JPH0892201A - Dihydroxyphenyl sulfide derivative or its salt, its synthesis and anti-melanoma agent containing the compound - Google Patents

Abstract

PURPOSE: To provide a new dihydroxyphenyl sulfide derivative or its salt having excellent cytotoxicity against amelanocyte and useful as an anti-melanoma agent. CONSTITUTION: This derivative is expressed by formula I (two of R1 to R5 are each OH and the other three are each H or a lower alkyl; R6 and R7 are each H, a lower alkyl or acetyl; (n) is 2 or 3) or its salt, e.g. 4-S- cysteaminylcatechol. The compound can be produced e.g. by adding cystamine, homocystamine or its salt and hydrobromic acid to pyrocatechol and refluxing the mixture under heating to obtain 4-S-cysteaminylcatechol derivative of formula II or adding cystamine, homocystamine or its salt and hydrobromic acid to hydroquinone and refluxing the mixture under heating to obtain a 2-S- cysteaminylhydroquinone derivative of formula II or converting pyrocatechol or 4-methylcatechol into an o-quinone compound and reacting with cysteamine or homocysteamine to obtain 3-S-cysteaminylcatechol of formula IV.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel dihydroxyphenyl sulfide derivative, a method for synthesizing the same, and an anti-melanoma agent containing the compound.

[0002]

BACKGROUND OF THE INVENTION Melanoma is a malignant tumor characterized by having melanin-forming ability, has a high resistance to chemotherapy, and has a poor prognosis such as difficult treatment after metastasis. In recent years, there is a tendency to increase not only in Europe and the United States but also in Japan, and there is an urgent need to develop an effective therapeutic agent for melanoma.

[0003]

[Problems to be Solved by the Invention] By the way, as a clinical therapeutic drug for melanoma at present, DTIC (5- (3,3-dimet
hyl-1-triazenyl) -1H-imidazole-4-carboxamide: NS
C45388) is the most well known, but has problems such as stability and liver damage. Hydroquinone derivatives are also known to have excellent melanin synthesis inhibitory action, but they have major drawbacks such as skin irritation and vitiligo.

Previously, the inventors of the present invention used cysteinylphenol and cysteinylphenol (Biochemical Pharmacolo).
gy Vol.36 No.12 p2007-2011), cystenylcatechol (Br. J. Cancer 1988 58 p776-778) was found to be selectively toxic to melanocytes, and its efficacy in melanoma treatment was confirmed. . However, the effect is still insufficient, and the present condition is that surgical excision must be relied upon as an effective treatment means for melanoma.

[0005]

Means for Solving the Problems The present inventors newly synthesized a dihydroxyphenyl sulfide derivative or a salt thereof, and these compounds have excellent cytotoxicity to melanin-producing cells, and further, melanoma cells. The present invention was completed because a remarkable life-prolonging effect was confirmed in the mice transplanted with.

That is, the novel dihydroxyphenyl sulfide derivative of the present invention has the general formula (1) (wherein R ₁
Of to R _5, 2 or hydroxyl group, three others represents a hydrogen atom or a lower alkyl group, R _6, R ₇ represents a hydrogen atom, a lower alkyl group or an acetyl group. n represents 2 or 3. ).

[Chemical 2]

For example, 3-S-cysteamine catechol, 3-S-homocysteamine catechol, 3-S
-Cysteininyl-5-methylcatechol, N-acetyl-3-S-cysteminylcatechol, 3-S-cysteminyl-N, N-dimethylcatechol, 4-S-cysteminylcatechol, 4-S-homocysteami Nilcatechol, N-acetyl-4-S-cysteaminoylcatechol, 2-S-cysteaminoylhydroquinone and salts thereof and the like can be mentioned. Among these, 4-S-cysteminyl catechol derivatives such as 4-S-cysteminyl catechol, 4-S-homocysteminyl catechol, N-acetyl-4-S-cysteminyl catechol and salts thereof are particularly preferable. It is preferable because it has an excellent anti-melanoma action. Examples of the salt include hydrochloride, sulfate, phosphate and the like.

The dihydroxyphenyl sulfide derivative of the present invention can be synthesized, for example, by the following method.

<Synthesis Method 1> Hydrobromic acid was added to one selected from pyrocatechol and cystamine, homocystamine or a salt thereof, and the mixture was heated under reflux and allowed to cool, and then the reddish brown reaction solution was concentrated to give ions. It can be purified by exchange chromatography to obtain a 4-S-cysteamine catechol derivative. For example, with cystamine 4
-S-Cysteinaminyl catechol is obtained, and if homocystamine is used, 4-S-homocysteamine catechol is obtained. Examples of the salt include hydrochloride, sulfate, phosphate and the like.

[Chemical 3]

<Synthesis Method 2> Hydroquinone and one of cystamine, homocystamine or a salt thereof are added with hydrobromic acid, and the mixture is heated under reflux and allowed to cool, then the reddish brown reaction solution is concentrated and ion-exchanged. It can be purified by chromatography to obtain a 2-S-cysteaminol hydroquinone derivative. For example, if cystamine is used, 2-S-cysteminyl hydroquinone is obtained, and if homocystamine is used, 2-S-homocysteminyl hydroquinone is obtained.

[Chemical 4]

<Synthesis Method 3> Pyrocatechol or 4-methylcatechol is dissolved in methanol and formic acid, and then silver oxide and anhydrous sodium sulfate are added to produce an o-quinone compound. This is added dropwise to a solution prepared by adding methanol and purified water to one selected from cysteamine, homocysteamine or a salt thereof. After stirring for 5 to 15 minutes, the reaction was stopped by adding aqueous sulfite, and the reaction solution was concentrated and purified by ion exchange chromatography.
By recrystallizing from ethanol, a 3-S-cysteamine catechol derivative is obtained. For example, if pyrocatechol and cysteamine are used, 3-S-cysteminylcatechol is obtained, and if pyrocatechol and homocysteamine are used, 3-S-homocysteminylcatechol is obtained, 4-methylcatechol and homocysteamine are obtained. If used, 3-S-cysteaminoyl-
5-Methylcatechol is obtained.

[Chemical 5]

[0012] Further, the compound has excellent cytotoxicity to melanin-producing cells, and further, a remarkable life-prolonging effect was confirmed in mice transplanted with melanoma cells.
Particularly, the 4-S-cysteamine catechol derivative is
An extremely excellent effect was confirmed. Regarding the cytotoxicity of catechols, the catechols are oxidized in the cells to form o-quinone bodies, which are inactivated by binding to SH enzymes such as DNA polymerase, thereby conferring cytotoxicity. Presumed.

[Chemical 6]

When the dihydroxyphenyl sulfide derivative of the present invention is used as an anti-melanoma agent, it can be used in any dosage form such as transdermal or oral administration. The compounding amount of the compound varies depending on the administration form, but in most cases, it is used in the range of 0.0001 to 10% by weight.
The administration method is according to a conventional method, but for example, in the case of topical application, propylene glycol, N 2
-Methyl-2-pyrrolidone, propylene glycol, etc., in addition to salicylic acid, sulfur, transretinic acid, retinoid, etc. as keratin layer solubilizers, fats, waxes, fatty acids
Surfactants, alcohols and the like can be appropriately added.

[0014]

EXAMPLES Next, the present invention will be described with reference to synthetic methods and anti-melanoma action.

<Synthesis Example 1> 4-S-Cysteinaminylcatechol Pyrocatechol (33.0 g, 300 mmol) and cystamine dihydrochloride (16.9 g, 75 mmol) were added with 500 ml of 47% hydrobromic acid, and 2
Heated to reflux for hours. After allowing to cool, concentrate the reddish brown reaction solution,
Purified by ion exchange chromatography (3M HCl), 4-S-Cysteinyl catechol hydrochloride (5.0
7g, 22.9mmol) was obtained. The yield is 30.5%, mp142 ~ 14
Colorless needle crystals at 5 ° C.

<Synthesis Example 2> 3-S-Cysteinaminylcatechol Methanol 100 ml, 98% formic acid 1 ml, pyrocatechol (1.10)
g, 10 mmol) was dissolved, silver oxide (4.70 g, 20 mmol) and anhydrous sodium sulfate (6 g) were added to generate o-quinone. This o-quinone solution was added to cysteamine hydrochloride (1.
(13 g, 10 mmol) was added dropwise to a solution prepared by adding 20 ml of methanol and 20 ml of water. After stirring for 10 minutes, 5 ml of 6% sulfite water was added to stop the reaction, the reaction solution was concentrated, purified by ion exchange chromatography (3M HCl), and then recrystallized from ethanol to give 3-S-cysteamine. Nilcatechol hydrochloride (1.45 g, 6.55 mmol) was obtained. The yield is 65.5%, and colorless needles with mp 141-144 ° C.

<Synthesis Example 3> 3-S-Cysteininyl-
5-Methylcatechol 200 ml methanol, 2% 98% formic acid 4-methylcatechol
(2.48g, 20mmol) dissolved in silver oxide (9.30g, 40mmo
l) and anhydrous sodium sulfate (9.3 g) were added to generate an o-quinone compound. This o-quinone solution was added to cysteamine hydrochloride (2.50 g, 22 mmol) in 50 ml of methanol and 50 ml of water.
Was added dropwise to the solution. After stirring for 10 minutes, 10% of 6% sulfite water was added to stop the reaction, the reaction solution was concentrated, purified by ion exchange chromatography (3M HCl), and recrystallized from ethanol to give 3-S-cysteamine. Nilcatechol hydrochloride (2.21 g, 9.4 mmol) was obtained. The yield is
It is 46.9% and is a pale yellow needle crystal having an mp of 162 to 164 ° C.

<Test Example 1> Life-prolonging effect on mice BDF1 mice aged 5 weeks were transplanted with B16 mouse melanoma cells, and as shown in Table 1, saline was used as a control group.
4-S-Cysteinaminylcatechol hydrochloride is 100 mg / kg and 200 mg / kg as an example, and 4-S-Cysteinaminylphenol is 300 mg / k as a comparative example.
g, DTIC (5- (3,3-dimethyl-1-triazenyl) -1H-imid
azole-4-carboxamide: NSC45388) 50mg
Each of 10 mice was administered daily for 9 days. Table 1 shows the average survival rate and the survival rate with respect to the control group.

[0019]

[Table 1] 4-S-Cysteinyl catechol hydrochloride of the present invention is
A significant life-prolonging effect was observed in mice transplanted with melanoma cells, as compared to 4-S-cysteaminoylphenol. Further, as compared with DTIC, which is currently used as a clinical remedy for melanoma, a life-prolonging effect of the same degree or more was recognized.

[0020]

[Effect] According to the novel dihydroxyphenyl sulfide derivative of the present invention or a salt thereof, melanoma can be effectively treated.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication C07C 323/39 (72) Inventor Kazumasa Wakamatsu 1-21, 38 Tachibana, Naka-ku, Nagoya-shi, Aichi (72) Inventor Hiroyuki Ozeki 12 Hoyu Co., Ltd. Research Institute at No. 1 Haki, Nagakute-cho, Aichi-gun, Aichi-gun

Claims (7)

[Claims] 1. A compound represented by the general formula (1) (wherein R _{1 to} R ₅ :
Two of them are a hydroxyl group, the other three are a hydrogen atom or a lower alkyl group, and R ₆ and R ₇ are a hydrogen atom, a lower alkyl group or an acetyl group. n represents 2 or 3. ) A dihydroxyphenyl sulfide derivative or a salt thereof. [Chemical 1] 2. A dihydroxyphenyl sulfide derivative or a salt thereof according to claim 1, which is a 4-S-cysteamine catechol derivative. 3. 4-S-Cysteinyl catechol, 4
The dihydroxyphenyl sulfide derivative or a salt thereof according to claim 1, which is -S-homocysteamine catechol or N-acetyl-4-S-cysteamine catechol. 4. A 4-S which is characterized in that pyrocatechol is added with one kind selected from cystamine, homocystamine or a salt thereof and hydrobromic acid, and the mixture is heated under reflux.
-A method for the synthesis of cysteamine catechol derivatives. 5. A 2-S characterized in that hydroquinone is added with one kind selected from cystamine, homocystamine or a salt thereof, and hydrobromic acid, and the mixture is heated under reflux.
-A method for synthesizing a cysteaminol hydroquinone derivative. 6. Dissolving pyrocatechol or 4-methylcatechol in methanol and formic acid, and then adding silver oxide and anhydrous sodium sulfate to produce an o-quinone compound, which is cysteamine, homocysteamine or a salt thereof. A method for synthesizing a 3-S-cysteamine catechol derivative, characterized in that the solution is added dropwise to a solution consisting of one selected from the group consisting of methanol and purified water. 7. An anti-melanoma agent comprising the dihydroxyphenyl sulfide derivative according to claim 1 or a salt thereof.