SK95894A3 - 11-benzaldoxim-17beta-metoxymethyl-estradiene, method of their preparation and treatments containing these compounds - 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

Other typical manifestations of pregnancy are also an expression of very high levels of progesterone. The enlargement of the mammary glands and the tight closure of the cervix until the time of delivery are an example of this effect.

Progesterone participates to a minor extent in the management of ovulatory authorities. Progesterone is known to have anti-ovulatory properties in large doses. These properties result from the inhibition of pituitary gonadotropin secretion, which is a prerequisite for maturation and ovulation of the follicle. On the other hand, it is evident that the comparatively lower secretion of progesterone in the ripening follicle plays an active role in the preparation and triggering of ovulation. Pituitary mechanisms (time-limited, even positive progesterone responses to gonadotropin secretion) (Loutradie, D.; Hunian Rprproduction 6, 1.991, 1238-1240) play a prominent role in this.

The functions of progesterone in the maturing follicle and the yellow body itself, which are undoubtedly in existence, are analyzed in less detail. After all, stimulating and inhibiting effects on the endocrine follicles and function are also contemplated here.

An important role of progesterone and progesterone receptors is also envisaged in pathopsychological processes. Progesterone receptors are detectable in endometrious foci, but also in tumors of the uterus, breast and central nervous system (meninges). The role of these receptors in the growth of these pathologically relevant tissues is not necessarily linked to the presence of blood levels of progesterone. There is evidence that substances which are characterized as progesterone antagon.i.sti, Oct = ^486: Mifepristone (LP-s) 057 115) and ZK 98299 onapristone (DE-OS-35 04 421), raise and then deep-reaching functional changes in these tissues when a negligible low level of progesterone is present in the blood. It seems possible. The role of altering the transcriptional effects not occupied by the progesterene receptor by antagonists plays a role in this (Chwal isz. K. et al., Endocr. no logy, 12.9, 31-7322, 1991).

The effects of p roges t (jer o n o v c h o and other receptors).

Progesterone in the tissues of genes and organs of the tissues occurs by interaction with the protesterone. In a cell, progesterone binds with high affinity to its receptor. Changes in receptor protein are influenced by the following factors: conformational changes. dimerization of the 2 receptor units into one complex, release of the binding site in the DNA receptor upon dissociation of a single protein (USP 90), and binding to the hormone responsible portion of DNA. Finally, the transcription of certain genes is 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 blood concentration. . The concentration of receptors in the cell is also highly regulated. Estrogens stimulate the synthesis of progesterone receptors in most tissues. Progesterone inhibits the synthesis of estrogen receptors and the synthesis of its own receptor. Probably these and other interactive relationships between, esrogens j. and progestagens, which can explain why genes and antigestagens can affect estrogen-dependent manifestations without being bound by the estrogen receptor. These relationships are naturally of great importance in the therapeutic use of antigestagens. These sub-stances seem to be suitable for interfering with the woman's reproductive actions, e.g. post-ovulatory, to prevent underestimation, in late pregnancy, to increase reaction readiness, uterus to prostaglandin and oxytocin, or to achieve cervix opening and softening (maturation).

Antigestagens inhibit ovulation in various non-human primate species. The mechanism of this effect is not clearly elucidated. In addition to the inhibition of gonadot oil sponges and ovarian mechanisms due to para- and auto-progesterone progesterone in the ovaries are discussed.

Antigestagens have a modular ability! or attenuate the effects of estrogens, although they themselves have largely no affinity for estrogen receptors at the cysteine level and although they may affect the concentration of the estrogen receptors. Possible effects in endometrious outbreaks, or in tumor tissues that are equipped with triphenyl or progesonone receptors, can be expected to have a beneficial effect on health. Extraordinary advantages. a beneficial effect on the health state of endometriosis could be given if the ovulatory braking effect of the antigestagens in the tissue was added to the braking effects.

With the inhibition of ovulation, part of the ovarian hormonal production and hence the stimulating effect on the pathologically altered tissue would be eliminated. In the presence of severe endoinetriosis, it would be desirable to inhibit ovulation and to list the ever-present tissues of the genital tract, reversible and in a normal state.

A contraceptive procedure is also discussed in which anti-estrogen treatment suppresses ovulation, and subsequent gestagen treatment induces a secretory transformation of the endometrium so that it retreats approx. 28-day cycle with regular bleeding (Baulieu, E.E., Advancies et al. Tracerpion 7, 345-351, 1991).

Ant i.gestagens may have various hormonal and antimony properties. At the same time i and n t i g 1 u k o t or i are a special therapeutic effect. k o i. d n v 1 ti s t n o s t. . uses in which a t th e t th e th e tical effects which may be present in which progesterone amounts are present

T i. e t o c t e r e p e 111 i c k e b i o n i) a n i o n d o. These include receptors which, if necessary, can lead to apl. k á c i. to discontinue indirectly therapeutically treatment. The partial mode of admixture and / or efficacy is an important prerequisite for therapy with ant i.gestagens, especially for those indications requiring more weekly or monthly treatment.

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It is an object of the present invention to provide new ones

1.1. β - I) e n z a 1 d o x i m - 4,9 - e s t r a d i. all derivatives of all formulas and I

<1 their; armaceu t .i cky pri j atelné so.Lj. , how and j the method of ii.cli production. It is a further object of the invention to provide medicaments comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

NOZ

Z is -CO-CH 3, -CO-O-C 2 H 4, -CO-NH-phenyl, -CO-NH-C 7 H 15,

-CO-C ₂ H _5, -CH or -CO-phenyl.

According to the invention, the following compounds are preferred:

11. β - [4- (acetoxyiminoine tyl) phenyl] -17β-methox y -1.7 a - methoxyinety 1 -

-4,9-esraden-3-one, β - {4 - [(ethoxycarbonyl) oxyimonylononyl] phenyl} -1,7β-methoxy-17a methoxymethyl-4,9-estraden-3 1-β - {4 - [(ethylaminocarbonyl) oxyimidomethyl] phenyl} -1,7β-methoxy-17α-methoxymethyl-4,9-estradien-3-one; 7β-methoxy-17α-methoxymethyl. - 1 1 β - {4 - [(phenylenediamine) oxylimino1] phenyl} -4,9-es t radien-3-one and β - | 4 - (propionyl 1 oxyimin oin ty1) beny1] - 1 7 β - not toxy - 1 7 a - mexy me Vy1-4,9-estradien-3-one, f 1. β - | 4 - (methyloxylmethyl) phenyl] - 17β - hyd 1.0 x y - 17a - me. toxymethy. -

- 4,9 - e s t ríl d i. é n-3-ó n,

1. 1 β - f 4 - (benzoyl x y im i nome t 1) ény..... Hyd r......

- 4,9-estradien-3-one,

The invention further relates to a process for the preparation of the compounds of formula I and their pharmaceutically acceptable salts. which is characterized in that the compound of formula II,

the compound is reacted to form este.ru or ether, optionally converted to a salt.

The esterification, etherification or in the compounds of the formula (I) is carried out in the form of anhydrides such as anhydrides.

in the presence of a carboxylic acid, the acid chlorides in the presence of a base can be obtained by means of acylating agents, the filtration can be carried out with the ethyl ester, preferably in the presence of tert. There is a diazomethane in methanol. Formation of the urethane by reaction with alkyl or aryl isocyanates in I, preferably in toluene, or by reaction in the presence of a base, preferably i.

i ne r known i al e bo

E is not a base, or it is also known that it will be delivered by three people.

The preparation of the starting compound of formula II is based on

5α, 1 (a) -Epox: de III

(H) [e.g. Nedelec, Bull. Soc. chim. conscript (1970), 2548.1.

Introduction of a phenyl residue into the β-position to form

From the (9), (5a) -hydroxy structure IV, the Cu (I) salt is obtained

kata'l y z ovan ou , 2051) G r i. g n a r d o o u r e c k. o u (Te t r a h c: d r o n Le t t: c i · s with a p-bromobenzaldehyde ketal, preferably

d.i.metes of p -bromobenzaldehyde at temperatures between 0 ° C and 30 ° C.

known

(IV)

Introducing the group way

-CH ₂ -O-CH ₃ to C-17 via spirorooxid position is done

In the reaction reaction with methylsulfonium iodide or tert. - butanoates of potassium in di.mety isu’l.foxide [Hubner e t. a 1 ..; .1. l’rak t. Chem. 314, 667 (1972); A.rznei. m. ľo.rseh. 30, 401 (1973)]

and subsequent ring-opening with alkoxides [Ponsold et al., Z. Chem. 11, 106 (1971)]. The thus prepared 17 N-Cl-O-Cl 2 compound VI

(VI) can be cleaved either by acid hydrolysis, preferably with p-toluenesulphonic acid in acetone (Teutsch et.al. DE 2801416), to the appropriate aldehydes or after etherification of the free hydroxyl group with alkyl halides in the presence of tert-butanolate of potassium stearate is first converted to 5 ', 17β-diethers by acid hydrolysis, in acetone,

290 893), which is then passed through a p-toluenesulfonic acid line (Kasch et al., A) and the aldehyde thus obtained is reacted with a hydroxy lane to convert a compound of formula (I).

The compound of the formula I obtained according to the invention can optionally be converted into an inorganic or organic acid addition salt, preferably a salt which is physiologically harmless. Conventional, physiologically acceptable inorganic and organic acids are, for example, hydrochloric acid, acidic to hydrobromic, oxalic,

i.a.

k y s e 1 i. n and malic acid; and i. described fumaric, acidic i. For example, m and tonic acid, benzoic acid.

l. tartaric acid, tartaric acid, tartaric acid, tartaric acid. Advances in drug research, vol. on pages 224-225, editors Birkhäuser, Base 1 and Stuttgart, 1966, and in Journal of Pharmaceutical Sciences, vol. 66.

pages 1-5 (1977).

Inorganic or organic acid addition salts are generally prepared in known manner, by mixing the free bases or their solutions with the appropriate acid, or by mixing their solutions in an organic solvent, for example in a lower alcohol such as methanol, ethanol, n-propane 1 or isopropanol, or a lower ketone such as acetone, methylthi ketone or methyl isobutyl ketone, or in an ether such as diethyl ether, tetrahydrofuran and dioxane. Better crystal excretion is obtained in use. mixtures of said solvents.

In this way, the addition salts can be prepared from acid solutions.

A d: i. 1 .i. The compounds of formula (I) may be reacted in a manner known per se by physiologically acceptable aqueous substances and reacted in a manner such as e.g. with organic bases or ion exchangers, whereby the free bases are released. with inorganic salts or organics are suitable for forming other salts. These salts,

From the free base, the reaction of acids, especially such therapeutic salts, or other salts of the novel compound can also be used to purify the free base into the salt to be separated and from the base.

p i. The free base can be released again

Subject i. Oral or intramuscular carriers of conventional excipients and diluents contain the formula I or an addition salt thereof. t common, r i e d .i. d .i e .1. and is acid. by means of a carrier or pre-treated invention, a subcutaneous application which, in addition to the additive compound with an inorganic or organic invention, is produced by the known solid or liquid use of the auxiliaries used in the application process and the preparation of such drug farms to be administered. Such obtainable forms of tablet coating, dragees, tablets and dragees

Of course, preparations such as p r. I measured p. R i. m e r a n e n d a n o n o n i u. They are suitable for oral administration. and whites, pills, powders, solutions.

capsules, tablets, deposition forms, and the like.

of substances, suppositories.

1.0

Appropriate tablets may be obtained, for example, by mixing the active ingredient with known ingredients. auxiliary. substances with, for example, inert diluents such as dextrose, sugar, sorbitol, niannit, polyvinylpyrrolidone, disintegrating agents. such as corn starch or alginic acid, binding agents, such as starch or gelatin, lubricants such as starch or amine. n and are carboxypolymethylene, po’lyv.i.ny.l acetate. The table can

v.rst lev.

a1 e b o t a 1 c u m a / a. 1 e b o s effect, such as acetate phthalate with a. they can reach the deposition carboxymethy I cell.), of cellulose, or of several

The dragees in question may be made with a plurality of holes, each with a plurality of dimensions. They are made analogous to the polyvinyl pyrrolidone or shellac used, usually for p.

t al k they, titanium dioxide consist of an excipient, or sugar. The two dragees may also have a plurality of layers, the ones mentioned in the manufacture of the tablets being used.

Solutions or suspensions of the invention protected by the active ingredient may additionally contain flavor enhancers such as saccharin, cyclamate or sugar, as well as e.g. aromatics such as vanillin or orange extract. In addition, they may contain suspending agents

j) flavoring agents, sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoic acid esters. Capsules containing the active ingredient can be prepared, for example, by mixing the additive with an inert carrier such as milk sugar or sorbi tol. will encapsulate me in the desire of new capsules.

Suitable suppositories may be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol, e.g. their derivatives.

According to this patent, 1,111-subsubstituted benzaldehyde-4,9-estadiene prepared as antioxidants is a gene-acting substance which, while predominant in vivo (cf. 2) have a clearly reduced anti-RU compared to RU 486. g (1) additional activity that has been demonstrated by diminished glucocorticoid receptor binding (cf. rab. I).

1

Table 1

Receptor binding of selected compounds prepared according to Examples 1 and 2

Merging into Relative Molar Affinity (RMVA) by Example % J to glucocorticoid receptor (Dexamethasone = 100%) (J914) 73

(.1900) 6 6 for comparison

R 486 (Mifepressone) 685

ZK 98299 (Onapri s t one) 3 9

In the invention, damping this combination. The properties of the prepared effects can be derived from the antioxidants of progesterone activity.

to expect a n t i g 1 u k o k r t i. k o i d n j with respect to pri

This concomitant advantage can also be used: i.a.

In particular, the mother tongue requiring extraordinary cycles is estrogen. Weight reduction of these estrogen functions. of the uterine weight in a cycle of 486, i.e. the (indirect) preparations of the present invention are expected to be extremely altered in which tissues (sources of endome triosis, myoins, genital prostate)

i, e. d is determined in accordance with this reduction, in particular the duration of which I endure.

circulate c. i m i. j e s s e d d om t .1 m e n i. and The predominant reduction found is that the antisense and estrogenic properties are reduced.

uterus by the action of RIJ according to the respective effects of influencing e pa tologically give growth impulses to kare.i. finger-like genius and other genes

1.2

Table 2

Accelerating the abortive effect of RU 486 and 1914 (Example 1) and J 900 (Example 2) in the rat after subcutaneous administration even from 5.

- 7th day of pregnancy (application of 0.2 ml / animal / day in benzyl benzoate / castor oil [1 + 4 v / v]) group, dose complete ED 50 -i + compound (mg / zv (i era / day) inhibition of pregnancy i / th i- (mg / zv.i era / day)

N * / N%

vehicle - 0/25 0 RU 486 3.0 5/5 1 00 1.0 2/5 40 .1, 1 0.3 0/5 0 J 900 1.0 9/10 90 0.6 0.3 0/5 0 .1 914 3.0 5/5 100 1.0 7/10 70 0.6 0.3 1/5 20 0.1 0/6 0

4- empty uterus;

N - number of all females;

N * - number of neg.r and vi days of females; ++ - graphical determination

The following examples illustrate the invention

DETAILED DESCRIPTION OF THE INVENTION

Example 1

180 mg of 11β - [4- (hydroxymethynyl) ethyl] 1 - 1 7 β-Methoxy-1 7α - MeL. oxy-methyl-estra-4,9-diphen-3-one is acetylated for 12 hours in 5 µl. acetic anhydride / pyridine (1: 1). After addition of water, the reaction mixture is extracted 3 times with ethyl acetate, the organic phase is washed neutral with dilute I-1CL and the water and the solvent are evaporated under reduced pressure. 172 mg of crude product is obtained, which is purified by means of an external chromatography on a silica gel thin layer of Kieselgel 754-1-366 ^with toluene / acetone (4: 1).

Gets sti. 115 mg L 1 β - [4- (acetyloxyiminomethyl) phenyl] -1,7β-methoxy-17α-methoxymethyl-4,9-estraden-3-iodine. The product is crystallized from ethyl acetate.

Melting point: 115 - 120 θϋ (ethylacetate) α _Ό = + 218 ° (CHCl ₃ )

IJV spectra in MeOH: lambda _ax

271 nm e ps ilon = 28 8 1.5 7 lambda _{| nax}

nm ^ Il-NMR spectrum of the in (s, 3H, OCOCH _3);

CDCl 3 [δ, ppm]: 0.51.1 (s,

3.247 (s, 311, 17β-0Ο1 _3);

31i, 1-1-18); 2,227

3.408 (s, 3H,

17a-CH ₂ OCH ₃ );

4.399 (d, 11-1,

3,386, 3,431, 3,544,

3.580 (m,

1 = 7.2 Hz, 14-1.1a); 5.785 (s, 114,

211, CH ₂ CH ₃ );

14-4); 7,242,

7,266, 7,618,

7.647 (m, 411, AA'Bromatic proton system); 8.315 (s, 1.14, C 14 = NOAc).

MS m / e: 446 ^C 28 ^H 32 ^NO 4 ^{m +} - ^{c, 120CH} 3

Example 2

K 21.0 mg 1 1 β - | 4- (hydroxyimidomethyl I.) phenyl I.] - .1 7β - me (.oxy - 17a -

-methoxymethyl-4,9-estradien-3-one v 5 ml. py ri hin is started cooling water at. Drops 0.3 m.l cty.lcste.ru acid i ny ch .l ó.rm ravčej created white betrayal on the. After 30 m i. n ú t a ch to k of the reaction mixture is added Water. created r oz t; OK . then vypadne b.iel and z razen i n and that is aspirated and washed with water. Yield after dry is 133 mg. Vodná 1 1 'a z a s a c x f. r a h u j e chlorofor mom , k t o r s s and rinsed with z i. eden o u chlorine acid-

The solvent was evaporated under reduced pressure. An additional 66 mg was obtained. The two were combined and purified by preparative thin layer chromatography Kieselgel 60 1 ^ 254 + 366 ^and a toluene / AEE signal (4: 1).

150 mg of lipo- {4 - [(ethoxycarbonyl) oxy: 1-aminomethyl] phenyl} -17β-methoxy-17α-methoxymethyl-estra-4,9-dlen-3-one is obtained, which is p. recrystallized from acetone / hexane.

Melting point: 137-14 ° C and _D - + 204 ° (CHC ₃ )

UV spectrum in MeOH: lambda _{| nax} = 270 nm s = 27 094 lainbda ,,,., _At - 297 nm s = 25 604 * liiťÄÄ are-H-NMR spectrum of ₃ C0Cl | δ, ppm]: 0.507 (s, 3H, 11-18); 1.383 (t, 311, J = 7.0 Hz, OCH ₂ CH ₃ ); 3.246 (s, 311, 17β-ΟΟΗ ₃ ); 3.410 (s, 311, 17 a -CH ₂ 0CH _3); 3.39 to 3.56 (m, 211, _{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, ΛΑ 'BB aromatic proton system); 8.303 (s, III,

CH = NR)

MS m / e: 431.24701 ^C 28 ^H 33 ^NO 3 ^{M +} C ₂ H ₅ OCOOH

Example 3

190 mg of 11β - [4- (hydroxyiminomethyl) phenyl] -1,7β-methoxy-17α-methoxymethyl-4,9-estradien-3-one is suspended in 10 ml of toluene . 0.5 ml is gradually added. phenyl isocyanate and 1 ml triethylamine. The reaction mixture was stirred at room temperature for 3 hours and then heated at room temperature for 2 hours. the reflux temperature. The white precipitate was filtered off with suction and the solvent was evaporated under reduced pressure. 31.0 mg of a pale brown solid is obtained, which is purified by preparative thin layer chromatography of Kieselgel 60 1'1'254 + 366 ^with a solvent mixture of toluene / acetone (9: 1).

65 mg of 17β-methoxy-17α-methylmethoxy-1-1-β - {4 - | (pheny 1 - a m i n k a r b o n y 1) o x y i. m i n e t y I J f e n y 1} - 4,9 - e s 11 · a d e n - 3 - o.

Melting point: 241-246 θθ (acetone) and _D = + 1.7 ° (CDCl ₃ )

UV spect rum in MeOH: ^.lambda.max lambda bl-NMR spectrum in CDC1 ₃ [δ, ppm]: 0.474 (s, 311, H-18); 3,245

3 H, 17-CH ₂ 0CH _3); 3.406 - 3.545

17a-CH ₂ OCH ₃ ); 4.413 (d, J = 6.8 Hz, 111)

1H, H-4); 7.264 (m, 5H, aromatics); 7.272 (m, 411)

CH = N- ( ^C 28 ^H 33 ^NO 3)

238 nm

300 nm (s, 3 H, (m, 2H)

H-11a);

7,293, protons);

MS in / e:

17β-OCH ₃ ); 3.405 (s, ΛΒΧ-system,

5,797

7,548,

8.0 (s,

431.24249

575

1H,

ΛΑ’BB’- sys themes

M ⁺ C ₆ H ₅ ^E No L and Ronia .i.okých + ^H 2 °

Example 4

708 mg of 11β- [4- (hydroxyimidomethyl) phenyl] -17β-ethoxy-17α-methoxymethyl 1. -4,9-estradien-3-one is dissolved in 15 ml of toluene. Then 1.5 ml of ethyl isocyanate is added to 3 ml of triethylamine. The reaction mixture was stirred at room temperature for 6 hours and then allowed to stand overnight. 20 ml of aqueous ammonia solution are added, the phases are separated and the aqueous vase is extracted with toluene. The combined organic phases are washed with aqueous ammonium chloride solution and water, dried over sodium sulfate and the solvent is evaporated off under reduced pressure. 800 g of a pale yellow solid are obtained, which is purified by preparative thin layer chromatography on Kieselgel 60 [ ^lambda] 254 + 366 ^{with a} 9: 1 toluene / acetone solvent.

610 mg of 11β- {4- | is isolated (ethylaminocarbonyl) oxyiminomethyl] phenyl} -17 β-methoxy-17α-methoxymethyl-4,9-estraden-3-one.

Melting point: 142 - 147 ° C (ether / acetone / hexane) decomposes on light 1 H-NMR spectrum in CDCl ₃ [δ, ppm]: 0.522 (s, (t, 311, J = 7.5 Hz, NHCH ₂ CH ₃ ); 3.253 (s, 3H,

3H, H-18);

17β-ΟΟΗ ₃ );

.24 1

3.415 (s, 3II, 17-C l _{2 OCH3);}

3,366

3.574 (m.

4H, ΛΒΧ-sys tem,

17 -CH ₂ OCH _3, NHCH. ₂ CH ₃ ); 4.410 (d,

1H, J = 7.2 Hz, II-11a); 5.790 (s, 1H, H-4); 6.238 (m,

11-1, NHCO); 7.258, 7.286, 7.56'1

7.58 9 (m.

4H, ΛΛ’BB´ aromatic proton system);

8.294 (s, 111,

CH = N).

Example 5

500 mg of 11β- [4- (hydroxyiminomethyl) 1.J-17β-pentoxy-β 7 -methoxy-methyl-4,9-estradien-3-one is mixed in an inert atmosphere 2, 5 hours a mixture of 4 ml of anhydride by id l _<; p ins electrically ropi ones of U / pyr .I of (J .1, ^f v / v). the reaction mixture was poured into ice 'water, sticky mass was ex traps, the chloroform The organic layer was washed with concentrated hydrochloric acid and water, dried over sodium sulfate, and the solvent was evaporated under reduced pressure.

Light yellow foam or those. chromatographically and recrystallized.

Ethyl acetate; Yield: 306 mg of 11β- [4- (propionyloxyiminomethyl) phenyl] N-.alpha.-N-ethoxy-17α-methoxymethyl-4,9-estraden-3-one.

Mp: 110-1 ° C r4 (ethyl acetate); ^H-NMR spectrum in CDC1 ₃ [δ., J ppm: 0.515 (s, 3H, H-18); 1.241 (t, 3H, 1 = 7.6 Hz, CH ₂ OCOCH _3); 3.253 (s, 3H, 17β-β, ₃ ); 3.415 (s, 3 H, 17-CII _{2 OCH3);} 3.4-3.6 (m, 2H, ABX system).

17a-CH ₂ OCH ₃ ); 4.128 (d, 1H, J = 7.2 Hz, H-11a); 5.790 (s, 1H, H-4); 7.24, 7.271, 7.627, 7.655 (m, 4H, ΛΑ 'BB' - aromatic proton system); 8.322 (s, 1H, CH = N-).

Example 6

170 mg of 11β - [4- (hydroxylminomethyl) phenyl] -1,7β-methoxy-17 α-methoxymethyl-4,9-estraden-3-one in 5 ml of methanol under ice-cooling, pour a solution of diazomelane in ether until a slightly yellow color is obtained. The reaction mixture was stirred at 5 ° C for 2 hours and then poured into concentrated sodium hydroxide. Extract with ether, wash to neutral, dry over sodium sulfate and evaporate the solvent under reduced pressure. The yellow resin is purified. T r i t e r e ronium togra.fi ou on a thin layer of Kiese l.ge.lu 60 PI ^- / SJi-6 6 ^{with <)} solvent mixture

t. o J uen / ace lon (4; .1.).

1.10 mg of 1.1 β - | is obtained 4- (methoxyinomethyl) phenyls J-17β-methoxyl-17α-methoxymethyl 1-4,9-esters. n-3-one in the form of security cards.

Melting point; 83

- 89 ° C and _D = 4- 197 ° (CHCl ₃ , ₃ ) 1 H spectrum in (C = CC = CC = O); 1590 UV spectrum in MeOH:

CI1C1 ₃ (cm ^-1):

(aromatic). lamhdamax oxygen and _{X m;} H-NMR spectrum in CDC1 ₃ [δ, ppm]: 0.529 (s, 3H, H-18); (s, 3 H, 17β-ΟΟΗ _3); 3.408 (s, 311, 17 a -CH ₂ 0CH _3); 3.39 (m, 2H, ABX system, 17α-CH ₂ OCH ₃ ); 4.381 (d, 111,

H-lla); 5.73 (s, 1H, H-4); 7.173, 7.201, 7.463,

4H, ΑΛ’BB’-aromatic proton system); 8.023 CH-phenyl).

1700 (C = NOCH ₃ );

649

275

300 eps.i. 1 on = 23,098 eps.il.on = 22,872

0.529 (s,

3,247

3,598 .1 = 7

7.49 1 (s.

Hz., (M.

1H,

Example 7-150

Add and then add pre-filtered mixture of 2 pyridine. The reaction mixture was poured into 2 ice water. The steroid precipitates as 5 ml of concentrated ethyl acetate. The layers are separated and

To 500 mg of 11β- [4- (hydroxyimino-ethyl) -phenyl] -1,7β-methoxy-1,7α-methoxymethyl-4,9-estradien-3-one was ml of benzoylchloride and 3 ml.

hours pour out sticky meat.

The organic layer was washed with aqueous sodium carbonate solution and water, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The yellow oil (1.57 g) was separated from the non-polar products by chromatography on 40 g of Kieselgel 60 with a solvent gradient, toluene / ethyl acetate. The main fraction was purified by vapor-phase chromatography on a Kieselgel 60 [mu] 2.54-1-366 thin layer ^{with a zinc chloroform} solvent. 410 mg of a colorless foam are obtained, which is recrystallized from methanol.

263 mg of 11β - [4- (benzoyloxymethyl) methyl] - j are obtained. 7 β-mcf o t m c: is from a f r e c t i c layer with toxy-1 7a-methoxymethyl! - 4,9 -radio i. n - 3 - one in crystals.

MP: 1.5 .1 - 122 ° C _D = + 21.6 ° (CHC1 ₃₎

UV spectrum in MeOH: "lambda 1 ,,,., Llama) _in that ,,,,,.

III cl X

9

299 eps i

M / e = 33,720 (s, 3H, 17β-OCH ₃ ); 3.415 (s, 311, _{17-CH2 OCH3);} 3.403-3.589 (m, 2H, ABX system, 17α-CH ₂ CH ₃ ); 4.416 (d, 1H, J = 7.2 Hz, H-11a); 5.792 (s, 1H, H-4); 7,299-7,615 (m, 511, aromatic protons, CO-phenyl); 7.701, 7.729, 8.1.11, 8.140 (m, 4H, AA'BB'-aromatic proton system); 8.520 (s, 1H, CH-phenyl).

Example 8

Measurement of receptor binding affinity:

Receptor Binding Affinity by Binding Specific Binding Compounds of Test Target and Reaction (Tracer) and Animal Receptors Incubation Conditions:

Glucocorticoid b .1. and the U - tagged horinone on the organs. Prite balance.

dochádzéx

Cytosoles were selected from the following receptor adrenalectomized rat, thymus Tracer: ~ H-dexamethasone,

poof; f e r: TED.

cyt osol.

stored at nM;

Team reference

0 ° C;

Dexamethasone.

After 18 hours the active and measurement were separated

i. In the case of bound and loose dextranes (1% / 0.1%), in excess, rows are at 0 ° C with teroids by addition of three. f ug o n i e stat.) 1 í

IC _{5 ()} for carbon or bonded H-activity

From the measurements of the concentration of test compound and for the reference substance as well as both values (x 100%) of the relative molar binding affinity.

Example 9

Reduction of early pregnancy in rats:

Female rats are mated in the prooestrus. After confirming that the sperm was also in vaginal stereo the second day counted as the first day (= dl) of pregnancy. Treatment with test, substances or vehicle follows from d5-d7, autopsies followed by d9. Substances were injected subcutaneously in 0.2 ml vehicle (benzyl benzoate / castor oil 14). The number of completely avoided pregnancies in the different groups is shown in Table 1. For .1 9 17 and .1 900 was at. RU 486 found to prevent n.i.dation.

Claims (4)

Patent claims A compound of the formula β-benzaldoxim-4,9-estradien NOZ where Z is -CO-Cl ₃ , -CO-OC ₂ H ₅ , -CO-NH-phenyl, -CO-NH-C ₂ H ₅ , -CO-C ₂ H ₃ , -CH ₃ , or -CO-phenyl, as well as pharmaceutically acceptable salts thereof. Compounds according to claim 1, namely 11β - [4- (acetoxyiminomethyl) phenyl. J-17β-methoxy-17α-methoxymethyl-4,9-estradien-3-one, 11β- {4 - [(ethoxycarbonyl). Oxyiminomethyl] phenyl} -17β-methoxy-17α-methoxymethyl-4,9-estradien-3-η, 11β- {4 - [(ethylaminocarbonyl) oxyiminomethyl. phenyl} -17β-methoxy-17α-methoxymethyl-4,9-estradien-3-one, 17β-Methoxy-17α-Methoxymethyl 1. -11β- {4 - [(Phenylamino) carbonyl.] Oxyiminoethyl] phenyl} -4,9-estradien-3-one . 11. β-1,4- (propionyl oxides and iminomethyls.1) phenyl. J-1 7 β-methoxy-1,7α-methoxy-methyl 1- 4,9-estradien-3-one, 11β - [4- (Methoxy oximidomethyl)] phenyl. J-1 7β-Hydroxy-1 7 α-mc toxymethyl I. -4,9- cst series i.en-3-one, 11β - [4- (Benzoyl-yimino-methyl) -phenyl. ] - 1 7β-Hydroxy-17a-methoxymethyl-4,9-estradien-3-one. A process for the preparation of the compounds according to claim 1 and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (I) is characterized in that: The NOH is reacted to form an ester or an ether, optionally converting the obtained compound into a salt. Pharmaceutical compositions comprising at least one of the compounds according to claims 1 to 2.