゲルマニウム化合
物は全般的に無色透明の結晶であつて、本発明抗
腫瘍剤は該有機ゲルマニウム化合物を主剤とし
て、従来公知の方法により錠剤、散剤、顆粒剤、
カプセル剤等々の適宜剤形に製剤したものであ
る。
而して、本発明は上記構成の抗腫瘍剤に係るも
のであつて、各種腫瘍に悩む患者に投与してその
生長の抑制や消失を図るものではあるが、この薬
理効果を実際の患者に本発明抗腫瘍剤を投与して
確認することには種々の問題があるので、動物実
験によりその投与量及び効果を確認することとし
た。
即ち、前記有機ゲルマニウム化合物を水に懸濁
し、これをIMC Carcinomaの1×106個皮下に移
植したマウスに経口的に一定期間投与したとこ
ろ、本発明抗腫瘍剤は下記表(1)に示すようにIMC
Carcinomaの生長を良く抑制したのである。
The present invention relates to an antitumor agent containing an organic germanium compound as a main ingredient. Germanium (Ge), a type of metal, has been the subject of research from this aspect for many years because it has a semiconductor effect similar to silicon (Si), which is a homolog of carbon. However, in recent years, as research into organic compounds has progressed and the results have been actively published, they have come to attract attention from various quarters, especially from pharmaceutical societies. For example, the compound carboxyethylgermanium sesquioxide, which is represented by the formula (GeCH 2 CH 2 COOH) 2 O 3 , exhibits extremely strong physiological activities such as hypotensive and antitumor effects, but has no toxicity or side effects. It is becoming a well-known fact in the medical academic society that this is not the case. On the other hand, research is being actively conducted on analogue compounds of sesquioxide type compounds represented by the above-mentioned compounds. A sesquisulfide type compound (Ge-C-C-CO-) 2 S 3 with a structure in which sulfur atom having similar bonding properties is substituted for is synthesized by one of the inventors of the present invention, and a patent application has already been filed along with its manufacturing method. (Unexamined Japanese Patent Publication No. 57-203090)
However, although the physiological activity of the sesquioxide-type compounds has not yet been clearly elucidated, the prevailing theory is that they originate from the germanium-oxygen bond in their structure. It is fully expected that sesquisulfide type compounds in which the oxygen atom of is replaced with its homologue sulfur will also exhibit excellent physiological activity. Against the background of the above-mentioned circumstances, the inventors of the present invention have energetically conducted various experiments, and as a result have learned that certain sesquisulfide-type organic germanium compounds exhibit extremely strong antitumor properties, and have developed the present invention. The antitumor agent of the present invention has been completed and has the general formula (In the formula, A represents a hydrogen atom, a lower alkyl group, or a phenyl group, B represents a hydrogen atom or a lower alkyl group, and Z represents a hydroxyl group or an amino group, respectively.) It is something. Next, the antitumor agent of the present invention will be explained in detail. As mentioned above, the antitumor agent of the present invention has an organic germanium compound represented by the general formula () as its main ingredient.
A molecular compound whose basic structure is a germylpropionic acid derivative to which propionic acid residues having -Z are bonded, and in which the germylpropionic acid and sulfur atoms are bonded alternately in a ratio of 2:3, and its general structure is Substituent A in the formula is a hydrogen atom or a so-called lower alkyl group such as a methyl group, ethyl group, propyl group or isopropyl group, or a substituted or unsubstituted phenyl group, and substituent B is a hydrogen atom or They are similar lower alkyl groups, and their bonding positions are such that substituent A is at the α-position of the germanium atom, and substituent B is at the β-position of the germanium atom. On the other hand, since the substituent Z related to the oxygen functional group represents either a hydroxyl group -OH or an amino group -NH 2 , the organic germanium compound which is the main ingredient of the antitumor agent of the present invention has, for example, the following: Contains things. Any of the organic germanium compounds having the above structure can be synthesized by various methods, but one example is the method shown in the reaction formula below, which is based on the method disclosed in JP-A No. 57-203090. Trichlorogermylpropionic acid derivative () obtained by adding trichlorogermane HGeCl 3 to acrylic acid derivative () is reacted with hydrogen sulfide in an anhydrous state and in the presence of a base to obtain trimercapto derivative (). ), and the trimercapto compound ( ) is desulfurized between molecules. (A, B and Z are the same as those mentioned above) In addition, substituted acrylic acid amides [(where Z=NH 2 ]) are not only expensive or difficult to obtain, but also Since the substituted acrylic acid amide is accompanied by an unfavorable side reaction in the addition reaction with trichlorogermane, especially those in which the substituent Z is NH 2 , as shown in the reaction formula below, substituted or unsubstituted acrylic acid is used as the starting material. In some cases, it may be better to use this method. In addition, in any of the above methods, the trimercapto compound () produced by the action of hydrogen sulfide
may or may not be isolated. Including compounds (1) to (7) obtained by the above method,
The organic germanium compound represented by the general formula () is generally a colorless and transparent crystal, and the antitumor agent of the present invention can be prepared into tablets, powders, granules, etc. using the organic germanium compound as a main ingredient by conventionally known methods.
It is formulated into an appropriate dosage form such as a capsule. The present invention relates to an antitumor agent having the above structure, which is administered to patients suffering from various tumors in order to suppress or eliminate their growth. Since there are various problems in administering and confirming the antitumor agent of the present invention, we decided to confirm the dosage and effect through animal experiments. That is, when the above-mentioned organic germanium compound was suspended in water and administered orally for a certain period of time to mice in which 1×10 6 IMC Carcinoma cells were subcutaneously implanted, the antitumor agent of the present invention showed the results shown in Table (1) below. Like IMC
The growth of Carcinoma was well suppressed.
【表】【table】
【表】
尚、セスキオキサイド型化合物の代表として挙
げた(GeCH2CH2COOH)2O3については記載しな
かつたが、10匹のマウスに対し100mg/Kg/日投
与した場合の腫瘍重量は0.95程度であるが、この
場合の量比(投与量/式量)は約0.3215と大きい
数値となり、このように考えれば本発明抗腫瘍剤
がいかに強くIMC Carcinomaの生長を抑制する
かが明らかとなる。
一方、人体に於ける腫瘍の生理は種々の要因に
より極めて複雑であるが、上記表(1)の結果をその
まま適用すれば、化合物(7)を主剤とする本発明抗
腫瘍剤は人体に対して1mg/Kg/日(体重50Kgの
人間の場合で1日当り50mg)の投与でマウスの場
合と同様の抑制率を示すことが期待され、現在実
際に抗腫瘍剤として治験が重ねられている前記セ
スキオキサイド型化合物の投与量がおよそ500乃
至2000mg/日であること、及び、有機ゲルマニウ
ム化合物によつても異るが、化合物(7)のLD50値
は560mg/Kgであるので投与量の上限にかなりの余
裕があることから、経口投与が可能なことと相俟
つて、本発明抗腫瘍剤はこれを人体の腫瘍に対し
て適用できるものである。
次に本発明の実施例について示す。
実験例 1
有機ゲルマニウム化合物の合成
化合物(1)の合成
2−カルボキシエチルトリクロルゲルマン
Cl3GeCH2CH2COOH25.2g(0.1モル)を無水
ベンゼン200mlに溶解し、無水ピリジン24g
(0.1モル)を加えてかくはん後、乾燥硫化水素
ガスを60分間通じた。生じた油状物に注意し乍
らベンゼンを除き、該油状物をメタノール100
mlに溶解し、これを精製水300mlに加え、析出
した結晶をメタノールから再結晶したところ、
2−カルボキシエチルゲルマニウムセスキスル
フイド(2)(GeCH2CH2COOH)2S3の無色板状結
晶16.8gが得られた。収率は86.7%であつた。
融点 200℃(DTAスペクトルによる計算
値)
溶解性 DMSO、ジオキサン、THF、アセト
ン等に易溶
元素分析 Ge2C6H10O4S3として
Ge C H S
計算値 37.44 18.61 2.62 24.83
分析値 37.21 18.69 2.68 24.89
IR(KBr、cm-1)、3420、1707、425
NMR(ジオキサン−d8、δ)1.97、2.57
化合物(2)〜(7)の合成
これら化合物も上記方法に準じて合成するこ
とができ、得られた化合物のうち(2)〜(5)は表(2)
に、又、(6)、(7)は表(3)に掲げたような物性を示
した。[Table] Although (GeCH 2 CH 2 COOH) 2 O 3 , which was listed as a representative sesquioxide type compound, was not listed, the tumor weight when administered at 100 mg/Kg/day to 10 mice was However, in this case, the amount ratio (dose/formula amount) is as large as approximately 0.3215, and when considered in this way, it is clear how strongly the antitumor agent of the present invention suppresses the growth of IMC Carcinoma. Become. On the other hand, the physiology of tumors in the human body is extremely complex due to various factors, but if the results in Table (1) above are applied as is, the antitumor agent of the present invention, which has compound (7) as its main ingredient, will be effective against the human body. It is expected that administration of 1mg/Kg/day (50mg per day for a human weighing 50Kg) will show the same inhibition rate as in mice, and the drug is currently undergoing repeated clinical trials as an antitumor agent. Although the dosage of sesquioxide-type compounds is approximately 500 to 2000 mg/day, and the LD50 value of compound (7) is 560 mg/Kg, although it varies depending on the organic germanium compound, the upper limit of the dosage is Due to this considerable margin, together with the fact that it can be administered orally, the antitumor agent of the present invention can be applied to tumors in the human body. Next, examples of the present invention will be described. Experimental example 1 Synthesis of organic germanium compound Synthesis of compound (1) 2-carboxyethyltrichlorogermane
Dissolve 25.2 g (0.1 mol) of Cl 3 GeCH 2 CH 2 COOH in 200 ml of anhydrous benzene and 24 g of anhydrous pyridine.
(0.1 mol) was added and stirred, and then dry hydrogen sulfide gas was passed through the mixture for 60 minutes. Benzene was removed while being careful of the oily substance formed, and the oily substance was dissolved in methanol 100%.
ml, this was added to 300 ml of purified water, and the precipitated crystals were recrystallized from methanol.
16.8 g of colorless plate-like crystals of 2-carboxyethylgermanium sesquisulfide (2) (GeCH 2 CH 2 COOH) 2 S 3 were obtained. The yield was 86.7%. Melting point 200℃ (value calculated by DTA spectrum) Solubility Easily soluble in DMSO, dioxane, THF, acetone, etc. Elemental analysis Ge 2 C 6 H 10 O 4 S 3 as Ge C H S Calculated value 37.44 18.61 2.62 24.83 Analysis value 37.21 18.69 2.68 24.89 IR (KBr, cm -1 ), 3420, 1707, 425 NMR (dioxane-d 8 , δ) 1.97, 2.57 Synthesis of compounds (2) to (7) These compounds can also be synthesized according to the above method. Among the obtained compounds, (2) to (5) are shown in Table (2).
In addition, (6) and (7) exhibited physical properties as listed in Table (3).
【表】【table】
【表】【table】
【表】【table】
【表】
実験例 2
本発明抗腫瘍剤の腫瘍抑制作用
CDF1系のマウスで9週令のメスを1群10匹と
し、対象群のみ20匹として、一匹当りIMC
Carcinomaの腫瘍細胞を1×106個皮下に移植
し、翌日から一般式()で表わされる有機ゲル
マニウム化合物を主剤とする本発明抗腫瘍剤を、
当該有機ゲルマニウム化合物の投与量が1mg乃至
100mg/Kg/日となるように5日間経口的に投与
し、1日休薬するサイクルを3回行つた。最終投
与日の翌々日に解剖して腫瘍重量を測定したとこ
ろ、前記表(1)に示したとおりの結果が得られた。[Table] Experimental Example 2 Tumor suppressive effect of the antitumor agent of the present invention CDF 1 strain mice, 9-week-old female mice were included in each group with 10 mice, and only the control group had 20 mice.
1×10 6 Carcinoma tumor cells were subcutaneously transplanted, and from the next day, the antitumor agent of the present invention containing an organic germanium compound represented by the general formula () was administered.
The dose of the organogermanium compound is 1 mg to
The drug was administered orally for 5 days at a dose of 100 mg/Kg/day, followed by 1 day off, three times. Two days after the final administration, the animals were dissected and tumor weights were measured, and the results shown in Table (1) above were obtained.
Claims (1)
はフエニル基、Bは水素原子又は低級アルキル
基、Zは水酸基又はアミノ基をそれぞれ示す) で表わされる有機ゲルマニウム化合物を主剤とす
ることを特徴とする抗腫瘍剤。[Claims] 1. General formula (In the formula, A represents a hydrogen atom, a lower alkyl group, or a phenyl group, B represents a hydrogen atom or a lower alkyl group, and Z represents a hydroxyl group or an amino group, respectively.) Antitumor agent.
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP58125726A JPS6016924A (en) | 1983-07-11 | 1983-07-11 | Antineoplastic agent |
GB08416634A GB2143128B (en) | 1983-07-11 | 1984-06-29 | Antineoplastic organogermanium compounds |
CH3344/84A CH661661A5 (en) | 1983-07-11 | 1984-07-10 | ANTINEOPLASTIC AGENT. |
DE3425404A DE3425404C2 (en) | 1983-07-11 | 1984-07-10 | Use of germanium sesquisulphides as antineoplastic agent |
FR8411038A FR2549066B1 (en) | 1983-07-11 | 1984-07-11 | NEW ORGANOGERMANIUM COMPOUND USEFUL AS ANTINEOPLASTIC AGENT |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP58125726A JPS6016924A (en) | 1983-07-11 | 1983-07-11 | Antineoplastic agent |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS6016924A JPS6016924A (en) | 1985-01-28 |
JPS6158449B2 true JPS6158449B2 (en) | 1986-12-11 |
Family
ID=14917251
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP58125726A Granted JPS6016924A (en) | 1983-07-11 | 1983-07-11 | Antineoplastic agent |
Country Status (5)
Country | Link |
---|---|
JP (1) | JPS6016924A (en) |
CH (1) | CH661661A5 (en) |
DE (1) | DE3425404C2 (en) |
FR (1) | FR2549066B1 (en) |
GB (1) | GB2143128B (en) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS60226592A (en) * | 1984-04-25 | 1985-11-11 | Asai Gerumaniumu Kenkyusho:Kk | Antioxidant |
JPS61145115A (en) * | 1984-12-18 | 1986-07-02 | Asai Gerumaniumu Kenkyusho:Kk | Preventive for cold syndrome for patient of pneumoconiosis |
US4772628A (en) * | 1985-12-28 | 1988-09-20 | Asai Germanium Research Institute | Organogermanium compound and antitumor agent composed mainly of this compound |
JPS63107920A (en) * | 1986-06-18 | 1988-05-12 | Asai Gerumaniumu Kenkyusho:Kk | Osteroblast activator |
US4973553A (en) * | 1987-09-09 | 1990-11-27 | Asai Germanium Research Institute | Salt or organogermanium compound and medicine containing the same |
CA1314210C (en) * | 1987-10-29 | 1993-03-09 | Norihiro Kakimoto | Agent for improving reduced functions of organs caused by inhibited blood circulation |
JP2698870B2 (en) * | 1987-10-29 | 1998-01-19 | 株式会社浅井ゲルマニウム研究所 | Agent for reducing nephrotoxicity by administration of cyclosporine |
JPH01117801A (en) * | 1987-10-29 | 1989-05-10 | Asai Gerumaniumu Kenkyusho:Kk | Washing and preserving solution for separated organ |
JP2652556B2 (en) * | 1988-08-29 | 1997-09-10 | 株式会社浅井ゲルマニウム研究所 | Organic germanium compound and method for producing the same |
AU635045B2 (en) * | 1989-07-20 | 1993-03-11 | Asai Germanium Research Institute Co., Ltd | Agent for preventing and treating opacity of lens |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1793288B1 (en) * | 1968-03-29 | 1971-05-27 | Daiichi Yakuhin Sangyo Kk | Process for the production of organogermanium oxides |
US4271084A (en) * | 1978-03-01 | 1981-06-02 | Ryuichi Sato | Germanium-containing organic polymer and the process for the production of the same |
JPS55122717A (en) * | 1979-03-15 | 1980-09-20 | Asai Gerumaniumu Kenkyusho:Kk | Interferon inducer |
JPS5935916B2 (en) * | 1981-06-09 | 1984-08-31 | 紀博 柿本 | Organic germanium compound and its manufacturing method |
JPS58174391A (en) * | 1982-04-07 | 1983-10-13 | Daiichi Yakuhin Sangyo Kk | Tetrakis(1-(n-carboxymethylcarbamoyl)ethylmercapto) germane and preparation thereof |
-
1983
- 1983-07-11 JP JP58125726A patent/JPS6016924A/en active Granted
-
1984
- 1984-06-29 GB GB08416634A patent/GB2143128B/en not_active Expired
- 1984-07-10 CH CH3344/84A patent/CH661661A5/en not_active IP Right Cessation
- 1984-07-10 DE DE3425404A patent/DE3425404C2/en not_active Expired
- 1984-07-11 FR FR8411038A patent/FR2549066B1/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
DE3425404C2 (en) | 1987-03-05 |
GB2143128A (en) | 1985-02-06 |
FR2549066B1 (en) | 1988-07-15 |
GB8416634D0 (en) | 1984-08-01 |
FR2549066A1 (en) | 1985-01-18 |
GB2143128B (en) | 1987-05-20 |
JPS6016924A (en) | 1985-01-28 |
CH661661A5 (en) | 1987-08-14 |
DE3425404A1 (en) | 1985-01-31 |
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