JPH0324094A - Organic germanium compound and production and use thereof - Google Patents
Organic germanium compound and production and use thereofInfo
- Publication number
- JPH0324094A JPH0324094A JP1155585A JP15558589A JPH0324094A JP H0324094 A JPH0324094 A JP H0324094A JP 1155585 A JP1155585 A JP 1155585A JP 15558589 A JP15558589 A JP 15558589A JP H0324094 A JPH0324094 A JP H0324094A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound according
- present
- group
- formulas
- 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.)
- Pending
Links
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- 239000000126 substance Substances 0.000 claims description 6
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000028996 humoral immune response Effects 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- CUILPNURFADTPE-UHFFFAOYSA-N hypobromous acid Chemical class BrO CUILPNURFADTPE-UHFFFAOYSA-N 0.000 description 1
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical class Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000033065 inborn errors of immunity Diseases 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003865 nucleic acid synthesis inhibitor Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000004967 organic peroxy acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 208000028529 primary immunodeficiency disease Diseases 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 230000003253 viricidal effect Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
(産業上の利用分野)
本発明は新規な有機ゲルマニウム化合物及びその塩、こ
れらの製法並びに薬剤組或物としての用途に係る.
(従来の技術及びその問題点〉
有機ゲルマニウム化合物は種々の薬理活性を示すために
、近年著しい注目を集めるに至っており、種々の研究報
告がなされている.
例えば、式
(式中、Etはエチル基を意味し、Meはメチル基を意
味する〉
にて示される化合物(本技術分野においてはr Y−9
577 ,として知られている)は抗炎症作用を有する
ことが報告されており (特開昭56−45492、9
9418、99491及び10870g公報)、又式
(式中、Et及びMeは前記の意味を有する)にて示さ
れる化合物(本技術分野においては「スビロゲルマニウ
ム」と称されている)は制癌作用を有していることが報
告されている[ r CancerResg、第42巻
、第2852頁(1982年)].一方、本発明者等も
従来から有機ゲルマニウム化合物に関する研究を行って
きており、3−オキシゲルミルブロビオン酸誘導体が優
れた免疫調整作用を有していることを報告している (
特開昭61− 151123).
このように、種々の有機ゲルマニウム化合物について種
々の薬理活性が報告されているにも拘らず、これらの有
機ゲルマニウム化合物の構造と薬理活性との相関関係乃
至有機ゲルマニウム化合物が薬理作用を発現する作用機
序について完全には解明されるに至っていないのが実情
である。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to novel organic germanium compounds and their salts, their production methods, and their use as pharmaceutical compositions. (Prior art and its problems) Organic germanium compounds have attracted considerable attention in recent years because they exhibit various pharmacological activities, and various research reports have been published. For example, the formula (where Et is ethyl group, and Me means a methyl group> (r Y-9 in this technical field)
577, known as ) has been reported to have anti-inflammatory effects (Japanese Patent Application Laid-Open No. 56-45492, 9
9418, 99491 and 10870g publications), and the compound represented by the formula (in which Et and Me have the above meanings) (referred to as "svirogermanium" in this technical field) has anticancer activity. [r Cancer Resg, Vol. 42, p. 2852 (1982)]. On the other hand, the present inventors have also been conducting research on organic germanium compounds, and have reported that 3-oxygermylbrobionic acid derivatives have excellent immunomodulatory effects (
JP-A-61-151123). As described above, although various pharmacological activities have been reported for various organogermanium compounds, it is unclear whether there is a correlation between the structure of these organogermanium compounds and their pharmacological activity, or the mechanism by which organogermanium compounds exert their pharmacological effects. The reality is that the sequence has not yet been fully elucidated.
(発明の目的)
上記の従来技術及び本発明者等の経験によれば、有機ゲ
ルマニウム化合物は、その構造が異なると薬理活性の種
類や程度に著しい差異が生じるようである.このことは
、逆説的に云えば、従来のものとは構造の異なる新規な
有機ゲルマニウム化合物を調製し且つその薬理作用を検
討すれば、構造と薬理活性との相関乃至薬理作用発現の
作用機序解明に寄与するのみならず、新たな薬理作用や
自体周知の薬理作用であっても活性の増強を期待できる
ことを意味している.
従って、本発明の基本的な目的は、種々の且つ優れた生
理活性を示す新規な有機ゲルマニウム化合物を提供する
ことにある。(Purpose of the Invention) According to the above-mentioned prior art and the experience of the present inventors, it appears that when organic germanium compounds have different structures, there are significant differences in the type and degree of pharmacological activity. Paradoxically speaking, this means that if we prepare a new organogermanium compound with a different structure from conventional ones and study its pharmacological action, we will be able to understand the relationship between structure and pharmacological activity and the mechanism of action of pharmacological action. This means that it not only contributes to elucidation, but also can be expected to enhance the activity of new or well-known pharmacological effects. Therefore, the basic object of the present invention is to provide novel organogermanium compounds that exhibit various and excellent physiological activities.
本発明の付随的な目的は、このような有機ゲルマニウム
化合物の製法を提供することにある.(目的を達戒する
ための手段及び作用)本発明者等は、優れた生理活性を
示す新規な有機ゲルマニウム化合物を開発するために鋭
意検討を重ねた結果、分子内にスルホン酸残基を有する
有機ゲルマニウム化合物が好ましいことを見い出して本
発明を完成する至った.
この有機ゲルマニウム化合物とは、式
(式中、Rl.R2、R3及びR4は、それぞれ水素原
子、置換基を有していることのできる低級アルキル基又
は置換基を有していることのできるフェニル基を意味し
、nは2又はそれ以上の整数を意味する〉
にて示される化合物及びその塩である.上記の化合物に
関して、置換基を有していることのできる低級アルキル
基の具体例としてはメチル、エチル、プロビル、イソプ
ロビル、ブチル、イソブチル、S−ブチル、t−ブチル
、ベンチル、ヘキシル基等の炭素数1−6の直鎖状又は
枝鎖状飽和炭化水素残基、フルオロメチル、クロロメチ
ル、ジフルオロメチル、トリフルオロメチル、フルオロ
エチル、クロロエチル、プロモエチル、ジフルオ口エチ
ル、ジクロロエチル、トリフルオロエチル、トリクロロ
エチル、フルオロブロビル、クロロプロビル、ジフルオ
ロブロビル,トリフルオロプロビル基等のハロゲノアル
キル基、ベンジル基、0−クロロベンジル、m−クロロ
ベンジル、pークロロベンジル、P−ニトロベンジル、
p−メトキシベンジル基等の置換ベンジル基等を例示す
ることができる.一方、置換基を有していることのでき
るフェニル′基の具体例としてはフェニル、2−クロロ
フエニル、3−クロロフェニル、4−クロロフェニル、
2−フルオロフェニル、3−フルオロフェニル、4−フ
ルオロフェニル、2−プロモフェニル、3−プロモフェ
ニル、4−プロモフエニル、2,3−ジクロロフェニル
、2,4−ジクロロフェニル、2.5−ジクロロフェニ
ル、2.6−ジクロロフェニル、3,4−ジクロロフェ
ニル、3.5−ジクロロフェニル、2.3−ジフルオロ
フェニル、2.4−ジフルオ口フェニル、2.5−ジフ
ルオロフェニル、2,6−ジフルオロフェニル、3.4
−ジフルオ口フェニル、3.5−ジフルオロフェニル、
2−ヒドロキシフェニル、3−ヒドロキシフェニル、4
−ヒドロキシフェニル、2.3−ジヒドロキシフェニル
、2,4−ジヒドロキシフェニル、2.5−ジヒドロキ
シフェニル、2.6−ジヒドロキシフェニル、3.4−
ジヒドロキシフェニル、3.5−ジヒドロキシフェニル
、2−メトキシフェニル、3−メトキシフエニル、4−
メl・キシフェニル、2,3−ジメトキシフェニル、2
,4〜ジメトキシフェニル、2.5−ジメトキシフェニ
ル、2.6−ジメトキシフェニル、3,←ジメトキシフ
ェニル、3.5−ジメトキシフェニル基等のようにフェ
ニル環上に置換基としてのハロゲン原子、水酸基、アル
コキシ基等を1−3個有するフェニル基を例示すること
ができる.
上記の有機ゲルマニウム化合物の塩としてはナトリウム
、カリウム、カノレシウム、マグネシウム、鉄、亜鉛、
銅、銀等の金属との塩、アンモニアとの塩、メチルアミ
ン、ジメチルアミン、エタノールアミン、エチレンジア
ミン、メグルミン、ジシクロヘキシルアミン、ペンジル
アミン等の有機塩基との塩、リジン、アルギニン、オル
ニチン、ヒスチジン、トリプトファン、オキシリジン、
オキシアルギニン、ホモアルギニン等の塩基性アミノ酸
との塩を例示することができる.本発明方法によれば、
上記の有機ゲルマニウム化合物及びその塩は、式
X,GeH
(式中、Xはハロゲン原子を意味する)にて示されるト
リハロゲルマンと式
(式中、R1、R2、R3及びR4は前記の意味を有す
る)
にて示される硫化エチレン誘導体とを反応させ、得られ
る式
(式中、R1、R2、R,、R4及びXは前記の意味を
有する)
にて示される2−トリハロゲルミルエタンチオール誘導
体を酸化し、得られる式
(式中、R,、R2、Rs 及U R4 及びXliT
il記の意味を有する〉
にて示される2−トリハロゲルミルエタンスルホン酸誘
導体を加水分解させ、次いで必要に応じて塩に変ずるこ
とにより製造することができる.この製法において、ト
リハロゲルマンと硫化エチレン誘導体との反応は溶媒の
存在下又は不在下にO − 80℃、好ましくは室温に
おいて攪拌することにより実施することができる.
この場合に生戒する2−トリハロゲルミルエタンチオー
ルを単離する必要性はなく、直ちに次の工程である酸化
処理に移行することができ、これによって2−トリハロ
ゲルミルエタンスルホン酸誘導体に変ずることができる
.この場合の酸化処理は、慣用の酸化剤、例えば過酸化
水素、有機過酸、ベルオキソ硫酸、過マンガン酸カリウ
ム、クロム酸、硝酸、臭化水素、次亜塩素酸塩、次亜臭
素酸塩、過酸化窒素、超酸化カリウム、ジメチルスルホ
キシド等を用いることにより容易に実施することができ
る.酸化剤として過酸化水素を用いるのが殊に好ましく
、この場合に反応は中性、酸性及びアルカリ性の如何な
る条件であっても差し支えなく、その際に酢酸、蟻酸、
メタンスルホン酸等の酸触媒又はタングステン、モリブ
デン、チタン、オスミウム、クロム等の金属触媒を共存
させることにより反応を著しく促進させることができる
.
反応混合物を常法により処理することにより、2−トリ
ハロゲルミルエタンスルホン酸誘導体を単離することが
でき、又生戒物にスルホン酸残基の存在することを利用
してイオン交換樹脂による処理を行えば、更に容易に2
−トリハロゲルミルエタンスルホン酸誘導体を得ること
ができる.本発明方法の最終工程であって、この2−ト
リハロゲルミルエタンスルホン酸誘導体を加水分解する
工程は水、塩基性水溶液又はこれらと有機溶媒との混合
液を用いて容易に実施することができ、所望物質である
2−オキシゲルミルエタンスルホン酸誘導体の単離も常
法により実施することができる.
この誘導体を塩に変ずる工程も常法により、例えば該誘
導体と所望の塩基とを単に混合することにより行うこと
ができ、凍結乾燥することにより又は適当な溶媒、例え
ばアセトン、メタノール、エタノール、ジオキサン等を
用いて処理することにより結晶乃至結晶性の粉末として
所望の塩を得ることができる.尚、上記の加水分解工程
を、所望の塩基含有水溶液中で実施すれば、2−オキシ
ゲルミルエタンスルホン酸誘導体の塩を直接的に得るこ
とができる.
(実施例等)
次に、製造例及び薬効薬埋試験例に関連して本発明を更
に詳細に且つ具体的に説明する.水酸化ゲルマニウム(
6.40g)に1.80M HCIエーテル溶液100
mlを添加し、室温下で攪拌し、次いで水冷下に硫化エ
チレン5.41gを滴下し、室温下で70時間攪拌した
.
不溶物を濾別し、濾液を減圧下に:a縮させた後に、水
6.0ml及びメタンスルホンPR 576Bを添加し
、100℃に加温し、攪拌下に31%過酸化水素水50
m lを2時間かけて滴下し、次いで更に30分間にわ
たり加熱した.
放冷後に、ダイヤイオンIJA−21により処理し、0
、5Nアンモニア水にて溶出させ、減圧下に濃縮させ、
メタノールに懸濁させて結晶を濾取した.この結晶を水
に溶解させ、ダイヤイオンPK−216により処理し、
流出液を減圧下に濃縮させることにより無色ガラス状物
質として所望のボリマーを得た(7.41g).
’H−NMRスペクトル(D20)δppm :1.6
− 2.0 (2H, m, −GeCi
ilCH2S−)2.9 − 3.3 (2H, m,
−GeCH2CH.S−>IRスペクトル(L”+
’a’x) CIO−’ :1150. 1030
(SO2). 820 (Ge−0−)水酸化ゲルマ
ニウム(3.20g)に1.80M HCIエーテル溶
液50m lを添加し、室温下で攪拌し、次いで水冷下
に硫化エチレン2.71gを滴下し、室温下で70時間
攪拌した.
不溶物を濾別し、濾液を減圧下に濃縮させた後に、水3
.0!II+及びメタンスルホン酸288+urを添加
し、100℃に加温し、攪拌下に31%過酸化水素水2
5l1を2時間かけて滴下し、次いで更に30分間にわ
たり加熱した.
放冷後に、ダイヤイオンIIA−21により処理し、0
.5Nアンモニア水にて溶出させ、減圧下に?縮させ、
メタノールに懸濁させて結晶を濾取した.この結晶を水
−メタノールから再結晶させることにより所望のボリマ
ーを得た (3.50g).融点: > 300℃
’H−NMRスペクトル(D20)δppm :1.6
− 2.0 (2H, m,−GeCHCH2S−)
2.9 − 3.3 (2H, m,−GeCH2CH
S−)IRスペクトル(νこ包) am−’ :340
0 − 2800 (NH4 >, 1400 (N}
!4 ), 1185.1040 (SO■), 79
0 (Ge−0−)艷先肚ユ
2−トリクロ口ゲルミルエタンスルホン酸製造例2によ
り得たアンモニウム2−オキシゲルミルエタンスルホネ
ート ボリマ−2.23gに1.80M MCI−エー
テル溶液25m lを添加した後にアセトン50m1を
添加し、析出する結晶を濾別し、濾液を減圧下に濃縮さ
せることにより無色油状物として所望の化合物を得た
(2.85g),’+4−NMRスペクトル(アセトン
ーd6)δ ppm :2.2 − 2.6 (2H,
l,−GeCHCH2S−)3.0 − 3.4 (
2t{, m, −GeCH2CiilS−)製造例1
により得た2−オキシゲルミルエタンスルホン酸ボリマ
ー(2.06g>を水30+slに溶解させ、1.OO
N Nail{ 10.0mlを添加した後に凍結乾燥
させることにより所望のボリマーを得た(2.28g)
。A further object of the present invention is to provide a method for producing such organogermanium compounds. (Means and effects for achieving the purpose) As a result of intensive studies to develop a novel organic germanium compound exhibiting excellent physiological activity, the present inventors discovered that the compound has a sulfonic acid residue in its molecule. The present invention was completed by discovering that organic germanium compounds are preferable. This organic germanium compound is a compound of the formula (where R1. group, and n means an integer of 2 or more〉 and its salts.With regard to the above compounds, specific examples of lower alkyl groups that can have substituents include: is a linear or branched saturated hydrocarbon residue having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl, t-butyl, bentyl, hexyl group, fluoromethyl, Halogens such as chloromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, chloroethyl, promoethyl, difluoroethyl, dichloroethyl, trifluoroethyl, trichloroethyl, fluorobrovir, chloroprovil, difluorobrovir, trifluoroprovir groups, etc. Alkyl group, benzyl group, 0-chlorobenzyl, m-chlorobenzyl, p-chlorobenzyl, P-nitrobenzyl,
Examples include substituted benzyl groups such as p-methoxybenzyl group. On the other hand, specific examples of phenyl groups that can have substituents include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-promophenyl, 3-promophenyl, 4-promophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2.5-dichlorophenyl, 2.6 -dichlorophenyl, 3,4-dichlorophenyl, 3.5-dichlorophenyl, 2.3-difluorophenyl, 2.4-difluorophenyl, 2.5-difluorophenyl, 2,6-difluorophenyl, 3.4
-difluorophenyl, 3,5-difluorophenyl,
2-hydroxyphenyl, 3-hydroxyphenyl, 4
-Hydroxyphenyl, 2.3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2.5-dihydroxyphenyl, 2.6-dihydroxyphenyl, 3.4-
Dihydroxyphenyl, 3.5-dihydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-
Mel xyphenyl, 2,3-dimethoxyphenyl, 2
, 4-dimethoxyphenyl, 2.5-dimethoxyphenyl, 2.6-dimethoxyphenyl, 3,←dimethoxyphenyl, 3.5-dimethoxyphenyl, etc., a halogen atom or hydroxyl group as a substituent on the phenyl ring, An example is a phenyl group having 1-3 alkoxy groups. Salts of the above organic germanium compounds include sodium, potassium, canolecium, magnesium, iron, zinc,
Salts with metals such as copper and silver, salts with ammonia, salts with organic bases such as methylamine, dimethylamine, ethanolamine, ethylenediamine, meglumine, dicyclohexylamine, penzylamine, lysine, arginine, ornithine, histidine, tryptophan, oxylysine,
Examples include salts with basic amino acids such as oxyarginine and homoarginine. According to the method of the present invention,
The above organic germanium compounds and salts thereof are trihalogermanes represented by the formula X, GeH (wherein, A 2-trihalogenylethanethiol derivative represented by the following formula (wherein R1, R2, R,, R4 and X have the above-mentioned meanings) obtained by reacting with a sulfurized ethylene derivative represented by and the resulting formula (where R,, R2, Rs and U R4 and XliT
It can be produced by hydrolyzing the 2-trihalogenmylethanesulfonic acid derivative shown in the following formula and then converting it into a salt as necessary. In this production method, the reaction between the trihalogermane and the sulfurized ethylene derivative can be carried out by stirring at O-80°C, preferably at room temperature, in the presence or absence of a solvent. In this case, there is no need to isolate the 2-trihalogermylethanethiol, which is to be taken into consideration, and the next step, oxidation treatment, can be carried out immediately, thereby converting it into a 2-trihalogermylethanesulfonic acid derivative. be able to. The oxidation treatment in this case can be carried out using conventional oxidizing agents such as hydrogen peroxide, organic peracids, peroxosulfuric acid, potassium permanganate, chromic acid, nitric acid, hydrogen bromide, hypochlorites, hypobromites, This can be easily carried out using nitrogen peroxide, potassium superoxide, dimethyl sulfoxide, etc. It is particularly preferred to use hydrogen peroxide as the oxidizing agent, in which case the reaction can be carried out under any conditions, neutral, acidic or alkaline, and in this case acetic acid, formic acid,
The reaction can be significantly accelerated by coexisting an acid catalyst such as methanesulfonic acid or a metal catalyst such as tungsten, molybdenum, titanium, osmium, or chromium. The 2-trihalogermylethanesulfonic acid derivative can be isolated by treating the reaction mixture in a conventional manner, and the 2-trihalogermylethanesulfonic acid derivative can also be treated with an ion exchange resin by taking advantage of the presence of sulfonic acid residues in the natural compound. If you do 2.
- A trihalogenmylethanesulfonic acid derivative can be obtained. The final step of the method of the present invention, which is the step of hydrolyzing the 2-trihalogenmylethanesulfonic acid derivative, can be easily carried out using water, a basic aqueous solution, or a mixture of these and an organic solvent. The desired substance, 2-oxygelmylethanesulfonic acid derivative, can also be isolated by conventional methods. The step of converting this derivative into a salt can also be carried out in a conventional manner, for example by simply mixing the derivative with the desired base, by lyophilization or in a suitable solvent such as acetone, methanol, ethanol, dioxane, etc. The desired salt can be obtained in the form of crystals or crystalline powder. Incidentally, if the above hydrolysis step is carried out in an aqueous solution containing a desired base, the salt of the 2-oxygermylethanesulfonic acid derivative can be directly obtained. (Examples, etc.) Next, the present invention will be explained in more detail and specifically in relation to production examples and medicinal efficacy test examples. Germanium hydroxide (
6.40 g) of 1.80 M HCI in ether solution 100
ml and stirred at room temperature. Next, 5.41 g of ethylene sulfide was added dropwise while cooling with water, and the mixture was stirred at room temperature for 70 hours. After filtering off insoluble materials and condensing the filtrate under reduced pressure, 6.0 ml of water and methanesulfone PR 576B were added, heated to 100°C, and mixed with 50 ml of 31% hydrogen peroxide solution while stirring.
ml was added dropwise over 2 hours and then heated for an additional 30 minutes. After cooling, it was treated with Diaion IJA-21 and
, eluted with 5N ammonia water and concentrated under reduced pressure,
The crystals were suspended in methanol and collected by filtration. This crystal was dissolved in water and treated with Diaion PK-216,
The effluent was concentrated under reduced pressure to yield the desired polymer as a colorless glass (7.41 g). 'H-NMR spectrum (D20) δppm: 1.6
−2.0 (2H, m, −GeCi
ilCH2S-)2.9-3.3 (2H, m,
-GeCH2CH. S->IR spectrum (L"+
'a'x) CIO-' :1150. 1030
(SO2). 820 (Ge-0-) To germanium hydroxide (3.20 g) was added 50 ml of 1.80 M HCI ether solution and stirred at room temperature. Next, 2.71 g of ethylene sulfide was added dropwise under water cooling, and the mixture was stirred at room temperature. The mixture was stirred for 70 hours. After filtering off insoluble materials and concentrating the filtrate under reduced pressure, 3
.. 0! Add II+ and 288+ ur of methanesulfonic acid, warm to 100°C, and add 288+ ur of 31% hydrogen peroxide while stirring.
5l1 was added dropwise over 2 hours and then heated for an additional 30 minutes. After cooling, it was treated with Diaion IIA-21 and
.. Elute with 5N ammonia water and under reduced pressure? Shrink it,
The crystals were suspended in methanol and collected by filtration. The desired polymer was obtained by recrystallizing the crystals from water-methanol (3.50 g). Melting point: > 300°C 'H-NMR spectrum (D20) δppm: 1.6
- 2.0 (2H, m, -GeCHCH2S-)
2.9 - 3.3 (2H, m, -GeCH2CH
S-) IR spectrum (ν envelope) am-': 340
0 - 2800 (NH4 >, 1400 (N}
! 4), 1185.1040 (SO■), 79
0 (Ge-0-) 2-triclogelmylethanesulfonic acid Add 25ml of a 1.80M MCI-ether solution to 2.23g of the ammonium 2-oxygelmylethanesulfonate polymer obtained in Production Example 2. After the addition, 50 ml of acetone was added, the precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure to obtain the desired compound as a colorless oil.
(2.85 g), '+4-NMR spectrum (acetone-d6) δ ppm: 2.2 - 2.6 (2H,
l, -GeCHCH2S-)3.0 - 3.4 (
2t{, m, -GeCH2CiilS-) Production Example 1
2-oxygelmylethanesulfonic acid polymer (2.06 g) obtained by was dissolved in 30+ sl of water, 1.OO
The desired polymer was obtained (2.28 g) by adding 10.0 ml of N Nail{ followed by lyophilization.
.
融点: > 300℃
H−NMRスペクトル(D20)δppm :1−6
− 2.0 (2}{, l, −GeCH1CH2S
−)2.9 − 3.3 (28, m, −GeCH
2C!liLS−)!Rスペクトル(νC!ご) c+
a−’ :1190. 1045 (SO2), 79
0 (Ge−0−)致m
製造例1により得た2−オキシゲルミルエタンスノレホ
ン酸ボリマー(1.03g>を水10ml Iこ’rW
解させ、1.OON NaOH 5.Omlを添加しタ
f& ニli 圧濃縮させ、次いで水−メタノールから
再結晶させることにより所望のボリマーを得た(1.0
8g>。Melting point: > 300°C H-NMR spectrum (D20) δppm: 1-6
- 2.0 (2}{, l, -GeCH1CH2S
-) 2.9 - 3.3 (28, m, -GeCH
2C! liLS-)! R spectrum (νC!go) c+
a-': 1190. 1045 (SO2), 79
0 (Ge-0-) 2-oxygelmylethanesnorefonic acid polymer (1.03 g) obtained in Production Example 1 was added to 10 ml of water.
Let me understand, 1. OON NaOH 5. The desired polymer was obtained by adding Oml and concentrating under pressure, followed by recrystallization from water-methanol (1.0
8g>.
このボリマーの物理化学的特性値は製造例4における値
と合致した。The physicochemical properties of this polymer matched those in Preparation Example 4.
製造例1により得た2−オキシゲルミルエタンスルホン
酸ボリマー(1.03g>を水20mlに溶解させ、1
.00Nアンモニア水5.0mlを添加した後に凍結乾
燥させることにより所望のボリマーを得た(1.11g
>.
このボリマーの物理化学的特性値は製造例2における値
と合致した。Dissolve the 2-oxygelmylethanesulfonic acid polymer (1.03 g) obtained in Production Example 1 in 20 ml of water,
.. The desired polymer was obtained by adding 5.0 ml of 00N ammonia water and freeze-drying it (1.11 g
>. The physicochemical properties of this polymer matched those in Preparation Example 2.
表遁』U【放讃ヱ[上
(抗体産生に及ぼす影響)
a) 目的
免疫応答の低下した動物として担癌マウスを用い、本発
明による化合物が抗体産生に及ぼす影響を調べる。1 (Effect on antibody production) a) Objective To examine the effect of the compound according to the present invention on antibody production using tumor-bearing mice as animals with reduced immune response.
b)操作
ICR系雄性マウス(6週令)の背部皮下にマウl
ス腫瘍細胞(ザルコーマ180)を2×10 個移植し
て固形癌を形戒させることにより担癌マウスとなした.
本発明による化合物として製造例4による化合物を採択
して4x牛血清アルプミンに溶解させ、担癌マウスに対
して、ザルコーマ180細胞の移植後9日目から0.1
、1.0及び10.Orag/kg/日の投与量で5日
間にわたり経口投与した.
ザルコーマ180 !f[l胞の移植から14日目に、
羊赤血球(SPBC) 2 x 10’個を担癌マウス
の尾静脈から靜注して感作させ、この感作から4日目に
牌臓を摘出し、牌細胞10 個中のPFC数を測定し
て抗体産生の指標とした.
C)結果及び考察
結果は下記の表1に示される通りであり、担癌により低
下した抗体産生能が、本発明による化合物を投与するこ
とにより回復し、その程度は投与量に準ずるものである
ことが判明した.Lユ
# :平均値士標準誤差(n・7)
* :胆癌マウスに対して有意差あり
(p < 0.05>
**本:胆癌マウスに対して有意差あり(p < 0.
001>
監隻羨生綬艷燵ユ
(抗体産生に及ぼす影響)
a) 目的
サブレッサーT細胞の機能低下に基因するB細胞のボリ
クローナルな活性化により自己免疫疾患を発症するNZ
B/WF.系マウスを用い、本発明による化合物が抗体
産生に及ぼす影響を調べる6
b)操作
NZB/WFI系雄性マウス(11週令〉を1群5匹で
使用し、羊赤血球(SPBC) 2 x 10?個を各
群のマウスの尾静脈から静注して感作させ、被験群には
感作の前日、直後及び1日後の3回にわたり本発明によ
る化合物として製造例4による化合物を採択して4x牛
血清アルブミンに溶解させて1.0及び10.O ra
g/kg/日の投与量で経口投与し、上記の感作開始か
ら4日目に牌臓を摘出し、牌細胞10′個中のPFC数
を測定して抗体産生の指標とした.
C)結果及び考察
結果は下記の表2に示される通りであり、薬物無投与の
対照群においてはPFC数が異常に増加していたが、被
験群においては有意に抑制された.
この結果と薬効薬埋試験例1に示されている結果、即ち
担癌により抑制された抗体産生能の回復の両者を考え併
せれば、本発明による化合物は免疫調整作用を有してい
ることが判る.東ユ
材
:平均値士標準誤差(n・5)
:対照群に対して有意差あり (p < 0.05)0
:対照群に対して有意差あり (p < 0.01>
粟金1144艷肚」一
(M延型過敏症に及ぼす影響〉
a) 目的
免疫応答の低下した動物として担癌マウスを用い且つ細
胞性免疫の指標として遅延型過敏症(DT}{)の実験
系を利用して、担癌により低下したDTH反応に及ぼす
、本発明による化合物の影響を調べる.
b)操作
ICR系雄性マウス(8週令)の腹腔内に、マウス腫i
細胞(ザルコーマ180) 10’個を移植し、約3時
間後に羊赤血球(SRBC) 10’個を尾静脈から靜
注して感作させ、該感作から4日後にSRBC 2 x
10’個を右後肢足踏内に注射してDT}!反応を惹
起させ、SRBC注射から24時間後に足踏の厚みを実
体顕微鏡により測定した.尚、被験群には、本発明によ
る化合物として、製造例4による化合物を4%牛血清ア
ルブミンに溶解させ、SRBC感作の4日前に0.1、
1.0、10、0mg/kgの用量で経口投与した.
C)結果及び考察
結果は下記の表3に示される通りであり、胆癌により低
下したDTH反応が、本発明による化合物の投与により
正常レベル程度まで回復することが判明した.このこと
は、本発明による化合物が4fIl胞性免疫賦活作用を
有していることを示している.
春一Σ
# :平均値士標準誤差
(x 0.01mm, n = 10)0*:担癌マウ
スに対して有意差あり
(p < 0.001)
菓拗(1u(艷匿」一
(遅延型過敏症に及ぼす影響)
a) 目的
正常マウスの遅延型過敏症反応に及ぼす、本発明による
化合物の影響を調べる.
b)操作
ICR系雄性マウス(8週令)に羊赤血球(SRBC)
10’個を尾静脈から靜注して惑作させ、該感作から
4日後に、被験群には、本発明による化合物として、製
造例4による化合物を4x牛血清アルブミンに溶解させ
、0.1、1.0、10.0mg/kgの用量で経口投
与し、この投与の直後にSRBC 2 x 10’個を
右後肢足踏内に注射してDTH反応を惹起させ、SRB
C注射から24時間後に足踏の厚みを実体顕微鏡により
測定した.C〉 結果及び考察
結果は下記の表4に示される通りであり、正常マウスに
関しては、本発明による化合物の投与によりDT}I反
応の有意に抑制されることが判明した.
この結果と、薬効薬理試験例 3により示される結果、
即ち胆癌により抑制されたDTH反応が本発明による化
合物の投与により回復したことを考え併せれば、この化
合物は免疫調整作用を有していることが明らかであり、
又薬効薬理試験例1及び2に示された結果、即ちこの化
合物は抗体産生能を調整することを考慮に入れると、本
発明による化合物は体液性免疫応答のみならす、細胞性
免疫応答も調整することが明らかである6東1
# :平均値士標準誤差
(x O.01mm, n = 10>* :対照群
に対して有意差あり
(p < 0.05)
*傘:対照群に対して有意差あり
(ρ< 0.01)
ネ**:対照群に対して有意差あり
(ρ< 0.001)
薬 薬理試 例5
(インターフェロン産生に及ぼす影響)a)目的
インターフェロンの産生に及ぼす、本発明による化合物
の影響を調べる.
b)操作
BALB/c系雄性マウス1群5匹を実験動物とし、イ
ンフルエンザウイルス (A/PR/8株)を9.0
PFυ/マウスの感染量で気管内感染させ、直ちに被験
群には、本発明による化合物として、製造例4による化
合物を信牛血清アルブミンに溶解させ、0.1、1.0
、10.0 mg/kgの用量で経口投与した。感染か
ら3日後に、肺臓を摘出し、ホモジナイズして2000
0 x gの遠心上清を得、この上清のインターフェロ
ン活性を水泡性口内炎ウィルス(VSV)によるL92
9細胞変性抑制作用にて測定した.
C)結果及び考察
結果は下記の表5に示される通りであり、本発明による
化合物は1.0及び10.0 mg/kgの投与量でイ
ンターフェロン産生をそれぞれ約2.5及び2.8倍に
向上させることが判明した。これは、本発明による化合
物がインターフェロン産生増強能を有していることを示
している。b) Operation: 2 x 10 mouse tumor cells (Sarcoma 180) were subcutaneously transplanted into the back of male ICR mice (6 weeks old) to induce solid tumors, thereby making them tumor-bearing mice. The compound according to Production Example 4 was adopted as a compound according to the present invention, dissolved in 4x bovine serum albumin, and administered to tumor-bearing mice at 0.1% from day 9 after transplantation of Sarcoma 180 cells.
, 1.0 and 10. It was orally administered for 5 days at a dose of Orag/kg/day. Sarcoma 180! On the 14th day after transplantation of f[l cells,
2 x 10' sheep red blood cells (SPBC) were injected into the tail vein of a tumor-bearing mouse to sensitize it, and on the fourth day after sensitization, the spleen was removed and the number of PFCs in 10 tile cells was measured. This was used as an indicator of antibody production. C) Results and Discussion The results are as shown in Table 1 below, and the antibody production ability, which decreased due to tumor bearing, was recovered by administering the compound according to the present invention, and the degree of recovery was in accordance with the dose administered. It has been found. Lyu#: Standard error of the mean (n 7) *: Significant difference for bile cancer mice (p <0.05> ** Book: Significant difference for bile cancer mice (p < 0.
001> Effects on antibody production a) Objective: New Zealand patients who develop autoimmune diseases due to voriclonal activation of B cells due to decreased function of sublessor T cells.
B/WF. Examining the effect of the compound according to the present invention on antibody production using strain mice 6 b) Operation NZB/WFI male mice (11 weeks old) were used in groups of 5, and sheep red blood cells (SPBC) 2 x 10? Each group of mice was sensitized by intravenous injection into the tail vein of each group, and the compound according to Production Example 4 was selected as the compound according to the present invention three times on the day before, immediately after, and one day after sensitization for the test group. 1.0 and 10.Ora dissolved in bovine serum albumin
The spleen was orally administered at a dose of 100 g/kg/day, and the spleen was removed on the 4th day from the start of the sensitization described above, and the number of PFCs in 10' tile cells was measured and used as an index of antibody production. C) Results and Discussion The results are shown in Table 2 below. In the control group to which no drug was administered, the number of PFCs increased abnormally, but in the test group, it was significantly suppressed. Considering this result and the result shown in Example 1 of the drug efficacy test, that is, the recovery of the antibody production ability suppressed by tumor bearing, it can be concluded that the compound according to the present invention has an immunomodulatory effect. It turns out. Toyu wood: Standard error of the mean (n・5): Significantly different from the control group (p < 0.05) 0
: Significant difference compared to control group (p <0.01>
Awakin 1144 艷肚'' 1 (Influence on M-prolonged hypersensitivity) a) Purpose Experiment using tumor-bearing mice as animals with reduced immune response and delayed-type hypersensitivity (DT) as an indicator of cell-mediated immunity. Using this system, the effect of the compound according to the present invention on the DTH response, which is decreased due to tumor bearing, is investigated. b) Inject mouse tumor i into the peritoneal cavity of a manipulated ICR male mouse (8 weeks old).
10' cells (Sarcoma 180) were transplanted, and about 3 hours later, 10' sheep red blood cells (SRBC) were injected into the tail vein for sensitization, and 4 days after the sensitization, SRBC 2 x
Inject 10' into the right hind foot and do DT}! A reaction was induced, and 24 hours after SRBC injection, the thickness of the foot was measured using a stereomicroscope. In addition, the test group was given a compound according to the present invention as a compound according to Production Example 4 dissolved in 4% bovine serum albumin, and 4 days before SRBC sensitization, 0.1,
It was administered orally at doses of 1.0, 10, and 0 mg/kg. C) Results and Discussion The results are shown in Table 3 below, and it was found that the DTH response, which had decreased due to bile cancer, was restored to a normal level by administration of the compound according to the present invention. This indicates that the compound according to the present invention has a 4fIl immunostimulatory effect. Spring Σ Effect on type hypersensitivity) a) Objective: To investigate the effect of the compound of the present invention on delayed type hypersensitivity reaction in normal mice. b) Manipulation Inject sheep red blood cells (SRBC) into male ICR mice (8 weeks old).
Four days after the sensitization, the test group was injected with 10' of the compound according to the present invention, prepared by Preparation Example 4, dissolved in 4x bovine serum albumin. Immediately after this administration, 2 x 10' SRBC were injected into the right hind paw to elicit a DTH response.
24 hours after C injection, the thickness of the foot was measured using a stereomicroscope. C> Results and Discussion The results are shown in Table 4 below, and it was found that administration of the compound according to the present invention significantly suppressed the DT}I response in normal mice. This result and the results shown by Pharmacology Test Example 3,
That is, considering that the DTH reaction suppressed by bile cancer was recovered by administration of the compound according to the present invention, it is clear that this compound has an immunomodulatory effect.
Furthermore, taking into account the results shown in Pharmacology Test Examples 1 and 2, that is, that this compound modulates antibody production ability, the compound according to the present invention modulates not only the humoral immune response but also the cellular immune response. 6 East 1 #: Standard error of the mean (x O.01mm, n = 10>*: Significant difference compared to the control group (p < 0.05) *Umbrella: Compared to the control group Significant difference (ρ < 0.01) Ne**: Significant difference compared to control group (ρ < 0.001) Drug Pharmacology Example 5 (Effect on interferon production) a) Target Effect on interferon production The effects of the compounds according to the invention are investigated. b) Operation: A group of 5 male BALB/c mice were used as experimental animals, and influenza virus (A/PR/8 strain) was infected at 9.0%.
Intratracheal infection was carried out at an infectious dose of PFυ/mouse, and the test group was immediately given 0.1 and 1.0 doses of the compound according to the present invention, the compound according to Production Example 4 dissolved in Shingyu serum albumin.
, administered orally at a dose of 10.0 mg/kg. Three days after infection, the lungs were removed and homogenized to 2000
Centrifugation supernatant at 0 x g was obtained, and the interferon activity of this supernatant was determined by L92 induced by vesicular stomatitis virus (VSV).
9 cell degeneration inhibitory effect. C) Results and Discussion The results are shown in Table 5 below, and the compound according to the present invention increased interferon production by about 2.5 and 2.8 times at doses of 1.0 and 10.0 mg/kg, respectively. It was found that it improved. This indicates that the compound according to the present invention has the ability to enhance interferon production.
表5
# :平均値士標準誤差
(HJ/B蛋白, n = 5)
**:対照群に対して有意差あり
(p < 0.01)
盈影及生4艷l玉
(抗癌作用)
a) 目的
ルイス肺癌に対する、本発明による化合物の抗癌作用を
調べる.
b〉 操作
C57BL/6系雄性マウス1群10匹を実験動物とし
、ルイス肺am胞1xlO’個を皮下に接種した.被験
群には、本発明による化合物として、製造例4による化
合物を4x牛血清アルブミンに溶解させ、0.1、1.
0、10.0 mg/kg/日の用量で、接種の翌日か
ら5日間にわたり経口投与した.
癌細胞の接種により形成された固形癌を14日後に摘出
して重量を測定し、又抗癌作用の指標として、固形癌(
M瘍)の重量減少から腫瘍の阻止率を計算した.
C)結果及び考察
結果は下記の表6に示される通りであり、本発明による
化合物はルイス肺癌に対して抑制作用を示すことが明ら
かになった.
老一五
# : 平均値士標準誤差(n = 10)傘 : 対
照群に対して有意差あり
(p < 0.05)
l惣l4絞艷燵ユ
(抗癌作用)
a) 目的
ザルコーマ180癌細胞に対する、本発明による化合物
の抗癌作用を調べる.
b)操作
ICR系雄性マウス1群10匹を実験動物とし、ザルコ
ーマ180癌細胞2 x 10’個を皮下に接種した.
被験群には、本発明による化合物として、製造例4によ
る化合物を4%牛血清アルブミンに溶解させ、0。1、
1、0、10.0 mg/kg/日の用量で、接種の翌
日から10日間にわたり経口投与した.
癌細胞の接種により形成された固形癌を20日後に摘出
して重量を測定し、又抗癌作用の指標として、固形癌(
腫瘍)の重f1滅少から腫瘍の阻止率を計算した。Table 5 #: Standard error of the mean (HJ/B protein, n = 5) **: Significant difference compared to control group (p < 0.01) a) Objective: To investigate the anticancer effect of the compound according to the present invention on Lewis lung cancer. b〉 Operation One group of 10 C57BL/6 male mice were used as experimental animals, and 1 x 10' of Lewis pneumonocytes were subcutaneously inoculated. For the test group, as a compound according to the present invention, the compound according to Production Example 4 was dissolved in 4x bovine serum albumin, and 0.1, 1.
The mice were orally administered at doses of 0 and 10.0 mg/kg/day for 5 days starting the day after vaccination. Solid tumors formed by inoculation of cancer cells were excised after 14 days and their weight was measured.
The tumor inhibition rate was calculated from the weight loss of M tumor). C) Results and Discussion The results are shown in Table 6 below, and it was revealed that the compound according to the present invention exhibits an inhibitory effect on Lewis lung cancer. Ryo Ichigo #: Standard error of the mean (n = 10) Umbrella: Significantly different from the control group (p < 0.05) l So l4 Strictly 艷燵yu (anticancer effect) a) Purpose Sarcoma 180 cancer The anticancer effect of the compound according to the present invention on cells is investigated. b) Operation One group of 10 male ICR mice were used as experimental animals, and 2 x 10' Sarcoma 180 cancer cells were inoculated subcutaneously.
For the test group, as a compound according to the present invention, the compound according to Production Example 4 was dissolved in 4% bovine serum albumin, and 0.1,
The mice were orally administered at doses of 1, 0, and 10.0 mg/kg/day for 10 days starting the day after vaccination. Solid tumors formed by inoculation of cancer cells were excised after 20 days and their weight was measured.
The tumor inhibition rate was calculated from the decrease in tumor f1.
C)結果及び考察
結果は下記の表6に示される通りであり、木発明による
化合物はザルコーマ180癌細胞に対しても抑制作用を
示すことが明らかになった。C) Results and Discussion The results are shown in Table 6 below, and it was revealed that the compound according to the tree invention also exhibited an inhibitory effect on Sarcoma 180 cancer cells.
宍一ヱ
# ; 平均値士標準誤差(n・10)* : 対照群
に対して有意差あり
(p < 0.05)
・ 理; 8
(抗ウィルス作用)
a) 目的
ワクシニアウイルスに対する、本発明による化合物の作
用を調べる.
b)操作
ddY系雄性マウス1群10匹を実験動物とし、ワクシ
ニアウィルス (DI株)を5 x 10’PFU/マ
ウスの感染価で尾静脈がら接種して感染させた.被験群
には、接種の直後に、本発明による化合物として、製造
例4による化合物を4%牛血清アルプミンに溶解させ、
1.0及びIO.Omg/kgの用量で経口投与した.
ウィルス感染の7日後に、尾に生じたボックを数え該ボ
ック数の減少から抑制率を計算して抗ウィルス活性の指
標とした.
C)結果及び考察
結果は下記の表8に示される通りであり、本発明による
化合物はワクシニアウィルスに対して抑制作用を示すこ
とが判明した。Shishiichi #; Standard error of the mean (n 10) *: Significantly different from control group (p < 0.05) ・Reason; 8 (Antiviral action) a) Objective The present invention against vaccinia virus Investigate the effects of compounds by b) Operation A group of 10 male ddY mice were used as experimental animals and infected with vaccinia virus (DI strain) by inoculation into the tail vein at an infectious titer of 5 x 10'PFU/mouse. Immediately after inoculation, the test group was given a compound according to Production Example 4 dissolved in 4% bovine serum albumin as a compound according to the present invention.
1.0 and IO. It was administered orally at a dose of Omg/kg. Seven days after virus infection, the number of bocks formed on the tail was counted, and the inhibition rate was calculated from the decrease in the number of bocks, which was used as an index of antiviral activity. C) Results and Discussion The results are shown in Table 8 below, and it was found that the compound according to the present invention exhibits an inhibitory effect on vaccinia virus.
老一主
# : 平均値士標準誤差〈n・10〉本 : 対照群
に対して有意差あり
(p < 0.001)
盈勲I』4り4鮫』−
(抗ウィルス作用)
a〉 目的
インフルエンザウィルス感染モデルにより、本発明によ
る化合物の抗ウイルス作用を調べる.b)操作
BALB/c系雄性マウス1群10匹を実験動物とし、
インフルエンザウイルス(A/PR/8株)を9.O
PFU/マウスの感染量で気管内感染させた。被験群に
は、本発明による化合物として、製造例4による化合物
を4x牛血清アルブミンに溶解させ、0.1、1、O、
10.0 mg/kg/日の用量で且つ感染処理直後、
感染処理から1、2、3、4及び5日目の計6回にわた
り経口投与した.ウィルス感染処理から20日間にわた
りマウスの生死をチェックした.
C〉 結果及び考察
結果は下記の表9に示される通りであり、化合物無投与
の対照群においては感染後8日目から死亡例が出初め、
10日目迄にすべて死亡してしまった.これに対して、
本発明による化合物の投与群である被験群においては、
殊に1.0 mg/kg投与群においては10日目から
感染死例が出たが、20日後の試験終了時においても4
匹の生存例があり、平均生存日数に関しては、対照群と
比較する場合に、何れの被験群においても有意差老−2
本 ・ 対照群に対して有意差あり
(p < 0.05)
**: 対照群に対して有意差あり
(p < O.Oi)
0* : 対照群に対して有意差あり
(p < 0.001)
薬 ・ 一二10
く急性肝障害に対する作用)
a) 目的
肝障害の実験的モデルであるガラクトサミン誘発急性肝
障害に対する、本発明による化合物の作用につき、血清
トランスアミナーゼを指標として調べる.
b)操作
ウィスタ一系雄性ラット1群10匹を実験動物とし、ガ
ラクトサミンを400 mg/kgの用量で6時間間隔
で2回腹腔内投与することにより急性肝障害を誘発させ
た.被験群には、本発明による化合物として、製造例4
による化合物を4x牛血清アルブミンに溶解させ、0.
1、1.0、10.0mg/kg/日の用量で且つガラ
クトサミン投与の3日前から5日間にわたり経口投与し
た。ガラクトサミンの初回投与から48時間経過した後
に採血して血清中のGOT及びGPT値を測定した.C
)結果及び考察
結果は下記の表lOに示される通りであり、本発明によ
る化合物は、ガラクトサミンの投与により上昇したGO
T及びGPT値を有意に低減させ表10
N
: 平均値士標準誤差〈n=10〉
: 対照群に対して有意差あり
(p < 0.05)
: 対照群に対して有意差あり
(p < 0.01>
ネ0 : 対照群に対して有意差あり
(p < 0.001)
・ ・ =11
(慢性肝障害に対する作用)
a) 目的
肝障害の実験的モデルである四塩化炭素誘発慢性肝障害
に対する、本発明による化合物の作用につき、血清トラ
ンスアミナーゼを指標として調べる.
b)操作
ウィスター系雄性ラット1群10匹を実験動物とし、四
塩化炭素を480 mg/kgの用量で週2回10週間
にわたり腹腔内投与することにより慢性肝障害を誘発さ
せた.被験群には、本発明による化合物として、製造例
4による化合物を4%牛血清アルブミンに溶解させ、0
.1、1.0、10.Otag/kg/日の用量で且つ
試験開始時から隔日的に10週間にわたり経口投与した
.四塩化炭素の最終投与から2日後に採血して血清中の
GOT及びGPT値を測定した.
C)結果及び考察
結果は下記の表11に示される通りであり、本発明によ
る化合物は、四塩化炭素の投与により誘発された肝障害
に伴うGOT及びGPT値の上昇を投与量1.O mg
lkgで有意に低減させることが判明した.
衣」よ
# : 平均値士標準誤差(n・10〉* : 対
照群に対して有意差あり
(p < 0.05>
傘*傘: 対照群に対して有意差あり(p < 0.
0Or)
薬理:12
(急性毒性)
ICR系マウス及びSD系ラットを実験動物とし、急性
毒性試験を実施した処、本発明による化合物は、経口投
与において、何れもLD,。値が2g/kg以上であり
、従って毒性が低く、使用安全性に優れていることが判
明した.
(発明の効果)
本発明による化合物は薬効薬埋試験例において示されて
いるように、種々の生埋活性、即ち免疫調整作用、イン
ターフェロン産生増強作用、抗癌作用、抗ウィルス作用
,肝保護作用等を有している.
従って、本発明による化合物は各種疾患、例えば免疫促
進系及び免疫抑制系の各種免疫疾患、各種のウィルス性
疾患、癌乃至腫瘍性疾患、肝疾患等の治療剤における有
効成分として利用することが期待される。Laoichi Master #: Standard error of the mean <n・10> Book: Significantly different from the control group (p < 0.001) Yingxun I'4 Ri4 Shark' - (Antiviral effect) a> Purpose The antiviral effects of the compounds of the present invention are investigated using an influenza virus infection model. b) Operation: One group of 10 BALB/c male mice were used as experimental animals.
Influenza virus (A/PR/8 strain) 9. O
Intratracheal infection was performed at an infectious dose of PFU/mouse. For the test group, as a compound according to the present invention, the compound according to Production Example 4 was dissolved in 4x bovine serum albumin, and 0.1, 1, O,
at a dose of 10.0 mg/kg/day and immediately after infection treatment.
It was orally administered six times on days 1, 2, 3, 4, and 5 after infection. The survival of the mice was checked for 20 days after virus infection. C> Results and discussion The results are shown in Table 9 below, and in the control group to which no compound was administered, death cases began to appear on the 8th day after infection.
All died by the 10th day. On the contrary,
In the test group, which is the administration group of the compound according to the present invention,
In particular, in the 1.0 mg/kg administration group, there were cases of infection and death from day 10, but even at the end of the test 20 days later, there were still 4 cases of infection.
Regarding the average survival time, there was a significant difference in both test groups when compared with the control group. - There was a significant difference compared to the control group (p < 0.05) * *: Significant difference compared to the control group (p < O.Oi) 0*: Significant difference compared to the control group (p < 0.001) Drugs / Effects on acute liver injury) a) Purpose The effects of the compounds of the present invention on galactosamine-induced acute liver injury, which is an experimental model of liver injury, will be investigated using serum transaminase as an indicator. b) Operation A group of 10 Wista male rats were used as experimental animals, and acute liver damage was induced by intraperitoneally administering galactosamine at a dose of 400 mg/kg twice at 6-hour intervals. The test group received Production Example 4 as a compound according to the present invention.
The compound was dissolved in 4x bovine serum albumin and diluted with 0.
It was orally administered at doses of 1, 1.0, and 10.0 mg/kg/day for 5 days starting 3 days before galactosamine administration. Blood was collected 48 hours after the first administration of galactosamine, and serum GOT and GPT values were measured. C
) Results and Discussion The results are shown in Table 1O below, and the compound according to the present invention shows that the GO
Table 10 N: Standard error of the mean <n=10>: Significantly different from the control group (p < 0.05): Significantly different from the control group (p <0.01> Ne0: Significant difference from control group (p < 0.001) ・ ・ = 11 (Effect on chronic liver damage) a) Carbon tetrachloride-induced chronic liver disease, which is an experimental model of objective liver damage The effect of the compound according to the present invention on liver damage is investigated using serum transaminase as an indicator. b) Operation A group of 10 Wistar male rats were used as experimental animals, and chronic liver damage was induced by intraperitoneal administration of carbon tetrachloride at a dose of 480 mg/kg twice a week for 10 weeks. For the test group, as a compound according to the present invention, the compound according to Production Example 4 was dissolved in 4% bovine serum albumin, and 0%
.. 1, 1.0, 10. It was orally administered at a dose of Otag/kg/day every other day for 10 weeks from the start of the study. Two days after the final administration of carbon tetrachloride, blood was collected and serum GOT and GPT values were measured. C) Results and Discussion The results are shown in Table 11 below, and the compound according to the present invention suppresses the increase in GOT and GPT values associated with liver damage induced by the administration of carbon tetrachloride at a dose of 1. Omg
It was found that it was significantly reduced by 1 kg. #: Standard error of the mean (n・10〉*: Significantly different from the control group (p <0.05>) Umbrella * Umbrella: Significantly different from the control group (p < 0.
0Or) Pharmacology: 12 (Acute Toxicity) Acute toxicity tests were conducted using ICR mice and SD rats as experimental animals, and the compound according to the present invention showed LD, when administered orally. The value was 2 g/kg or more, and it was therefore found that the toxicity was low and the safety of use was excellent. (Effects of the Invention) As shown in the medicinal efficacy test examples, the compound according to the present invention has various bioimbalance activities, namely, immunomodulatory action, interferon production enhancement action, anticancer action, antiviral action, and hepatoprotective action. etc. Therefore, the compound according to the present invention is expected to be used as an active ingredient in therapeutic agents for various diseases, such as various immunological diseases of the immunostimulatory system and immunosuppressive system, various viral diseases, cancer or tumor diseases, liver diseases, etc. be done.
尚、近年、後天性免疫不全症候群(エイズ)の蔓延が社
会問題となっており、このエイズを惹起させるウイルス
はl{uman ImmunodericiencyV
irus (HIV)とされている。エイズの治療には
、現在、主として核酸合成阻害剤が用いられているが、
この系統の薬物は殺ウィルス作用を有するも副作用が強
く、正常組織も破壊する傾向があるので、これに代わる
べき安全な薬物の開発が急務とされている。ところで、
本発明による化合物は、上記のように、生体内において
賦活を含めて免疫を調整する作用と、強力な抗}11V
物質として既に立証されているインターフェロンの産生
を増強させる作用とを併せ有しているので、エイズ治療
用の新しい薬物として利用し得る可能性が極めて高い.
手続補正書(自発)
平或l年8月17日In recent years, the spread of acquired immunodeficiency syndrome (AIDS) has become a social problem, and the virus that causes AIDS is human immunodeficiency syndrome.
irus (HIV). Currently, nucleic acid synthesis inhibitors are mainly used for the treatment of AIDS.
Although this class of drugs has virucidal effects, they have strong side effects and also tend to destroy normal tissue, so there is an urgent need to develop safe drugs to replace them. by the way,
As mentioned above, the compound according to the present invention has an effect of regulating immunity including activation in vivo, and a strong anti-11V
Since it also has the effect of enhancing the production of interferon, which has already been proven as a substance, it has an extremely high possibility of being used as a new drug for the treatment of AIDS. Procedural amendment (voluntary) August 17, 2016
Claims (4)
れ水素原子、置換基を有していることのできる低級アル
キル基又は置換基を有していることのできるフェニル基
を意味し、nは2又はそ れ以上の整数を意味する) にて示される有機ゲルマニウム化合物及びその塩。(1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. (n is an integer of 2 or more) and salts thereof.
れ水素原子、置換基を有していることのできる低級アル
キル基又は置換基を有していることのできるフェニル基
を意味する) にて示される硫化エチレン誘導体とを反応させ、得られ
る式 ▲数式、化学式、表等があります▼ (式中、R_1、R_2、R_3、R_4及びXは前記
の意味を有する) にて示される2−トリハロゲルミルエタンチオール誘導
体を酸化し、得られる式 ▲数式、化学式、表等があります▼ (式中、R_1、R_2、R_3、R_4及びXは前記
の意味を有する) にて示される2−トリハロゲルミルエタンスルホン酸誘
導体を加水分解させ、次いで必要に応じて塩に変ずるこ
とを特徴とする、式 ▲数式、化学式、表等があります▼ (式中、R_1、R_2、R_3及びR_4は前記の意
味を有し、nは2又はそれ以上の整数を意味す る) にて示される有機ゲルマニウム化合物及びその塩の製法
。(2) Trihalogermane represented by the formula X_3GeH (in the formula, atom, a lower alkyl group which may have a substituent, or a phenyl group which may have a substituent), and the resulting formula ▲ formula, There are chemical formulas, tables, etc. ▼ (In the formula, R_1, R_2, R_3, R_4 and , tables, etc. ▼ (In the formula, R_1, R_2, R_3, R_4 and There are formulas ▲mathematical formulas, chemical formulas, tables, etc., which are characterized by changing to A method for producing an organic germanium compound and its salt shown in
れ水素原子、置換基を有していることのできる低級アル
キル基又は置換基を有していることのできるフェニル基
を意味し、nは2又はそ れ以上の整数を意味する) にて示される有機ゲルマニウム化合物又はその塩を有効
成分とする薬剤組成物。(3) Formulas ▲ Numerical formulas, chemical formulas, tables, etc. a phenyl group that can contain a phenyl group, and n means an integer of 2 or more).
剤及びインターフェロン産生増強剤であることを特徴と
する、請求項(1)に記載の薬剤組成物。(4) The pharmaceutical composition according to claim (1), which is an immunomodulator, an anticancer agent, an antiviral agent, a liver disease treatment agent, and an interferon production enhancer.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1155585A JPH0324094A (en) | 1989-06-20 | 1989-06-20 | Organic germanium compound and production and use thereof |
US07/540,535 US5008416A (en) | 1989-06-20 | 1990-06-19 | Organogermanium compound, process for the preparation of same as well as use thereof |
EP19900111565 EP0404062A3 (en) | 1989-06-20 | 1990-06-19 | Organogermanium compound, process for preparation of same as well as use thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1155585A JPH0324094A (en) | 1989-06-20 | 1989-06-20 | Organic germanium compound and production and use thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH0324094A true JPH0324094A (en) | 1991-02-01 |
Family
ID=15609260
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP1155585A Pending JPH0324094A (en) | 1989-06-20 | 1989-06-20 | Organic germanium compound and production and use thereof |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0324094A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002193814A (en) * | 2000-12-25 | 2002-07-10 | Asai Germanium Research Inst | Secretion accelator of bile or bile pigments |
KR100532380B1 (en) * | 1998-05-12 | 2006-01-27 | 삼성전자주식회사 | Cleaning method for semiconductor device |
-
1989
- 1989-06-20 JP JP1155585A patent/JPH0324094A/en active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100532380B1 (en) * | 1998-05-12 | 2006-01-27 | 삼성전자주식회사 | Cleaning method for semiconductor device |
JP2002193814A (en) * | 2000-12-25 | 2002-07-10 | Asai Germanium Research Inst | Secretion accelator of bile or bile pigments |
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