FI112948B - Process for the Preparation of Drug Usable 11beta-benzaldoxime-17beta-methoxy-17alpha-methoxymethyl-estra-4,9-diene derivative - Google Patents

Abstract

11-Benzaldoxime-oestradiene derivatives of the general formula I <IMAGE> and their pharmaceutically acceptable salts, a process for their preparation and pharmaceutical compositions containing them are described. The described compounds display potent antigestagenic effects with lower glucocorticoid activity.

Description

112948

A process for the preparation of 11 β-benzaldoxime-1β-methoxy-14a-methoxymethyl-estra-4,9-diene derivatives useful as a medicament

The invention relates to a process for the preparation of new 11β-3-benzaldoxime-cstra-4,9-diene-derivatives-5.

Β-substituted phenyl estratrienes are already known. The preparation of 11 β-aryl-17α-propynyl-estra-4,9-dienes has already been described, for example, in EP 057115 and 11 in the reaction of β- (4-formylphenyl) -estra-4,9-dien-3-ones with hydrocarbons. DE 3 504 421. In the process described 10, both the 11 β-formylphenyl group and also the 3-keto group are oxidized. In addition, syn and anti isomers are formed in C-3. The effect of the compounds described is not yet known.

Progesterone is excreted extensively from the ovaries and placenta during menstruation and pregnancy. Its regulatory importance is not expected to be fully explained.

It is certain that progesterone, together with estrogens, contributes to the rhythmic changes of the endometrium during menstruation and pregnancy. As a result of increased progesterone levels, after ovulation, the endometrium changes to allow the embryo (blastocyst) to attach to the uterine wall. Progesterone also depends on the survival of the tissues in which the growing embryo develops.

There is a dramatic change in uterine muscle function during pregnancy. Gravidi's uterine muscle responds very poorly or not at all to the hormonal and mechanical stimuli that cause pain without pregnancy. There is no doubt that progesterone plays a key role here, albeit in many stages of pregnancy, for example immediately before delivery, with a good response, with extremely high blood progesterone levels.

Further, pregnancy is also characterized by very high levels of progesterone. The structure of the mammary gland and the closure of the uterus until the time of birth is closer to 30 are examples.

Progesterone is a great contributor to ovulation control. Progesterone is known to have antiovulatory properties at high doses. These are the result of inhibition of gonadotropin secretion by the brain 2 112948, a prerequisite for follicular maturation and ovulation. On the other hand, it is noticeable that the relatively low progesterone secretion in the mature follicle plays an active role in the preparation and induction of ovulation. Here, pituitary mechanisms (a time-limited so-called positive feedback effect of pro-5 gesterone on gonadotropin secretion) are of great importance (Loutradie, D .; Human Reproduction 6. 1991, 1238-1240).

Instead, less analysis has been made of the functions of progesterone in the mature follicle and in the corpus luteum itself, the existence of which is beyond doubt. Finally, the stimulatory and inhibitory effects on endocrine follicle and coronary function must also be recognized here.

Progesterone and progesterone receptors also play an important role in pathophysiological processes. Progesterone receptors can be detected in endometriosis colonies, but also in tumor cells of the uterus, mammary gland, and central nervous system (meningeal tumor). The importance of these receptors in the growth of the latter pathologically relevant tissues is not necessarily related to blood progesterone levels. Substances characterized as progesterone antagonists RU 486 = Mifepriston (EP-0 057 115) and ZK 98299 = Onapriston (DE-OS-35 04 421) have been shown to produce marked changes in function in these tissues, Cloning concentration is observed to be very low. It seems possible that when progesterone is not bound to the progesterone receptor by antagonists, so; changes in the transcriptional effects of the progesterone receptor are of great importance (Chwvalisz, K. et al., Endocrinology, 129, 317-322, 1991).

• ': Effects of progesterone on genital and other organ tissues interact with the progesterone receptor. Progesterone binds to the cell:. with high affinity for its receptor. This causes changes in the receptor protein, conformational changes, dimerization of the 2 receptor units into the complex, exposing the receptor binding site of the receptor upon protein break (HSP 90), binding to the hormone-responsive (hormone responsive) portions of the DNA. Finally, a certain-; The transcription of the genes of the 30 j is tightly regulated. (Gronemeyer, H. et al., J. Steroid.

:: Biochem. Molec. Biol. 41, 3-8, 1992).

The effect of progesterone or progesterone antagonists is not only dependent on \! their concentration in the blood. The concentration of receptors in the cell is likewise accurate: '; not regulated. Estrogens stimulate the synthesis of progesterone receptors in most tissues. Progesterone inhibits the synthesis of estrogen receptors and its own receptor 112948. Presumably, these and other interactions between estrogens and gestagens may explain why gestagens and antigestagens may influence estrogen-dependent events without binding to the estrogen receptor itself. These relationships are of course of great importance for the therapeutic use of antigestagens. These agents appear to be capable of deliberately influencing female reproductive events, e.g., after ovulation, to prevent the fertilized egg from attaching to the uterine mucosa, to increase uterine contractility for prostaglandins and oxytocin in late pregnancy, or to open and soften ("cook").

Antigestagens inhibit ovulation in various non-human primates. This mechanism of action has not been explicitly explained. In addition to inhibition of gonadotropin secretion, ovarian mechanisms that interfere with para and autocrine functions of progesterone in the ovaries are also discussed.

Antigestagens have the ability to alter or attenuate the effects of estrogens, although they themselves do not have any affinity for the estrogen receptor at the cytoplasmic level and although they may cause an increase in estrogen receptor concentration. It is expected that similar properties may obtain a beneficial effect in endometriosis colonies or tumor tissues with estrogen and progesterone receptors. Particular advantages are expected for a beneficial effect on diseases such as endometriosis when the anti-gestagenic inhibitory effects are achieved by inhibiting ovulation in the tissues. In addition to suppressing ovulation, some of the ovarian hormone would also be missed; ' stimulation of the production and thus also of this pathologically altered tissue. In the case of severe endometriosis, it would be possible to: 25 prevent ovulation and otherwise permanently surround the genital tissues! Sleep mode.

Also, in the context of contraception, a method whereby antigen antigen treatment, eh-, ovulation is followed, and subsequent gestagen treatment causes secretory transformation of the endometrium, resulting in 28 days of antigen and gestagen treatment days and no treatment days: menstrual cycle with regular menstrual bleeding (Baulieu, EE, Ad- vances in Contraception 7, 345-1991).

, '· Antigestagens may have different hormonal and anti-hormonal properties. : mouths. The antiglucocorticoid properties are of particular therapeutic significance. These are detrimental to therapeutic use, where inhibition of the progesterone receptor 112948 4 is most important in therapy because it produces unwanted side effects at therapeutically required doses, prevents the use of a therapeutically significant dose, or may lead to treatment interruption. Partial or complete reduction of the properties of antiglucocorticoids is a prerequisite for treatment with an-5 tigestagen, particularly in indications requiring weeks or months of treatment.

It is an object of the present invention to provide a process for the preparation of novel lipobenzaldoxime ester-4,9-diene derivatives of general formula I for use in pharmaceutical compositions having antigenic activity and low glucocorticoid activity.

NOZ

0CH3. / JUch2-o-ch3 ^ 1 ^ 1 (i)

In the general formula I

NOZ

: OCH 3 - (CH 2) -CH 2 - (I): Z is -CO-CH 3, -CO-O-C 2 H 5, -CO-NH-phenyl, -CO-NH-C 2 H 5, -CO-C 2 H 5, -CH 3. or -CO-phenyl.

112948 5

Preferred compounds of the invention include: 11β- [4- (acetoxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4.9-dien-3-one, 11β- {4 - [(ethoxycarbonyl) oxy] iminomethyl] phenyl} -17β-methoxy-17α-methoxy-5-methyl-estra-4,9-dien-3-one, 11β- {4 - [(ethylaminocarbonyl) oxyiminomethyl] phenyl} -17β-methoxy-17α -methoxymethyl-estra-4,9-dien-3-one, 17β-methoxy-17α-methoxymethyl-11β- {4 - [(phenylaminocarbonyl) oximino-methyl] phenyl} -estra-4, 9-dien-3-one, 10β- [4- (propionyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one, 11β- [4- ( methyloxyiminomethyl) phenyl] -173-methoxy-17α-methoxymethyl-estra-4.9-dien-3-one and 1β- [4- (benzoyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-15-estra-4 , 9-dien-3-one.

The process according to the invention is characterized in that the compound of the general formula II

NOH

: CH ’(CH3 (II)) is esterified or etherified with acylating agents.

The preparation of the compounds of general formula I by esterification, etherification or formation of methane can be carried out in a manner known per se with acylating agents such as acid anhydrides or acid chlorides in the presence of bases, preferably pyridine, with methyl iodide-bases or diazomethane in methanol and formation of the urethane by reaction with alkyl or aryl isocyanates in inert solvents, preferably toluene, or by reaction with carbamoyl chlorides in the presence of bases, preferably triethylamine.

The starting compound of general formula II is prepared from 5a, 10a-epoxide III

o ΗΛ I _ (III) h3co ^ ^ '° h3co ^ N / [compare e.g. Nedelec Bull. Soc. chim. France (1970), 2548],

The coupling of the phenyl group to the Ιΐβ position of A9 (10), 5a-hydroxy structure IV form 10 is achieved by a Cu (I) salt catalyzed Grignard reaction (Tetrahedron Letters 1979, 2051) with p-bromobenzaldehyde ketal, preferably p-bromobenzaldehyde dimethyl Between 30 ° C and 30 ° C.

OCH 3

h3co ^ I

- (IV} h3co ^ '' ·: h3co ^ '...' '): The coupling of the -CH2-O-CH3 moiety to the 17-position is carried out according to a method known per se through spiroepoxide V by reaction with trimethylsulfone. with sodium iodide and potassium tert-butanolate in dimethyl sulfoxide [Hubner et al.

Oh.; J. Pract. Chem. 314, 667 (1972); Arzneim. Forsch. 30, 401 (1973) and 7112948-0CH3 H3CO3 (V).

H3C ° J

h3co ^

OH

followed by opening the ring with alcoholates [Ponsold et. Oh.; Z. Chem. 11, 106 (1971)]. 17a-CH2-O-CH3 compounds VI are formed

OCH 3

h3co ^ I

^ J ^ ch2-o-ch3 ^ _ (VI)

h3co ^ I

H3CO ^ 1 * i

OH

5 may be cleaved either by acidic hydrolysis, preferably p-toluenesulfonic acid in acetone (Teutsch et al. DE 2801416), to the corresponding aldehydes or; After the free hydroxyl groups have been etherified with alkyl halides in the presence of potassium tert-butanolate, they can first be converted to 5a, 17β-diethers (Kasch et al. DD 290 893), which can then be converted by acid hydrolysis, preferably p-toluenesulfonic acid in acetone to give the corresponding aldehydes, then the resulting aldehydes are then converted to the compounds of general formula II with anhydrous thallareactive hydroxylamine.

:: A compound of the general formula I prepared by the process of the invention. *. ; optionally converted into an acid addition salt, preferably a salt of the * 1: 15 physiologically usable acid. Conventional physiologically usable inorganic and organic acids include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, 1129488 oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicic acid. Other useful acids are described, for example, in Fortschritte der Arzneimittel-Forschung, Bd. 10, pages 224-225, Birkhäuser Verlag, Basel und Stuttgart, 1966 and 5 Journal of Pharmaceutical Sciences, Bd. 66, pages 1-5 (1977).

Acid addition salts are generally obtained in a manner known per se by mixing the corresponding acid or solutions thereof in an organic solvent, such as a lower alcohol such as methanol, ethanol, n-propanol or isopropanol or a lower ketone such as acetone, methyl 10 an ether such as diethyl ether, tetrahydrofuran or dioxane. Mixtures of the said solvents may also be used to better distinguish the crystals. In addition, physiologically acceptable aqueous solutions of the acid addition salts of a compound of formula I can be prepared.

The acid addition salts of the compounds of general formula I may be converted into the free base in a manner known per se, for example by alkali or ion exchangers. Other salts may be obtained from the free base by reaction with inorganic or organic acids, in particular those suitable for the formation of therapeutically useful salts. These or other salts of the new compound, such as a picrate, may also be used to purify the free base by converting the free base into a salt, separating it and salting it; it is obtained again as a base.

The compounds of the present invention can be used for • · drug substances intended for oral, rectal transit! 25 injected into a subcutaneous tissue, intravenous or intramuscular injection containing; in addition to conventional carriers and diluents, the active ingredient is a compound of general formula I or an acid addition salt thereof.

•: - Such drugs are prepared in a known manner in conventional, solid or. ·. liquid carriers or diluents, and pharmaceutical excipients commonly used, for the desired mode of administration; · 'When appropriate. Preferred formulations consist of a dosage form suitable for oral use. Such administration forms include, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions, or depot forms.

112948 9

Of course, parenteral formulations such as injection solutions are also contemplated. Further, suppositories may also be mentioned as preparations.

Similar tablets may be obtained, for example, by admixing the active ingredient with excipients known in the art, for example, inert diluents such as dextrose, so-5, sorbitol, mannitol, polyvinylpyrrolidone, disintegrating agents such as corn starch or algrinic acid, binders such as starch, magnesium stearate or talc and / or agents for depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also consist of several layers.

Correspondingly, the drug granules may be prepared by coating the core parts prepared according to the tablets with substances commonly used in the coating of the drug granules, for example polyvinylpyrrolidone or shellac, acacia, talc, titanium dioxide or sugar. In this case, the shell of the drug granule may also consist of multiple layers, whereby the excipients mentioned above for tablets may be used.

The solutions or suspensions containing the active ingredient prepared by the process of the invention may additionally contain flavoring agents such as saccharin, cyclamate or sugar as well as, for example, flavoring agents such as vanillin or orange extract. In addition, they may contain suspending excipients such as sodium kar-boxoxymethylcellulose or preservatives such as p-hydroxybenzoates. Capsules containing the active ingredients may be prepared, for example, by mixing the active ingredient with an inert carrier such as milk sugar or sorbitol and sealing them in gelatin capsules.

Suitable suppositories may be prepared, for example, by mixing carriers suitable for the active ingredient, such as neutral fats or polyethylene glycol or derivatives thereof.

The β-substituted benzaldoxime-estra-4,9-dienes produced by the process of the invention are antigenically active agents which are clearly detectable in vivo when compared to RU 486; Reduced anti-glucocorticoid activity, which can be demonstrated by decreased: glucocorticoid receptor binding (see Table 1).

ίο 112948

table 1

Receptor binding of selected substances shown in Examples 1 and 2

Relative molar binding affinity (RBA) [%] to glucocorticoid receptor (Dexamethasone = 100%) 1 (J914) __ 73_ 2 (J900) __ 66_ according to the following example

Comparison RU 486 (Mifepristone) __ 685_ ZK 98299 (Onapristone) __ 39_

It is expected that the antigestagens-5 produced by the method of the invention will cause this combination of properties to inhibit progesterone by suppressing the antiglucocorticoid activity at the same time. This benefit is particularly relevant in indications that require particularly good tolerability due to the duration of treatment. During the menstrual cycle, circulating estrogens play a crucial role in uterine weight. Loss of uterine weight indicates the inhibition of this function by estrogens. The observed superior inhibition of the effect of uterine weight over RU 486 on guinea pig cycling suggests (indirect) anti-estrogenic properties of the compounds of the invention. Of similar properties, a particularly favorable effect on pathologically altered tissues in which estrogens are depleted can be expected; 15 are associated with growth impulses (endometriosis colonies, myomas, breast and genital: carcinomas of the organs, malignant tumors of the prostate, or hyperplasia).

112948 11

Table 2 Effect of rat miscarriage of RU 486 and J 914 (Example 1) and J 900 (Example 2) on pregnancy at 5-7. after subcutaneous administration (0.2 ml / animal / day in benzyl benzoate / castor oil [1 + 4 v / v]).

Group Dose Complete pregnancy inhibition 50 ++

Substance_mg / animal / day n + __ mg / animal / day __N * / N _% __

Carrier _0 / 25_0__ RU 486 3,0_5 / 5_JOO__ _ 10_2 / 5_40__U_ _0J_0 / 5_0__ J 900_Ιβ_9 / 10_90_0,6_ _0J_0 / 5_0__ J 914_3J0_5 / 5_ ^ 00__ __M> _7 / 10_70_Ο__ _ _ _ _ _ _ _ _ _ _ _ _ _ ~ _ _ _ _ _ _ _ _ _ ~ _ _ _ _ _ I _ _ _ _ _ _ _ _ _ I _ O ~ 5 + = empty uterus,, N = number of all females' · * N * = number of non-pregnant females: -H- = graphical determination The following examples illustrate the invention.

eXAMPLES

EXAMPLE 1 180 mg of lipo [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one was acetylated in 5 ml of acetic anhydride / pyridine (1: 1). . After addition of water, the organic phase is extracted three times with ethyl acetate. washed with dilute hydrochloric acid and water, dried over sodium sulphate and evaporated under reduced pressure. 172 mg of crude product are obtained, which is purified by preparative layer chromatography on silica gel 60 with PF254 + 366 using 4: 1 toluene / acetone as eluent.

12 112948

115 mg of lipo [4- (acetyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one is obtained. The product crystallizes from an ethyl acetate.

Melting point: 115-120 ° C (acetic ester) αϋ = + 218 ° (CHCl13) δ IR spectrum in KBr (cm'¹): 1754 (OAc); 1654 (C = C-C = C-C = O); 1602 (phenyl) UV spectrum in MeOH Xmax = 271 nm ε = 28,157 ληιαχ; 297 nm ε δ 26 369 1 H-NMR spectrum in CDCl 3 [δ, ppm]: 0.511 (s, 3H, H-18); 2.227 (s, 3H, 10 OCOCH 3); 3.247 (s, 3H, 17β-ΟΟΗ3); 3.408 (s, 3H, 17a-CH2OCH3); 3.386, 3.431, 3.544, 3.580 (m, 2H, CH2 OCH3); 4.399 (d, 1H, J = 7.2 Hz, H-11a); 5.785 (s, 1H, H-4); 7,242, 7,266, 7,618, 7,647 (m, 4H, AA'BB 'system for aromatic protons); 8.315 (s, 1H, CH = NOAc) MS m / e: 446 C 28 H 32 NO 4 M + - CH 2 OCH 3 +.

Example 2 210 mg of 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one are added in 5 ml of pyridine 0, 3 ml of chloroformic acid ethyl ester under cooling with water. A white precipitate is formed. After 30 minutes, water is added to form a solution, then a white precipitate forms. . 20 g of a precipitate which is filtered off with suction and washed with water. The yield after drying is 133 mg. The aqueous phase is extracted with chloroform, washed with dilute brine; And water, dried and evaporated under reduced pressure. The yield is 66 mg.

The two solids are combined and subjected to preparative layer chromatography on silica gel 60 with PF254 + 366 using toluene / acetone as eluent ;; 25: 4.

150 mg of 11β- [4- (ethoxycarbonyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one are obtained, which is recrystallized from acetone / hexane.

Melting point: 137-148 ° C

30D = + 204 ° (CHCl 3); - 'UV spectrum in MeOH λmax = 270 nm ε = 27,094 λmax = 297 nm ε = 25,604

> I

112948 13 H-NMR spectrum in CDCl3 [δ, ppm]: 0.507 (s, 3H, H-18); 1.383 (t, 3H, J = 7.0 Hz, OCH 2 CH 3); 3.246 (s, 3H, 17β-OCH3); 3,410 (s, 3H, 17a-CH2OCH3); 3.39 - 3.56 (m, 2H, CH2 OCH3); 4.35 (d, 1H, J = 7.0 Hz, H-11a); 5.784 (s, 1H, H-4); 7.23, 7.26, 7.61, 7.64 (m, 4H, AA'BB 'system for aromatic protons); 8.303 (s, 1H, 5 CH = NR) MS m / e: 431.24701 for C28H33NO3 M + - C2H5OCOOH.

Example 3 190 mg of 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one is suspended in 10 ml of toluene. Then 0.5 ml of phenyl isocyanate and 1 ml of triethylamine are successively added. After stirring for 3 hours at room temperature, the mixture is heated under reflux for 2 hours, the white precipitate is suction filtered and the solvent is evaporated under reduced pressure. 310 mg of a light brown solid are obtained, which is purified by preparative layer chromatography on silica gel 60 with PF-254 + 366, eluting with toluene / acetone 9: 1.

65 mg of 17β-methoxy-17α-methoxymethyl-11β- {4 - [(phenylaminocarbonyl) oxyiminomethyl] phenyl} estra-4,9-dien-3-one are isolated.

Melting point: 241-246 ° C (acetone) • 0 aD = + 178 ° (CHCl3) · '·', * 20 UV spectrum in MeOH Xmax = 238 nm ε = 29 444: _: ': λιηηχ = 300 nm ε = 29,649 ί. 1 H NMR Spectrum in CDCl 3 [δ, ppm]: 0.474 (s, 3H, H-18); 3.245 (s, 3H, 17β-, j * OCH3); 3.405 (s, 3H, 17a-CH2OCH3); 3,406-3,545 (m, 2H, ABX system, 17α-CH CHOCH3); 4.413 (d, 1H, J = 6.8 Hz, H-11a); 5.797 (s, 1H, H-4); 7.264 (m, 5H, 25 aromatics); 7.272, 7.293, 7.548, 7.575 (m, 4H, AA'BB'-aromatic proton system: ···); 8.0 (s, 1H, CH = N -) MS m / e: 431.24249 for C28H33NO3 M + -C6H5CNO + H2O.

: Example 4 708 mg of lipo [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl: estra-4,9-dien-3-one is dissolved in 15 ml of toluene. Then, 1.5 ml of ethyl isocyanate and 3 ml of triethylamine are successively added. After stirring for 6 hours at room temperature, allow to stand overnight, add 20 ml of aqueous ammonia solution, separate the phases, extract with toluene, wash with water, aqueous ammonium chloride solution and water, dry over sodium sulfate and evaporate under reduced pressure. 800 mg of a pale yellow solid are obtained, which is purified by preparative layer chromatography on silica gel 60 with PF254 + 366 using toluene / acetone (9: 1) as eluent.

610 mg of 11β- {4 - [(ethylaminocarbonyl) oxyiminomethyl] phenyl} -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one are isolated.

Melting point: 142-147 ° C light decomposition (ether / acetone / hexane) 1 H-NMR spectrum in CDCl 3 [δ, ppm]: 0.522 (s, 3H, H-18); 1.241 (t, 3H, J = 7.5 Hz, NHCH 2 CH 3); 3.253 (s, 3H, 17β-OCH3); 3.415 (s, 3H, 17a-CH2OCH3); 3.366-10 3.574 (m, 4H, ABX system, 17a-CH2OCH3, NHCH2CH3); 4.410 (d, 1H, J = 7.2)

Hz, H-11a); 5.790 (s, 1H, H-4); 6.238 (m, 1H, NHCO); 7.258, 7.286, 7.561, 7.589 (m, 4H, AA'BB 'system for aromatic protons); 8.294 (s, 1H, CH = N -).

Example 5 500 mg of 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-15-estra-4,9-dien-3-one are mixed in 4 ml of propionic anhydride / pyridine 1: 1 ( v / v) for 2.5 hours in a protective atmosphere. Pour into ice water, extract the glueous mass with chloroform, wash the organic phase with dilute hydrochloric acid. y and water, dried over sodium sulfate and evaporated under reduced pressure. Whoa. . ·. the lean yellow foam is purified by chromatography and recrystallized from ethyl acetate, 20 kaesters. Yield: 306 mg of 1- [4- (propionyloxyiminomethyl) phenyl] -17β-. ! methoxy-17α-methoxymethyl-estra-4,9-dien-3-one.

m.p .: 110-114 ° C (ethyl ester) 1 H-NMR spectrum in CDCl 3 [δ, ppm]: 0.515 (s, 3H, H-18); 1.241 (t, 3H, J = 7.6 Hz, OCOCH 2 CH 3); 3.253 (s, 3H, 17β-ΟΟί3); 3.415 (s, 3H, 17a-CH2OCH3); 3.4-3.6 (m, 2H, ABX system, 17a-CH2OCH3); 4.128 (d, 1H, J = 7.2 Hz, H-11a); 5.790 (s, 1H, H-4); 7,244, 7,271, 7,627, 7,655 (m, 4H, AA'BB'-system of aromatic protons: '' theme); 8.322 (s, 1H, CH = N -).

Example 6 To 170 mg of 11β- [4- (hydroxyiminomethyl) phenyl] -17β-methoxy-17α-methoxime-30-yl estra-4,9-dien-3-one in 5 ml of methanol is added under ice-cooling. ether-diazomethane solution until slight yellow coloration occurs. The mixture is stirred for 2 hours at 5 ° C, diluted with sodium hydroxide solution, extracted with ether, washed with neutral, dried over sodium sulfate and the organic phase is evaporated under reduced pressure. The yellow resin is purified by preparative layer chromatography on silica gel 60 with PF254 + 366 using toluene / acetone (4: 1) as eluent.

110 mg of 11β- [4- (methoxyiminomethyl) phenyl] -17β-hydroxy-17α-methoxymethyl-estra-4,9-dien-3-one are obtained in the form of colorless sheets.

Melting point: 83-89 ° C α D = + 197 ° (CHCl 3) δ IR spectrum CHCl 3 (cm -1): 1700 (C = NOCH 3>; 1649 (C = CC = CC = 0); 1590 (aromatic)). spectrum in MeOH λ max = 275 nm ε = 23 098 λ max = 300 nm ε ε 22 872 1 H-NMR spectrum in CDCl 3 [δ, ppm]: 0.529 (s, 3H, H-18), 3.247 (s) , 3H, 17β-15 OCH3), 3.408 (s, 3H, 17a-CH2OCH3), 3.39-3.598 (m, 2H, ABX system, 17a-CH2OCH3), 4.381 (d, 1H, J = 7.5 Hz, H-11a), 5,773 (s, 1H, H-4), 7,173, 7,201, 7,463, 7,491 (m, 4H, AA'BB 'system for aromatic protons), 8,023 (s, 1H, CH-phenyl).

Example 7 To a 500 mg solution of lipo [4- (hydroxyiminomethyl) phenyl] -173-methoxy-17a-methoxy-N-methyl-estra-4,9-dien-3-one is added a filtered mixture of 2 ml. benzoyl chloride and 3 ml of pyridine. After 2 hours, stir in 150 ml of ice water. The steroid is formed as an adhesive mass. To this is added 5 ml of dilute hydrochloric acid,; dissolved in ethyl acetate, the phases are separated, the organic phase is washed with aqueous bicarbonate atmosphere and water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The yellow oil (1.57 g) is removed from the non-polar products by chromatography on 40 g of silica gel 60 using a toluene / ethyl acetate gradient. The main fraction (0.7 g) is purified by preparative sandwich chromatography. ; silica gel 60 PF254 + 366'Ha using chloroform / acetone as eluent. 410 mg of a colorless foam are obtained, which is recrystallized from methanol.

263 mg of lipo [4- (benzoyloxyiminomethyl) phenyl] -17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one are obtained in the form of colorless crystals.

112948 16

Melting point: 115-122 ° C (methanol) λmax + 216 ° (CHCl3) UV spectrum in MeOH λmax = 279 nm ε = 33720 λmax = 299 nm ε = 301205 @ 1 H-NMR spectrum in CDCl3: in [δ, ppm]: 0.527 (s, 3H, H-18); 3.253 (s, 3H, 17β-OCH3); 3.415 (s, 3H, 17a-CH2OCH3); 3.403-3.589 (m, 2H, ABX system, 17a-CH2OCH3); 4.416 (d, 1H, J = 7.2 Hz, H-11a); 5.792 (s, 1H, H-4); 7.299-7.615 (m, 5H, aromatic protons, CO-phenyl); 7,701, 7,729, 8,111, 8,140 (m, 4H, AA'BB 'system of aromatic-tiprotones); 8.520 (s, 1H, CH-phenyl).

Example 8

Measurement of receptor binding affinity: 3

The receptor binding affinity was determined by the specific binding of the binding H-labeled hormone (Tracer) and the test compound to the receptors of the cytosol from the target organs of animals. In this case, receptor-M-15 and reaction equilibrium were sought. The following incubation conditions were selected:

Glucocorticoid Receptor: thymus cytosol, obtained from the rat with 3 extra kidneys removed, stored at -30 ° C; Bumper: TED. Tracer: H-dexame-level, 20 nM; Reference substance: dexamethasone.

After incubation for 18 hours at 0-4 ° C, separation of bound and free ': 20 steroid occurred by mixing activated carbon / dextran (1% / 0.1%), centrifuging and measuring bound H activity. from the top layer.

; From the measurement series of the concentration series, the IC50 for the test compound and reference substance was determined and the relative molar binding affinity as a proportion (x 100%) of both values.

; 25 Example 9

To prevent rat pregnancy:

Female rats are allowed to mate in the proestrus phase. By pointing the semen. occurrence in vaginal smears the following day is counted as this day, the first day of the ras (= dl) period. Treatment with the test substance or vehicle takes place from 5-7. on the 9th. The agents are administered in 0.2 ml of vehicle (benzyl benzoate / castor oil 1 + 4) by injection into subcutaneous tissue. The values of completely inhibited pregnancies in the various groups are shown in Table 1. It was found that J 917 and J 900 significantly inhibited uterine adhesion to the fertilized ovum compared to RU 486.

Claims (2)

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