JP2003517001A - 11β-phenylestradiene derivative having a fluoroalkyl group in the aromatic side chain, method for producing the same, and pharmaceutical composition containing the compound - Google Patents

Abstract

(57) The present invention provides a compound represented by the general formula (I): The present invention relates to a novel 11β-phenylestradiene derivative having a fluoroalkyl group in an aromatic side chain, its production and a pharmaceutical preparation containing the compound. The compounds according to the invention are useful for treating diseases stimulated by cortisol or corticoids, reducing secreted cortisol, stimulating lactation, treating dysmenorrhea and fibroids, treating Cushing's disease and cervical ripening, cognitive performance Suitable for amelioration, treatment of endometriosis or hormone replacement therapy (HRT).

Description

Detailed Description of the Invention

The present invention relates to a novel 11β-phenylestradiene derivative having a fluoroalkyl group in the aromatic side chain, its production and a pharmaceutical composition containing the compound. The compounds according to the invention treat cortisol- or corticoid-stimulated diseases, reduce secreted cortisol, stimulate milk secretion, treat dysmenorrhea and myomas, treat Cushing's disease and cervical maturation, of cognitive ability. Suitable for amelioration, treatment of endometriosis or hormone replacement therapy (HRT).

11β-Substituted phenylestradienes are already known. The preparation of 11β-aryl-17α-propynyl-oestra-4,9-dienes is described, for example, in EP 0057115 and 11β- (4-formylphenyl) -oestra-4,9-dienes. The reaction of -3-one with hydroxylamine is described in DE-A-3504421. During the reaction with hydroxylamine, the 11β-formylphenyl group as well as the 3-keto group are oxime-ized. Furthermore, at C-3, the syn-isomer and anti
-Isomers arise. Furthermore, from EP 0 411 733, 11β-
11β-Aryl-gona-4,9- having different substituents at the 4-position of the phenyl group
Dien-3-one is known. The EP 0648779, hydrogen atom of the oxime group is a _{group: -COCH 3, -COOC 2 H 5} , -CONH
- phenyl, -CONHC ₂ H _5, has been replaced by -COC ₂ H ₅ or -CO- phenyl 11β- benzaldoximes -17β- methoxy -17α
-Methoxymethyl-estradiene derivatives have been described. These compounds are antigestagen agents and have a clearly reduced antiglucorticoid activity compared to RU486. The 11β-phenylestradiene derivative having a fluoroalkyl group in the side chain of an aromatic compound does not exist in the compounds disclosed so far.

[0003]   The present invention has the general formula (I):

[Chemical 4] [In the formula, R₁Is C₁~ C₆An alkyl group, R₂Is a hydrogen atom, C₁~ C ₆ -Alkyl group or C₁~ C₆Represents an acyl group, X represents a hydroxyl group
Or Y represents a trimethylsiloxy group, and Y represents a hydrogen atom or a general formula: C_nF_{2n + 1} Represents a perfluoroalkyl group represented by or X and Y together
Oxo group or oxyimino group: NOR₃Represents a hydrogen atom, C₁ ~ C₆-Alkyl group or substituted methylene group: CH₂W (in this case W is
Hydroxyl group, C₁~ C₆-Alkoxy group, C₁~ C₆-Alkylthio group, ha
Is a rogen atom or a pseudohalogen), and A is an oxo group or oximino.
Group: NOR₃, 1,3-dithiane group, 1,3-dithiolane group, in which case
, R₃Is a hydrogen atom, C₁~ C₈-Alkyl group, aryl group, alkylaryl
Group or arylalkyl group, C₁~ C₈-Acyl group, group: CONHR_Four, CO
SR_FourOr COOR_Four, In this case R_FourIs a hydrogen atom or C₁~ C ₈ Represents an alkyl group, an aryl group, an aralkyl group or an alkylaryl group
And n represents an integer of 1 to 4] in the aromatic side chain
Group-containing 11β-phenylestradiene derivative and its pharmaceutically acceptable
Provides a sex salt.

Pharmaceutically acceptable salts within the scope of the present invention are alkali metal or alkaline earth metal salts, especially sodium, potassium or ammonium salts. “Alkyl”, within the scope of the present invention, is a branched or straight-chain alkyl group. Examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group or tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, 2-methylpentyl group, 3-methylpentyl group,
A 2,2-dimethylbutyl group or a 2,3-dimethylbutyl group may be mentioned. C _n F _{2n + 1} - A group refers to a branched or straight-chain fluoroalkyl group having 1 to 3 carbon atoms, in this case, examples are a trifluoromethyl group, pentafluoroethyl It is an ethyl group, a heptafluoro-n-propyl group or a heptafluoro-isopropyl group.

The term “aryl” refers within the scope of the invention to substituted or unsubstituted aryl groups having 5 to 10 carbon atoms. Examples of aryl groups are phenyl groups, halogenated phenyl groups, nitrophenyl groups or naphthyl groups. The term “aralkyl” refers within the scope of the invention to an arylalkyl group having 6 to 15 carbon atoms. Examples of aralkyl groups are free benzyl groups or benzyl groups substituted in aromatic compounds, for example benzyl groups or halogenated benzyl groups. The term "alkylaryl" refers to an alkylaryl group having 6 to 15 carbon atoms. Examples of alkylaryl groups are methylphenyl groups, halogenated methylphenyl groups, ethylphenyl groups, dimethylphenyl groups or trimethylphenyl groups. The term “halogen” refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

X preferably represents a hydroxyl group. When X is a hydroxyl group,
Y represents a hydrogen atom or a trifluoromethyl group, a pentafluoroethyl group, a heptafluoro-isopropyl group or a heptafluoro-n-propyl group, preferably a trifluoromethyl group. X and Y together form an oxo group or group: NOR ₃ , in which R ₃ is preferably a hydrogen atom, a methyl group, an ethyl group, a phenyl group, a tolyl group, a benzyl group, a formyl group. Or an acetyl group or a group: CONHR ₄ , COSR ₄ or COOR ₄ , wherein R ₄ is a methyl group or an ethyl group, a phenyl group, a 4-fluorophenyl group, a trifluoromethylphenyl group, a trifluoromethoxymethyl group. , Trifluoromethoxyphenyl group or benzyl group or tolyl group.

When A represents the group: NOR ₃ , R ₃ is preferably hydrogen, methyl, ethyl, phenyl, tolyl, benzyl, formyl or acetyl or the group: CONHR ₄ , COSR ₄ or COOR _{4 in} which R ₄ is preferably methyl or ethyl, phenyl, 4-fluorophenyl,
Represents a benzyl group or a tolyl group. R ₁ preferably represents a methyl group or an ethyl group. R ₂ preferably represents a hydrogen atom or an alkyl group, especially a methyl group or an ethyl group. Z represents a hydrogen atom, a C ₁ -C ₆ -alkyl group, especially a methyl group or an ethyl group, or a substituted methylene group: CH ₂ W (where W is a hydroxyl group, C ₁ -C) ₆ -alkoxy groups, especially methoxy or ethoxy groups, C ₁ -C ₆ -alkylthio groups, especially methylthio or ethylthio groups, halogen atoms such as fluorine, chlorine, bromine or iodine atoms or pseudohalogens,
For example, it represents a cyanide group or a thiocyanide group). According to the invention, the compounds in which R ₁ and R ₂ represent a methyl group and Z represents a group: CH ₂ W, in which W is a methoxy group and A represents an oxo group are particularly preferred. is there.

The compounds described below are particularly advantageous according to the invention: 1) 11β- [4- (2,2,2-trifluoro-1-hydroxyethyl) phenyl] -17β-methoxy-17α -(Methoxymethyl) estra-4,9-dien-3-one, 2) 11β- [4- (2,2,3,3,3-pentafluoro-1-hydroxypropyl) phenyl] -17β-methoxy- 17α- (methoxymethyl) -oestra-4,9-dien-3-one, 3) 11β- [4- (2,2,3,3,4,4,4-heptafluoro-1-hydroxybutyl) phenyl ] -17β-Methoxy-17α- (methoxymethyl)-
Estra-4,9-dien-3-one, 4) 11β- {4- [2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl] phenyl} -17β-methoxy-17α -(Methoxymethyl) -estra-4,9-dien-3-one, 5) 11β- [4- (2,2,2-trifluoroacetyl) phenyl] -17β
-Methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one, 6) 11β- [4- (2,2,2-trifluoroacetyl) phenyl] -17β
-Hydroxy-17α- (methoxymethyl) -oestra-4,9-diene-3-
On, 7) 11β- [4- (2,2,3,3,3-pentafluoro-propan-1-one) phenyl] -17β-methoxy-17α- (methoxymethyl) -estradi-
4,9-Dien-3-one, 8) 11β- [4- (2,2,3,3,4,4,4-heptafluoro-butane-
1-one) phenyl] -17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one, 9) 2,2,2-trifluoro-1- [4- (17β-methoxy) -17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl) phenyl] -ethan-1-one- (E) -oxime,

10) 2,2,2-trifluoro-1- [4- (17β-methoxy-17α- (
Methoxymethyl) -3-oxoestra-4,9-dien-11β-yl) phenyl] -ethan-1-one- (Z) -oxime, 11) 4- [3,3-ethylenedithio-17β-methoxy- 17α- (Methoxymethyl) -estra-4,9-dien-11β-yl] phenyl-2,2,2-
Trifluoroethane-1-one- (E / Z) -oxime, 12) 11β- [4- (2,2,2-trifluoroacetyl) phenyl] -17
β-methoxy-17α- (methoxymethyl) -estra-4,9-diene- (3
E) -oxime, 13) 11β- [4- (2,2,2-trifluoroacetyl) phenyl] -17
β-methoxy-17α- (methoxymethyl) -estra-4,9-diene- (3
Z) -oxime, 14) 4-{[17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] phenyl} -2,2,2-trifluoroethane- 1-one- (1Z)-[O- (N-4-fluorophenylamino) carbonyl] oxime, 15) 4-{[17β-methoxy-17α- (methoxymethyl) -3-oxooestra-4,9- Dien-11β-yl] phenyl} -2,2,2-trifluoroethan-1-one- (1E)-[O- (N-4-fluorophenylamino) carbonyl] oxime, 16) 4-{[17β -Methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] phenyl} -2,2,2-trifluoroethan-1-one- (Z)-[O- ( N Ethylamino) carbonyl] oxime, 17) 4-{[17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] phenyl} -2,2,2-trifluoro Ethan-1-one- (Z)-(O-acetyl) oxime, 18) 4-{[17β-methoxy-17α- (methoxymethyl) -3-oxooestra-4,9-dien-11β-yl] phenyl } -2,2,2-Trifluoroethan-1-one- (Z)-[O- (S-ethylthio) carbonyl] oxime, 19) 4-{[17β-methoxy-17α- (methoxymethyl) -estra -4
, 9-Diene- (3Z) -oxime-11β-yl] -2,2,2-trifluoroacetophenone- (1Z) -oxime and 20) 4-{[17β-methoxy-17α- (methoxymethyl) -estra -4
, 9-Diene- (3E) -oxime-11β-yl] -2,2,2-trifluoroacetophenone- (1Z) -oxime.

Further, the present invention relates to a method for regioselectively introducing a fluoroalkyl group into an 11β-phenylestradiene derivative of the general formula (I) and a pharmaceutically acceptable salt thereof. , In this case the general formula (II):

[Chemical 5] [Wherein R ₁ has the above-mentioned meaning] 11β-benzaldehyde is reacted with perfluoroalkyltrimethylchlorosilane to form a fluoroalkylsilyl ether (IIIa), which is hydrolyzed to give a compound represented by the general formula ( IIIb)
Secondary alcohol:

[Chemical 6] And then oxidized to form formula (IV):

[Chemical 7] To 11β-fluoroalkyl phenyl ketone, which is optionally reacted with C-3 with a hydroxyl group or ethanedithiol to give a derivative and / or the other oxo group of said compound, in a manner known per se. Convert to a free or substituted oxime of formula (I).

Starting materials of the general formula (II) which are useful for the preparation of compounds of the general formula (I) are described in German Patent Application DE 43 32 283 A1 (European Patent Application Publication No. 0648).
779) or German Patent Application DE 43 32 824 A1 (European Patent Application EP 0 648 778 A1). The subject of the invention is also pharmaceutical compositions containing at least one 11β-phenylestradiene derivative of the formula (I), optionally together with pharmaceutically acceptable auxiliaries and / or carriers. is there. Said pharmaceutical composition may be provided for subcutaneous, oral, buccal, rectal, implantable, intravenous or intramuscular use. Said pharmaceutical composition contains at least one compound of general formula (I) or a pharmaceutically acceptable salt thereof together with customary carriers, diluents and / or colorants.

The medicaments according to the invention are prepared in a manner known per se in the appropriate dose according to the desired application, together with customary solid or liquid carriers and / or diluents and generally customary auxiliaries. To be done. In the case of one advantageous oral dosage form, it is preferably prepared as a tablet, film tablet, dragee, capsule, pill, powder, solution or suspension, or also as a depot dosage form. Together with these, parenteral pharmaceutical forms, such as injection solutions and also suppositories are also considered. The pharmaceutical forms as tablets are, for example, the active substance and known auxiliaries, such as dextrose, sugar, sorbit, mannitol, polyvinylpyrrolidone, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as stearin. Magnesium acid or talc and / or agents capable of achieving depot formulation effects, such as carboxylpolymethylene, carboxymethylcellulose,
Obtained by mixing with cellulose acetate phthalate or polyvinyl acetate. These tablets may be multi-layered or may have break cuts.

Implants are obtained, for example, by implantation in a polymer, which can be injected under the skin, for example, and release the drug in vivo by diffusion from the polymer or biodegradation of the polymer. Furthermore, dragees can be prepared by coating the cores, like tablets, with the agents normally used in dragee coatings, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. . In this case, the dragee coating may be composed of multiple layers, in which case the above-mentioned auxiliaries are used, for example.

Solutions or suspensions containing the active substances according to the invention are added with substances such as saccharin, cyclamate or sugar and / or aroma substances such as vanillin or orange extract for the improvement of taste. May be done. Furthermore, these solutions or suspensions may be mixed with suspension aids such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoic acid. Capsules can be prepared by mixing the drug with a carrier such as lactose or sorbit, followed by introduction into capsules. The preparation of suppositories is preferably carried out by mixing the active substances with suitable carrier materials, such as neutral fats or polyethylene glycols or their derivatives. Furthermore, pharmaceutical dosage forms may be transmucosal, buccal, sublingual or transdermal dosage forms such as matrix formulations (adhesive matrices, liquid storage systems), transdermal therapeutic systems (TT).
S) or gels, sprays or salves or intranasal dosage forms, such as nasal sprays or nasal drops.

A suitable dose of the compound according to the invention depends on the weight, age and condition of the patient,
The daily dose is 0.001 to 100 mg, in which case the required daily dose can be dosed in a single dose or in multiple doses. 11 according to the invention of the general formula (I) having a fluoroalkyl group in the aromatic side chain
The β-phenylestradiene derivative is a compound having an antihormonal action.
Thus, the compounds listed in Table 1, on the one hand, bind more strongly to the progesterone receptor than at the glucocorticoid receptor and therefore the compound RU384
Decomposes better than 86. On the other hand, this compound has no sterility when administered to animals (rats) at 1 mg every 4 days in animal experiments. This compound is particularly suitable for the treatment of endometriosis and for hormone replacement therapy with reduced side effect potential because of its reduced sterility and apparently selective effects.

Table 1: Receptor binding to preferably progesterone receptors. Relative binding affinity (RBA-value) [%] ┌─────┬────────────┬────────────┐ │ Example │ Progesterone receptor │ Glucocorticoid receptor │ │ │ (Progesterone = 100%) │ (Texamethasone = 100%) │ ├────┼────────────┼─────── Example 5│ 200 │ 113 │ │ Example 6 │ 190 │ 71 │ │ Example 8 │ 113 │ 76 │ │ Example 10 │ 270 │ 94 │ └ ─── ┴ ─ ───────────┴────────────┘

On the other hand, the compounds listed in Table 2 are more strongly bound by the glucocorticoid receptor than the progesterone receptor. These substances are suitable for the treatment of diseases which are stimulated by cortisol or corticoids such as diabetes, hypertension, memory loss (or senile dementia) due to depression aging, Cushing's syndrome, and these substances are also suitable for cortisol. It is also suitable for inhibiting the formation of and its action (eg stress-induced secretion of cortisol) and for stimulating an increase in cognitive ability.

Table 2: Receptor binding, preferably to the glucocorticoid receptor. Relative binding affinity (RBA-value) [%] ┌─────┬────────────┬────────────┐ │ Example │ Progesterone Receptor │ Glucocorticoid receptor │ │ │ (Progesterone = 100%) │ (Texamethasone = 100%) │ ├─────┼────────────┼─────── ──────┤ │Example 9 ^* │ 68 │ 134 │ │ Example 14 ^** │ 7 │ 40 │ └─────┴────────────┴── ──────────┘ * 4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] -phenyl-2,2,2- Trifluoroethane-1-one- (Z)-[N- (ethylamino) carbonyl] -oxime. ** 11β- [4- (2,2,2-trifluoroacetyl) phenyl] -17β-
Methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one- (E) -oxime.

These test results show that the compounds according to the invention of general formula (I) reduce secreted cortisol, stimulate milk secretion, treat dysmenorrhea and myoma, treat Cushing's disease and cervical maturation. , Improve cognitive ability, treat endometriosis or use for hormone replacement therapy (HRT).

The following examples serve to illustrate the invention in detail, but without limiting it. Example 1 11β- [4- (2,2,2-trifluoro-1-hydroxyethyl) phenyl] -17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one 4- A mixture of [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-17β-yl] benzaldehyde (2 g) and molecular sieves (1 g) was mixed with anhydrous tetrahydrofuran and anhydrous dimethylformamide (1 : 1, v: v) suspended in 30 ml and with stirring 50 mg tetrabutylammonium fluoride-trihydrate. Then cool to 0 ° C,
Trifluoromethyltrimethylsilane is gradually added. The temperature is gradually raised to room temperature, the mixture is stirred for another 30 minutes, filtered off, diluted with tetrahydrofuran, 1N hydrochloric acid is added, and the mixture is further stirred for 3 hours. Dilute with water, add ethyl acetate, separate the phases, wash the organic phase with saturated aqueous sodium hydrogen carbonate solution, then saturated sodium chloride solution, dry over sodium sulfate and dry in vacuo. Evaporate and concentrate until. The remaining foam is purified on silica gel using flash chromatography. By recrystallization from diethyl ether / n-hexane, 11β-
[4- (2,2,2-trifluoro-1-hydroxyethyl) phenyl] -17
β-methoxy-17α- (methoxymethyl) -estra-4,9-diene-3-
This yields 1.48 g on. Melting point: 138-147 ° C .; ¹ H-NMR (300 MHz, CDCl ₃ , δ in ppm with TMS as internal standard): 0.50 (s, 3H, H-18),
3.24 and 3.41 (2s, 6H, 2 × OCH 3), 3.42 and 3.5
8 (2d, J = 10.6 Hz, 2H, OCH ₂ ), 4.38 (d, J = 6.6H)
z, 1H, H-11), 4.99 (m, 1H, CH-OH), 5.77 (s, 1)
H, H-4), 7.20 and 7.37 (2d, 4H, CH-aromatic compounds).

Example 2 11β- [4- (2,2,3,3,4,4,4-heptafluoro-1-hydroxybutyl) phenyl] -17β-methoxy-17α- (methoxymethyl) -estradi 4,9-Dien-3-one 4- (17β-methoxy- (17α-methoxymethyl) -3-oxoestra-4,9-dien-11β-yl) benzaldehyde 1.74 g, molecular sieve 1 g and heptafluoro A mixture consisting of 1 ml of propyltrimethylsilane is suspended in 30 ml of anhydrous tetrahydrofuran and 100 mg of tetramethylammonium fluoride trihydrate are added at −20 ° C. with stirring. Gradually warm to room temperature, stir for another 12 hours, filter and evaporate to dryness in vacuo to dryness. The residue is taken up in 100 ml of tetrahydrofuran / methanol (1: 1) and hydrolyzed with 2N hydrochloric acid at 5 ° C. The solution is concentrated in vacuo, water is added and extracted twice with dichloromethane. The organic phase is washed successively with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo to dryness. The remaining foam is purified on silica gel using flash chromatography. By recrystallization from acetone / n-hexane, 11β- [4- (2,2
2,3,3,4,4,4-heptafluoro-1-hydroxybutyl) phenyl]
This gives 223 mg of -17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one. Melting point: 199-202 ° C; ¹ H-NMR (300 MHz, CDCl ₃ , δ in ppm with TMS as internal standard): 0.50 (s, 3H, H-18),
3.25 and 3.41 (2s, 6H, 2 × OCH 3), 3.41 and 3.5
7 (2d, J = 10.6 Hz, 2H, OCH ₂ ), 4.39 (d, J = 6.4H
z, 1H, H-11), 5.16 (m, 1H, CH-OH), 5.77 (s, 1
H, H-4), 7.23 and 7.36 (2d, 4H, CH-aromatic compounds).

Example 3 11β- [4- (2,2,2-trifluoroacetyl) phenyl] -17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one in 60 ml dichloromethane. 11β- [4- (2,2,2-trifluoro-1
-Hydroxyethyl) phenyl] -17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one 3.11 g pyridine / SO in 8.6 ml triethylamine and 30 ml dimethyl sulfoxide at 0 ° C. _A solution of 8 g of ₃ -complex is dispensed. The temperature is raised to room temperature and the mixture is further stirred for 12 hours. 0
125 ml of ammonium chloride aqueous solution adjusted to pH 4.5 with concentrated hydrochloric acid in advance at ℃
Is added little by little. After phase separation, the organic phase is washed with water and saturated sodium chloride solution, dried with sodium sulphate and concentrated by evaporation in a vacuum. The crude product is purified on silica gel using flash chromatography. Recrystallization from diethyl ether / n-hexane gave 11β- [4- (2,2,2
-Trifluoroacetyl) phenyl] -17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one. Melting point: 92-113 ° C., ¹ H-NMR (300 MHz, CDCl ₃ , δ in ppm with TMS as internal standard): 0.50 (s, 3H, H-18), 3
． 25 and 3.42 (2s, 6H, 2 × OCH 3), 3.43 and 3.55
(2d, J = 10.6 Hz, 2H, OCH ₂ ), 4.45 (d, J = 7.1 Hz
, 1H, H-11), 5.80 (s, 1H, H-4), 7.39 and 7.99.
(2d, 4H, CH-aromatic compound).

Example 4 11β- [4- (2,2,3,3,4,4,4-heptafluoro-butane-1-
On) -phenyl] -17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one 11β- [4- (2,2,3,3,4,4,4 in 5 ml of dichloromethane. 4-heptafluoro-1-hydroxybutyl) phenyl] -17β-methoxy-17α
210 mg of-(methoxymethyl) -estra-4,9-dien-3-one, 0
A solution consisting of 920 mg of pyridine / SO3-complex in 0.48 ml of triethylamine and 4.2 ml of dimethylsulfoxide at 0 ° C. is added dropwise. This is allowed to warm to room temperature and post-react for at least a further 48 hours. PH at 0 ℃ in advance with concentrated hydrochloric acid
15 ml of an ammonium chloride aqueous solution adjusted to 4.5 is added little by little. After phase separation, the organic phase is washed with saturated sodium chloride solution and water, dried with sodium sulphate and concentrated under vacuum. 272 mg of a brown resin are obtained as a crude product, which is purified by preparative layer chromatography on silica gel 60 _{254 + 366 nm} . 11β- (4- (2,2,3,3,4,4,4-heptafluorobutan-1-one) -phenyl) -17β-methoxy-17α- (methoxymethyl) -estra-4,9-diene 59 mg of -3-one are isolated as colorless foam. ([Α _D ] = + 155 ° (CHCl ₃ ); ¹ H-NMR (300 MHz, CDC
l ₃ , δ in ppm with TMS as internal standard: 0.50 (s, 3H,
H-18), 3.25 and 3.41 (2s, 6H, 2 × OCH 3), 3.43
And 3.55 (2d, J = 10.6 Hz, 2H, OCH ₂ ), 4.45 (d,
J = 7.1 Hz, 1H, H-11), 5.80 (s, 1H, H-4), 7.38.
And 7.99 (2d, 4H, J = 8.1 Hz, CH-aromatic compound).

Example 5 4- [17β-Methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one-11β-yl] -phenyl-2,2,2-trifluoro-ethane- 1-one- (Z) -oxime 4- [3,3-ethylenedithio-17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-11β-yl] -phenyl-2,2,2 -Trifluoroethane-1-one- (Z) -oxime (3.49 g) in ethanol 150
Dissolve in ml and raise to 50 ° C. 15 ml of water and 3.49 g of silver nitrate
Is added, the mixture is stirred at 50 ° C. for 20 minutes, the mixture is allowed to cool and some ethanol is distilled off in vacuo. The residue is taken up in methylene chloride and water, the phases are separated and the organic phase is washed neutral with water. After drying with sodium sulfate, concentrate under vacuum. 2.58 g of crude product are obtained as a yellow foam,
This is flash chromatographed (methylene chloride / acetic acid ester 8: 1).
Purify on silica gel using. After recrystallization from diethyl ether / n-hexane, 4- [17β-methoxy-17α- (methoxymethyl) -estradi-4
2.1 g of 9,9-dien-3-one-11β-yl] phenyl-2,2,2-trifluoroethan-1-one- (Z) -oxime are isolated. _{Mp: 145~154 ℃, [α D]} : + 131 ° (CHCl 3); 1 H-NM
R (300 MHz, CDCl ₃ , δ in ppm relative to TMS as internal standard)
): 0.53 (s, 3H, H-18), 3.26, 3.41 (2s, each 3H, 2)
× OCH ₃ ), 3.43 to 3.60 (m, 2H, OCH ₂ ), 4.38 (d, J
= 6.6 Hz, 1H, H-11), 5.81 (s, 1H, H-4), 7.21,
7.40 (2d, 4H, J = 8.4 and 8.1 Hz, CH-aromatic compound),
10.34 (s, 1H, OH).

Preparation of Starting Compound 11β- [4- (2,2,2-Trifluoroacetyl) phenyl] -17β-
Dissolve 10.07 g of methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one in 103 ml of diethyl ether and add 0 under argon.
Cool to ° C. 103 ml of glacial acetic acid, 2.0 ml of ethanedithiol and 10.3 ml of boron trifluoride-ethyl ether acid are successively added. The mixture is left in the refrigerator at 0 ° C overnight. 100 ml each of water and methylene chloride are added, the phases are separated and the organic phase is neutralized with sodium hydrogen carbonate and water. After drying with sodium sulfate, the solution is concentrated by evaporation in a vacuum. 4- as a yellow form
(3,3-ethylenedithio-17β-methoxy-17α- (methoxymethyl)-
12.72 g (109% of theory) of estra-4,9-dien-11β-yl) phenyl-2,2,2-trifluoroethan-1-one are obtained. This crude product is used in the next reaction without purification. 4- [3,3-ethylenedithio-17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-11β-yl] phenyl-2,2,2-trifluoro-ethan-1-one 11 0.7 g was dissolved in 110 ml of pyridine,
Stir under argon. After the addition of 2.05 g of hydroxylammonium chloride, the solution is stirred at 60 ° C. for 3.5 hours. The reaction solution is cooled and ice water 2
． Stir into 5 l. After 1 hour, suction filter and post-wash with water. After drying in a stream of air, 4- (3,3-ethylenedithio-17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-11β-yl) phenyl-2,2.
, 2-trifluoro-ethan-1-one- (E / Z) -oxime ([α _D ]: +
A mixture consisting of 172 ° and CHCl ₃ (98% of theory) is obtained. The crude product was flash chromatographed (tert-butyl methyl ether / n-
Purify on silica gel with hexane 1: 3) and separate the isomers. acetone/
After recrystallization from n-hexane, 4- [3,3-ethylenedithio-17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-11β-yl] phenyl-2, respectively. 2,2-trifluoroethane-1-one- (E
) -Oxime [melting point: 209 to 212 ° C., [α _D ]: + 163 ° (CHCl ₃ ).
¹ H-NMR (300 MHz, CDCl ₃ , δ in ppm relative to TMS as internal standard): 0.48 (s, 3H, H-18), 3.26, 3.41 (2s
, 3H, 2 × OCH ₃ ), 3.22 to 3.57 (m, 6H, OCH ₂ , 2 × S)
CH ₂ ), 4.27 (d, J = 7.2 Hz, 1H, H-11), 5.62 (s,
1H, H-4), 7.33, 7.49 (2d, 4H, J = 8.4 and 8.1H
z, CH-aromatic compound), 8.61 (s, 1H, OH)] 1.81 g and 4
-[3,3-ethylenedithio-17β-methoxy-17α- (methoxymethyl)
-Estra-4,9-dien-11β-yl] phenyl-2,2,2-trifluoroethan-1-one- (Z) -oxime [melting point: 200 to 208 ° C, [α _D ]]
: + 195 ° (CHCl ₃ ); ¹ H-NMR (300 MHz, CDCl ₃ , δ in ppm relative to TMS as internal standard): 0.48 (s, 3H, H-18).
3.25, 3.41 (2s, 3H each, 2 × OCH ₃ ), 3.25 to 3.60 (
m, 6H, OCH ₂ , 2 × SCH ₂ ), 4.26 (d, J = 7.2 Hz, 1H,
H-11), 5.62 (s, 1H, H-4), 7.25, 7.39 (2d, 4H
, J = 8.4 and 7.5 Hz, CH-aromatic compound), 8.60 (s, 1H,
OH)] 3.64 g are obtained.

Example 6 4- [17β-Methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one-11β-yl] phenyl-2,2,2-trifluoro-ethane-1 -On- (E) -oxime 4- (3,3-ethylenedithio-17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-11β-yl) phenyl-2,2,2-tri 1.7 g of fluoro-ethane-1-one- (E) -oxime (see Example 4) are dissolved in 180 ml of ethanol at 50 ° C. 30 ml of water and 1.7 g of silver nitrate are added, the mixture is stirred for 20 minutes at 50 ° C., the mixture is cooled and some ethanol is distilled off in vacuo. The residue is taken up in methylene chloride and water, the phases are separated and the organic phase is washed neutral with water. After drying over sodium sulfate, concentrate in vacuo. 1.22 g are obtained as a yellow foam, which is purified using flash chromatography on silica gel (methylene chloride / acetic ester 8: 1). After recrystallization from tert-butyl methyl ether, 4- (17β
-Methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one-11β-yl) phenyl-2,2,2-trifluoro-ethan-1-one-
0.83 g of (E) -oxime is obtained. Melting point: 125-127 ° C., [α _D ] = + 115 ° (CHCl ₃ ); ¹ H-NM
R (300 MHz, CDCl ₃ , δ in ppm relative to TMS as internal standard)
): 0.54 (s, 3H, H-18), 3.28, 3.42 (2s, 3H, 2 each)
× OCH ₃ ), 3.44 to 3.58 (2d, 2H, OCH ₂ ), 4.41 (d,
J = 7.2 Hz, 1H, H-11), 5.82 (s, 1H, H-4), 7.29.
, 7.59 (2d, 4H, J = 8.7 and 8.4 Hz, CH-aromatic compound)
, 9.96 (s, 1H, OH).

Example 7 4- [17β-Methoxy-17α- (methoxymethyl) -3-oxo-oestra-4,9-dien-11β-yl] phenyl-2,2,2-trifluoro-ethane-1 -One- (E)-[N- (4-fluorophenylamino) carbonyl]-
Oxime 4- [17β-methoxy-17α- (methoxymethyl) -oestra-4,9-
411 mg of dien-3-one-11β-yl] phenyl-2,2,2-trifluoroethane-1-one- (E) -oxime are dissolved in 5 ml of toluene and 0.28 ml of 4-fluorophenylisocyanate is added. And raise the temperature to 55 ° C. The mixture is stirred at 55 ° C. for 6 hours, subsequently cooled to 10 ° C., 20 ml of an aqueous ammonia solution are added and after stirring for 30 minutes. After phase separation, the organic phase is washed with water until neutralized, dried with sodium sulphate and concentrated under vacuum. 527 mg of crude product are obtained as a brown foam, which is purified on silica gel using preparative layer chromatography. After subsequent recrystallisation from diethyl ether / n-hexane, 4- [17β-methoxy-17α- (methoxymethyl) -3-oxo-oestra-4,9-dien-11β-yl] phenyl-2.
225 mg of 2,2,2-trifluoroethane-1-one- (E)-(N- (4-fluorophenylamino) -carbonyl) -oxime are obtained. Melting point: 114 to 123 ° C., [α _D ] = + 103 ° (CHCl ₃ ); ¹ H-NM
R (300 MHz, CDCl ₃ , δ in ppm relative to TMS as internal standard)
): 0.53 (s, 3H, H-18), 3.26, 3.42 (2s, 3H, 2 each)
× OCH ₃ ), 3.43, 3.56 (2d, 2H, J = 10.5 Hz, OCH2
), 4.43 (d, J = 7.5 Hz, 1H, H-11), 5.80 (s, 1H,
H-4), 7.05 (t, 2H, J = 8.7 Hz, CH-aromatic compound), 7.
33 (2d, 2H, J = 6.9 Hz, CH-aromatic compound), 7.44 (m, 2
H, CH-aromatic compound), 7.54 (d, 2H, J = 7.8Hz, CH-aromatic compound), 8.03 (s, 1H, OH).

Example 8 4- [17β-methoxy-17α- (methoxymethyl) -3-oxaestra
4,9-Dien-11β-yl] phenyl-2,2,2-trifluoro-ethan-1-one- (Z)-[N- (4-fluorophenylamino) carbonyl] -oxime 4- [17β- Methoxy-17α- (methoxymethyl) -estra-4,9-
518 mg of dien-3-one-11β-yl] phenyl-2,2,2-trifluoro-ethan-1-one- (Z) -oxime was dissolved in 5 ml of toluene and 4-
0.58 ml of fluorophenyl isocyanate is added and the temperature is raised to 55 ° C. The mixture is stirred at 55 ° C. for 6 hours. Subsequently, it is cooled to 10 ° C., 40 ml of aqueous ammonia solution are added and after stirring for 30 minutes. After phase separation, the organic phase is washed with water until neutralized, dried with sodium sulphate and concentrated under vacuum. 660 mg of crude product are obtained as a foam, which is purified on silica gel using flash chromatography (tert-butyl methyl ether / n-hexane 1: 1). After subsequent recrystallization from tertiary butyl methyl ether / n-hexane, 4- [17β-methoxy-17α- (methoxymethyl) -3
-Oxaestra-4,9-dien-11β-yl] phenyl-2,2,2-trifluoroethan-1-one- (Z)-[N- (4-fluorophenylamino)
249 mg of carbonyl] -oxime are obtained. Melting point: 130 to 133 ° C., [α _D ] = + 150 ° (CHCl ₃ ); ¹ H-NM
R (300 MHz, CDCl ₃ , δ in ppm relative to TMS as internal standard)
): 0.53 (s, 3H, H-18), 3.26, 3.42 (2s, 3H, 2 each)
× OCH ₃ ), 3.43, 3.57 (2d, 2H, J = 10.5 Hz, OCH2
), 4.43 (d, J = 6.9 Hz, 1H, H-11), 5.80 (s, 1H,
H-4), 7.05 (m, 2H, CH-aromatic compound), 7.31 (d, 2H,
J = 8.4 Hz, CH-aromatic compound), 7.47 (m, 2H, CH-aromatic compound), 7.52 (d, 2H, J = 7.8 Hz, CH-aromatic compound), 7 .7
5 (s, 1H, NH).

Example 9 4- [17β-methoxy-17α- (methoxymethyl) -3-oxo estra-
4,9-Dien-11β-yl] phenyl-2,2,2-trifluoro-ethan-1-one- (Z)-[N- (ethylamino) carbonyl] -oxime 4- [17β-methoxy-17α -(Methoxymethyl) -oestra-4,9-
Dien-3-one-11β-yl] -2,2,2-fluoro-acetophenone-
414 mg of (Z) -oxime are dissolved in 10 ml of toluene and 1 ml of triethylamine and 0.4 ml of ethylisocyanate are added with stirring at room temperature.
After 48 hours at room temperature, it was cooled to 10 ° C., 10 ml of aqueous ammonia solution was added, and 1
After stirring for 5 minutes, 1 ml of ethanol is added, and the mixture is again stirred for 15 minutes. The phases are separated and washed until neutralized with 10% ammonium chloride solution and water. After drying with sodium sulfate, concentrate under vacuum. Crude product 54
6 mg are obtained as a foam, which is purified on silica gel using flash chromatography (tertiary butyl methyl ether / n-hexane 3: 1).
After recrystallisation from tert-butyl methyl ether / n-hexane, 4- [17β-
Methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] -2,2,2-trifluoroacetophenone- (1Z)-[N
280 mg of-(ethylamino) -carbonyl-oxime are obtained. Melting point: 66 to 78 ° C., [α _D ] = + 133 ° (CHCl ₃ ); ¹ H-NMR (
300 MHz, CDCl ₃ , δ in ppm relative to TMS as internal standard:
0.53 (s, 3H, H- 18), 1.23 (t, 3H, NCH 2 C H 3), 3
． 26, 3.41 (2s, 3H each, 2 × OCH ₃ ), 3.40 to 3.60 (m,
2H, OCH ₂ ), 3.75 (q, 2H, J = 2.5 and 4.7 Hz, CH ₂ CH ₃ ), 4.41 (d, J = 6.9 Hz, 1H, H-11), 5 0.78 (s,
1H, H-4), 5.82 (t, 1H, J = 6.0Hz, NH), 7.28, 7
． 47 (2d, 4H, J = 8.4 Hz, CH-aromatic compound).

Example 10 4- [17β-methoxy-17α- (methoxymethyl) -3-oxaestra
4,9-Dien-11β-yl] phenyl-2,2,2-trifluoroethane-
1-one- (Z)-(O-acetyl) oxime 4- [17β-methoxy-17α- (methoxymethyl) -oestra-4,9-
Dien-3-one-11β-yl] -2,2,2-trifluoroacetophenone- (1Z) -oxime 250 mg, pyridine 2.5 ml and acetic anhydride 2.5 ml.
Add a mixture consisting of and stir at room temperature. After 2 hours, the solution is poured into ice water. It is suction filtered, washed with water and dried. 4- [17β-
Methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] phenyl-2,2,2-trifluoroethan-1-one- (Z
236 mg of)-(O-acetyl) oxime are obtained. Melting point: 54-66 ° C. (amorphous product), [α _D ] = + 150 ° (CHCl ₃ ).
¹ H-NMR (300 MHz, CDCl ₃ , δ in ppm relative to TMS as internal standard): 0.52 (s, 3H, H-18), 2.28 (s, 3H, OC
OCH _3), 3.26,3.41 (2s, each _{3H, 2 × OCH 3),} 3.40,
3.58 (2d, 2H, J = 10.2 Hz, OCH ₂ ), 4.41 (d, J = 6
． 6 Hz, 1H, H-11), 5.80 (s, 1H, H-4), 7.28, 7.
52 (2d, 4H, J = 7.8Hz, CH-aromatic compound).

Example 11 4- [17β-methoxy-17α- (methoxymethyl) -3-oxaestra
4,9-Dien-11β-yl] -2,2,2-trifluoroacetophenone-
(1Z)-(O- (methoxy) carbonyl) -oxime 4- [17β-methoxy-17α- (methoxymethyl) -oestra-4,9-
300 mg of dien-3-one-11β-yl] -2,2,2-trifluoroacetophenone- (1Z) -oxime are dissolved in 6 ml of pyridine and 0.3 ml of chloroformic acid methyl ester are added under ice cooling. After 20 minutes, the solution is poured into ice water, the agglomerated material is suction filtered through a frit and washed with water. 4-
[17β-methoxy-17α- (methoxymethyl) -3-oxaestra-4,
9-Dien-11β-yl] -2,2,2-trifluoroacetophenone- (1
267 mg of Z)-[O- (methoxy) carbonyl] -oxime are obtained as an amorphous product. [Α _D ] = + 156 ° (CHCl ₃ ); ¹ H-NMR (300M
Hz, CDCl ₃ , δ) in ppm relative to TMS as internal standard: 0.52
(S, 3H, H-18 ₃ ), 3.25, 3.41 (2s, each 3H, 2 × OCH ₃ ), 3.41, 3.57 (2d, 2H, J = 10.2 Hz, OCH ₂ ) 3.9
8 (s, 3H, C = OOCH 3), 4.41 (d, J = 7.2Hz, 1H, H-
11), 5.79 (s, 1H, H-4), 7.29 (d, 2H, J = 9.0Hz).
, CH-aromatic compound), 7.52 (d, 2H, J = 7.5 Hz, CH-aromatic compound).

Example 12 4- [17β-methoxy-17α- (methoxymethyl) -3-oxo estra-
4,9-Dien-11β-yl] -2,2,2-trifluoroethane-1-one- (1Z)-[O- (ethylmercapto) carbonyl] oxime 4- [17β-methoxy-17α- (methoxy Methyl) -estra-4,9-
260 mg of dien-3-one-11β-yl] -2,2,2-trifluoroacetophenone- (1Z) -oxime are dissolved in 5 ml of pyridine and cooled to 0 ° C.
Under argon, add 0.1 ml chloroformic acid thiol ethyl ester. After 1 hour, the solution was poured into ice water, taken up in acetic ester and the organic phase separated,
Wash with dilute HCl and neutralize with H ₂ O. After drying over Na ₂ SO ₄ , it is concentrated under vacuum. The crude product is purified using preparative layer chromatography on silica gel 60PF _{254 + 366 nm} . 4- [17β-methoxy-17α- (
Methoxymethyl) -3-oxooestra-4,9-dien-11β-yl] -2
228 mg of 2,2,2-trifluoroethane-1-one- (Z)-[O- (ethylmercapto) carbonyl] oxime are obtained as a colorless foam. [Α _D ] = + 154 ° (CHCl ₃ ); ¹ H-NMR (300 MHz, CDC
l ₃ , δ in ppm relative to TMS as internal standard: 0.53 (s, 3H,
H-18), 1.38 (t , 3H, SCH 2 C H 3), 2.98 (q, 2H, J
= 7.5 and _{14.7Hz, SCH 2), 3.26,3.41 (} 2s, each 3H
, 2 × OCH ₃ ), 3.42, 3.56 (2d, 2H, J = 10.5 Hz, OC
H ₂ ), 3.75 (q, 2H, J = 2.5 and 4.7 Hz, CH ₂ CH ₃ ),
4.41 (d, J = 6.9 Hz, 1H, H-11), 5.79 (s, 1H, H-
4), 7.29, 7.53 (2d, 4H, J = 8.4Hz, CH-aromatic compound).

Example 13 11β- [4- (2,2,2-trifluoroacetyl) phenyl] -17β-hydroxy-17α- (methoxymethyl) -estradi-4,9-dien-3-one , Manufactured in accordance with Example 3. [Α _D ] = + 114 ° (CHCl ₃ ); ¹ H-NMR (300 MHz, CDC
l ₃ , δ in ppm with TMS as internal standard: 0.50 (s, 3H,
H-18), 3.42 (s , 3H, OCH 3), 3.43 and 3.55 (2d
, J = 10.6 Hz, 2H, OCH ₂ ), 4.44 (d, J = 7.1 Hz, 1H
, H-11), 5.80 (s, 1H, H-4), 7.39 and 8.01 (2d.
, 4H, CH-aromatic compound).

[0034] Example 14 11β-4- (2,2,2-trifluoroacetyl) phenyl] -17β-meth
Xy-17α- (methoxymethyl) -estra-4,9-dien-3-one- (
3E) -oxime and-(3Z) -oxime   11β- [4- (2,2,2-trifluoroacetyl) phenyl] -17β-
Methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one
Dissolve 538 mg in 5.5 ml pyridine and cool to about 0 ° C. under argon.
To do. After the addition of 74.5 mg of hydroxylammonium chloride, this solution is
Hold at 0 ° C. for 24 hours. This is stirred into 300 ml of ice water. One hour later
, Suction filtered and post-washed with water. After drying in a stream of air, the crude product E / Z-O
479 mg of chyme were obtained, which was subjected to flash chromatography (n-hex).
Purify on silica gel with sun / acetate 1: 1) and separate into isomers
It 11β- [4- (2,2,2-trifluoroacetyl) phenyl] -17β
-Methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-o
95 mg of N- (3Z) -oxime is in the form [[α_D]: + 160 ° C (CHCl ₃ )] And after recrystallization from diethyl ether / n-hexane
, 11β- [4- (2,2,2-trifluoro-acetyl) phenyl] -17β
-Methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-o
-(E) -oxime 134 mg [[α_D]: + 187 ° C. (CHCl₃)] Got
To be

Example 15 11β- [4- (2,2,2-Trifluoro-1-hydroxyethyl) phenyl] -17β-methoxy-17α- (methoxymethyl) -oestra-4,9-diene-3- On The target compound is prepared analogously to Example 1 from 4- [17β-hydroxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehyde. [Α _D ] = + 107 ° (CHCl ₃ ); ¹ H-NMR (300 MHz, CDC
l ₃ , δ in ppm with TMS as internal standard: 0.49 (s, 3H,
H-18), 2.69 (s , 1H, OH), 3.41 (s, 3H, OCH 3),
3.20 and 3.55 (2d, J = 9.9Hz, 2H, OCH 2), 4.38
(D, J = 6.6 Hz, 1H, H-11), 4.99 (m, 1H, CH-OH)
5.77 (s, 1H, H-4), 7.21 and 7.38 (2d, 4H, J =
8.1 Hz, CH-aromatic compound).

[0036] Example 16 4- [17β-methoxy-17α- (methoxymethyl) -estra-4,9-di
Ene- (3Z) -hydroxymino-11β-yl] phenyl-2,2,2-tri
Fluoroethan-1-one- (Z) -oxime   11β- [4- (2,2,2-trifluoroacetyl) phenyl] -17β-
Methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one
1.04 g are dissolved in 15 ml pyridine. Hydroxylammonium chloride
After the addition of 578 mg of sodium chloride, the solution is stirred for 2 hours at 60 ° C. under argon protection.
It This is stirred into 400 ml of ice water. Suction filtered after 1 hour and washed with water
To wash. The crude product of the E / Z-oxime mixture after drying in a stream of air 1.1
8 g was obtained, which was subjected to preparative layer chromatography on silica gel 60PF. _{254 + 366nm} Purify with and separate into isomers. Diethyl ether / n-hexane
Was recrystallized from 4- [17β-methoxy-17α- (methoxymethyl)
-Estra-4,9-diene- (3Z) -hydroxymino-11β-yl] phen
Nyl-2,2,2-trifluoroethane-1-one- (1Z) -oxime 160
yields mg.   Melting point: 154-156 ° C (diethyl ether / n-hexane), [α_D]: +
128 ° (CHCl₃),¹H-NMR (300 MHz, CDCl₃, Internal standard
Δ in ppm using TMS as: 0.50 (s, 3H, H-18), 3
． 26 (s, 3H, OCH₃) 3.42 (s, 3H, OCH₃) 3.4 and
And 3.59 (2d, J = 10.8Hz, 2H, OCH₂), 4.31 (d, J =
6.6 Hz, 1H, H-11), 6.51 (s, 1H, H-4), 7.20 (d
, 2H, J = 8.1 Hz, CH-aromatic compound), 7.24 (s, 1H, OH)
, 7.35 (d, 2H, 7.8 Hz, CH-aromatic compound), 7.42 (d, 1
H, 7.8 Hz, OH).

Example 17 4- [17β-Methoxy-17α- (methoxymethyl) -estra-4,9-diene- (3E) -hydroxymino-11β-yl] phenyl-2,2,2-trifluoroethane -1-On- (1Z) -oxime The target compound was prepared according to Example 16 by using 11β- [4- (2,2,2-trifluoroacetyl) -phenyl] -17β-methoxy-17α- (methoxymethyl). −
Prepared from estra-4,9-dien-3-one and purified using chromatography. Melting point: 171-178 ° C (diethyl ether / n-hexane), [α _D ]: +
164 ° (CHCl ₃ ), ¹ H-NMR (300 MHz, CDCl ₃ , δ in ppm with TMS as internal standard): 0.50 (s, 3H, H-18), 3
． 26 (s, 3H, OCH ₃ ), 3.41 (s, 3H, OCH ₃ ), 3.41 (
s, 3H, OCH ₃ ) 3.4 and 3.59 (2d, J = 10.6 Hz, 2H
, OCH ₂ ), 4.32 (d, J = 7.1 Hz, 1H, H-11), 5.89 (
s, 1H, H-4), 7.22 (2d, 4H, J = 7.8Hz, CH-aromatic compound), 7.35 (s, 1H, OH), 7.38 (d, 2H, J). = 7.8 Hz,
CH-aromatic compound) 7.45 (d, 1H, J = 7.5 Hz, OH).

[0038] Example 18 11β- {4- [2,2,2-trifluoro-1-hydroxy-1- (triflu
Oromethyl) ethyl] phenyl} -17β-methoxy-17α- (methoxymethyl)
) -Estra-4,9-dien-3-one   6126? ? ? Suspend 775 mg in 70 ml of ethanol and raise the temperature to 50 ° C.
And dissolve. 6 ml of water and 609 mg of silver nitrate were added and this mixture was added.
Was stirred at 50 ° C. for 20 minutes, the mixture was cooled and some ethanol was distilled under vacuum.
Leave. The residue is taken up in methylene chloride and water, the phases are separated and
The organic phase is washed with water until neutralized. After drying with sodium sulfate, the true
Evaporate and concentrate in the air. 902 mg of crude product are obtained as a brown foam, which
Use this with flash chromatography (n-hexane / acetic acid ester 2: 1)
And purify with silica gel. From methyl-tert-butyl ether / n-hexane
After recrystallization, 11β- {4- [2,2,2-trifluoro-1-hydroxy-
1- (trifluoromethyl) ethyl] phenyl} -17β-methoxy-17α-
154 mg of (methoxymethyl) -estra-4,9-dien-3-one were obtained.
It   Melting point: 195 to 200 ° C. (tertiary butyl methyl ether / n-hexane), [α _D ]: + 84 ° (CHCl₃),¹H-NMR (300 MHz, CDCl₃Within
Δ in ppm using TMS as part standard: 0.49 (s, 3H, H-18
) 3.25 and 3.41 (2s, 6H, 2xOCH₃) 3.41 and 3
． 57 (2d, J = 10.7Hz, 2H, OCH₂), 4.41 (d, J = 6.
7 Hz, 1H, H-11), 4.45 (s, 1H, OH), 5.79 (s, 1H)
, H-4), 7.27 and 7.62 (2d, J = 8.2 Hz, 4H, CH-yoshi.
Aromatic compounds).

Preparation of Starting Compound 4- [3,3-Ethylenedithio-17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-11β-yl] phenyl-2,2,2-trifluoro Ethan-1-one 11β- (4-2,2,2-trifluoroacetyl) phenyl] -17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one 1
0.07 g is dissolved in 103 ml of diethyl ether and 0 under argon.
Cool to ° C. 103 ml of glacial acetic acid, 2.0 ml of ethanedithiol and 10.3 ml of boron trifluoride-ethyl ether acid are successively added. The mixture is left in the refrigerator at 0 ° C. overnight, 100 ml each of water and methylene chloride are added, the phases are separated and the organic phase is washed until neutralized with sodium hydrogen carbonate and water. After drying with sodium sulfate, the solution is concentrated in vacuo. 4- [3,3-ethylenedithio-17β-methoxy-17α- (methoxymethyl) -estra-4,
9-Dien-11β-yl] phenyl-2,2,2-trifluoroethane-1-
12.72 g of on are obtained as a yellow foam (109% of theory). This crude product is used in the next step without purification. 4- [3,3-ethylenedithio-17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-11β-yl] phenyl-2,2,2-trifluoroethan-1-one (578 mg) Dissolve in 15 ml of anhydrous tetrahydrofuran under argon, add 0.5 g of molecular sieves (ground 3Å) and stir for 30 minutes at room temperature. Subsequently, it is cooled to 0 ° C. 0.75 ml trifluoromethyltrimethylsilane are added and the mixture is post-stirred for 10 minutes. Then, to this suspension was added tetramethylammonium fluoride-tetrahydrate 26 m.
g and post-stir at room temperature for 2 hours. The molecular sieve is suction filtered through a frit, post-washed with tetrahydrofuran and 7 ml of 1N hydrochloric acid are added. After 24 hours, water and acetate are added, the phases are separated and the organic phase is washed with sodium hydrogen carbonate solution and water until neutralized. After drying with sodium sulfate, the solution is concentrated under vacuum. 4- [3,3-ethylenedithio-17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-11β-yl] phenyl-2,2,2-trifluoroethane-1- (trifluoro 821 mg of methyl) -1-ol are obtained as yellow crystals, which are purified by recrystallization from acetone and used directly for the thioketal separation.

Example 19 Determination of Receptor-Binding Affinity Receptor-binding affinity is specifically bound by ³ H-marked hormones (tracers) and compounds to be tested in cytosol from target organs of animals. Was measured by competitive binding with the receptor. In this case, the aim was for receptor saturation and reaction equilibrium. The following culture conditions were selected: Progesterone-Receptor: Urine rabbit-cytosol stored at -30 ° C and sensitized with estradiol. Buffer for homogenization and culture: 25
TED-buffer containing 0 mM saccharose (20 mM Tris / HCl, pH =
7.4; 1 mM ethylenediamine tetraacetate, 2 mM dithiothreitol). Tracer: ³ H-ORG 2058, 5 nM: Reference substance: progesterone. Glucocorticoid-receptor: Adrenalectomized rat thymus-cytosol. Thymus stored at -30 ° C. Buffer: TED-buffer, tracer: ³ H-dexamethasone, 20 nM. Reference substance: dexamethasone. Receptor fraction, tracer and competitor (Competitor) at 0-4 ℃ 1
After culturing for 8 hours, separation of bound and free steroids was determined by activated charcoal / dextran (1% / 0.1%) contamination, centrifugation and measurement of receptor bound ³ H-activity in the supernatant. I did. The IC ₅₀ for the reference substance and the compound to be tested was determined by measuring a series of concentrations, and the quotient of both values (× 100%) was used to determine the relative molar binding affinity (R
BA).

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 15/00 A61P 15/00 15/14 15/14 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ , BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR , KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Kaufmann Günter Germany Jena 07743 Silbach Schutrase 41 F Term ( Reference) 4C086 AA02 AA03 DA09 MA02 MA05 NA14 ZA81 ZC02 ZC03 4C091 AA01 BB05 BB09 CC01 DD01 EE07 EE10 FF01 GG01 HH01 JJ01 KK05 LL01 MM01 NN01 PA03 PA05 PA09 PB01 PB02 QQ01 RR09

Claims (13)

[Claims] 1.   General formula (I):   [Chemical 1] [In the formula, R₁Is C₁~ C₆An alkyl group, R₂Is a hydrogen atom, C₁~ C ₆ -Alkyl group or C₁~ C₆An acyl group, X is a hydroxyl group or
Represents a trimethylsiloxy group, Y represents a hydrogen atom or a general formula: C_nF_{2n + 1}so
Represents a perfluoroalkyl group as shown, or X and Y are taken together
Oxo group or oxyimino group NOR₃Represents a hydrogen atom, C₁~ C ₆ -Alkyl group or substituted methylene group CH₂W (where W is hydro
Xyl group, C₁~ C₆-Alkoxy group, C₁~ C₆-Alkylthio group, halogen
Atom or pseudohalogen),   A is an oxo group, an oximino group NOR₃, 1,3-dithian group or 1,3
Represents a dithiolane group,   In this case, R₃Is a hydrogen atom, C₁~ C₈-Alkyl group, aryl group, alk
Ruaryl group or arylalkyl group, C₁~ C₈-Acyl group, group: CONH
R_Four, COSR_FourOr COOR_FourRepresents,   In this case, R_FourIs a hydrogen atom or C₁~ C₈-Alkyl group, aryl group,
Represents an aralkyl group or an alkylaryl group, and n is an integer of 1 to 4] Having a fluoroalkyl group in the aromatic side chain represented by
Radiene derivatives and their pharmaceutically acceptable salts. 2. The group according to claim ₁ , wherein the group of the general formula: C _n F _{2n + 1} is a trifluoromethyl group, a pentafluoroethyl group or a heptafluoropropyl group.
1β-phenylestradiene derivative. 3. The 11β- according to claim 1 or 2, wherein X represents a hydroxyl group and Y represents a hydrogen atom or a trifluoromethyl group, a pentafluoromethyl group or a heptafluoropropyl group. Phenyl estradiene derivative. 4. X and Y together form an oxo group or group: NOR ₃ , wherein R ₃ is a hydrogen atom, a methyl group, an ethyl group, a phenyl group, a tolyl group, a benzyl group, A formyl group, an acetyl group or a group: CONHR ₄ , COSR ₄ or COOR ₄ , wherein R ₄ is a methyl group, an ethyl group, a phenyl group, a 4-fluorophenyl group, a trifluoromethylphenyl group or a trifluoromethoxy group. The 11β-phenylestradiene derivative according to any one of claims 1 to 3, which represents a methyl group, a trifluoromethoxyphenyl group, a benzyl group or a tolyl group. 5. A represents a group: NOR ₃ , in which R ₃ is a hydrogen atom, a methyl group, an ethyl group, a phenyl group, a tolyl group, a benzyl group, a formyl group or an acetyl group, or a group: CONHR ₄ , COSR ₄ or COOR _{4 in} which R ₄ represents a methyl group or an ethyl group, a phenyl group, a 4-fluorophenyl group, a benzyl group or a tolyl group. 11. The 11β-phenylestradiene derivative according to any one of 1. 6. R ₁ represents a methyl group or an ethyl group, characterized in that
11. The 11β-phenylestradiene derivative according to any one of items 1 to 8 above. 7. The 11β-phenylestradiene derivative according to claim 1, wherein R ₂ represents a hydrogen atom or a methyl group or an ethyl group. 8. Z is a substituted methylene group: CH ₂ W, wherein W is hydroxyl group, methoxy group, ethoxy group, methylthio group, ethylthio group, fluorine atom, chlorine atom, bromine atom or The 11β-phenylestradiene derivative according to any one of claims 1 to 7, which represents an iodine atom or a cyanide group or a thiocyanide group. 9. 1) 11β- [4- (2,2,2-trifluoro-1-hydroxyethyl) phenyl] -17β-methoxy-17α- (methoxymethyl) estra-4,9-diene-3- On, 2) 11β- [4- (2,2,3,3,3-pentafluoro-1-hydroxypropyl) phenyl] -17β-methoxy-17α- (methoxymethyl) -estra-4,9-diene- 3-one, 3) 11β- [4- (2,2,3,3,4,4,4-heptafluoro-1-hydroxybutyl) phenyl] -17β-methoxy-17α- (methoxymethyl)-
Estra-4,9-dien-3-one, 4) 11β- {4- [2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl] phenyl} -17β-methoxy-17α -(Methoxymethyl) -estra-4,9-dien-3-one, 5) 11β- [4- (2,2,2-trifluoroacetyl) phenyl] -17β
-Methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one, 6) 11β- [4- (2,2,2-trifluoroacetyl) phenyl] -17β
-Hydroxy-17α- (methoxymethyl) -oestra-4,9-diene-3-
On, 7) 11β- [4- (2,2,3,3,3-pentafluoro-propan-1-one) phenyl] -17β-methoxy-17α- (methoxymethyl) -estradi-
4,9-Dien-3-one, 8) 11β- [4- (2,2,3,3,4,4,4-heptafluoro-butane-
1-one) phenyl] -17β-methoxy-17α- (methoxymethyl) -estra-4,9-dien-3-one, 9) 11β- [4- (17β-methoxy-17α- (methoxymethyl) -3. -Oxoestra-4,9-dien-11β-yl) phenyl] -2,2,2-trifluoroethan-1-one- (E) -oxime, 10) 11β- [4- (17β-methoxy-17α) -(Methoxymethyl) -3-
Oxoestra-4,9-dien-11β-yl) phenyl] -2,2,2-trifluoroethan-1-one- (Z) -oxime, 11) 4- [3,3-ethylenedithio-17β- Methoxy-17α- (methoxymethyl) -oestra-4,9-dien-11β-yl] phenyl-2,2,2-
Trifluoroethane-1-one- (E / Z) -oxime, 12) 11β- [4- (2,2,2-trifluoroacetyl) phenyl] -17
β-methoxy-17α- (methoxymethyl) -estra-4,9-diene- (3
E) -oxime, 13) 11β- [4- (2,2,2-trifluoroacetyl) phenyl] -17
β-methoxy-17α- (methoxymethyl) -estra-4,9-diene- (3
Z) -oxime, 14) 4-{[17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] phenyl} -2,2,2-trifluoroethane- On- (1Z)-[O- (N-4-fluorophenylamino) carbonyl] oxime, 15) 4-{[17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-diene- 11β-yl] phenyl} -2,2,2-trifluoroethane-one- (1E)-[O- (N-4-fluorophenylamino) carbonyl] oxime, 16) 4-{[17β-methoxy-17α. -(Methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] phenyl} -2,2,2-trifluoroethan-1-one- (Z)-[O- (N-ethyl Mino) carbonyl] oxime, 17) 4-{[17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] phenyl} -2,2,2-trifluoroethane -1-one (Z)-(O-acetyl) oxime, 18) 4-{[17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] phenyl}- 2,2,2-trifluoroethan-1-one (Z)-[O- (S-ethylthio) carbonyl] oxime,
19) 4-{[17β-methoxy-17α- (methoxymethyl) -estradi-4
, 9-Diene- (3Z) -oxime-11β-yl] -2,2,2-trifluoroacetophenone- (1Z) -oxime or 20) 4-{[17β-methoxy-17α- (methoxymethyl) -estra -4
, 9-Diene- (3E) -oxime-11β-yl] -2,2,2-trifluoroacetophenone- (1Z) -oxime, 11β-phenylestradiene according to claim 1. Derivative. 10. A method for producing an 11β-phenylestradiene derivative according to any one of claims 1 to 9, wherein the fluoroalkyl silyl ether of formula (IIIa) is hydrolyzed. Secondary alcohol of: And oxidize it to give formula (IV): To a 11β-fluoroalkyl phenyl ketone, which is optionally reacted with C-3 with hydroxylamine or ethanedithiol to give a derivative, and / or another oxo group of said compound in the free oxime or substitution To the oxime, and optionally the 11β-phenylestradiene derivative of formula (I) converted to a pharmaceutically acceptable salt, in which case R ₁ , R ₂ , A, n
, Y and Z have the meaning given in claim 1.
10. A method for producing the 11β-phenylestradiene derivative according to any one of 1 to 9. 11. Containing at least one 11β-phenylestradiene derivative according to any one of claims 1 to 9 optionally together with pharmaceutically acceptable auxiliaries and support materials. A pharmaceutical composition comprising: 12. An 11β-phenylestradiene derivative according to any one of claims 1 to 9 for use as a therapeutic agent. 13. Treatment of diseases stimulated by cortisol or corticoid, reduction of secreted cortisol, stimulation of milk secretion, treatment of dysmenorrhea and myoma, treatment of Cushing's disease and cervical maturation, improvement of cognitive ability. 1 according to any one of claims 1 to 9 for the treatment of endometriosis or hormone replacement therapy (HRT).
Use of a 1β-phenylestradiene derivative or a mixture of said 11β-phenylestradiene derivatives.