JPH0144169B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a powerful opioid-degrading enzyme inhibitor containing an organic germanium compound as a main ingredient. Germanium (Ge), known as a homolog of carbon, has been the subject of research for many years due to its unique property of exhibiting a semiconductor effect, just like silicon (Si). As research into organic compounds and the presentation of their results became more active, they began to attract attention from all quarters. For example, carboxyethylgermanium sesquioxide (GeCH ₂ CH ₂ COOH) ₂ O 3 is a propionic acid derivative of germanium and is a sheet-like compound whose unit structure is a 12-membered ring in which germanium atoms and oxygen atoms are alternately _bonded. It is becoming a well-known fact through various study groups and literature publications that it is a compound that exhibits excellent physiological activities such as extremely strong blood pressure lowering effects and antitumor effects, but exhibits no toxicity or side effects at all. Furthermore, it has been reported that when the organogermanium compound is administered to patients complaining of pain such as cancer pain, it is possible to suppress the growth of cancer and reduce the dose of narcotic substances such as morphine required for analgesia. There have been reports of this, but there are some hypotheses as follows. In other words, the pharmacological effects of morphine, etc. are due to the fact that peptides, collectively called opioids, are liberated in the body upon administration, and these opioids control automatic analgesia in the body by sharing receptors with the above-mentioned morphine, etc. The reason why the dose of morphine etc. can be reduced by administering the organic germanium is that the organic germanium compound inhibits the action of the opioid degrading enzyme that decomposes and deactivates the opioid in the living body, This is because it aims to effectively utilize opioids in the body. However, the mechanism of physiological activity exhibited by the organic germanium compounds has not been clearly elucidated.
However, some researchers have proposed that its antitumor properties originate from the germanium-oxygen bond in its composition, so organic germanium compounds in which the oxygen atom is replaced with other closely related atoms are , is expected to be useful in a different aspect from the known organic germanium compounds. The present invention was completed as a result of research against the background of the above-mentioned circumstances, and its structure is based on the general formula (In the formula, R ₁ to R ₃ are: when R ₁ is a lower alkyl group, one of R ₂ and R ₃ is a lower alkyl group, the other is a hydrogen atom or a lower alkyl group, and R ₁ is a phenyl group. R ₂ and R ₃ each represent a hydrogen atom or a lower alkyl group, and Z represents a hydroxyl group or an amino group, respectively. The present invention will be explained in detail below. First, to explain the organic germanium compound used in the present invention agent, propionic acid (in the case of Z=OH) or its amide (in the case of Z=NH ₂ ) is bonded to the germanium atom, and on the propionic acid skeleton. Substituent at α position of germanium atom
R ₁ and R ₂ have a basic skeleton of germylpropionic acid with a substituent R ₃ bonded to the β position, and the germanium atom of the basic skeleton and the sulfur atom are in a ratio of 2:3.
It is ethylgermanium sesquisulfide combined in a ratio of . As for the substituents R ₁ to R ₃ , R ₁
is a lower alkyl group such as a methyl group, ethyl group, or propyl group, one of R ₂ and R ₃ is the same lower alkyl group as R ₁ , and the other is a hydrogen atom or a lower alkyl group, and R When ₁ is a substituted or unsubstituted phenyl group, R ₂ and R ₃ represent a hydrogen atom or a lower alkyl group. Therefore, examples of the organic germanium compounds used in the present agent include the following. (hereinafter referred to as compound (1)). As mentioned above, the organic germanium compound having the above structure is a compound in which germylpropionic acid and sulfur atoms are bonded in a ratio of 2:3, and therefore, it is expressed as above using that ratio, but the present invention The organic germanium compound used in the agent is or It can also be expressed as Organic germanium compounds having such a structure can be produced by various methods. That is, in the general formula (), Z=OH (') is obtained by drying the corresponding trichlorogermanium compound () in an organic solvent in the presence of a base such as pyridine, as shown in the following reaction formula (1). hydrogen sulfide
All you have to do is apply H ₂ S gas, In addition, in the general formula (), Z=NH ₂ ('') is, as shown in the reaction formula (2) below, ammonia after once converting the same trichlorogermanium compound () as above into the corresponding acid chloride (). (NH ₃ ) to form an amide compound ( ), and then dry hydrogen chloride gas is allowed to act on this in an organic solvent in the presence of a base as described above. In addition, in the above reaction formulas (1) and (2), the trimercapto compound is formed at the stage of acting with hydrogen sulfide.

[Formula] or

[Formula] is produced, but this trimercapto compound may or may not be isolated; if isolated, an intermolecular desulfurization reaction tends to occur, resulting in the structure of the general formula (). In addition, the trichlorogermanium compound () used in the above reaction can be prepared, for example, according to the method disclosed in Japanese Patent Publication No. 46-2964, It can be produced as follows, but it can also be produced by directly reacting with an acrylic acid derivative. You can also get it like this. The organic germanium compounds produced in this way, including the examples (1) to (6), are generally colorless and transparent crystals with a melting point (or decomposition point) of 200°C or higher, and experimental values of elemental analysis matches the calculated value calculated from each molecular formula within the error range, and
Infrared absorption (IR) spectra and nuclear magnetic resonance absorption (NMR) spectra both strongly support the fact that these compounds are represented by the above general formula (). In addition, while the carboxyethyl germanium sesquioxide is slightly soluble in water and completely insoluble in organic solvents, the organic germanium compound used in the present agent is slightly soluble in water and is miscible with water, such as acetone and alcohol. It is characterized by being soluble in organic solvents, that is, being fat-soluble. Since the above-mentioned organic germanium compound has a germanium-sulfur bond similar to the germanium-oxygen bond of carboxyethylgermanium sesquioxide, which is a known compound, if it is administered to a living body, it has antitumor properties as well. However, the usefulness of these organic germanium compounds was found in that they strongly inhibited the opioid degrading action of the aforementioned opioid degrading enzyme. That is, as mentioned above, substances collectively called opioids, which are peptides in the body, are extremely important compounds that control automatic analgesia in the body, and in 1975, Hughes et al. There are several types of enkephalin, including H ₂ N-Tyr-Gly-Gly-Phe-Met-OH, which was isolated from the brains of cows and cows, and whose structure was determined. On the other hand, there are various enzymes that degrade opioids such as enkephalin. A large number of dipeptidyl aminopeptides and aminopeptides isolated and purified from biological tissues have been discovered. When allowed to act on the enzyme, it was found that the organic germanium compound strongly inhibited the action of the enzyme. The above action is extremely strong; for example, compound (1) suppresses the degrading action of aminopeptidase derived from bovine longitudinal muscle on enkephalin, a type of opioid, by as much as 97.0%. The opioid-degrading enzyme inhibitor of the present invention, which is prepared as a base agent and is prepared into an appropriate solid form such as a tablet, powder, granule, or capsule, or a water solution such as an injection, can be administered to a living body to prevent the opioid-degrading enzyme As the effect of morphine is strongly inhibited and the effective utilization rate of opioids is improved, the medicinal effects of narcotic-like substances such as morphine become more pronounced, and the amount of narcotic-like substances used to obtain the same medicinal effect can be reduced. This makes it possible to reduce side effects such as habit-forming and addictive properties caused by prolonged use. Dipeptidylcarboxypeptidase, a type of opioid degrading enzyme, is also an angiotensin-converting enzyme that acts on angiotensin, a precursor of the enzyme angiotensin, which has an extremely strong pressor effect, so inhibiting this action means simultaneously renin-angiotensin
By acting on the aldosterone system, it can also be expected to have a favorable effect on living organisms, particularly on the blood pressure maintenance mechanism. Next, examples of synthesis of organic germanium compounds and examples of the present invention will be described. Synthesis Example 1 Production of compound (') First, 20.02 g of (E)-2-methyl-2-butenoic acid
(0.2 mol) in 100 ml of dry ethyl ether,
After adding 36.0 g (0.2 mol) of trichlorogermane under ice cooling and stirring for 2 hours, the precipitated crystals were recrystallized from n-hexane to obtain 2-methyl-3-(trichlorogermyl)butanoic acid (colorless plate-like crystals, yield
42.86g, yield 76.5%). Then, 5.6 g of 2-methyl-3-(trichlorogermyl)butanoic acid prepared as above.
(0.02 mol) was dissolved in 100 ml of anhydrous benzene, 5.2 g (0.066 mol) of anhydrous pyridine was added, and after stirring, dry hydrogen sulfide gas was passed through the solution for 60 minutes. By separating the precipitated compound and recrystallizing it from aqueous acetone or isolating and purifying it with a molecular sieve such as Sephadex LH-20 (trade name) using methanol as a developing solvent, compound (1) can be obtained in 3.2 I got g.
The yield was 72.1%. Compound (1)

[Table] Other compounds could also be produced according to the above method, and the physical properties of the obtained compound (') were as shown in Table (1). Synthesis Example 2 Production of the compound of the present invention ('') First, 2-methyl-3-(trichlorogermyl)
After treating 28.0 g (0.1 mol) of butanoic acid with 100 ml of thionyl chloride, it was distilled under reduced pressure to obtain 2-methyl-3-(trichlorogermyl)butanoic acid chloride in a pale yellow distillate with a boiling point of 99-100°C/6 mmHg. (yield 27.0 g, yield 90.4%). Then, 5.8 g (0.02 mol) of this acid chloride
was dissolved in 50 ml of anhydrous benzene, and dried ammonia was introduced for 1 hour under ice-cooling, followed by 1 hour of dry hydrogen chloride gas.
After introducing 100 ml of acetic acid methyl ester, stirring and filtration, the filtrate was distilled off, and the residue was recrystallized from an acetone-benzene mixture (1:2) to form 2-methyl-3-(trichlorogel). mill) butanoic acid amide (yield: 4.1 g, yield: 76.0%). Furthermore, 2-methyl- produced as above
3-(Trichlorogermyl)butanoic acid amide 10.8
g (0.04 mol) in 200 ml of anhydrous benzene,
After adding 9.5 g (0.12 mol) of anhydrous pyridine and stirring, dry hydrogen sulfide gas was passed through the mixture for 60 minutes. By separating the precipitated compound and recrystallizing it from aqueous acetone, or by isolating and purifying it with a molecular sieve such as Sephadex LH-20 (trade name) using methanol as a developing solvent, compound (5) was obtained at 7.8%. I got g. The yield was 88.3%. Compound (5)

[Table] Other compounds could also be produced according to the above method, and the physical properties of the obtained compound ('') were as shown in Table (2). Organic germanium compounds synthesized in this way The toxicity of compounds is low, and when we examine their LD ₅₀ values, for example, compound (3) has a low toxicity of 400 at po.
mg/Kg or more, SC is 700 mg/Kg or more, and
For compound (7), 2500mg/Kg for both po and sc
That's all.

【table】

【table】

[Table] Examples Pharmacological action of the agent of the present invention As mentioned above, the agent of the present invention strongly inhibits the action of opioid-degrading enzymes, but there are relatively few cases in which narcotic substances are used to treat diseases. Moreover, the symptoms are often severe, so there are various problems in confirming the effectiveness of the present drug to the same extent as regular drugs. Since the opioids that are liberated and the enzymes that degrade them have been identified,
The effect of the agent of the present invention was determined by the inhibition rate when a degrading enzyme was allowed to act on the opioid in vitro. That is, the present invention agent was added to an opioid such as enkephalin or its model compound, and after incubation for a certain period of time, the inhibition rate of the present invention agent against opioid degrading enzymes was determined for various opioids, as shown in Table (3). It showed a high overall inhibitory effect.

[Table] Furthermore, in order to confirm the inhibitory effect of the present agent, 50
When the percent inhibition rate (IC50) was measured, the results shown in Table (4) were obtained, making the effect of the present agent more clear.

[Table] In particular, the inhibition of the action of the aminopeptidase derived from bovine longitudinal muscle on enkephalin by the agent of the present invention, which has compound (3) as the main agent, is extremely high at IC50 = 19 μg/ml, which is because the agent is a reagent for the enzyme. It can also be used as a Therefore, when actually administering the agent of the present invention to the human body, for example, 100% of the organic germanium compound
Capsules containing 300 mg to 300 mg of the drug and a known pharmaceutical carrier may be prepared and administered orally. In addition, as mentioned above, the mechanism of action of the present agent is to effectively utilize opioids in the body, and therefore, the effective dose varies depending on the condition of the living body, the content of the concomitant drugs, etc. It doesn't make much sense. In addition, the preparation of various opioid-degrading enzymes from bovine longitudinal muscle in the above example was described by Goreustein and
The method of Snyder SH et al. (Life Sci.25, 2065
[1979]), and the inhibitory effect of the present agent on opioid degrading enzymes was measured using, for example, dipeptidyl aminopeptidase.
T. Hazato, M. Shimamura, T. Katayama and
The method of T. Yamamoto et al. (BBRCvol105 470~
475 [1982]), and regarding aminopeptides.
This was carried out by the method of M. Shimamura, T. Hazato and T. Katayama et al. (BBAvol 756 223-229 [1983]) or a method similar thereto.

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ to R ₃ are: when R ₁ is a lower alkyl group, one of R ₂ and R ₃ is a lower alkyl group, the other is a hydrogen atom or a lower alkyl group, and R ₁ is a phenyl group. An opioid degrading enzyme inhibitor characterized in that the main ingredient thereof is an organic germanium compound represented by the following formula: where R ₂ and R ₃ represent a hydrogen atom or a lower alkyl group, and Z represents a hydroxyl group or an amino group, respectively.