JPS61267591A - Organogermanum compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R1 is methyl or ethyl; R2-R4 are H, the same lower alkyl as that of R1, phenyl, or substituted phenyl). USE:An analgesic by inhibiting an enzyme to decompose opioid. PREPARATION:For example, a trihalogenogermylpropionic acid derivative shown by the formula II (X is halogen) is reacted with a Grignard reagent shown by the formula R1MgBr, etc. to give a trialkylgermylpropionic acid derivative, this compound is treated with bromine, etc., to scissor a Ge-R1 bond and germanium is brominated to give a monobromoform derivative shown by the formula III. Then, this compound is hydrolyzed with water, neutralized with an aqueous solution of sodium hydroxide, water is distilled away, precipitated crystal is extracted with acetone, acetone is distilled away and the resulting substance is recrystallized with benzene, etc., to give a compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel organogermanium compound.

[Conventional technology]

Germanium Ge, a type of metal, has long been the subject of research as a semiconductor, but recently research into its organic compounds has progressed and research results have been actively published. As a result, germanium, especially its organic compounds, has attracted attention from various technical fields.

For example, the formula (G e CH>CH> COOH)s
It is a well-known fact in the medical academic community that the compound carboxyethyl germanium sesquioxide, represented by Os Te, exhibits extremely strong physiological activities such as blood pressure lowering and antitumor effects, but has no toxicity or side effects. It seems that

[Problem that the invention seeks to solve]

Although the mechanisms by which carboxyethylgermanium sesquioxide exerts its antihypertensive and antitumor effects have not yet been clearly elucidated, some researchers believe that its pharmacological effects are due to the germanium-oxygen bond. Therefore, it is necessary to synthesize a new compound containing a different type of germanium-oxygen bond than that in the aforementioned carboxyethyl germanium sesquioxide, which is a network-like and sheet-like compound. If possible, it is expected that the compound will exhibit pharmacological effects as excellent as those of the above-mentioned known compounds.

[Means for solving problems]

The present invention was made with the purpose of providing a novel and useful organic germanium compound against the background of the above-mentioned circumstances. Alkyl group, R, R,,R
is a hydrogen atom, a lower alkyl group similar to R1, or a substituted or unsubstituted phenyl group, respectively).

The present invention will be explained in detail below.

The compound of the present invention has a germanium atom having two substituents R1 and one hydroxyl group OH, and a substituent R1.
The hydroxygermylpropionic acid derivative to which propionic acid residues having , , R, and R were bonded formed an ester bond within the molecule. That is, it is a γ-lactone type compound.

Here, the substituent R/ in formula 1 CI) represents a lower alkyl group such as a methyl group, an ethyl group or a propyl group.

Furthermore, the m substituents R, , R, and R each represent a hydrogen atom, a lower alkyl group similar to R, or a substituted or unsubstituted phenyl group, and therefore, the organogermanium compound of the present invention has 1 For example, it is typified by the compounds shown below.

(I a) (r b) (I
c) (I d) (Ie
) (If) (I g)
(I h) (I i)
(I j) The compound of the present invention having such a structure can be synthesized by various methods, but 1
For example, as shown in the reaction formula below, substituents R,, R,, R
Trihalogenogel milpropionic acid derivative with ψ (
II) with a Grignard reagent (m) containing a substituent R, to obtain a trialkylgermylpropionic acid derivative (
Ge
What is necessary is to cleave the -R bond and bromine germanium to form a monobromine (V), and then subject the monobromine (■) to a hydrolysis reaction.

Reaction Formula %Formula %() Note that the final hydrolysis reaction may be carried out using only water, but it may also be carried out in the presence of a base or a salt such as Ag or 0.

All of the compounds of the present invention obtained as described above are colorless crystals that exhibit both hydrophilicity and lipophilicity, and the results of elemental analysis (EA), mass spectrometry (MASS), and nuclear magnetic resonance absorption (NMR) spectrum and infrared absorption (IR)
The spectrum results show that all synthesized compounds have the general formula (
1), which strongly supports the idea that it should be expressed as 1).

(Effects of the Invention) The organic germanium compound of the present invention is a compound with a γ-lactone structure containing a germanium-oxygen bond, which is not found in conventionally known compounds, so it is not a known compound as mentioned at the beginning. It is expected to exhibit excellent pharmacological effects comparable to those of carboxyethyl germanium sesquioxide.

In fact, the compound of the present invention is made to act on an opioid-degrading enzyme that degrades peptides collectively called opioids (which are released into the body upon administration of morphine, etc., and are said to exert a self-analgesic effect in the body). As a result, the compound of the present invention exhibited a strong inhibitory effect on specific opioid degrading enzymes even at extremely low concentrations.

Therefore, the compound of the present invention can be used as an opioid degrading enzyme inhibitor to effectively utilize administered morphine, etc. in the body, and to reduce the dose of morphine, etc., which is highly addictive. .

〔Example〕

3-Trichlorogermylpropionic acid (R,=R3=RP=H,X=C117) compound in (■)) 100
g (0.40 mol) was dissolved in anhydrous ethyl ether,
After adding an ether solution containing 1.80 mol of methylmagnesium iodite (a compound of R, = CHj in (■)) under water cooling, the mixture was heated under reflux for 30 minutes. After the reaction is complete, hydrolyze with dilute hydrochloric acid (3.5%), separate the ether layer, add anhydrous sodium sulfate to dehydrate the ether layer, distill off the ether, and distill the remaining liquid under reduced pressure. When attached, the compound (CHa )s GeCHL CHz C
In OOH ((■), R, = (lJ, RJL = R, =
60.9 g of a colorless and transparent fraction of a compound with Rψ=l+ was obtained.

Since other compounds (IV) could also be obtained by substantially the same synthetic operations as above, the physicochemical data of compound (IV), which is the starting material for synthesizing the compounds of the present invention, are shown in Tables 18 and b below. Shown below.

h part 381ha υ! Also, (CHi)3GeCHzCt(2COOH
A carbon tetrachloride solution of 32.0 g (0.2 mol) of bromine (Brz) was added to 2 g (0.2 mol) of 3B under water cooling, and the mixture was stirred for 1 hour.

After the reaction is complete, the precipitated crystals are recrystallized from hexane to form Dr((JIB), GeCH, C11zCOOH((
V) in R,=CH,.

47°Og of a compound of R,=R,=Rψ=J was obtained.

Other compounds (V) could also be obtained by the same synthetic procedure as above, so the physicochemical data of compound (V), which is an intermediate for synthesizing the compound of the present invention, is shown in Table 2 below.
8 and b.

3 pieces of C ■ Metallic materials (■ fir (CHI) synthesized above, GeCl1.CI, C
50 ml of water was added to 25.5 g (0.0 In+ol) of 0OH and stirred. After the reaction is complete, the liquid is neutralized with an aqueous sodium hydroxide solution, the water is distilled off, the precipitated crystals are extracted with acetone, and the crystals obtained by distilling off the acetone are recycled from benzene. When it crystallizes.

Compound δ <(■) in which R,=C11,, R,=Rs=Rφ=
1.54 g of compound No. 11 was obtained.

Since the other compound (1) could also be obtained by substantially the same synthetic procedure as above, the physicochemical data of (I), which is the target compound of the present invention, are shown in the following Tables 38 and b.

2. Cooperative action of the organogermanium compound of the present invention Since many types of opioid peptides and corresponding opioid peptide-degrading enzymes have been discovered at present, the pharmacological activity of the compound of the present invention is assayed for its inhibitory effect on opioid peptide-degrading enzymes using 1nVitro. I decided to do so.

That is, the inhibitory effect of the compound of the present invention was measured by causing an opioid peptide degrading enzyme to act on an opioid peptide or its model compound in the presence of the compound of the present invention. As a result, as shown in Table 4 below, the inhibitory effect of the compound of the present invention was It effectively inhibits the action of opioid peptide-degrading enzymes even at low concentrations, and the opioid peptide-degrading enzymes used this time are either aminopeptidase or dipeptidyl derived from monkey brain, depending on the type of substituent bonded to germanium. It was revealed that it inhibits one of the aminopeptides, that is, it has selectivity.

Table 4 The items listed in Table 4 are (I a)
(I c), and the numerical values in Table 4 are the inhibition rates expressed in % when the compound of the present invention is used at a concentration of 1 mg/ni1. Further, AP is aminopeptidase and DPP is dipeptidyl aminopeptidase.

ACE stands for angiotensin converting enzyme, respectively.

Furthermore, for the compounds (Ia) and (Ic), 50
When calculating the % rejection rate (rcso), it was 17 for each.
Good values were 0 μg/tolerance and 190 μg/ml.

Since the present invention is as described above, it has great industrial applicability as an organic germanium compound.

Claims (1)

[Claims] General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
(I) (In the formula, R_1 represents a lower alkyl group such as a methyl group or 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, respectively.) An organic germanium compound characterized by: