JPH10316700A - D-homo-17-oxa-1,3,5 (10) -estraditriene derivative - Google Patents

Abstract

(57) [Problem] To provide a compound which has an antioxidant activity and is useful as a preventive or therapeutic agent for diseases such as arteriosclerosis, preeclampsia, and aging. The present invention relates to a compound represented by the formula: Wherein X represents C ＝ O or CH ₂ , and R ¹ and R
^{One of the two} represents a hydrogen atom and the other represents a hydroxy group, or X represents CH ₂ and R ¹ and R 2
² represents an estratriene derivative, each of which represents a hydrogen atom.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel D-homo-1
It relates to a 7-oxa-1,3,5 (10) -estraditriene derivative. The compound of the present invention has an antioxidant effect, and is useful for, for example, prevention or treatment of a disease associated with active oxygen or lipid peroxide.

[0002]

2. Description of the Related Art In recent years, it has been revealed that active oxygen is one of the causes of aging and the occurrence of adult diseases. Active oxygen is also involved in biological defense reactions, but causes tissue damage such as cell membrane damage and vascular endothelial cell damage due to lipid peroxidation, and is a factor in the onset and exacerbation of various diseases. To that end, research and development of so-called antioxidants, which have an active oxygen elimination effect and an inhibitory effect on the production of lipid peroxide, have been conducted as substances aimed at preventing or treating diseases involving active oxygen and lipid peroxide. I have. And those antioxidants are arteriosclerosis, hyperlipidemia, cerebral infarction, heart disease, ischemic disorders such as stress ulcer,
Some applications as therapeutic agents for rheumatism, preeclampsia, adult respiratory compression syndrome, ulcerative colitis, pulmonary edema, emphysema, endotoxemia, cutaneous vasculitis, aging, etc. have been attempted. However, at present, a compound capable of sufficiently coping with these diseases as an antioxidant has not been found yet.

[0003] On the other hand, estrogen is one of the compounds having an antioxidant effect, and its main metabolite, catechol estrogen, has a stronger antioxidant effect, and is applied to clinical applications. Is expected. However, catechol estrogens do not contain catechol-O in erythrocytes.
It has a high affinity for -methyltransferase, is rapidly O-methylated in blood, and is converted to guaiacol estrogen, which has a weak antioxidant effect.

[0004] In terms of chemical structure, compounds similar to the compounds of the present invention include certain D-homo-17-oxa- compounds having a blood cholesterol-lowering effect.
1,3,5 (10) -estraditriene derivatives are known (Journal of Medicinal Chemistry, 10, 1039-1047 (1967)).

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a compound which exhibits excellent antioxidant activity and is less susceptible to metabolic inactivation.

[0006]

Means for Solving the Problems The present inventors have developed a novel D-homo-1 in which an oxygen atom is introduced into the D ring of a steroid.
A 7-oxa-1,3,5 (10) -estraditriene derivative was created and found to exhibit excellent antioxidant activity and to be less susceptible to metabolic inactivation.

According to the present invention, the compound represented by the general formula (I)

[0008]

Embedded image

Wherein X represents C ＝ O or CH ₂ and ^one of R ¹ and R ² represents a hydrogen atom and the other represents a hydroxy group, or X represents CH ₂ and R ¹
And R ² both represent a hydrogen atom.

A preferred group of compounds in the above formula (I) is that X represents C ＝ O or CH ₂ and R ¹ and R
² is a compound of formula (I) wherein one of the two represents a hydrogen atom and the other represents a hydroxy group. A particularly preferred group of compounds in the above formula (I) are those of the formula (I) wherein R ¹ represents a hydroxy group and R ² represents a hydrogen atom.

According to the present invention, in the above formula (I), X
Represents C ＝ O or CH ₂ , and ^one of R ¹ and R ² represents a hydrogen atom and the other represents a hydroxy group (hereinafter referred to as compound IA).

[0012]

Embedded image

Wherein one of R ³ and R ⁴ represents a formyl group or a lower alkanoyl group (eg, acetyl, propionyl, etc.) and the other represents a hydrogen atom, and X
Has the above-mentioned meaning, a compound represented by the buyer-
It can be produced by subjecting to a biliger reaction and a subsequent hydrolysis reaction.

The Bayer-Villiger reaction is represented by the above formula (II)
By treating the compound with a peroxide, for example, hydrogen peroxide, peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid or the like in an inert solvent such as tetrahydrofuran or dichloromethane. it can. The reaction temperature at that time is generally from 0 ° C. to the reflux temperature of the reaction mixture, preferably around room temperature. In addition, the Bayer-Villiger reaction can be generally carried out using at least 1 mole, preferably about 1.1 to 2 moles of peroxide per mole of the compound of the formula (II).

The subsequent hydrolysis reaction can be easily carried out by treating the reaction mixture produced by the Bayer-Villiger reaction with an alkali hydroxide according to a conventional method.

Thus, the compound IA targeted by the present invention
Is obtained.

Further, in the above formula (I), X is CH ₂
Wherein R ¹ and R ² both represent a hydrogen atom (hereinafter referred to as compound IB),

[0018]

Embedded image

Reducing the compound of the formula

[0020]

Embedded image

The compound can be produced by subjecting the compound to a ring closure reaction.

The reduction of the compound of formula (III) can be carried out, for example, by treating with triethylsilane and boron trifluoride diethyl ether complex in an inert solvent such as dichloromethane.

The ring-closing reaction of the compound of the formula (IV) is carried out, for example, in an inert solvent such as toluene and benzene.
It can be carried out by treating with an arylsulfonic acid such as p-toluenesulfonic acid and benzenesulfonic acid.

In the above-mentioned reaction of the present invention, the compound of the formula (II) used as a starting material is a novel compound which has not been described in a conventional literature. For example, when both R ³ and R ⁴ are hydrogen atoms Can be produced by subjecting a compound of the formula (II) represented by the formula to a Friedel-Crafts lower alkanoylation reaction or a formylation reaction. Also,
The compound of the formula (III) used as a starting material is also a novel compound which has not been described in the conventional literature.
It can be produced by reducing the compound of the formula (III) when the 7a-position is an oxo group. Further, the compound of the formula (IV) used as a starting material is also a novel compound which has not been described in the conventional literature.
16α-dihydroxyestradi-1,3,5 (10)-
Subjected to a reaction to open the D ring part of trien-17-one,
Then, it can be produced by reduction. For details of reaction conditions and the like, refer to Examples and Production Examples described later.

Thus, the compounds of formula (I), ie compounds IA and IB, prepared according to the process of the present invention
Can be isolated and purified from the reaction mixture by a means known per se, for example, a method such as recrystallization, distillation, column chromatography, or thin layer chromatography.

[0026]

The estratriene derivative represented by the formula (I) of the present invention described above has an excellent antioxidant effect, and is a disease involving active oxygen and lipid peroxide, such as arteriosclerosis. Disease, hyperlipidemia, cerebral infarction, heart disease, ischemic disorder such as stress ulcer, cancer, diabetes, nephritis, hepatitis, Behcet's disease, Coulomb disease, Parkinson's disease, rheumatism, preeclampsia, adult respiratory compression syndrome , Ulcerative colitis, pulmonary edema, emphysema, endotoxemia, cutaneous vasculitis, aging and the like.

The thus obtained estratriene derivative of the formula (I) of the present invention can be used as an antioxidant by oral administration or parenteral administration (for example, intramuscular injection, intravenous injection, Rectal administration, transdermal administration, etc.)
can do.

When the compound according to the present invention is used as a drug, it may be in a solid form (for example, tablet, hard capsule, soft capsule, granule, powder, fine granule, pill, troche tablet) depending on the use. ), Semisolid forms (eg, suppositories, ointments, etc.) or liquid forms (injections, emulsions, suspensions, lotions, sprays, etc.). Non-toxic additives that can be used in the above formulation, for example, starch, gelatin, glucose, lactose,
Fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, gum arabic, polyethylene glycol, alkyl p-hydroxybenzoate, syrup, ethanol, propylene glycol, petrolatum, carbowax, glycerin, chloride Sodium, sodium sulfite, sodium phosphate, citric acid and the like. The agent can also contain other therapeutically useful agents.

The content of the compound of the present invention in the medicament varies depending on the dosage form, but is generally in a concentration of 0.1 to 50% by weight in solid and semi-solid forms, and in liquid form. In this case, it is desirable that the compound be contained at a concentration of 0.05 to 10% by weight.

The dosage of the compound of the present invention can be varied widely depending on the kind of human or other warm-blooded animal, the administration route, the severity of the symptoms, the diagnosis of a doctor, and the like.
Generally, it can be 0.05 to 10 mg / kg, preferably 0.1 to 5 mg / kg per day. However, it is, of course, possible to administer an amount smaller than the lower limit or larger than the upper limit of the above range depending on the severity of the symptoms of the patient and the diagnosis of the doctor as described above. The above dose can be administered once or several times a day.

[0031]

The present invention will be more specifically described below with reference to examples and production examples.

Example 1 D-homo-17-oxaestra was prepared under a nitrogen atmosphere.
264 mg of 1,3,5 (10) -triene-3,17aξ-diol was suspended in 7 ml of dichloromethane, and while cooling with ice, 0.24 ml of triethylsilane and 0.14 ml of a boron trifluoride etherate were added thereto. Stirred under for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was returned to room temperature, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, dried over magnesium sulfate, and the solvent was distilled off. The resulting crude product was subjected to thin layer chromatography (developing solvent, chloroform: acetone = 9: 1). Purified, D-homo-
164 mg of 17-oxaestra-1,3,5 (10) -trien-3-ol were obtained.

¹ H-NMR (CDCl ₃ , δ): 1.01 (3H, s), 3.05, 3.48
(2H, ABq, J = 11Hz), 3.3-3.6 (1H, m), 4.0-4.2 (1H, m), 6.56-
6.68 (2H, m), 7.15 (1 H, d, J = 8 Hz) MS (m / z): 272 (M ⁺ ) Example 2 3-hydroxy-16-oxo-16,17-secoestradi-1,3,3 5 (10) -triene-17-acid
4 g, dioxane 1000 ml, tetrahydrofuran 1
A mixture of 000 ml and 10 g of lithium aluminum hydride was stirred under water cooling for 5 hours. To the reaction mixture was added 5% hydrochloric acid, the product was extracted with ethyl acetate, and the organic layer was washed with water and dried over magnesium sulfate. The solvent is distilled off and 1
There was obtained 29.2 g of 6,17-secoestra-1,3,5 (10) -triene-3,16,17-triol.

16,17-seco estra-1,3,5
(10) -triene-3,16,17-triol 2
A mixture of 9.2 g, 1.0 g of p-toluenesulfonic acid and 500 ml of toluene was slowly distilled. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the organic layer was washed with water and dried over magnesium sulfate. The crude product obtained by distilling off the solvent was subjected to column chromatography (elution solvent,
Purification with chloroform: acetone = 50: 1) and D-
Homo-17-oxaestra-1,3,5 (10) -trien-3-ol was obtained.

Example 3 2-Acetyl-3-hydroxy-D-homo-17-oxaestra-1,3,5 (10) -triene-17a-
To a mixture of 253 mg of ON and 19.4 ml of tetrahydrofuran, 0.92 ml of a 1N aqueous sodium hydroxide solution and 1.08 ml of 3% aqueous hydrogen peroxide were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. Acetic acid was added to the reaction mixture to make it acidic. The residue obtained by concentration under reduced pressure was purified by thin-layer chromatography (developing solvent, chloroform: acetone = 4: 1) to give 2,3-dihydroxy-D-homo-17-oxaestra-1,3,3. 110 mg of 5 (10) -trien-17a-one was obtained.

¹ H-NMR (CDCl ₃ , δ): 1.25 (3H, s), 4.1-4.7 (2
H, m), 6.59 (1H, s), 6.81 (1H, s) MS (m / z): 302 (M ⁺ ) Example 4 In Example 3, 2-acetyl-3-hydroxy-D
-Homo-17-oxaestra-1,3,5 (10)-
Instead of trien-17a-one, 2-formyl-D
-Homo-17-oxaestra-1,3,5 (10)-
Trien-3-ol and 4-formyl-D-homo-1
7-oxaestra-1,3,5 (10) -triene-
Operating similarly with a mixture of 260 mg of 3-ols,
The obtained crude product was purified by thin-layer chromatography (developing solvent, chloroform: acetone = 19: 1),
D-homo-17-oxaestra as a highly polar compound
1,3,5 (10) -triene-2,3-diol 13
7 mg were obtained.

¹ H-NMR (CDCl ₃ , δ): 1.01 (3H, s), 3.08, 3.45
(2H, ABq, J = 11Hz), 3.3-3.6 (1H, m), 4.0-4.3 (1H, m), 6.57 (1
H, s), 6.80 (1H, s) MS (m / z): 288 (M ⁺ ) Further, D-homo-17-oxaestra-1,3,5 (10) -triene-3 is used as a low-polarity compound. 23 mg of 1,4-diol were obtained.

¹ H-NMR (CDCl ₃ , δ): 1.01 (3H, s), 3.08, 3.45
(2H, ABq, J = 11Hz), 3.3-3.6 (1H, m), 4.0-4.3 (1H, m), 6.70 (1
H, d, J-9 Hz), 6.75 (1 H, d, J = 9 Hz) MS (m / z): 288 (M ⁺ ) Example 5 In Example 3, 2-acetyl-3-hydroxy-D
-Homo-17-oxaestra-1,3,5 (10)-
Instead of trien-17a-one, 2-acetyl-D
-Homo-17-oxaestra-1,3,5 (10)-
The same operation was carried out using trien-3-ol to obtain D-homo-17-oxaestra-1,3,5 (10) -trien-2,3-diol.

Production Example 1 3-Hydroxy-D-homo-17-oxaestra
1,3,5 (10) -trien-17a-one 286m
g was suspended in 2.5 ml of tetrahydrofuran, and lithium tri-t-butoxyaluminohydride 40 was added under ice cooling.
After adding 0 mg, the mixture was stirred under ice-cooling for 30 minutes. Water and 5% hydrochloric acid were added to the reaction mixture, and the product was extracted with ethyl acetate. After washing the organic layer with water and drying over magnesium sulfate,
The solvent was distilled off, and D-homo-17-oxaestradi-
324 mg of 1,3,5 (10) -triene-3,17a'-diol was obtained.

¹ H-NMR (CD ₃ OD, δ): 0.92 (3H, s), 6.47-6.60
(2H, m), 7.06 (1H, d, J = 8 Hz) MS (m / z): 288 (M ⁺ ), 214 Production Example 2 3,16α-dihydroxyestra-1,3,5 (1
A mixture of 155 mg of orthoperiodic acid and 0.55 ml of water was added to a mixture of 167 mg of 0) -trien-17-one and 1 ml of dioxane under cooling with water, followed by stirring for 1 hour. Water was added to the reaction mixture, the product was extracted with ethyl acetate, and the organic layer was washed with water and dried over magnesium sulfate. The crude product obtained by evaporating the solvent was purified by thin-layer chromatography (developing solvent, chloroform: acetone = 4: 1) to give 3-hydroxy-16-oxo-16,17-secoestradi-1,3. 107 mg of 5,5 (10) -triene-17-acid were obtained.

¹ H-NMR ((CD ₃ ) ₂ SO, δ): 1.04 (3H, s), 6.3-6.7
(2H, m), 7.02 (1H, d, J = 8Hz), 9.44 (1H, br) Production Example 3 3-Hydroxy-D-homo-17-oxaestra
1,3,5 (10) -trien-17a-one 850 m
g, 68 ml of 1,2-dichloroethane, 1.7 g of aluminum chloride and 0.7 ml of acetyl chloride at 0 ° C.
For 1 hour and at 70 ° C. for 6 hours. 5% reaction mixture
The product was extracted with ethyl acetate, and the organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off, and the resulting crude product was purified by thin-layer chromatography (developing solvent, chloroform: acetone = 19: 1) to give 2-acetyl-3-hydroxy-D-homo-17-oxaestradiol. 1,3,5 (10) -trien-17a-one 47
mg was obtained.

¹ H-NMR (CDCl ₃ , δ): 1.26 (3H, s), 2.61 (3H,
s), 4.1-4.7 (2H, m), 6.70 (1H, s), 7.61 (1H, s) Production Example 4 4.6m of 3M ethylmagnesium bromide ether solution
l and 85 ml of ether, a mixture of 845 mg of D-homo-17-oxaestra-1,3,5 (10) -trien-3-ol and 230 ml of benzene was added, followed by 710 mg of paraformaldehyde and hexamethylphosphoramide. 1.2 ml was added, and the mixture was refluxed for 6 days under a nitrogen atmosphere. To the reaction mixture was added 5% hydrochloric acid, the product was extracted with ethyl acetate, and the organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off, and the resulting crude product was purified by thin-layer chromatography (developing solvent, chloroform: acetone = 19: 1) to give 2-formyl-D-homo-17-oxaestra-1,3,3. 440 mg of a mixture of 5 (10) -trien-3-ol and 4-formyl-D-homo-17-oxaestra-1,3,5 (10) -trien-3-ol were obtained.

Production Example 5 In Production Example 3, 3-hydroxy-D-homo-17-
Oxaestra-1,3,5 (10) -triene-17
Instead of a-one, D-homo-17-oxaestra-1,3,5 (10) -trien-3-ol 500 m
g, 2-acetyl-D-homo-
60 mg of 17-oxaestra-1,3,5 (10) -trien-3-ol were obtained.

¹ H-NMR (CDCl ₃ , δ): 1.03 (3H, s), 2.60 (3H,
s), 3.08,3.46 (2H, ABq, J = 11Hz), 3.3-3.6 (1H, m), 3.9-4.3
(1H, m), 6.69 (1H, s), 7.60 (1H, s)

Claims (4)

[Claims] 1. A compound of the general formula Wherein X represents C ＝ O or CH ₂ , and ^one of R ¹ and R ² represents a hydrogen atom and the other represents a hydroxy group, or X represents CH ₂ and R ¹ and R ² Is an estratriene derivative, each of which represents a hydrogen atom. ^2. The estratriene derivative according to claim 1, wherein X represents C ＝ O or CH ₂ , and ^one of R ¹ and R ² represents a hydrogen atom and the other represents a hydroxy group. 3. The estratriene derivative according to claim 2, wherein R ¹ represents a hydroxy group and R ² represents a hydrogen atom. 4. An antioxidant comprising the estratriene derivative according to claim 1 as an active ingredient.