JPH0699312B2 - Opioid-degrading enzyme inhibitor - Google Patents
Opioid-degrading enzyme inhibitorInfo
- Publication number
- JPH0699312B2 JPH0699312B2 JP33503592A JP33503592A JPH0699312B2 JP H0699312 B2 JPH0699312 B2 JP H0699312B2 JP 33503592 A JP33503592 A JP 33503592A JP 33503592 A JP33503592 A JP 33503592A JP H0699312 B2 JPH0699312 B2 JP H0699312B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- opioid
- degrading enzyme
- formula
- enzyme inhibitor
- 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 - Lifetime
Links
- 229940125532 enzyme inhibitor Drugs 0.000 title claims description 10
- 239000002532 enzyme inhibitor Substances 0.000 title claims description 10
- 150000002291 germanium compounds Chemical class 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 102000001490 Opioid Peptides Human genes 0.000 description 7
- 108010093625 Opioid Peptides Proteins 0.000 description 7
- 230000000593 degrading effect Effects 0.000 description 7
- 229910052732 germanium Inorganic materials 0.000 description 7
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 7
- 239000003399 opiate peptide Substances 0.000 description 7
- 150000005599 propionic acid derivatives Chemical class 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- -1 compound carboxyethylgermanium sesquioxide Chemical class 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229960005181 morphine Drugs 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PASQIOIGIYDQGX-UHFFFAOYSA-N 3-trimethylgermylpropanoic acid Chemical compound C[Ge](C)(C)CCC(O)=O PASQIOIGIYDQGX-UHFFFAOYSA-N 0.000 description 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 2
- XBAFGPKYONHVOP-UHFFFAOYSA-N BrCC(C(=O)O)[GeH](C)C Chemical compound BrCC(C(=O)O)[GeH](C)C XBAFGPKYONHVOP-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- XEABSBMNTNXEJM-UHFFFAOYSA-N propagermanium Chemical compound OC(=O)CC[Ge](=O)O[Ge](=O)CCC(O)=O XEABSBMNTNXEJM-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-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
- 102000004400 Aminopeptidases Human genes 0.000 description 1
- 108090000915 Aminopeptidases Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- WOPFYEBXNBBNKV-UHFFFAOYSA-N O[GeH2]C(C)C(O)=O Chemical class O[GeH2]C(C)C(O)=O WOPFYEBXNBBNKV-UHFFFAOYSA-N 0.000 description 1
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229930188620 butyrolactone Natural products 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000000457 gamma-lactone group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 125000000082 organogermanium group Chemical group 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 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
- 150000003839 salts Chemical class 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【０００１】[0001]
【産業上の利用分野】本発明は有機ゲルマニウム化合物
を有効成分とするオピオイド分解酵素阻害剤に関するも
のである。FIELD OF THE INVENTION The present invention relates to an opioid-degrading enzyme inhibitor containing an organic germanium compound as an active ingredient.
【０００２】[0002]
【従来の技術】金属の一種であるゲルマニウムＧｅは、
半導体として旧くから研究の対象になっていたものであ
るが、最近になってその有機化合物に関する研究が進ん
で研究成果の発表が活発に行なわれるようになった結
果、ゲルマニウム、とりわけその有機化合物は種々の技
術分野から注目されるようになった。2. Description of the Related Art Germanium Ge, which is a type of metal,
Although it has been the subject of research for a long time as a semiconductor, as a result of the recent progress in research on organic compounds and active publication of research results, germanium, especially organic compounds, It has come to receive attention from various technical fields.
【０００３】例えば、式（ＧｅＣＨ2ＣＨ2ＣＯＯＨ）2
Ｏ3で表わされるカルボキシエチルゲルマニウムセスキ
オキサイドという化合物が、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半面、全く毒性や副作
用が見られないものであることは医薬学会では周知の事
実をなっている如くである。For example, the formula (GeCH 2 CH 2 COOH) 2
It is well known in the Pharmaceutical Society of Japan that the compound carboxyethylgermanium sesquioxide represented by O 3 exhibits extremely strong physiological activities such as antihypertensive action and antitumor action, while showing no toxicity or side effect. It seems to be the case.
【０００４】[0004]
【発明が解決しようとする課題】而して、前記カルボキ
シエチルゲルマニウムセスキオキサイドの発揮する血圧
降下作用や抗腫瘍作用等のメカニズムは未だ明確には解
明されてはいないが、網目状で且つシート状の化合物で
ある前記カルボキシエチルゲルマニウムセスキオキサイ
ドとは異なったゲルマニウム含有化合物が、上述した公
知化合物と異なる薬理作用を発揮することは十分に期待
される。The mechanism of the above-mentioned carboxyethyl germanium sesquioxide, such as antihypertensive action and antitumor action, has not been clarified yet, but it is a mesh-like and sheet-like form. It is fully expected that the germanium-containing compound different from the above-mentioned carboxyethylgermanium sesquioxide, which is the above-mentioned compound, exerts a pharmacological action different from that of the above-mentioned known compound.
【０００５】[0005]
【課題を解決するための手段】本発明は上述した従来技
術を背景として、有機ゲルマニウム化合物を有効成分と
するオピオイド分解酵素阻害剤を提供することを目的と
してなされたもので、その構成は、一般式The present invention has been made with the background of the above-mentioned prior art for the purpose of providing an opioid-degrading enzyme inhibitor containing an organic germanium compound as an active ingredient, and its constitution is generally formula
【化２】 （式中、Ｒ1はメチル基、エチル基等の低級アルキル基
を、Ｒ2、Ｒ3、Ｒ4は水素原子又はＲ1と同様の低級アル
キル基若しくは置換或いは無置換のフェニル基をそれぞ
れ表わす）で表わされる有機ゲルマニウム化合物を有効
成分とすることを特徴とするものである。[Chemical 2] (In the formula, R 1 represents a lower alkyl group such as a methyl group and an ethyl group, and R 2 , R 3 and R 4 represent a hydrogen atom or a lower alkyl group similar to R 1 or a substituted or unsubstituted phenyl group. ) Is used as an active ingredient.
【０００６】以下本発明を詳細に説明する。The present invention will be described in detail below.
【０００７】本発明のオピオイド分解酵素阻害剤は、上
記式（１）で表わされる有機ゲルマニウム化合物を有効
成分とするので、まずこの化合物について説明すれば、
これは、あたかも、二つの置換基Ｒ1及び一つの水酸基
ＯＨを有するゲルマニウム原子に、置換基Ｒ2、Ｒ3、Ｒ
4を有するプロピオン酸残基の結合したハイドロキシゲ
ルミルプロピオン酸誘導体が、当該分子内でエステル結
合を形成した、即ち、γ−ラクトン型の化合物である。Since the opioid-degrading enzyme inhibitor of the present invention contains an organic germanium compound represented by the above formula (1) as an active ingredient, first, this compound will be described.
This is as if the germanium atom having two substituents R 1 and one hydroxyl group OH has substituents R 2 , R 3 and R 2 .
The hydroxygermylpropionic acid derivative having a propionic acid residue having 4 has an ester bond in the molecule, that is, a γ-lactone type compound.
【０００８】ここで、式（１）中の置換基Ｒ1はメチル
基、エチル基又はプロピル基等の低級アルキル基を表わ
し、又、置換基Ｒ2、Ｒ3、Ｒ4は水素原子又はＲ1と同様
の低級アルキル基若しくは置換され或いは無置換のフェ
ニル基をそれぞれ表わしており、従って、本発明で使用
する有機ゲルマニウム化合物は、例えば以下に示すよう
な化合物により代表される。Here, the substituent R 1 in the formula (1) represents a lower alkyl group such as a methyl group, an ethyl group or a propyl group, and the substituents R 2 , R 3 and R 4 are a hydrogen atom or R. Each represents a lower alkyl group similar to 1 or a substituted or unsubstituted phenyl group. Therefore, the organic germanium compound used in the present invention is represented by, for example, the compounds shown below.
【化３】 [Chemical 3]
【０００９】このような構造の有機ゲルマニウムは種々
の方法により合成することができるが、例えば下記反応
式に示すように、置換基Ｒ2、Ｒ3、Ｒ4を有するトリハ
ロゲノゲルミルプロピオン酸誘導体（２）を、置換基Ｒ
1を含むグリニャール試薬（３）と反応させてトリアル
キルゲルミルプロピオン酸誘導体（４）とし、このトリ
アルキルゲルミルプロピオン酸誘導体（４）に例えばブ
ロムＢｒ2等を作用させてＧｅ−Ｒ1結合を切断すると共
にゲルマニウムをブロム化してモノブロム体（５）と
し、該モノブロム体（５）を加水分解反応に付せば良い
のである。The organic germanium having such a structure can be synthesized by various methods. For example, as shown in the following reaction formula, a trihalogenogermylpropionic acid derivative having substituents R 2 , R 3 and R 4 is shown. (2) is a substituent R
A trialkylgermyl propionic acid derivative (4) is reacted with a Grignard reagent (3) containing 1 and the trialkylgermyl propionic acid derivative (4) is reacted with, for example, bromine Br 2 or the like to form a Ge—R 1 bond. Is cleaved and germanium is brominated to form a monobromo compound (5), and the monobromo compound (5) is subjected to a hydrolysis reaction.
【化４】 [Chemical 4]
【００１０】尚、最後の加水分解反応は水のみにより行
ってもよいが、塩基若しくはＡｇ2Ｏのような塩類の存
在下に反応させてもよい。The final hydrolysis reaction may be carried out only with water, but may be carried out in the presence of a base or salts such as Ag 2 O.
【００１１】以上のようにして得られた有機ゲルマニウ
ム化合物は、いずれも無色の結晶であって、親水性と親
油性の双方を示し、元素分析（ＥＡ）や質量分析（ＭＡ
ＳＳ）の結果及び核磁気共鳴吸収（ＮＭＲ）スペクトル
や赤外線吸収（ＩＲ）スペクトルの結果は、すべて合成
した化合物が一般式（１）で表わされるべきものである
ことを良く支持するものであった。The organogermanium compounds obtained as described above are all colorless crystals, exhibiting both hydrophilicity and lipophilicity and exhibiting elemental analysis (EA) and mass spectrometry (MA).
The results of SS) and the results of nuclear magnetic resonance absorption (NMR) spectrum and infrared absorption (IR) spectrum well supported that all the synthesized compounds should be represented by the general formula (1). .
【００１２】そして、上記有機ゲルマニウム化合物を、
オピオイドと総称されるペプタイド（モルヒネ等の投与
により生体内に遊離し当該生体の自己鎮痛作用を営むと
されている）を分解してしまうオピオイド分解酵素に対
し作用させてみると、当該化合物は、極めて低い濃度に
おいて、しかも特定のオピオイド分解酵素に対し、強力
な阻害作用を示した。Then, the above organic germanium compound is
Peptide, which is generically called opioid (which is said to be released in the body by administration of morphine and said to exert a self-analgesic effect on the body), and acting on an opioid-degrading enzyme, the compound is It showed a strong inhibitory effect on a specific opioid-degrading enzyme even at an extremely low concentration.
【００１３】従って、上記有機ゲルマニウム化合物を有
効成分とする本発明オピオイド分解酵素阻害剤は、投与
されるモルヒネ等の生体内での有効利用を図ると共に、
耽溺性の強いモルヒネ等の投与量を減ずることができる
優れたものである。Therefore, the opioid-degrading enzyme inhibitor of the present invention containing the above-mentioned organic germanium compound as an active ingredient is intended to be effectively utilized in vivo such as administered morphine.
It is an excellent drug that can reduce the dose of morphine, which is highly addictive.
【００１４】以下に本発明を実施例により説明する。The present invention will be described below with reference to examples.
【００１５】[0015]
１．有機ゲルマニウム化合物の合成 ａ．化合物（４）の合成 ３−トリクロルゲルミルプロピオン酸〔式（２）におい
てＲ2＝Ｒ3＝Ｒ4＝Ｈ、Ｘ＝Ｃｌの化合物〕１００ｇ
（０．４０ｍｏｌ）を無水エチルエーテルに溶解し、氷
冷下メチルマグネシウムヨーダイド〔式（３）において
Ｒ1＝ＣＨ3の化合物〕を１．８０ｍｏｌ含有するエーテ
ル溶液を加えた後、３０分間加熱還流した。反応終了
後、希塩酸（３．５％）で加水分解し、エーテル層を分
取してから該エーテル層に無水硫酸ナトリウムを加えて
脱水し、エーテルを留去してから残渣を減圧蒸留に付す
と、３−トリメチルゲルミルプロピオン酸〔式（４）に
おいてＲ1＝ＣＨ3、Ｒ2＝Ｒ3＝Ｒ4＝Ｈの化合物〕の無
色透明の留分を６０．９ｇ得た。1. Synthesis of organic germanium compound a. Synthesis of compound (4) 3-trichlorogermylpropionic acid [compound of formula (2) wherein R 2 = R 3 = R 4 = H and X = Cl] 100 g
(0.40 mol) was dissolved in anhydrous ethyl ether, and an ether solution containing 1.80 mol of methylmagnesium iodide [compound of R 1 ═CH 3 in formula (3)] was added under ice-cooling, and then heated for 30 minutes. Refluxed. After completion of the reaction, hydrolyze with dilute hydrochloric acid (3.5%), separate the ether layer, dehydrate by adding anhydrous sodium sulfate to the ether layer, distill off the ether, and subject the residue to distillation under reduced pressure. Then, 60.9 g of a colorless and transparent fraction of 3-trimethylgermylpropionic acid [a compound of the formula (4) in which R 1 = CH 3 , R 2 = R 3 = R 4 = H] was obtained.
【００１６】他の化合物（４）も上記と略同様の合成操
作により得ることができた。合成した化合物（４）の物
理化学的データを次の表１及び表２に例示する。The other compound (4) could also be obtained by the same synthetic procedure as described above. The physicochemical data of the synthesized compound (4) are shown in Tables 1 and 2 below.
【表１】 [Table 1]
【表２】 [Table 2]
【００１７】ｂ．化合物（５）の合成 上記合成した３−トリメチルゲルミルプロピオン酸３
８．２ｇ（０．２ｍｏｌ）に対し、氷冷下で臭素（Ｂｒ
2）３２．０ｇ（０．２ｍｏｌ）の四塩化炭素溶液を加
えて１時間攪拌した。反応終了後、析出する結晶をヘキ
サンより再結晶すると、３−ブロモジメチルゲルミルプ
ロピオン酸〔式（５）においてＲ1＝ＣＨ3、Ｒ2＝Ｒ3＝
Ｒ4＝Ｈの化合物〕を４７．０ｇ得た。B. Synthesis of compound (5) 3-trimethylgermylpropionic acid 3 synthesized above
8.2 g (0.2 mol) of bromine (Br
2 ) 32.0 g (0.2 mol) of carbon tetrachloride solution was added and stirred for 1 hour. After completion of the reaction, the precipitated crystals were recrystallized from hexane to give 3-bromodimethylgermylpropionic acid [in the formula (5), R 1 = CH 3 , R 2 = R 3 =
R 4 = H compound] was obtained.
【００１８】他の化合物（５）も上記と略同様の合成操
作により得ることができた。合成した化合物（５）の物
理化学的データを次の表３及び表４に例示する。The other compound (5) could also be obtained by the same synthetic procedure as described above. The physicochemical data of the synthesized compound (5) are shown in Tables 3 and 4 below.
【表３】 [Table 3]
【表４】 [Table 4]
【００１９】ｃ．化合物（１）の合成 上記合成した３−ブロモジメチルゲルミルプロピオン酸
２５．５ｇ（０．０１ｍｏｌ）に対し水５０ｍｌを加
え、攪拌した。反応終了後、水酸化ナトリウム水溶液に
より液性が中性となるように中和し、水を留去して、析
出する結晶をアセトン抽出し、アセトンを留去して得ら
れる結晶をベンゼンから再結晶すると、４，４−ジメチ
ル−４−ゲルマガンマブチロラクトン〔式（１）におい
てＲ1＝ＣＨ3、Ｒ2＝Ｒ3＝Ｒ4＝Ｈの化合物〕を１．５
４ｇ得た。C. Synthesis of Compound (1) 50 ml of water was added to 25.5 g (0.01 mol) of 3-bromodimethylgermylpropionic acid synthesized above and stirred. After the reaction was completed, the solution was neutralized with an aqueous sodium hydroxide solution to neutrality, the water was distilled off, and the precipitated crystals were extracted with acetone. When crystallized, 4,4-dimethyl-4-germana butyrolactone [a compound of the formula (1) in which R 1 = CH 3 , R 2 = R 3 = R 4 = H] was added to 1.5
4 g was obtained.
【００２０】他の化合物（１）も上記と略同様の合成操
作により得ることができた。本発明オピオイド分解酵素
阻害剤の有効成分である化合物（１）の物理化学的デー
タを次の表５及び６に例示する。The other compound (1) could also be obtained by the same synthetic procedure as described above. The physicochemical data of the compound (1), which is the active ingredient of the opioid-degrading enzyme inhibitor of the present invention, is shown in Tables 5 and 6 below.
【表５】 [Table 5]
【表６】 [Table 6]
【００２１】２．本発明オピオイド分解酵素阻害剤の薬
理作用 現在では多種類のオピオイドペプタイド及び対応するオ
ピオイドペプタイド分解酵素が発見されているので、本
発明オピオイド分解酵素阻害剤の薬理作用活性はオピオ
イドペプタイド分解酵素の阻害効果をｉｎ Ｖｉｔｒｏ
で検定することとした。2. Pharmacological action of the opioid degrading enzyme inhibitor of the present invention Since various types of opioid peptides and corresponding opioid peptide degrading enzymes are currently discovered, the pharmacological activity of the opioid degrading enzyme inhibitor of the present invention is the inhibitory effect of opioid peptide degrading enzymes. In in vitro
I decided to test it.
【００２２】即ち、上記有機ゲルマニウム化合物の存在
下、オピオイドペプタイド又はそのモデル化合物にオピ
オイドペプタイド分解酵素を作用させ、上記有機ゲルマ
ニウム化合物の阻害効果を測定したのであり、この結
果、下記の表７に示すように、上記有機ゲルマニウム化
合物は低濃度であってもオピオイドペプタイド分解酵素
の作用を良く阻害し、しかも今回使用したオピオイドペ
プタイド分解酵素に関しては、ゲルマニウムに結合する
置換基の種類によって、猿脳由来のアミノペプチデース
或いはジペプチジルアミノペプチデースの一方を阻害
し、つまり選択性を有していることが明らかとなったの
である。That is, the opioid peptide degrading enzyme was allowed to act on the opioid peptide or its model compound in the presence of the organogermanium compound, and the inhibitory effect of the organogermanium compound was measured, and the results are shown in Table 7 below. As described above, the organogermanium compound well inhibits the action of the opioid peptide degrading enzyme even at a low concentration, and as for the opioid peptide degrading enzyme used this time, depending on the type of the substituent bonded to germanium, it is derived from monkey brain. It was clarified that it inhibits one of aminopeptidase or dipeptidylaminopeptidase, that is, has selectivity.
【表７】 [Table 7]
【００２３】尚、上掲の表７に示した数値は、有機ゲル
マニウム化合物を１ｍｇ／ｍｌの濃度で使用した場合の
阻止率を％で表示したものであり、又、ＡＰはアミノペ
プチデース、ＤＰＰはジペプチジアルアミノペプチデー
ス、ＡＣＥはアンジオテンシン変換酵素をそれぞれ表わ
している。The numerical values shown in Table 7 above represent the inhibition rate in% when the organic germanium compound is used at a concentration of 1 mg / ml, and AP is aminopeptidice, DPP. Represents dipeptidial aminopeptidice, and ACE represents angiotensin converting enzyme.
【００２４】更に、有機ゲルマニウム化合物（１ａ）及
び（１ｃ）について５０％阻止率（ＩＣ50）を算出して
みると、それぞれ１７０μｇ／ｍｌ、１９０μｇ／ｍｌ
と良好な値であった。Further, when the 50% inhibition rate (IC 50 ) of the organic germanium compounds (1a) and (1c) was calculated, they were 170 μg / ml and 190 μg / ml, respectively.
And was a good value.
【００２５】本発明は以上の通りであるから、オピオイ
ド分解酵素阻害剤として産業上の利用性大なるものがあ
る。Since the present invention is as described above, it has a great industrial utility as an opioid-degrading enzyme inhibitor.
Claims (1)
を、Ｒ2、Ｒ3、Ｒ4は水素原子又はＲ1と同様の低級アル
キル基若しくは置換或いは無置換のフェニル基をそれぞ
れ表わす）で表わされる有機ゲルマニウム化合物を有効
成分とすることを特徴とするオピオイド分解酵素阻害
剤。1. A general formula: (In the formula, R 1 represents a lower alkyl group such as a methyl group and an ethyl group, and R 2 , R 3 and R 4 represent a hydrogen atom or a lower alkyl group similar to R 1 or a substituted or unsubstituted phenyl group. ) An opioid-degrading enzyme inhibitor comprising an organic germanium compound represented by the formula (1) as an active ingredient.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59-281002 | 1984-12-29 | ||
| JP28100284 | 1984-12-29 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27175085A Division JPS61267591A (en) | 1984-12-29 | 1985-12-03 | Organogermanum compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH05238935A JPH05238935A (en) | 1993-09-17 |
| JPH0699312B2 true JPH0699312B2 (en) | 1994-12-07 |
Family
ID=17632898
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27175085A Granted JPS61267591A (en) | 1984-12-29 | 1985-12-03 | Organogermanum compound |
| JP33503592A Expired - Lifetime JPH0699312B2 (en) | 1984-12-29 | 1992-11-19 | Opioid-degrading enzyme inhibitor |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27175085A Granted JPS61267591A (en) | 1984-12-29 | 1985-12-03 | Organogermanum compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (2) | JPS61267591A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2724397B2 (en) * | 1989-01-30 | 1998-03-09 | 株式会社浅井ゲルマニウム研究所 | Organic germanium compound and method for producing the same |
-
1985
- 1985-12-03 JP JP27175085A patent/JPS61267591A/en active Granted
-
1992
- 1992-11-19 JP JP33503592A patent/JPH0699312B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH05238935A (en) | 1993-09-17 |
| JPS61267591A (en) | 1986-11-27 |
| JPH0583558B2 (en) | 1993-11-26 |
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