JPS6152824B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a metal salt of a sulfur drug and a method for producing the same. Specifically, it relates to gold salts and platinum salts of sulfur drugs that are effective against Gram-positive bacteria and Gram-negative bacteria, and the gold salts of sulfur drugs are characterized in that they are treated with gold salts or platinum salts under alkaline conditions. and regarding a method for producing platinum salts. As antibacterial substances, sulfur drugs have been widely used in chemotherapy, but in recent years they have become less common due to concerns about bacterial resistance and cross-resistance, and with the advent of better antibiotics. There is. Attempts have been made to widen the range of applications of sulfur drugs as chemotherapeutic agents by replacing various substituents in the sulfonamide skeleton, but the resistance acquired by one sulfur drug derivative is This has resulted in the drawback of causing so-called cross-resistance. Many of the metabolic pathways, mechanisms of action, and side effects of sulfur drugs in the body are well understood, and they are also listed in official official documents, making it possible to develop drugs with more effective medicinal effects. desirable. We have discovered a new antibacterial substance derivative that disrupts the recognition site for antibiotics in resistant bacteria by coordinating a metal to the previously used antibacterial substance that has become resistant to bacteria. . In other words, by selecting gold and platinum as metals that are not toxic to living organisms and coordinating them with sulfur agents, we succeeded in producing new antibacterial substances that have the respective advantages of gold or platinum and sulfur agents. , completed the invention. The sulfur drug metal salts invented by the present inventors are all new compounds, with the general formula (Here, M represents a gold atom or a platinum atom, and R represents a heterocyclic residue with or without a substituent.) Sulfur agents that coordinate to metals

For example, [formula] is sulfadiazin

[Formula] Sulfur melazine

[Formula] Sulfapelin

[Formula] Sulfamesazine

[Formula] Sulfisomidine

[Formula] Sulfametail

[Formula] Sulfamomonomethoxy hmm

[Formula] Sulfadimethoxine

[Formula] Sulfadoxin

[Formula] Sulfabromomethazine

[Formula] Sulfamethomidine

[Formula] Sulfapyrazine

[Formula] Sulfarene

[Formula] Sulfamethoxypyridadi hmm

[Formula] Sulfaethoxypi Ridazine

[Formula] Sulfacro Ropyridazine

[Formula] Sulfapyri gin

[Formula] Sulfamethizole

[Formula] Sulfaethidol

[Formula] Sulfathiazole

[Formula] Sulfasomizole

[Formula] Sulfamethylthiazole

[Formula] Sulfuisomesole

[Formula] Sulfisoxazole

[Formula] Sulfamoxol

[Formula] Sulfafenazole

[Formula] Sulfamethylphenazole

Examples include [Formula]. The gold salts and platinum salts of these sulfur drugs are listed in Table 1.
As shown in Figure 2, it has stronger antibacterial activity than the original sulfur agent, is particularly effective against Gram-negative bacteria, and can be used for bacterial infections. Until now, sodium salts, silver salts, zinc salts, etc. have been known as metal salts of sulfanilamides, and among these, silver sulfadiazine (U.S. Patent Nos. 3761590 and 3792161) is used as an external preparation. It is used to prevent infection in burns and burns.
However, when exposed to light, silver salt liberates silver, causing the wound surface to turn black, which is undesirable. Additionally, gold was once used as an anti-inflammatory fungicide to treat asthma, syphilis, tuberculosis, and leprosy, and colloidal gold and gold derivatives are still used today to treat rheumatoid arthritis and skin diseases. For these reasons, the substance of the present invention is expected to be used as an anti-inflammatory antibacterial agent that has both antibacterial and anti-inflammatory effects.

【table】

[Table] Next, a manufacturing method which is one of the present invention will be described. A sulfur drug is suspended or dissolved in 5 to 100 times the volume of water, and an equivalent or slightly excess 5 to 20% aqueous solution of alkali hydroxide is added. At this time,
Insoluble sulfur drugs dissolve by forming alkaline salts and the suspension becomes clear. A 5% to 40% aqueous solution of gold salt or platinum salt is added to this solution and stirred at room temperature, whereby the desired product is precipitated.
The desired product is obtained by continuing stirring for another 1 to 6 hours and centrifuging or filtering. As a gold salt that can be used, sodium chloraurate ( _{Na2AuCl4 .}
2H ₂ O), ferrous cyanide (AuCN), and platinum salts include potassium chloroplatinate (K ₂ PtCl ₄ ). The manufacturing method of the present invention will be specifically illustrated below with examples. Example 1 Method for producing gold sulfadiazine 2.5 g of sulfadiazine is suspended in 5 ml of purified water, and an equivalent amount (4.0 ml) of 10% sodium hydroxide is added dropwise with thorough stirring to make the suspension clear. Add 4g of sodium chloraurate (Na ₂ AuCl ₄ ) to this for 10 minutes.
When a solution (yellow color) dissolved in ml of water is dropped, the target object, gold sulfadiazine, precipitates out. Continue stirring for one hour, then centrifuge at 3000 rpm for 3 minutes, add a small amount of water to the precipitate, wash well, and centrifuge again. The brown precipitate is collected and thoroughly dried under reduced pressure to obtain the desired product (melting point: 236-242°C). UV: λmax 265nm (dilute hydrochloric acid) NMR: 5.90 (s.2H), 6.54 (d.2H), 6.91
(t.1H), 7.59 (d.2H), 8.42 (d.2H), ppm,
(−SO ₂ NH − (11.21 ppm) disappeared), 100 MHz, d ₆
-CH ₃ SOCH _3- element analysis: C ₁₀ H ₉ AuN ₄ O ₂ S (446.26) Calculated value: C: 26.92, H: 2.03, Au: 44.14,
N: 12.56, S: 32.06 Actual value: C: 26.54, H: 2.43, Au: 44.17,
N: 13.30, S: 31.84 Examples 2 to 8 Sulfamethizole gold (AuSM), sulfisomidine gold (AnSI), sulfisoxazole gold ( AuSIX), sulfisomezole gold (AuSIM), sulfadimethoxine gold (AuSDM), sulfaenazole gold (AuSPh),
Sulfamomonomethoxygold (AuSMM) was produced. The respective melting points and elemental analysis values are shown in Table 2.

[Table] Examples 9 to 11 Potassium chloroplatinate (K ₂ AuCl ₄ ) as metal salt
Using the same method as in Example 1, sulfadiazine platinum (PtSD), sulfadimethoxine platinum (PtSDM), and sulfamomonomethoxine platinum (PtSMM) were obtained from sulfadiazine, sulfadimethoxine, and sulfamomonomentoxine, respectively. Ta. The melting point and elemental analysis values are shown below.

【table】

Claims (1)

[Claims] First-order general formula () (Here, M represents a gold atom or a platinum atom, and R represents a heterocyclic residue with or without a substituent.) A metal salt of a sulfur agent. 2. In the compound according to claim 1, M
is a gold atom and R is 2-pyrimidine, sulfadiazine gold. 3. Sulfadiazine platinum, in which M is a platinum atom and R is 2-pyrimidyl, among the compounds according to claim 1. 4 General formula () A method for producing a metal salt of a sulfur agent (wherein R represents a heterocyclic residue with or without a substituent) by treating the sulfur agent with a gold salt or a platinum salt under alkaline conditions.