JPH06145193A - New androstenedione derivative - Google Patents

Abstract

PURPOSE:To provide the subject new compound derivative having a specific structure, exhibiting aromatase-inhibiting action and useful as an estrogen biosynthesis inhibiting agent for the prevention and treatment of diseases such as cancer and endometriosis by oral or parenteral administration. CONSTITUTION:The objective new androstenedione derivative having aromatase activity inhibiting action and expressed by formula III (R1 is OH or 2-8C alkoxycarbonyl; dotted line represents the presence or absence of double bond; wavy line represents the alpha- or beta-configuration) is produced by reducing 6- alkoxycarbonyl-14alpha-hydroxy-androsta-4,5-diene-3,17-dione of formula I (R2 is oxo or 2-8C alkoxycarbonyl) with sodium cyanoborohydride in tetrahydrofuran to obtain a 14-dihydroxy derivative of formula II and esterifying the 3-hydroxyl group with an acylation agent such as acetic anhydride in an organic solvent such as pyridine.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel androstenedione derivative represented by the following general formula (I). The compound of the present invention has an aromatase inhibitory action and is expected to be used as an estrogen biosynthesis inhibitor in the field of medicine.

[Chemical 2] [Wherein R ₁ is a hydroxyl group or a straight-chain or branched alkoxycarbonyl having 2 to 8 carbon atoms, R ₂ is oxo or a straight-chain or branched alkoxycarbonyl having 2 to 8 carbon atoms, and the dotted line is two Presence or absence of heavy bond, wavy line is α-
Alternatively, each represents β-coordinate. ]

[0002]

Regarding the androstanedione derivative, hormones such as androsterone and androstanedione are known in nature, and many derivatives having physiological activity have been synthesized. The inventors of the present invention have variously reduced the carbonyl group at the 3-position from the ester derivative of 14α-hydroxy-4-androstene-3,6,17-trione (see JP-A-1-131193) developed previously. It was found that these compounds can be synthesized, and these compounds have an activity of inhibiting estrogen synthase (aromatase) activity. Therefore, it is an object of the present invention to provide a novel androstenedione derivative having an activity of inhibiting estrogen synthase (aromatase) activity.

[0003]

The compounds of the present invention represented by the general formula (I) can be further represented by the following general formulas (Ia) and (Ib).

[Chemical 3] [However, in the formula, R ₁ and the wavy line have the same meaning as described above. R
₂ represents alkoxycarbonyl. ] The alkoxycarbonyl represented by R ₁ and R ₂ in the above general formula means a linear or branched alkoxycarbonyl having 2 to 8 carbon atoms, specifically, formyloxy,
Acetyloxy, propionyloxy, isopropionyloxy, butyroyloxy, isobutyroyloxy,
Pentanoyloxy, benzyloxy etc. can be illustrated. The compound of the general formula (Ia) is a known compound represented by the general formula (VIII), 6-alkoxycarbonyl-14.
α-hydroxy-androsta-4,5-diene-3,
It can be produced by using 17-dione (see JP-A-1-131193) as a starting material to undergo a reduction reaction and an esterification reaction as follows.

[Chemical 4] [However, in the formula, R ₁ , R ₂ and the wavy line have the same meaning as described above. ]

The reduction reaction of 1) in this reaction may be carried out under the conditions of ordinary reduction reaction, for example, sodium cyanoborohydride and hydrogen in an organic solvent such as tetrahydrofuran, 1,4-dioxane, diethyl ether and the like. It is recommended to react with a reducing agent such as sodium iodide or lithium aluminum hydride. Regarding other reaction conditions, the reaction may be carried out by appropriately selecting reaction conditions corresponding to the properties of each reaction reagent. The esterification reaction of the intermediate (IX) of 2) is carried out with an acid anhydride, for example, an acid anhydride of a lower fatty acid such as formic anhydride, acetic anhydride, propionic anhydride or a lower fatty acid halide in a suitable organic solvent such as pyridine. Good to react. Regarding other reaction conditions, the reaction may be carried out by appropriately selecting reaction conditions corresponding to the properties of each reaction reagent.

The compound of the general formula (Ib) is a novel compound represented by the general formula (IX): 3α (β), 14α-dihydroxy-6-alkoxycarbonyl-androsta-4,5-
It can be produced by carrying out a deesterification reaction and an esterification reaction as described below using dien-17-one as a starting material.

[0006]

[Chemical 5] [However, in the formula, R ₁ , R ₂ and the wavy line have the same meaning as described above. ]

The deesterification reaction of 1) in this reaction formula may be carried out according to the usual conditions of the deesterification reaction, for example, in a polar solvent such as methanol, aqueous ammonia or dilute sodium hydroxide solution, sodium methylate. It is recommended to react with an alkali such as. For other reaction conditions,
The reaction may be performed by appropriately selecting reaction conditions corresponding to the properties of each reaction reagent. The esterification reaction of the intermediate (X) of 2) is carried out in an appropriate organic solvent such as pyridine with an acid anhydride such as formic acid anhydride, acetic anhydride, propionic anhydride, or the like. It is better to react with a compound. Regarding other reaction conditions, the reaction may be carried out by appropriately selecting reaction conditions corresponding to the properties of each reaction reagent.

Hereinafter, the present invention will be described more specifically by showing examples.

Example 1 3α, 14α-Dihydroxy-6-propionyloxy-androst-4,6-diene-17-
One (IIa) and 3β, 14α-dihydroxy-6-propionyloxy-androst-4,6-diene-1
7-on (IIb)

[Chemical 6]

[Chemical 7] 2 g of 6-propionyloxy-14α-hydroxy-androst-4,6-diene-3,17-dione was dissolved in 40 ml of tetrahydrofuran, and 1 ml of concentrated sulfuric acid was added to this solution.
ml was added, and sodium cyanoborohydride was further added.
After adding a solution of 68 g dissolved in 10 ml of tetrahydrofuran, the mixture was stirred at room temperature for 18 hours. The solvent of the reaction mixture was concentrated under reduced pressure to 10 ml, 100 ml of water was added, and the mixture was extracted 3 times with ethyl acetate (50 ml). The obtained ethyl acetate extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure at 40 ° C. The resulting residue (1.5
2 g of 6 g) was fractionated by preparative high performance liquid chromatography under the following conditions and recrystallized from methanol to give 3α, 14α-dihydroxy-6-propionyloxy-androst-4,6-diene. -17-
On (IIa) 265 mg (yield 13.2%), melting point 170
~ 171 ° C and 3β, 14α-dihydroxy-6-propionyloxy-androst-4,6-diene-1
7-one (IIb) 560 mg (yield 27.9%), melting point 2
21-223 ° C was obtained. Preparative high-performance liquid chromatography operating conditions Column used: Senshu-pak Silica 30φ x 250 mm Solvent used: Chloroform: Methanol = 98: 2 Flow rate: 28 ml / min, Detection: 254 nm

This reaction formula is shown below.

[Chemical 8]

The physical constants of this product are as follows. 3α, 14α-Dihydroxy-6-propionyloxy-androst-4,6-dien-17-one (IIa): Melting point: 170-171 ° C. IR: FIG. 1 NMR: FIG. 2 FAB Mass (M + H): 375 3β, 14α-Dihydroxy-6-propionyloxy-androst-4,6-dien-17-one (IIb): Melting point: 221-223 ° C. IR: FIG. 3 NMR: FIG. 4 FAB Mass (M + H): 375

[0011]

Example 2 3α, 14α-Dihydroxy-androst-4-ene-6,17-dione (IIIa) and 3β, 14
α-dihydroxy-androst-4-ene-6,17
-Zion (IIIb)

[Chemical 9]

[Chemical 10] 3α, 14α-Dihydroxy-6-propionyloxy-androst-4,6-dien-17-one (IIa) 1
To a solution of 98 mg dissolved in 20 ml of methanol was added 3 ml of concentrated ammonia, and the mixture was stirred at room temperature for 18 hours. The solvent of the reaction mixture was distilled off under reduced pressure, and the obtained reaction product was recrystallized from 2 ml of acetone to obtain 3α, 14α-dihydroxy-androst-4-ene-6,17-dione (IIIa).
20.8 mg (yield 12.4%), melting point 274-276
C was obtained. Also, 3β, 14α-dihydroxy-6-propionyloxy-androst-4,6-diene-1
When 198 mg of 7-one (IIb) was used to carry out the same reaction operation as above, 3β, 14α-dihydroxy-androst-4-en-6,17-dione (IIIb) 56.8 m
g (yield 33.8%), melting point 198-200 ° C were obtained.

The reaction formula is shown below.

[Chemical 11]

The physical constants of this product are as follows. 3α, 14α-dihydroxy-androst-4-ene-6,17-dione (IIIa): Melting point: 274 to 276 ° C. IR: FIG. 5 NMR: FIG. 6 FAB Mass (M + H): 319 3β, 14α-dihydroxy. -Androst-4-ene-6,17-dione (IIIb): Melting point: 198 to 200 ° C IR: Fig. 7 NMR: Fig. 8 FAB Mass (M + H): 319

[0014]

Example 3 3α-acetoxy-14α-hydroxy-
Androst-4-ene-6,17-dione (IVa) and 3β-acetoxy-14α-hydroxy-androst-4-ene-6,17-dione (IVb)

[Chemical 12]

[Chemical 13] 60 mg of 3α, 14α-dihydroxy-androst-4-ene-6,17-dione (IIIa) was added to pyridine 0.5
0.25 ml of acetic anhydride was added to the solution dissolved in ml,
The mixture was stirred at room temperature for 21 hours. 50 ml of water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 ml). The extract was washed twice with 0.1N hydrochloric acid (40 ml), and further washed with water (4
It was washed twice with 0 ml) and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was applied to a silica gel column (30 g, 10φ × 300 mm) and eluted with a solvent of hexane: ethyl acetate = 3: 1. When the obtained compound was crystallized with acetone: hexane = 2: 1, 3α-acetoxy-14α-hydroxy-androst-4-ene-6,17-dione (IVa) 26.2 mg (yield 38.6%) , Mp 176-177 ° C. Also,
When the same reaction operation as above was carried out using 60 mg of 3β, 14α-dihydroxy-androst-4-ene-6,17-dione (IIIb), 3β-acetoxy-14α-hydroxy-androst-4-ene- 6,17-dione
(IVb) 18.5 mg (yield 27.2%), melting point 224-
225 ° C was obtained.

The reaction formula is shown below.

[Chemical 14]

The physical constants of this product are as follows. 3α-acetoxy-14α-hydroxy-androst-4-ene-6,17-dione (IVa): Melting point: 176 to 177 ° C. IR: FIG. 9 NMR: FIG. 10 FAB Mass (M + H): 361 3β-acetoxy. -14α-Hydroxy-androst-4-ene-6,17-dione (IVb): Melting point: 224-225 ° C IR: Fig. 11 NMR: Fig. 12 FAB Mass (M + H): 361

[0017]

Example 4 3α-acetoxy-6-propionyloxy-14α-hydroxy-androst-4,6-dien-17-one (Va) and 3β-acetoxy-6-propionyloxy-14α-hydroxy-androst- 4,6-dien-17-one (Vb)

[Chemical 15]

[Chemical 16] 3α, 14α-Dihydroxy-6-propionyloxy-androst-4,6-dien-17-one (IIa) 5
0.25 ml of acetic anhydride was added to a solution of 4.3 mg dissolved in 0.5 ml of pyridine, and the mixture was stirred at room temperature for 18 hours. 50 ml of water was added to the reaction mixture, and ethyl acetate (30 m
Extracted twice with l). Extract the 0.1N hydrochloric acid (40m
It was washed twice with l), further twice with water (40 ml) and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was treated with a silica gel column (30 g,
10φ × 300 mm) and hexane: ethyl acetate =
Elute with 3: 1 solvent. When the obtained compound was crystallized with acetone, 3α-acetoxy-6-propionyloxy-14α-hydroxy-androst-4,6-dien-17-one (Va) was 18.9 mg (yield 27.8).
%), Mp 108-109 ° C. Also, 3β, 14
α-dihydroxy-6-propionyloxy-androst-4,6-dien-17-one (IIb) 61.0 mg
When the completely same reaction operation as above is carried out using the above, 3β-acetoxy-6-propionyloxy-14α-hydroxy-androst-4,6-dien-17-one (Vb) 1
5.2 mg (yield 25.2%), melting point 102-103 ° C
Got

This reaction formula is shown below.

[Chemical 17]

The physical constants of this product are as follows. 3α-acetoxy-6-propionyloxy-14α-
Hydroxy-androst-4,6-dien-17-one (Va): Melting point: 108-109 ° C IR: Figure 13 NMR: Figure 14 FAB Mass (M + H): 417 3β-acetoxy-6-propionyloxy- 14α-
Hydroxy-androst-4,6-dien-17-one (Vb): Melting point: 102-103 ° C IR: Fig. 15 NMR: Fig. 16 FAB Mass (M + H): 417

[0020]

Example 5 3α, 6-dipropionyloxy-14α
-Hydroxy-androst-4,6-diene-17-
One (VIa) and 3β, 6-dipropionyloxy-1
4α-hydroxy-androst-4,6-diene-1
7-on (VIb)

[Chemical 18]

[Chemical 19] 3α, 14α-Dihydroxy-6-propionyloxy-androst-4,6-dien-17-one (IIa) 5
To a solution prepared by dissolving 9.2 mg in 0.5 ml of pyridine, 0.25 ml of propionic anhydride was added, and the mixture was stirred at room temperature for 18 hours. 50 ml of water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 ml). The extract was washed twice with 0.1N hydrochloric acid (40 ml) and further washed with water (40 ml).
It was washed twice and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue is applied to a silica gel column (30 g, 10φ × 300 mm) and eluted with a solvent of hexane: ethyl acetate = 3: 1. When the obtained compound was crystallized with ether, 25.1 mg of 3α, 6-dipropionyloxy-14α-hydroxy-androst-4,6-dien-17-one (VIa) (yield 36.9) was obtained.
%), Mp 94-96 ° C. Also, 3β, 14α-
Using 58.0 mg of dihydroxy-6-propionyloxy-androst-4,6-dien-17-one (IIb), the same reaction procedure as above was carried out to obtain 3β, 6-dipropionyloxy-14α-hydroxy- Androst-4,6-dien-17-one (VIb) 20.7 mg
(Yield 31.1%) and a melting point of 97-98 ° C were obtained.

This reaction formula is shown below.

[Chemical 20]

The physical constants of this product are as follows. 3α, 6-dipropionyloxy-14α-hydroxy-androst-4,6-dien-17-one (VIa): Melting point: 94-96 ° C. IR: FIG. 17 NMR: FIG. 18 FAB Mass (M + H): 431 3β, 6-dipropionyloxy-14α-hydroxy-androst-4,6-dien-17-one (VIb): melting point: 97-98 ° C IR: FIG. 19 NMR: FIG. 20 FAB Mass (M + H) : 431

[0023]

Example 6 3α-propionyloxy-14α-hydroxy-androst-4-ene-6,17-dione (VIIa) and 3β-propionyloxy-14α-hydroxy-androst-4-ene-6,17- Zion (VIIb)

[Chemical 21]

[Chemical formula 22] 55.1 mg of 3α, 14α-dihydroxy-androst-4-ene-6,17-dione (IIIa) was added to pyridine.
0.25 ml of propionic anhydride in a solution dissolved in 5 ml
Was added and stirred at room temperature for 18 hours. 50 ml of water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 ml). The extract was washed twice with 0.1N hydrochloric acid (40 ml),
Further, it was washed twice with water (40 ml) and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was treated with a silica gel column (30 g, 10φ × 300 m).
m) and eluted with a solvent of hexane: ethyl acetate = 3: 1. The obtained compound is acetone: hexane = 1: 1.
When crystallized with 3α-propionyloxy-14α-hydroxy-androst-4-ene-6,17-dione (VIIa) 15.6 mg (yield 24.1%), melting point 155
~ 156 [deg.] C was obtained. Also, 3β, 14α-dihydroxy-androst-4-ene-6,17-dione (IIIb)
When 60.8 mg was used to carry out the same reaction procedure as above, 3β-propionyloxy-14α-hydroxy-androst-4-ene-6,17-dione (VIIb) 2
8.1 mg (yield 39.3%), melting point 274 (decomposition)
(Crystalline from acetone) was obtained.

This reaction formula is shown below.

[Chemical formula 23]

The physical constants of this product are as follows. 3α-propionyloxy-14α-hydroxy-androst-4-ene-6,17-dione (VIIa): Melting point: 155-156 ° C IR: FIG. 21 NMR: FIG. 22 FAB Mass (M + H): 375 3β- Propionyloxy-14α-hydroxy-androst-4-ene-6,17-dione (VIIb): Melting point: 274 ° C. (decomposition) IR: FIG. 23 NMR: FIG. 24 FAB Mass (M + H): 375

[0026]

【The invention's effect】

Aromatase Inhibitory Action The usefulness of the compounds of the present invention represented by the general formula (I) was examined for the aromatase inhibitory action. Test Example EAThompson et al. Method (J. Biol. Chem. 249, 5364-53
(Page 72, 1974), aromatase was extracted and purified from human placenta, and the inhibition rate was calculated from the value in the enzyme activity measurement method using [1β, 2β- ³ H] androstenedione as a substrate.

The inhibition rate was calculated based on the following formula. Inhibition rate (%) = (1-test plot enzyme activity value / control plot enzyme activity value) × 100

[0028]

[Table 1] ──────────────────────── Inhibition rate (%) Test compound ──────── 100 μM ^a) ──── ──────────────────── IIa 31.8 IIb 42.4 IIIa 14.3 IIIb 23.7 IVa 59.2 IVb 9.0 Va 65.5 Vb 11 .2 VIa 65.7 VIb 10.0 VIIa 44.0 VIIb 8.0 ───────────────────────── a) Test compound concentration The test compound number of corresponds to the compound number in the examples.

As described above, the compound of the present invention markedly inhibits aromatase and is useful as an estrogen biosynthesis inhibitor. In addition, the ester bond of these compounds is cleaved by esterase in vivo,
Cancer, which may be converted to more active compounds,
It has excellent properties as a drug such as endometriosis.
Compounds of the invention are generally administered via the small intestine (orally or from the anus), parenterally (eg subcutaneous injection, intravenous injection, intramuscular injection) or topically (via the skin or mucous membranes by inhalation etc.) , Powders, capsules, microcapsules, aerosols, emulsions, suspensions, by conventional methods or in combination with usual formulation adjuvants as necessary.
It can be administered in the form of suppositories or ointments. The daily dose of the compound of the present invention for an adult is 10 to 1000 mg for oral administration and 10 for intramuscular administration.
˜600 mg, and 10 to 200 mg for intravenous administration. The compound of the present invention can prevent or treat diseases such as cancer and endometriosis by administering the above-mentioned content.

[Brief description of drawings]

1 is the IR of the compound (IIa) obtained in Example 1.

FIG. 2 NMR of the compound (IIa) obtained in Example 1.

FIG. 3 IR of compound (IIb) obtained in Example 1

FIG. 4 NMR of the compound (IIb) obtained in Example 1.

FIG. 5: IR of compound (IIIa) obtained in Example 2

FIG. 6 NMR of the compound (IIIa) obtained in Example 2.

FIG. 7: IR of compound (IIIb) obtained in Example 2

FIG. 8: NMR of the compound (IIIb) obtained in Example 2

FIG. 9: IR of compound (IVa) obtained in Example 3

FIG. 10: NMR of the compound (IVa) obtained in Example 3

FIG. 11: IR of compound (IVb) obtained in Example 3

FIG. 12: NMR of the compound (IVb) obtained in Example 3

FIG. 13: IR of compound (Va) obtained in Example 4

FIG. 14 NMR of compound (Va) obtained in Example 4

FIG. 15: IR of compound (Vb) obtained in Example 4

FIG. 16: NMR of the compound (Vb) obtained in Example 4

FIG. 17: IR of compound (VIa) obtained in Example 5

FIG. 18: NMR of compound (VIa) obtained in Example 5

FIG. 19: IR of compound (VIb) obtained in Example 5

FIG. 20: NMR of the compound (VIb) obtained in Example 5

FIG. 21: IR of compound (VIIa) obtained in Example 6

FIG. 22: NMR of the compound (VIIa) obtained in Example 6.

FIG. 23 shows the compound (VIIb) IR obtained in Example 6.

FIG. 24 is the compound (VIIb) NMR obtained in Example 6.

Claims (1)

[Claims] 1. A novel androstenedione derivative represented by the following general formula (I): [Wherein R ₁ is a hydroxyl group or a straight-chain or branched alkoxycarbonyl having 2 to 8 carbon atoms, R ₂ is oxo or a straight-chain or branched alkoxycarbonyl having 2 to 8 carbon atoms, and the dotted line is two Presence or absence of heavy bond, wavy line is α-
Alternatively, each represents β-coordinate. ]