JP3331028B2 - Spiro compounds and their production - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to tyrosinase inhibitors.

[0002]

2. Description of the Related Art The blackening of skin due to spots, freckles and sunburn is due to the formation of melanin in melanocytes present in the epidermal basal cell layer of the skin.

Regarding the production of melanin, a pathway is known in which tyrosine is oxidized by tyrosinase enzyme in cytoplasmic granule melanosomes in melanocytes and is produced via dopa, dopaquinone and indolequinone.
It is also known that in this pathway, the production of melanin is promoted by autoxidation with ultraviolet light.

Therefore, it inhibits the production of melanin,
As a means for preventing the blackening of the skin due to freckles or sunburn, a method of inhibiting an enzyme reaction by a tyrosinase enzyme and a method of blocking ultraviolet rays are considered.

[0005] In addition, the blackening of the surface of fresh foods such as fish and shellfish, fruits and vegetables is also caused by the production of melanin pigment, and the blackening can be prevented by inhibiting the enzyme reaction by tyrosinase.

[0006]

DISCLOSURE OF THE INVENTION The present inventors provide a novel compound which inhibits a reaction by tyrosinase and is useful for the above-mentioned various uses.

[0007]

Means for Solving the Problems The present invention provides the following (A)
To (K). (A) Formula (I)

[0008]

Embedded image [In the formula (I), R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently a hydroxyl group or a lower acyloxy group, and n means 0 or 1. A spiro compound represented by the formula:

(B) In the formula (I), R ¹ , R ² , R ³ and R ⁴ are hydroxyl groups and n is 0, a spiro compound;

(C) In the formula (I), R ¹ , R ² , R ³ and R ⁴ are an acetoxy group and n is 0, a spiro compound;

(D) In the formula (I), R ¹ , R ² , R ³ ,
R ⁴ and R ⁵ are hydroxyl groups, and n is 1; a spiro compound;

(E) In the formula (I), R ¹ , R ² , R ³ ,
R ⁴ and R ⁵ are an acetoxy group, and n is 1;

(F) A compound of the formula (I) characterized by reacting phloroglucinol with pentose or hexose.

[0014]

Embedded image [In the formula (I), R ¹ , R ² , R ³ , R ⁴ and R ⁵ are hydroxyl groups, and n means 0 or 1. A process for producing a spiro compound represented by the formula:

(G) a compound of the formula (I) characterized in that a pentose or a hexose is reacted with phloroglucinol and then acylated if desired.

[0016]

Embedded image [In the formula (I), R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently a hydroxyl group or a lower acyloxy group, and n means 0 or 1. A process for producing a spiro compound represented by the formula:

(H) A tyrosinase inhibitor comprising a spiro compound represented by the formula (I):

(I) A cosmetic comprising a spiro compound represented by the formula (I),

(J) A whitening cosmetic comprising a spiro compound represented by the formula (I), and

(K) An anti-blackening agent for food, comprising a spiro compound represented by the formula (I).

The lower acyloxy group which is one of the substituents in the spiro compound of the present invention represented by the formula (I) will be described below.

Examples of the lower acyloxy group include an acetoxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, a valeryloxy group, an isovaleryloxy group, a pivaloyloxy group and a hexanoyloxy group.

Hereinafter, specific examples of the spiro compound of the present invention and the formula (II) in the case where n represents 0 in the formula (I) will be described.

[0024]

Embedded image

(1) Substituents R ¹ , R ² , R ³ and R
A spiro compound represented by the formula (II), wherein all of ⁴ are hydroxyl groups.

(2) Substituents R ¹ , R ² , R ³ and R
^4. A spiro compound represented by formula (II), wherein any one of the substituents ⁴ is a lower acyloxy group and the other substituents are hydroxyl groups.

(3) Substituents R ¹ , R ² , R ³ and R
^4. A spiro compound represented by formula (II), wherein any two of the substituents ⁴ are lower acyloxy groups and the other substituents are hydroxyl groups.

(4) Substituents R ¹ , R ² , R ³ and R
^4. A spiro compound represented by formula (II), wherein any three of the substituents ⁴ are lower acyloxy groups and the other substituents are hydroxyl groups.

(5) Substituents R ¹ , R ² , R ³ and R
A spiro compound represented by the formula (II), wherein all ⁴ are lower acyloxy groups.

In the following, specific examples of the spiro compound of the present invention and formula (III) in the case where n represents 1 in the formula (I) are shown.

[0031]

Embedded image

(6) A spiro compound represented by the formula (III), wherein all of the substituents R ¹ , R ² , R ³ , R ⁴ and R ⁵ are hydroxyl groups.

(7) A compound represented by the formula (II), wherein one of the substituents R ¹ , R ² , R ³ , R ⁴ and R ⁵ is a lower acyloxy group and the other substituents are hydroxyl groups.
Spiro compounds represented by I).

(8) Formula (II) wherein any two of the substituents R ¹ , R ² , R ³ , R ⁴ and R ⁵ are a lower acyloxy group and the other substituents are hydroxyl groups.
Spiro compounds represented by I).

(9) A compound of the formula (II) in which any three of the substituents R ¹ , R ² , R ³ , R ⁴ and R ⁵ are a lower acyloxy group and the other substituents are hydroxyl groups.
Spiro compounds represented by I).

(10) Substituents R ¹ , R ² , R ³ and R ⁴
And any one of R 4 and R ⁵ is a lower acyloxy group, and the other substituents are hydroxyl groups.
Spiro compounds represented by I).

(11) Substituents R ¹ , R ² , R ³ and R ⁴
And a spiro compound represented by formula (III), wherein all of R ⁵ are lower acyloxy groups.

In the above specific examples, when there are a plurality of lower acyloxy groups, each lower acyloxy group may be the same or different.

The following are representative examples of the spiro compound of the present invention in the formula (II).

(A) 4,6,3 ', 4'-tetrahydroxy-
4 ', 5'-dihydrospiro [benzofuran-2 (3H), 2'(3'H)
-Dihydrofuran]

(B) 4-acetoxy-6,3 ', 4'-trihydroxy-4', 5'-dihydrospiro [benzofuran-2 (3
H), 2 '(3'H) -dihydrofuran]

(C) 4,6-diacetoxy-3 ′, 4′-dihydroxy-4 ′, 5′-dihydrospiro [benzofuran-2 (3
H), 2 '(3'H) -dihydrofuran]

(D) 4-acetoxy-6-isovaleryloxy-3 ', 4'-dihydroxy-4', 5'-dihydrospiro [benzofuran-2 (3H), 2 '(3'H) -dihydro Franc]

(E) 4,6,3'-triacetoxy-4'-hydroxy-4 ', 5'-dihydrospiro [benzofuran-2 (3
H), 2 '(3'H) -dihydrofuran]

(F) 4-acetoxy-6-isovaleryloxy-3'-pivaloyloxy-4'-hydroxy-4 ',
5'-dihydrospiro [benzofuran-2 (3H), 2 '(3'H)-
Dihydrofuran]

(G) 4,6,3 ', 4'-tetraacetoxy-
4 ', 5'-dihydrospiro [benzofuran-2 (3H), 2'(3'H)
-Dihydrofuran]

(H) 4-acetoxy-6-isovaleryloxy-3'-pivaloyloxy-4'-propionyloxy-4 ', 5'-dihydrospiro [benzofuran-2 (3H),
2 '(3'H) -dihydrofuran]

The following are representative examples of the spiro compound of the present invention in the formula (III).

(I) 4,6,3 ', 4', 5'-pentahydroxy-3 ', 4', 5 ', 6'-tetrahydrospiro [benzofuran-2
(3H), 2 '(2'H) -pyran]

(J) 4-acetoxy-6,3 ', 4', 5'-tetrahydroxy-3 ', 4', 5 ', 6'-tetrahydrospiro [benzofuran-2 (3H), 2' (2 'H) -Pyran]

(K) 4,6-diacetoxy-3 ', 4', 5'-
Trihydroxy-3 ', 4', 5 ', 6'-tetrahydrospiro [benzofuran-2 (3H), 2'(2'H) -pyran]

(L) 4-acetoxy-6-butyryloxy-3 ', 4', 5'-trihydroxy-3 ', 4', 5 ', 6'-tetrahydrospiro [benzofuran-2 (3H), 2'(2'H) -pyran]

(M) 4,6,3'-triacetoxy-4 ', 5'
-Dihydroxy-3 ', 4', 5 ', 6'-tetrahydrospiro [benzofuran-2 (3H), 2'(2'H) -pyran]

(N) 4-acetoxy-6-butyryloxy-3 ', 4'-dihydroxy-5'-propionyloxy-
3 ', 4', 5 ', 6'-tetrahydrospiro [benzofuran-2 (3
H), 2 '(2'H) -pyran]

(O) 4,6,3 ', 4'-tetraacetoxy-
5'-hydroxy-3 ', 4', 5 ', 6'-tetrahydrospiro [benzofuran-2 (3H), 2'(2'H) -pyran]

(P) 4-acetoxy-6-butyryloxy-3'-hydroxy-4'-propionyloxy-5'-valeryloxy-3 ', 4', 5 ', 6'-tetrahydrospiro [benzofuran-2 (3H ), 2 '(2'H) -pyran]

(Q) 4,6,3 ', 4', 5'-pentaacetoxy-3 ', 4', 5 ', 6'-tetrahydrospiro [benzofuran-2
(3H), 2 '(2'H) -pyran]

The representative examples of the spiro compound of the present invention described above are examples of the spiro compound of the present invention, and the spiro compound of the present invention is not limited thereto.

Since the spiro compound of the present invention has three or four asymmetric carbons (*) as shown below, there are various optical isomers, but all optical isomers are within the scope of the present invention. And these isomers, whether alone or as a mixture, are included in the compounds of the present invention.

[0060]

Embedded image

[0061]

Embedded image

The spiro compound of the present invention can be produced by the following method.

That is, a spiro compound represented by the formula (I) is produced by reacting phloroglucinol with pentose or hexose (reaction step [I]) and, if desired, further acylating. be able to.

[0064]

Embedded image

[Wherein R ¹ , R ² , R ³ , R ⁴ and R
⁵ is each independently a hydroxyl group or a lower acyloxy group, and n means 0 or 1. ]

The reaction step [I] can be carried out in a solvent. The solvent used in this reaction step [I] is not particularly limited as long as it does not hinder the progress of the reaction. For example, a solvent such as dimethylsulfoxide, dimethylformamide, etc. may be used alone or in a mixture of any combination of two or more. Solvents can be mentioned.

In the reaction step [I], an organic sulfonic acid such as paratoluenesulfonic acid, a mineral acid such as hydrochloric acid and sulfuric acid, zinc chloride, trifluoroacetic acid and the like can be used as a catalyst.

The temperature range in which the reaction step [I] can be carried out is usually in the range of several tens degrees (° C.) to several hundred degrees (° C.), preferably in the range of 50 ° C. to 120 ° C., and more preferably in the range of 60 ° C. to 90 ° C.
The range of ° C. is particularly preferred.

The reaction time in the reaction step [I] can be appropriately adjusted depending on the type of saccharide (pentose and hexose). Specifically, when the pentose is reacted with phloroglucinol, The reaction can be carried out usually for several hours to several tens of hours. Preferred reaction times are in the range from 1 hour to 10 hours, and particularly preferred reaction times are in the range from 2 hours to 8 hours.

In the case of reacting hexose, the reaction can be carried out usually for a period of from several tens of hours to several tens of hours. Preferred reaction times range from 12 hours to 72 hours, and particularly preferred reaction times range from 12 hours to 48 hours.

If desired, for further acylation, an acid, acid anhydride or acid chloride corresponding to the acyl group of the lower acyloxy group may be allowed to act as an acylating agent. Propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride, pivalic anhydride, acetyl chloride, propionyl chloride And butyryl chloride.

In the acylation, it is preferable to add a deoxidizing agent, and specific examples include pyridine, triethylamine and dimethylaniline.

When it is desired to selectively (partially) desire a compound in which the hydroxyl group is acylated, of the substituents of the spiro compound represented by the formula (I), the hydroxyl group not desired to be acylated is known in advance. A desired spiro compound can be obtained by protecting with a group and finally removing the protecting group.

The pentose, which is a raw material for producing the spiro compound of the present invention, is represented by the general formula C ₅ (H ₂ O) ₅ among monosaccharides, and includes aldopentoose and ketopentose.
Specific examples include arabinose, xylose, ribulose, xylulose, ribose, and lyxose. Among them, aldpentose, arabinose, xylose, ribose, and lyxose are particularly preferable.

The hexacarbon sugar as a raw material for producing the spiro compound of the present invention is represented by the general formula C ₆ (H ₂ O) ₆ among monosaccharides, and includes aldohexose and ketohexose. Specific examples include mannose, glucose, galactose, fructose, tagatose, sorbose, and the like. Among them, aldohexose mannose, glucose, and galactose are particularly preferable.

Saccharides such as pentose and hexose are D-forms and L-forms.
There are two types of isomers, both of which can be used as raw materials for producing the spiro compound of the present invention.

The spiro compound of the present invention has a tyrosinase inhibitory action and suppresses the production of melanin. Therefore, the spiro compound is used in the fields of cosmetics, pharmaceuticals, food additives, feeds, etc., which have an action mechanism of suppressing melanin production. be able to.

Accordingly, the spiro compound of the present invention can be used as a tyrosinase inhibitor, that is, as a cosmetic, particularly preferably as a whitening cosmetic, as an anticancer agent against black tumors such as melanoma, and as an anti-blackening agent for foods, especially fish and shellfish. , And can be used as a blackening inhibitor for fresh foods such as fruits and vegetables.

When the tyrosinase inhibitor of the present invention is used as a cosmetic, especially as a whitening cosmetic, the application method is as follows:
It is generally applied to the skin, but other application methods such as systemic administration such as oral administration are also possible.

When used as the cosmetic, dosage forms include ointments, creams, emulsions, liniments, lotions and the like.

These cosmetics can be used in combination with the spiro compound of the present invention, such as aqueous components, powder components, humectants, surfactants, preservatives, thickeners, ultraviolet absorbers, ultraviolet scattering agents, and fragrances. The components can be appropriately blended and manufactured using known formulation techniques, but these various components can be used within a quantitative and qualitative range that does not impair the effects of the present invention.

The amount and method of application of the cosmetics of the present invention, especially the whitening cosmetics, are as follows.
0.0002-5% (W / W), preferably 0.005
~ 1% (W / W), once a day for spots such as the face, neck, arms and hands, spots or susceptible areas such as freckles, and tan-prone or tanned areas An appropriate amount may be applied several times or several times.

The amount and method of application of the food blackening inhibitor of the present invention are as follows. The spiro compound of the present invention is contained in the blackening inhibitor in an amount of 0.0002 to 5% (W / W), preferably 0.0
An aqueous solvent is prepared so as to contain 0.05 to 1% (W / W),
If the food is seafood, mix it in the feed in an appropriate amount and ingest, or inject, spray, apply,
If the food is a fruit or vegetable, an appropriate amount may be sprayed, applied, dipped, or the like.

[0084]

The spiro compound according to the present invention has a tyrosinase inhibitory action and is useful for various uses based on this inhibitory action. Specifically, it is very useful as a cosmetic, especially a whitening cosmetic, an anticancer agent for black tumors, a blackening agent for foods, especially a blackening agent for foods such as fresh foods.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention should not be limited to these.

[0086]

【Example】

Example 1 4,6,3 ', 4', 5'-Pentahydroxy-3 ', 4', 5 ', 6'-tetrahydrospiro [benzofuran-2 (3H), 2'(2'H ) -Pyran] (fraction A)

5 g of phloroglucinol, 5 g of D-glucose and 300 mg of paratoluenesulfonic acid were added to 10 ml of dimethyl sulfoxide.
The reaction was performed for hours. The reaction solution was purified by silica gel and Sephadex LH20 chromatography,
Fraction A and Fraction B each yielded a slight amount of 100 mg of a slightly yellow powder. Fraction A obtained
Its physical properties are as follows.

[Α] _D ²⁴ -157 (C 1.64, MeOH) mp 148.5-151.5 ° C. ¹ H-NMR (CD ₃ OD): 2.88 (1 H, d), 3.35 (1 H, d), 3.66 (1 H, d) ), 3.86-3.95 (3H,
m), 4.06 (1H, d), 5.88 (1H, s), 5.90 (1H, s)

Example 2 4,6,3 ', 4', 5'-pentaacetoxy-3 ', 4', 5 ', 6'-tetrahydrospiro [benzofuran-2 (3H), 2'(2'H ) -Pyran]

The 4,6,3 ', 4', 5'-pentahydroxy-3 ', 4', 5 ', 6'-tetrahydrospiro [benzofuran-2 (3H), 2 1.5 ml of pyridine and 1 ml of acetic anhydride were added to 55 mg of the powder of '(2'H) -pyran] (fraction A), the mixture was allowed to stand at room temperature for 48 hours, the reaction solution was poured into ice water and extracted with chloroform. The organic layer is washed with water, dehydrated with anhydrous sodium sulfate, concentrated to dryness,
Crystallization was performed with a mixed solution of methanol and ethanol to obtain 68 mg of the title colorless prism compound. Physical properties of the obtained compound were as follows.

Mp 167.5-168.5 ° C. ¹ H-NMR (CDCl ₃ ): 1.97 (3H, s), 2.00 (3H, s), 2.16 (3H, s), 2.23 (3H, s), 2.
26 (3H, s), 3.05 (1H, d), 3.11 (1H, d), 3.79 (1H, dd), 4.24 (1H, d),
5.42 (1H, m), 5.46 (1H, dd), 5.57 (1H, d), 6.49 (1H, d), 6.55 (1H, d)

Example 3 Acylated Fraction B

The same operation as in Example 2 was performed to obtain a small amount of an acylated fraction B as a white powder. The physical properties of the obtained compound were as follows, and the compound was estimated to be a diastereomer of the compound obtained in Example 2.

¹ H-NMR (CDCl ₃ ): 2.08 (3H, s), 2.16 (3H, s), 2.17 (3H, s), 2.26 (3H, s), 2.
27 (3H, s), 3.09 (1H, d), 3.23 (1H, d), 4.21 (1H, dd), 4.37 (1H, m),
5.02 (1H, d), 5.44 (1H, dd), 6.50 (1H, d), 6.55 (1H, d)

Example 4 4,6,3 ', 4'-Tetraacetoxy-4', 5'-dihydrospiro [benzofuran-2 (3H), 2 '(3'
H) dihydrofuran]

In a flask containing 5 g of phloroglucinol, 5 g of D-xylose and 270 mg of paratoluenesulfonic acid, 10 ml of dimethyl sulfoxide was added.
The reaction was performed at 80 ° C. for 6 hours. After cooling the obtained reaction solution, it was purified by silica gel and Sephadex LH20 chromatography to obtain a fraction containing the target compound. 5 ml of pyridine and 3 ml of acetic anhydride were added to this fraction, and the mixture was left at room temperature for 24 hours to perform acetylation. After the acetylated fraction was poured into ice water and extracted with chloroform,
The organic layer was concentrated. The obtained syrup was purified by Sephadex and silica gel column chromatography to obtain a trace amount of the title compound. The chemical properties of the obtained compound were as follows.

Mp 88.5-91.5 ° C. ¹ H-NMR (CDCl ₃ ): 2.24 (6H, s), 2.25 (3H, s), 2.26 (3H, s), 3.04 (1H, d), 3.
56 (1H, d), 3.72 (1H, dd), 3.82 (1H, s), 3.84 (1H, d), 4.98 (1H, d),
6.44 (1H, d), 6.48 (1H, d)

[0099]

[0100]

[Test example]

 Test Example 1 Tyrosinase inhibition by colorimetric method

A sample solution (compound obtained in Example 1 (hereinafter referred to as Compound X), compound obtained in Example 2) prepared with M / 15 phosphate buffer (pH 6.8) to a predetermined final concentration. (Hereinafter, compound Y) and arbutin) 0.2 ml
The mushroom-derived tyrosinase solution prepared in 0.2 ml with the phosphate buffer was adjusted to 0.25 mg / ml.
was added and incubated at 37 ° C. for 10 minutes. Next, 0.2 ml of a dopa solution adjusted to 0.3 mg / ml with the phosphate buffer was added to make the final reaction solution 0.6 ml. After incubating the final reaction for an additional minute, the specific absorption of dopaquinone, 475 n
m was measured with a spectrophotometer (Ubest-50, manufactured by JASCO Corporation). The tyrosinase inhibition rate was calculated by the following equation.

Tyrosinase inhibition rate (%) = ((AB)
/ A) × 100 A: Absorbance when no sample is added, B: Absorbance when sample is added

[0103]

[Table 1]

As is clear from Table 1, Compound X and Compound Y inhibited the tyrosinase reaction to the same extent as arbutin.

Test Example 2 Tyrosinase inhibition by oxygen electrode method

Oxygen electrode reaction layer (Oriental Electric)
1 ml of M / 15 phosphate buffer (pH 6.8) and 20 μl of a mushroom-derived tyrosinase solution prepared with the phosphate buffer to a concentration of about 2000 units / ml.
Then, 10 μl of a sample solution (compound X) prepared with the phosphate buffer to a predetermined final concentration was added. Further, 60 μl of an L-dopa solution prepared with the phosphate buffer to a concentration of 1 mg / ml was added and reacted for 5 minutes. After the reaction was completed, the oxygen consumption of the sample solution was determined, and the inhibition rate was calculated by the following equation.

Tyrosinase inhibition rate (%) = ((CD)
/ C) × 100 C: Oxygen consumption when no sample is added, D: Oxygen consumption when sample is added

[0108]

[Table 2]

As is clear from Table 2, Compound X inhibited the reaction with tyrosinase in a concentration-dependent manner.

Test Example 3 Inhibition of Melanin Production by Mouse Melanoma B-16 Cells

In a Petri dish with a diameter of 60 mm, 1 × 10 ⁵ mouse per melanoma B-16 cells (per dish) were inoculated, and 5 ml of Eagle's MEM medium (containing 10% FBS) was added.
And incubated at 37 ° C for 24 hours. Next, 40 μl of a solution containing the specimen (compound X and compound Y) (final concentration of the specimen was 0.01 mM, 0.1 mM, 1.0 mM)
M) was added to 5 ml of the same medium, and the cells were collected two days after the addition. After the cell count, 2 ml of 5% trichloroacetic acid was added to the pellet obtained by centrifugation. Further, 1 ml of 0.85N sodium hydroxide was added to the obtained precipitate by ether treatment, and the mixture was heated at 100 ° C. for 30 minutes,
The amount of melanin produced was calculated from the absorbance at 00 nm. The melanin production inhibition rate was calculated in comparison with the amount of melanin when no sample was added.

[0112]

[Table 3]

As apparent from Table 3, Compound X and Compound Y strongly suppressed melanin formation.

[0114]

[Prescription example]

Formulation Example 1 Ointment An ointment was prepared according to the following formulation by a conventional method.

White Vaseline 25.0 g Stearyl alcohol 25.0 g Propylene glycol 11.5 g Sodium lauryl sulfate 2.0 g 4,6,3 ′, 4 ′, 5′-Pentahydroxy-3 ′, 4 ′, 5 ′, 6 '-Tetrahydrospiro [benzofuran-2 (3H), 2' (2'H) -pyran] 0.05 g Methyl parahydroxybenzoate 0.025 g Propyl parahydroxybenzoate 0.015 g Purified water 100 g

Formulation Example 2 Lotion A lotion was prepared according to the following formula by a conventional method.

Stearyl alcohol 3.0 g Light liquid paraffin 24.5 g Sodium lauryl sulfate 1.5 g Propylene glycol 4,6,3 ', 4', 5'-Pentahydroxy-3 ', 4', 5 ', 6'- Tetrahydrospiro [benzofuran-2 (3H), 2 '(2'H) -pyran] 0.05 g Methyl parahydroxybenzoate 0.025 g Propyl parahydroxybenzoate 0.015 g Purified water 100 g

Formulation Example 3 Anti-Blackening Agent According to the following formulation, an anti-blackening agent was prepared by a conventional method.

L-ascorbic acid 1.0 g sodium L-ascorbate 4.5 g lactose 14.0 g 4,6,3 ′, 4 ′, 5′-pentahydroxy-3 ′, 4 ′, 5 ′, 6′- Tetrahydrospiro [benzofuran-2 (3H), 2 '(2'H) -pyran] 0.05 g Sorbitol 1.5 g Alum 1.3 g The total volume was adjusted to 100 ml with purified water.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 7/48 A61K 7/48 31/343 31/343 31/352 31/352 A61P 17/00 A61P 17/00 43/00 111 43/00 111 C12N 9/99 C12N 9/99 (56) References THE JOURNAL OF AN TIBIOTICS, Feb. 26, 1993, p. 356-358 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 493/10 A61K 7/00 A61K 7/48 A61K 31/343 A61K 31/352 CA (STN) REGISTRY (STN)

Claims (11)

(57) [Claims] 1. A compound of the formula (I) [In the formula (I), R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently a hydroxyl group or a lower acyloxy group, and n means 0 or 1. ] The spiro compound represented by these. 2. The spiro compound according to claim ¹ , wherein in formula (I), R ¹ , R ² , R ³ and R ⁴ are hydroxyl groups and n is 0. 3. The spiro compound according to claim ¹ , wherein in formula (I), R ¹ , R ² , R ³ and R ⁴ are an acetoxy group, and n is 0. 4. In the formula (I), R ¹ , R ² , R ³ , R ⁴
2. The spiro compound according to claim 1, wherein R ⁵ is a hydroxyl group, and n is 1. 5. In the formula (I), R ¹ , R ² , R ³ , R ⁴
The spiro compound according to claim 1, wherein R ⁵ is an acetoxy group, and n is 1. 6. A compound of the formula (I), wherein pentose or hexose is reacted with phloroglucinol. [In the formula (I), R ¹ , R ² , R ³ , R ⁴ and R ⁵ are hydroxyl groups, and n means 0 or 1. A method for producing a spiro compound represented by the formula: 7. A compound of the formula (I) characterized in that phloroglucinol is reacted with pentose or hexose and then acylated if desired. [In the formula (I), R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently a hydroxyl group or a lower acyloxy group, and n means 0 or 1. A method for producing a spiro compound represented by the formula: A tyrosinase inhibitor comprising the spiro compound according to claim 1. 9. A cosmetic comprising the spiro compound according to claim 1. 10. A whitening cosmetic comprising the spiro compound according to claim 1. 11. A food blackening inhibitor comprising the spiro compound according to claim 1.