KR100825534B1 - 8?-Hydrocarbyl-Substituted Estratrienes For Use As Selective Estrogens - Google Patents

Abstract

The present invention relates to novel 8β-substituted estradione of formula (I). In ^{formula, R 2, R 3, R} 6, R 7, R 7 ', R 9, R 11, R 11', R 12, R 14, R 15, R 15 ', R 16, R 16', R ¹⁷ and R ^{17 '} have the meaning as indicated herein and R ⁸ has up to 5 carbon atoms and is optionally partially or fully halogenated straight or branched chain alkyl or alkenyl radical, ethynyl- or prop -1-ynyl radicals. The compounds of the present invention have a higher in vitro affinity for the estrogen receptor preparations of the rat prostate than the estrogen receptor preparations of the rat uterus, and preferentially act on the bone over the uterus in vivo and / or 5HT2a-receptor and 5HT2a- Stimulating the expression of the transporter (transporter) is to play a significant role. The present invention also relates to methods for their preparation, their therapeutic use and pharmaceutical dispersed forms comprising the novel compounds of the invention. The present invention also relates to the use of these compounds in the treatment of diseases and conditions induced by estrogen deficiency, as well as to the 8β-substituted estririenes in the overall structure of the compounds being isolated for estrogenous action on the bone rather than the uterus. It relates to how to use the structural part.

Estratrien.

Description

8beta-Hydrocarbyl-Substituted Estratrienes For Use As Selective Estrogens

The present invention has a high affinity for estrogen receptor preparations derived from the rat prostate, as compared to estrogen receptor preparations derived from the rat uterus in vitro, and preferential action on bone over the uterus and / or 5HT2a-receptor and in vivo in vivo. A novel compound which is a pharmaceutical active ingredient having a pronounced action on the stimulation of expression of the 5HT2a-carrier, a method for preparing the same, a therapeutic use, and a pharmaceutical dispersed form comprising the novel compound of the present invention. The compounds of the present invention are novel steroidal tissue selective estrogens.

Estrogen therapy for the treatment of symptoms caused by hormone deficiency and the protective action of estrogens on bone, brain, blood vessels and other organ systems are established.

Estrogen therapy for the efficacy of estrogen in the treatment of symptoms caused by hormonal deficiencies such as hot flash, atrophy of estrogen target organs and incontinence, and prevention of bone mass loss in postmenopausal and postmenopausal women Successful use is well known and generally accepted (Grady et al. 1992, Ann Intern Med 117: 1016-1037). Estrogen replacement therapy in postmenopausal women or women with ovarian dysfunction due to other causes is also known to reduce the risk of cardiovascular disease as compared to women with estrogen untreated (Grady et al., Loc. Cit. ).

In addition, more recent studies have shown the protective action of estrogens against neurodegenerative diseases such as Alzheimer's disease (Henderson 1997, Neurology 48 (Suppl 7): pp. 27-35; Birge 1997, Neurology 48 (Suppl 7): pp, 36- 41), protective action against brain functions such as memory and learning ability (McEwen et al., 1997, Neurology 48 (Suppl 7); pp. 8-15; Sherwin 1997, Neurology 48 (Suppl 7); pp. 21- 26), as well as the protective action against mood fluctuations caused by hormone deficiency (Halbreich 1997, Neurology 48 (Suppl 7): pp. 16-20).

In addition, estrogen replacement therapy has been shown to be effective against the reduction of colorectal carcinoma (Calle, E.F. et al., 1995, J Natl Cancer Inst 87: 517-523).

In conventional estrogen or hormone replacement therapy (= HRT) conjugated estrogens consisting of natural estrogens such as estradiol and horse urine are used alone or in combination with progesterone. Instead of natural estrogens, derivatives obtained by esterification, for example 17β-estradiol valerate, may also be used.

Because of the stimulating action of estrogen on the endometrium causing an increased risk of endometrial carcinoma (Harlap, S. 1992, Am J Obstet Gynecol 166: 1986-1992), estrogen / progesterone combinations are preferably used in hormone replacement therapy . The progesterone component in the estrogen / progesterone complex avoids endometrial hypertrophy, but undesirable intracyclic menstrual bleeding is also associated with the progesterone containing complex.

Selective estrogens are a more recent replacement for estrogen / progesterone combination formulations. To date, selective estrogens have been defined as compounds that have estrogen-like effects on the brain, bone and vascular system due to antihypertrophic (ie antiestrogenic) partial action, but do not have a proliferative effect on the endometrium.

A substance in the group that partially satisfies the desired profile of selective estrogens is the so-called "selective estrogen receptor modulator" (SERM) (RF Kauffman, HU Bryant 1995, DNAP 8 (9): 531-539). In this case they are partial agonists of the estrogen receptor subtype "ERα". However, these types of substances have no effect on the treatment of acute postmenopausal symptoms such as hot flashes. An example of SERM is raloxifene, which has recently been introduced as an indication for osteoporosis.

Estrogen Receptor Beta (ERβ)

Estrogen receptor β (ERβ) has recently been discovered as the second subtype of estrogen receptor (Kuiper et al. (1996), Proc. Natl. Acad. Sci. 93: 5925-5930; Mosselman, Dijkema (1996) Febs Letters 392: 49-53; Tremblay et al. (1997), Molecular Endocrinology 11: 353-365). The expression pattern of ERβ is different from ERα (Kuiper et al. (1996), Endocrinology 138: 863-870). Thus, ERβ is superior to ERα in the rat prostate, while ERα is superior to ERβ in the rat uterus. Regions in which only one of the two ER-subtypes are expressed have been identified in the brain (Shugrue et al. (1996), Steroids 61: 678-681; Li et al. (1997), Neuroendocrinology 66: 63-67). ERβ is expressed in regions that are considered important for cognitive processes and “mood” (Shugrue et al. 1997, J Comparative Neurology 388: 507-525).

Molecular targets for ERβ in this brain region may be 5HT2a-receptors and serotonin transporters (G. Fink & B.E.H. Sumner 1996 Nature 383: 306; B.E.H. Sumner et al. 1999 Molecular Brain Research, in press). The neurotransmitter serotonin (5-hydroxytrytamine) is involved in the regulation of a number of processes that can be damaged during menopause. In particular, the effects of menopause on emotion and cognition are associated with the serotonergic system. Estrogen replacement therapy has proven to be effective in treating symptoms caused by these estrogen deficiencies, perhaps by modulating serotonin receptor and transporter expression.

Other organ systems with significantly higher ERβ expression include bone (Onoe, Y. et al. 1997, Endocrinology 138: 4509-4512), vascular system (Register, TC, Adams, MR 1998, J. Steroid Molec Biol 64: 187-191), Urinary tract (Kuiper, GJM et al. 1997, Endocrinology 138: 863-870), gastrointestinal tract (Campbell-Thopson 1997, BBRC 240: 478-483), as well as semen (Shugrue et al. 1998, Steroids 63L 498-504). Testicles (Mosselmann, S. et al. 1996 Febs Lett 392 49-53). Tissue distribution suggests that estrogens regulate tissue function through ERβ. The fact that ERβ is functional in this respect has also been recognized by studies in ERα- (ERKO) or ERβ- (βERKO) -knockout mice, where ovarian dissection results in bone mass loss in ERKO-mouse, which is an estrogen substitution. (Kimbro et al. 1998, Abstract OR7-4, Endocrine Society Meeting New Orleans). Estradiol in the blood vessels of female ERKO mice also inhibits vascular media and muscle cell proliferation (Iafrati, M.D. et al. 1997, Nature Medicine 3: 545-548). The protective action of estrodiol is presumed to be via ERβ, presumably in ERKO mice.

Observation of βERKO mice indicates the function of ERβ in the prostate and bladder. In older male mice, prostate and bladder hypertrophy symptoms occur (Krege, J. H. et al. 1998, Proc Natl Acad Sci 95: 15677-15682). In addition, female βERKO mice (Lubahn, DB et al. 1993, Proc Natl Acad Sci 90: 11162-11166) and male ERKO mice (Hess, RA et al. 1997, Nature 390: 509-512) as well as female βERKO mice ( Krege, JH, 1998) have a fertility disorder. As a result, the prostate and ovarian functions as well as the important functions of estrogens for maintaining fertility have been identified.

It was possible to achieve selective estrogen action on specific target organs by subtype specific ligands based on different tissue or organ distributions of the two subtypes of ER. Materials with higher affinity for ERβ as compared to ERα in in vitro receptor binding tests are described in Kuiper et al. (Kuiper et al. (1996), Endocrinology 138: 863-870). The selective action of subtype selective ligands of the estrogen receptor on estrogen sensitivity parameters in vivo has not previously been shown.

Accordingly, it is an object of the present invention to prepare compounds having a separation for binding to estrogen receptor preparations obtained from rat prostate and rat uterus in vitro and having a separation for bone against uterine action in vivo. The compound has a higher affinity for estrogen receptor preparations from the rat prostate than the estrogen receptor preparations from the rat uterus in vitro and bone mass caused by hormone deficiency compared to uterine stimulation in the uterus in vivo. Higher potency against protection against loss and / or significant action on stimulation of expression of 5HT2a-receptors and 5HT2a-carriers.

In a broader sense, a structure-action correlation is made possible by the present invention that allows access to a compound having the above-described pharmacological profile of better estrogenous action on the bone than on the uterus.

According to the invention, this object is achieved by the 8β-substituted estra-1,3,5 (10) -triene derivative of formula (I ′) for the treatment of diseases and conditions caused by estrogen deficiency.

Where

Where

R ² is a hydrogen atom, a halogen atom, a R ¹⁸ -or R ¹⁸ -O- radical, where R ¹⁸ is a hydrogen atom or a straight or branched chain saturated or unsaturated hydrocarbon radical having up to 6 carbon atoms, a trifluoromethyl group ), R ¹⁹ SO ₂ -O- group, wherein R ¹⁹ is a R ²⁰ R ²¹ N group, R ²⁰ and R ²¹ are independently of each other a hydrogen atom, a C ₁ -C ₅ -alkyl radical, C (O) R ^{Is a 22} group, R ²² is 10 or less carbon atoms, unsaturated or optionally partially or completely halogenated hydrocarbon radical, optionally substituted C ₃ -C _7- A cycloalkyl radical, an optionally substituted C ₄ -C ₁₅ -cycloalkylalkyl radical or an optionally substituted aryl, heteroaryl or aralkyl radical, or a polymethyleneimino radical having 4 to 6 carbon atoms with N-atoms or Morpholino radicals;

R ³ is an R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -OC (O) R ²² group (R ¹⁸ , R ¹⁹ and R ²² in each case have the same meaning as indicated for R ² , R ¹⁸ may be an aryl, heteroaryl or aralkyl radical;

R ⁶ and R ⁷ are each hydrogen atoms or together represent additional bonds;

R ^{6 '} and R ^7' are independently of each other a hydrogen atom, a halogen atom, R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² groups (R ¹⁸ , R ¹⁹ and R ²² in each case are R Meaning as indicated in ² );

R ⁸ is up to 5 carbon atoms and is a straight or branched chain alkyl or alkenyl radical, ethynyl or prop-1-ynyl radical, optionally partially or fully halogenated;

R ⁹ is a hydrogen atom, a straight or branched chain, saturated or unsaturated hydrocarbon radical having up to 5 carbon atoms, or represents an additional bond with R ¹¹ ;

R ¹¹ is a hydrogen atom or represents an additional bond together with R ⁹ or together with R ¹² ;

R ^{11 '} is a hydrogen atom, a halogen atom, optionally partially or fully halogenated (F, Cl) saturated or unsaturated hydrocarbon radical (the hydrocarbon radical has a maximum straight chain length of 4 carbon atoms), or -XR ^{18 Is a} group wherein X is an oxygen or sulfur atom and R ¹⁸ is an alkyl radical of 1 to 3 carbon atoms;

R ¹² is a hydrogen atom or represents an additional bond with R ¹¹ ;

R ¹⁴ is a hydrogen atom or represents an additional bond with R ¹⁵ ;

R ¹⁵ is a hydrogen atom or represents an additional bond together with R ¹⁴ or together with R ¹⁶ ;

R ¹⁶ is a hydrogen atom or represents an additional bond with R ¹⁵ ;

R ^{15 '} and R ^16' are independently of each other a hydrogen atom, a halogen atom, R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² groups (R ¹⁸ , R ¹⁹ and R ²² in each case are R Meaning as indicated in ² );

R ¹⁷ and R ^{17 '} are hydrogen atoms; Hydrogen atom and halogen atom; Hydrogen atom and benzyloxy group; Hydrogen atom and R ¹⁹ SO ₂ —O— group; R ¹⁸ groups and —C (O) R ²² or —OC (O) R ²² groups; R ¹⁸ -O- and R ¹⁸ -groups; R ¹⁸ —O— and —OC (O) —R ²² groups (in all cases R ¹⁸ , R ¹⁹ and R ²² in each case have the meaning as indicated for R ² ); or

R ¹⁷ and R ^{17 '} together are a = CR ²³ R ²⁴ group, wherein R ²³ and R ²⁴ are independently of each other a hydrogen atom and a halogen atom or together are an oxygen atom.

Possible substituents on the carbon atoms, 6, 7, 9, 11, 15, 16 and 17 can be in the α- or β-position individually.                 

According to a variant of the invention, preferred compounds of formula I 'are used, wherein

R ² is hydrogen or a halogen atom or a hydroxy group;

R ³ represents an R ¹⁸ —O—, R ¹⁹ SO ₂ —O— or —OC (O) R ²² group (R ¹⁸ , R ¹⁹ and R ²² in each case have the meaning as indicated in R ² of claim 1). And further R ¹⁸ may be an aryl or aralkyl radical);

R ⁶ and R ⁷ are each a hydrogen atom;

R ^{6 '} is a hydrogen atom, a hydroxy group, a R ²² group (R ²² group has the same meaning as indicated in R ² );

R ^{7 ′} is a hydrogen atom, a halogen atom, R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or a R ²² group (R ¹⁸ , R ¹⁹ and R ²² in each case have the meaning as indicated for R ² )ego;

R ⁸ is up to 5 carbon atoms and is a straight or branched chain alkyl or alkenyl radical, ethynyl- or prop-1-ynyl radical, optionally partially or fully halogenated;

R ⁹ is a hydrogen atom or represents an additional bond with R ¹¹ ;

R ¹¹ is a hydrogen atom or represents an additional bond with R ⁹ ;

R ^{11 '} is a hydrogen atom, a halogen atom, optionally partially or fully halogenated (F, Cl) saturated or unsaturated hydrocarbon radical, wherein the hydrocarbon radical has a maximum straight chain length of 4 carbon atoms in length, or -XR ^{18 Is a} group wherein X is a sulfur atom and R ¹⁸ is an alkyl radical of 1 to 3 carbon atoms;

R ¹² , R ¹⁴ , R ¹⁵ and R ¹⁶ in each case represent a hydrogen atom;

R ^{16 '} is a hydrogen atom, a halogen atom, R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or a R ²² group (R ¹⁸ , R ¹⁹ and R ²² in each case have the meaning as indicated for R ² )ego;

R ¹⁷ and R ^{17 '} are at each occurrence a hydrogen atom; Hydrogen atom and halogen atom; Hydrogen atom and benzyloxy group; Hydrogen atom and R ¹⁹ SO ₂ —O— group; R ¹⁸ groups and —C (O) R ²² or —OC (O) R ²² groups; R ¹⁸ -O- and R ¹⁸ -groups; R ¹⁸ —O— and —OC (O) —R ²² groups (in all cases R ¹⁸ , R ¹⁹ and R ²² in each case have the meaning as indicated for R ² ); or

R ¹⁷ and R ^{17 '} together are a = CR ²³ R ²⁴ group, wherein R ²³ and R ²⁴ are independently of each other a hydrogen atom and a halogen atom or together are an oxygen atom.

Another preferred variant of the invention relates to the use of a compound of formula I 'wherein                 

R ² is hydrogen or a fluorine atom or a hydroxyl group;

R ³ is an R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -OC (O) R ²² group (R ¹⁸ , R ¹⁹ and R ²² in each case have the same meaning as indicated for R ² , R ¹⁸ may be an aryl or aralkyl radical;

R ⁶ and R ⁷ are at each occurrence a hydrogen atom;

R ^{6 '} is a hydrogen atom or a hydroxy group;

R ^{7 '} is a hydrogen atom, a fluorine or chlorine atom, R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or a R ²² group (R ¹⁸ , R ¹⁹ and R ²² in each case are as defined for R ² Has;

R ⁸ is 5 or fewer carbon atoms and is a straight or branched chain alkyl or alkenyl radical, ethynyl radical or prop-1-ynyl radical, optionally partially or fully halogenated;

R ⁹ are independently of each other a hydrogen atom, or represent an additional bond with R ¹¹ ;

R ^{11 '} is a hydrogen atom, a fluorine or chlorine atom, a saturated straight or branched C ₁ -C ₄ -alkyl group, a -XR ^18' group where X is a sulfur atom and R ^{18 '} is a saturated straight or branched chain C ₁ -C ₃ -alkyl group, chloromethyl or chloroethyl group;

R ¹² , R ¹⁴ , R ¹⁵ and R ¹⁶ are in each case a hydrogen atom;

R ^{16 '} is a hydrogen atom, a fluorine or chlorine atom, a R ¹⁸ -O- or R ²² group (R ¹⁸ and R ²² in each case have the meaning as indicated for R ² );

R ¹⁷ and R ^{17 '} are at each occurrence a hydrogen atom; Hydrogen atom and halogen atom; Hydrogen atom and benzyloxy group; Hydrogen atom and R ¹⁹ SO ₂ —O— group; R ¹⁸ groups and —C (O) R ²² or —OC (O) R ²² groups; R ¹⁸ -O- and R ¹⁸ -groups; R ¹⁸ —O— and —OC (O) —R ²² groups (in all cases R ¹⁸ , R ¹⁹ and R ²² in each case have the meaning as indicated for R ² ); or

R ¹⁷ and R ^{17 '} together are a = CR ²³ R ²⁴ group, wherein R ²³ and R ²⁴ are independently of each other a hydrogen atom and a halogen atom or together are an oxygen atom.

According to another variant, an 8β-substituted estra-1,3,5 (10) -triene derivative of formula I 'is used, wherein

R ^{6 '} , R ^7' , R ⁹ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ^{15 '} and R ¹⁶ represent a hydrogen atom in each case, or R ^6' , R ^{7 '} , R ¹⁴ , R ¹⁵ , R ^{15 ′} and R ¹⁶ in each case represent a hydrogen atom, R ⁹ and R ¹¹ together represent an additional bond and all other substituents have the meanings as indicated in claim 1.

If the estritriene derivative of formula (I ') comprises additional double bonds in the B-, C- and / or D-rings, one double bond is preferably at positions 9 (11), 14 (15) or 15 (16), or two double bonds are present at positions 9 (11) and 14 (15) or 15 (16).

Another variation of the invention is an estritriene derivative of formula I 'wherein R ¹⁷ and R ^17' are R ¹⁸ -O- and R ¹⁸ -groups; R ¹⁸ -group and —OC (O) R ²² group, R ¹⁸ and R ²² in each case have the meaning as indicated for R ² .

Among the above-mentioned ones, preferred are gonatiene derivatives in which R ¹⁷ and R ^{17 '} are a hydroxy group and a hydrogen atom, a C ₁ -C ₄ -alkyl group or a C ₂ -C ₄ -alkenyl group, particularly preferred are R ¹⁷ and R ^{17 '} is a hydroxyl group and a hydrogen atom, methyl, ethyl or prop-1-ynyl group.

Finally, in one embodiment R ^{16 ′} is a R ¹⁸ —O— or R ¹⁹ SO ₂ —O— group and R ¹⁸ and R ¹⁹ in each case have the meaning as indicated for R ² ; R ¹⁷ and R ^{17 '} are each a hydrogen atom and all other substituents may have the meanings as shown in formula (I').

Preferably, the present invention relates to the use of one or more of the following compounds:

8β-methyl-estra-1,3,5 (10), 9 (11) -tetraene-3,17β-diol

3-methoxy-8β-methyl-estra-1,3,5 (10), 9 (11) -tetraen-17β-ol

8β-methyl-estra-1,3,5 (10) -triene-3,17β-diol

3-methoxy-8β-methyl-estra-1,3,5 (10) -trien-17β-ol

8β-vinyl-estra-1,3,5 (10), 9 (11) -tetraene-3,17β-diol

3-methoxy-8β-vinyl-estra-1,3,5 (10), 9 (11) -tetraen-17β-ol

8β- (2 ', 2'-difluorovinyl) -estra-1,3,5 (10), 9 (11) -tetraene-3,17β-diol

8β- (2'2'-difluorovinyl) -3-methoxy-estra-1,3,5 (10), 9 (11) -tetraen-17β-ol

8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17β-ol

8β- (2 ', 2'-difluorovinyl) -estra-1,3,5 (10) -triene-3,17β-diol

8β- (2 ', 2'-difluorovinyl) -3-methoxy-estra-1,3,5 (10) -trien-17β-ol

8β-ethyl-estra-1,3,5 (10) -triene-3,17β-diol

8β-ethyl-3-methoxy-estra-1,3,5 (10) -trien-17β-ol

8β-vinyl-estradiol-3-sulfate

8β-vinyl-estradiol-3,17-disulfamate

8β-vinyl-estradiol-3- (N-acetyl) -sulfate                 

8β-vinyl-estrone-3-sulfate

8β-vinyl-estrone-3-acetate

8β-vinyl-estriol

8β-vinyl-estriol-3-sulfate

8β-methyl-estrone-3-sulfate

8β-methyl-estriol

8β- (prop- (Z) -enyl) -estradiol

8β- (n-propyl) -estradiol

8β-ethynyl-estradiol

17α-ethynyl-8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

17α-methyl-8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

16α-fluoro-8β-methyl-estra-1,3,5 (10) -triene-3,17β-diol

8β-vinyl-estra-1,3,5 (10) -triene-3,17α-diol

8β-methyl-estra-1,3,5 (10) -triene-3,17α-diol

8β-vinyl-estradiol-diacetate

8β-methyl-estradiol-diacetate

8β-vinyl-estradiol-17-valerate

17β-acetoxy-8β-vinyl-estra-1,3,5 (10) -trien-3-ol

8β-vinyl-9β-estra-1,3,5 (10) -triene-3,17β-diol

8β-ethyl-9β-estra-1,3,5 (10) -triene-3,17β-diol.                 

Other possible arrangements of the invention may be included in the dependent claims.

In addition to the use of the compounds of formula (I ′) above, the invention also relates to the compounds of formula (I) per se. These are

R ³ is a hydroxy, methoxy or acetyl group and at the same time

R ² is a hydrogen atom,

R ⁶ , R ^{6 '} , R ⁷ and R ^7' in each case are hydrogen atoms,

R ⁸ is a methyl group,

R ⁹ is a hydrogen atom, or

R ⁹ and R ¹¹ together represent an additional bond,

R ^{11 '} and R ¹² are in each case a hydrogen atom,

R ¹⁴ , R ¹⁵ , R ^{15 '} , R ¹⁶ and R ^16' in each case represent a hydrogen atom,

R ¹⁷ and R ^{17 '} are a β-hydroxy group and a hydrogen atom; β- (2-bromoacetyl) oxy group and hydrogen atom; β-acetyl group and hydrogen atom; or represent a β-carboxyl group and a hydrogen atom, or

R ¹⁷ and R ^{17 '} together are compounds of formula I' except for compounds of formula I 'which are oxygen atoms.

Such groups of compounds not claimed in the scope of formula (I ′) are those already known from the following patents and literature:

FR M2743

Los, Marinus; US 3806546

Los, Marinus; US 3736345

Los, Marinus; US 3681407

Los, Marinus; US 3501530

Nagata, Wataru; Itazaki, Hiroshi; JP 45024573

Nagata, Wataru; Itazaki, Hiroshi; Takegawa, Bunich; JP 45024139

Nagata, Wataru; Aoki, Tsutomu; Itazaki, Hiroshi; JP 45004060

Nagata, Wataru; Aoki, Tsutomu; Itazaki, Hiroshi, JP 45004059

Nagata, Wataru; Aoki, Tsutomu; Itazaki, Hiroshi; JP 45004058

Sakai, Kiyoshi; Amemiya, Shigeo; Chem. Pharm. Bull (1970), 18 (3), 641-3

Yoshioka, Kouichi; Goto, Giichi; Hiraga, Kentaro; Miki, Takuichi; Chem. Pharm. Bull. (1973), 21 (11), 2427-31

Tori, K; Editor (s): James, Vivian H.T .: Horm. Steroids, Proc. Int. Congr., 3rd (1971), Meeting Date 1970, 205-13

Tsukuda, Yoshisuke; Sato, Tomohiro; Shiro, Motoo; Koyama, Hirozo; J. Chem. Soc. B (1969), (4), 336-41

Tsukuda, Yoshiko; Itazaki, Hiroshi; Nagata, Wataru; Sato, Tomohiro; Shiro, Motoo; Koyama, Hirozo; Chem. Ind. (London) (1967), (48), 2047-8

Nakai, Hisayoshi; Koyama, Hirozo; Acta Crystallogr. (1967), 23 (4), 674.

However, the use of the known compounds and the selective estrogen action of the present invention have not been described.

In most cases, the already known estririenes are commonly described as being used as intermediate compounds of the estrogen or in the analytical process.

In the formulas (I) and (I ') and in the substructures (II) and (II') described below, fluorine, chlorine, bromine or iodine atoms can always represent halogen atoms, with fluorine atoms being preferred in each case. For the 11β-position, specifically also the chlorine atom may be mentioned as a substituent. Specifically, hydrocarbon radicals that can be partially or fully halogenated are fluorinated radicals.

Hydrocarbon radicals R ¹⁸ are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl or hexyl radicals.

The alkoxy group OR ¹⁸ in the compounds of the formulas (I) and (I ') and in the substructures (II) and (II') described below may in each case contain 1 to 6 carbon atoms, And t-butyloxy group are preferred.

Representative of the C ₁ -C ₅ -alkyl radicals R ²⁰ and R ²¹ are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and neopentyl.

Representative of straight or branched chain hydrocarbon radicals R ²² having 1 to 10 carbon atoms are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neonetyl , Heptyl, hexyl and decyl, with methyl, ethyl, propyl and isopropyl being preferred.

Examples of the perfluorinated alkyl group include trifluoromethyl, pentafluoroethyl, and nonafluorobutyl. Representatives of partially fluorinated alkyl groups are, for example, 2,2,2-trifluoroethyl, 5,5,5,4,4-pentafluoropentyl, 6,6,6,5,5,4 , 4,3,3, -nonafluorohexyl and the like.

Examples of the C ₃ -C ₇ -cycloalkyl group include a cyclopropyl, butyl, pentyl, hexyl or heptyl group.

C ₄ -C ₁₅ -cycloalkylalkyl radicals have 3 to 7 carbon atoms in the cycloalkyl moiety, typical examples being the cycloalkyl groups mentioned above. The alkyl moiety has up to eight carbon atoms.

Examples of C ₄ -C ₁₅ -cycloalkylalkyl radicals include cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylpropyl groups, and the like.

In the context of the present invention, the aryl radicals are phenyl, 1- or 2-naphthyl radicals, with phenyl radicals being preferred.

Aryl also always includes heteroaryl radicals. Examples of heteroaryl radicals are 2-, 3- or 4-pyridinyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imida Zolyl, pyrazinyl, 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radicals.

Substituents for aryl or heteroaryl radicals are, for example, methyl-, ethyl-, trifluoromethyl-, pentafluoroethyl-, trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cya No-, halogen- (fluorine, chlorine, bromine, iodine), hydroxy-, amino-, mono (C _1-8 -alkyl) _-or di (C _1-8 -alkyl) amino (where the alkyl groups are all the same) Or different) and di (aralkyl) amino, wherein the aralkyl groups are all the same or different.

Aralkyl radicals are radicals containing up to 14, preferably 6 to 10 carbon atoms in the ring and 1 to 8, preferably 1 to 4 carbon atoms in the alkyl chain. Thus, as aralkyl radicals, for example benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl and pyridylpropyl are suitable. The ring may be halogen, OH, O-alkyl, CO ₂ H, CO ₂ -alkyl, -NO ₂ , -N ₃ , -CN, -C ₁ -C ₂₀ -alkyl, C ₁ -C ₂₀ -acyl Or a C ₁ -C ₂₀ -acyloxy group.

The alkyl group or hydrocarbon radical may be partially or fully fluorinated or substituted by 1-5 halogen atoms, hydroxy groups or C ₁ -C ₄ -alkoxy groups.

Vinyl or allyl radicals are essentially defined as C ₂ -C ₅ -alkenyl radicals.

Other variations of the invention include one or more optionally conjugated double bonds in rings B, C and D of the estradione backbone, specifically positions 6, 7; 7, 8; 9, 11; 11, 12; 14, 15 and 15, 16 provide one or more double bonds. In this case, one double bond at positions 7, 8 or 11, 12 or two double bonds at positions 6, 7 and 8. 9 are preferred (ie the naphthalene system is formed with an aromatic A-ring).

One or more hydroxyl groups of carbon atoms 3, 16 and 17 are aliphatic, straight or branched, saturated or unsaturated C ₁ -C ₁₄ -mono- or polycarboxylic acids or aromatic carboxylic acids or α- or β-amino acids It can be esterified.

Suitable carboxylic acids for esterification include, for example:

Monocarboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, Oleic acid and elideic acid.

Preference is given to esterification with acetic acid, valeric acid or pivalic acid.

Dicarboxylic acids: oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, muconic acid, citraconic acid and mesaconic acid.

Aromatic carboxylic acids: benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, o-, m- and p-toluic acid, hydratroic acid, atroic acid, cinnamic acid, nicotinic acid and isnicotinic acid.

Preference is given to esterification with benzoic acid.                 

As amino acids, representative of these groups of compounds well known to those skilled in the art, for example, alanine, β-alanine, arginine, cysteine, cystine, glycine, histidine, leucine, isoleucine, phenylalanine, proline and the like are suitable.

Preference is given to esterification with β-alanine.

Preferred compounds according to the invention are as follows:

8β-vinyl-estra-1,3,5 (10), 9 (11) -tetraene-3,17β-diol

3-methoxy-8β-vinyl-estra-1,3,5 (10), 9 (11) -tetraen-17β-ol

8β- (2 ', 2'-difluorovinyl) -estra-1,3,5 (10), 9 (11) -tetraene-17β-diol

8β- (2 ', 2'-difluorovinyl) -3-methoxy-estra-1,3,5 (10), 9 (11) -tetraen-3,17β-ol

8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17β-ol

8β- (2 ', 2'-difluorovinyl) -estra-1,3,5 (10) -triene-3,17β-diol

8β- (2 ', 2'-difluorovinyl) -3-methoxy-estra-1,3,5 (10) -trien-17β-ol

8β-ethyl-estra-1,3,5 (10) -triene-3,17β-diol

8β-ethyl-3-methoxy-estra-1,3,5 (10) -trien-17β-ol

8β-vinyl-estradiol-3-sulfate

8β-vinyl-estradiol-3,17-disulfamate

8β-vinyl-estradiol-3- (N-acetyl) -sulfate

8β-vinyl-estrone-3-sulfate                 

8β-vinyl-estrone-3-acetate

8β-vinyl-estriol

8β-vinyl-estriol-3-sulfate

8β-methyl-estrone-3-sulfate

8β-methyl-estriol

8β- (prop- (Z) -enyl) -estradiol

8β- (n-propyl) -estradiol

8β-ethynyl-estradiol

17α-ethynyl-8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

17α-methyl-8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

16α-fluoro-8β-methyl-estra-1,3,5 (10) -triene-3,17β-diol

8β-vinyl-estra-1,3,5 (10) -triene-3,17α-diol

8β-methyl-estra-1,3,5 (10) -triene-3,17α-diol

8β-vinyl-estradiol-diacetate

8β-methyl-estradiol-diacetate

8β-vinyl-estradiol-17-valerate

17β-acetoxy-8β-vinyl-estra-1,3,5 (10) -trien-3-ol

8β-vinyl-9β-estra-1,3,5 (10) -triene-3,17β-diol

8β-ethyl-9β-estra-1,3,5 (10) -triene-3,17β-diol.

Another aspect of the invention is a component of the total structure of a compound having an in vitro separation of binding to the estrogen receptor preparations of the rat prostate and the rat uterus, in particular a compound that is predominantly isolated for estrogenous action on bone than the uterus. And to the use of the structural moiety (8β-substituted estra-1,3,5 (10) triene-structural moiety), which is one element of the total structure of.

Wherein R ⁸ represents a straight or branched chain alkyl or alkenyl radical, ethynyl or prop-1-ynyl radical having up to 5 carbon atoms and optionally partially or fully halogenated.

In addition to the aromatic A-ring, one or more double bonds may be selected from position 6 (7) in the B-, C- and / or D-rings; 9 (11); 11 (12); 14 (15) and 15 (16).

Possible substituents for the carbon atoms 6, 7, 11, 15 and 16 may be in the α- or β-position individually.

The present invention preferably relates to the structural moiety of the formula (II ′).                 

Wherein R ⁸ is 5 or fewer carbon atoms and is a straight or branched chain alkyl or alkenyl radical, ethynyl or prop-1-ynyl radical, optionally partially or completely halogenated.

In the same way, these structural moieties may have one or more double bonds in the B-, C- and / or D-rings in addition to the aromatic A-rings.

Possible substituents of 6, 7, 11, 15, 16 and 17 carbon atoms may in each case be in the α- or β-position in turn.

As prodrugs, the esters of 8β-substituted estritriene according to the present invention have advantages in terms of mode of administration, mode of action, strength of action and duration as compared to their unesterified active ingredients.

The sulfamate of 8β-substituted estradione according to the present invention also has pharmacodynamic and pharmacokinetic advantages. Related effects have already been described for other steroid-sulfamates (J. Steroid Biochem. Molec. Biol, 55, 395-403 (1995); Exp. Opinion Invest. Drugs 7, 575-589 (1998)).

Herein, steroids based on the 8β-substituted estra-1,3,5 (10) triene backbone have in vitro isolation with respect to binding to the estrogen receptor preparations of the rat prostate and rat uterus, It is preferably described for the treatment of estrogen receptor β-mediated diseases and conditions as, for example, selective estrogens with separation for bone function rather than uterine action. These components act in a bone-protective manner over a wide range of doses without irritating the uterus.

In addition, in male rats the substance may have a protective action against bone mass loss caused by prostatectomy without inhibiting the secretion of the pituitary hormones LH and FSH. Their liver action is small in the same dose range.

In addition, the substance exerts an estrogen-like action on the vascular system and brain function. The material, which has a higher binding capacity to the rat prostate as compared to the rat uterine estrogen receptor, is more potent in increasing the expression of serotonin receptors and transporters compared to the positive effect on LH release. Thus, the processes involved in the regulation of the neurotransmitter serotonin are advantageously affected, and the compounds according to the invention particularly have a beneficial effect on mood and cognition.

They can be used as estrogens described in WO 97/45125 for the manufacture of drugs which affect the level of serotonin or serotonin mRNA in humans.

The 8β-substituted estra-1,3,5 (10) trienes according to the present invention are characterized by a greater amount of estrogen receptor β than the estrogen receptor α in the corresponding target tissues or target organs. It is suitable as a selective estrogen for therapy.                 

The present invention also provides the use of a compound of formula (I ') for the preparation of a pharmaceutical formulation containing one or more compounds of formula (I or its physiologically suitable salts with organic and inorganic acids) and in particular pharmaceutical actives such as the following indications: It is about.

The compounds can be used in the following indications after oral and parenteral administration.

The novel selective estrogens described herein can be used as individual components in pharmaceutical formulations or in particular with antiestrogens or progesterone. Particularly preferred are combinations of selective estrogens with ERα-selective antiestrogens, or combinations of antiestrogens with peripheral selective activity (ie, not passing through the brain-blood barrier).

Such substances and pharmaceutical actives containing them are particularly suitable for the treatment of pre and postmenopausal and postmenopausal symptoms, particularly emotional disorders caused by hot flashes, sleep disorders, irritability, mood fluctuations, incontinence, vaginal atrophy and hormonal deficiency. Also suitable are hormone replacements and substances for the treatment of symptoms caused by hormone deficiency in the case of ovarian dysfunction caused by surgery, drugs or other methods. Loss of bone mass is also part of postmenopausal women and male menopause, hysterectomy women, or women receiving LHRH agonists or LHRH antagonists.

The compounds are also suitable for alleviating the symptoms of male and female menopause, i.e. both male and female hormone replacement therapy (HRT), specifically for the prevention and treatment of symptoms associated with the treatment of menstrual irregularities and acne.

In addition, the substance may be used for the prevention of bone mass loss and osteoporosis caused by hormone deficiency, prevention of cardiovascular diseases, in particular vascular diseases such as vascular atherosclerosis, inhibition of arterial smooth muscle proliferation, treatment of primary pulmonary hypertension, and Alzheimer's disease as well. But can also be used to prevent neurodegenerative diseases caused by hormonal deficiencies, such as impairment of memory and learning ability caused by hormonal deficiency.

The substance can also be used for the treatment of inflammatory diseases and diseases of the immune system, in particular autoimmune diseases such as rheumatoid arthritis.

The compounds can also be used for the treatment of male infertility disorders and prostate disease.

The compounds may also be used with natural vitamin D3 or in combination with calcitriol analogs for bone formation or as adjuvant therapy of therapies that cause bone mass loss (eg, glucocorticoid therapy, harmonization).

Finally, the compounds of formula (I ′) can be used in combination with progesterone receptor antagonists, in particular for hormone replacement therapy and for the treatment of gynecological disorders.

Therapeutic products containing estrogens and pure anti-estrogens used simultaneously, sequentially or separately as a selective estrogen therapy in premenopausal or postmenopausal states are already described in EP-A 0 346 014.

The amount of the compound of formula I 'administered may vary over a wide range and may include all effective amounts. Based on the condition treated and the mode of administration, the amount of the compound administered is 0.01 μg to 10 mg / kg body weight per day, preferably 0.04 μg to 1 mg / kg body weight per day.                 

In humans, this corresponds to a dose of 0.8 μg to 800 mg, preferably 3.2 μg to 80 mg per day.

According to the invention, the dosage unit contains 1.6 μg to 200 mg of at least one compound of formula (I ′).

The compound according to the invention is an acid addition salt suitable for the preparation of pharmaceutical compositions and formulations. A pharmaceutical composition or pharmaceutically active substance comprises, as active ingredient, at least one compound according to the invention or acid addition salts thereof in admixture with other pharmacological or pharmaceutically active substances. The preparation of pharmaceutical actives is carried out by known methods, in which known and commonly used pharmaceutical adjuvants as well as other commonly used vehicles and diluents can be used.

As such vehicles and auxiliaries, for example, those recommended or indicated in the literature as auxiliaries for pharmaceuticals, cosmetics and related fields are suitable: Ullmans Encyklopaedie der technischen Chemie [Ullman's Encyclopedia of Technical Chemistry], Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 ff., Issued by Czetsch-Lindenwald, Hilfsstoffe fuer Pharmazie und angrenzende Gebiete [Adjuvants for Pharmaceutics and Related Fields]; Pharm. Ind., Issue 2, 1961, p. 72 and ff .: H.P. Fiedler, Lexikon der Hilfsstoffe fuer Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics, Cosmetics and Related Fields], Cantor KG, Aulendorf in Wuerttemberg 1971.                 

The compound may be administered orally or parenterally, eg, intraperitoneally, intramuscularly, subcutaneously or transdermally. The compound may also be implanted in tissue.

For oral administration, capsules, pills, tablets, coated tablets and the like are suitable. In addition to the active ingredient, the dosage unit may contain pharmaceutically suitable vehicles such as starch, sugars, sorbitol, gelatin, glidants, silicic acid, talc, and the like.

For parenteral administration, the active ingredient may be dissolved or dispersed in a physiologically suitable diluent. As diluents, oils are very often used together or alone with solubilizers, surfactants, dispersants or emulsifiers. Examples of oils used include olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.

The compounds may also be used in the form of depot injection or implantable preparations which may be formulated to allow delayed release of the active ingredient.

As the inert material, the implant may include, for example, a biodegradable polymer, or synthetic silicone, such as silicone rubber. In addition, for transdermal administration, the active ingredient may be added to the patch, for example.

A variety of polymers for the preparation of intravaginal systems (e.g. vaginal rings) or intrauterine systems (e.g. pessaries, coils, IUDs, Mirena) for loading the active compounds of formula I 'for topical administration Silicone polymers, ethylene vinyl acetate, polyethylene or polypropylene are used, for example.

In order to obtain better bioavailability of the active ingredient, the compounds may also be formulated into cyclodextrin inclusions. For this purpose, the compounds react with α-, β- or γ-cyclodextrins of PCT / EP95 / 02656.

According to the invention, the compounds of the formula I 'can also be enclosed in liposomes.

Way

Estrogen Receptor Binding Study

The binding affinity of the novel selective estrogens was tested in a competitive experiment using 3H-estradiol as a ligand for estrogen receptor preparations in the rat prostate and rat uterus. Preparation of the prostate cytoplasm and testing of estrogen receptors into the prostate cytoplasm are described in Testas et al. (1981) [Testas, J. et al., 1981, Endocrinology 109; 1287-1289.

Preparation of the rat uterine cytoplasm and receptor testing using the ER-containing cytoplasm are basically as described by Stack and Gorski (1985) (Stack, Gorski 1985, Endocrinology 117, 2024-2032). Furrmann et al. (1995), Fuhrmann, U. et al. 1995, Contraception 51: 45-52].

The materials described herein have a higher binding affinity for the estrogen receptors of the rat prostate than the estrogen receptors of the rat uterus. In this case, it is assumed that ERβ prevails over ERα in the rat prostate, and ERα prevails over ERβ in the rat uterus. Table 1 shows that the ratio of binding to prostate and uterine receptors matches the ratio of relative binding affinity (RBA) to rat human ERβ and ERα (Kuiper et al. (1996), Endocrinology 138: 863-870). (Table 1).

^* Kuiper et al. (1996), Endocrinology 138: 863-870.

Table 2 shows the results for the compounds 8β-methyl-estra-1,3,5 (10) -triene-3,17β-diol (compound D) used according to the invention as well as the following compounds according to the invention .

8β-vinyl-estra-1,3,5 (10), 9 (11) -tetraene-3,17β-diol (A)

8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (B)

8β- (2,2-difluorovinyl) -estra-1,3,5 (10) -triene-3,17β-diol (C) and                 

8β-ethyl-estra-1,3,5 (10) -triene-3,17β-diol (E).

Compounds A, B, C, D and E show higher binding affinity for the estrogen receptors of the rat prostate than the estrogen receptors of the rat uterus.

In addition, the predictability of the “prostate-ER versus uterine-ER test system” has been confirmed for tissue selective action by in vivo studies. Substances that are preferred for prostate-ER are separated in vivo, preferably for bone and uterine action, with predominantly action on the bone. In addition, substances with higher affinity for the rat prostate compared to the rat uterine estrogen receptor are more potent in increasing the expression of serotonin receptors and transporters compared to the positive effects on LH release.

Bone research

Three month old female rats were ovarian resected and treated once daily for 28 days with test compounds. Percutaneously administered with arachis oil / ethanol. Animals were sacrificed the day after the last dose and the tibia and uterus were removed. The uterus was weighed, fixed and walked up for histological study. Bone density measurements were performed on iliac bone produced in vitro by pQCT (quantitative computer x-ray tomography). Measurements were made at the 4-6 mm position from the proximal tibia joint ball.

Ovarian ablation reduces the bone density of striae in the measurement area from about 400 mg Ca ²⁺ / cm 3 to about 300 mg Ca ²⁺ / cm 3. By treatment with a compound of formula (I) according to the invention, the degeneration of bone density is prevented or inhibited. The bone density of the proximal tibia was measured.

The higher binding affinity of the estrogen receptors of the rat prostate to the estrogen receptors of the rat uterus is represented in vivo, preferably by a significantly smaller amount of the compound according to the invention, and in contrast to complete animals undergoing false surgery, 28 days of ovarian resection 50% bone protection is generated (compared to the amount causing 50% uterine stimulation) against bone mass loss measurable in subsequent ovarian untreated female rats.

Vascular action of estrogens according to the present invention is not only a model of ApoE-knockout mice as described by R. Elhage et al. (1997) but also a model of vascular damage caused by balloon-catheter (a restenosis model). (Elhage, R. et al. 1997, Arteriosclerosis, Thrombosis and Vascular Biology 17: 2679-2684).

To detect the action of estrogens on brain function, oxytocin-, oxytocin receptor- or vasopressin-mRNA expression is used as a surrogate parameter (Hrabovszky, E. et al. 1998, Endocrinology 1339: 2600-2604). Ovariectomized mice are treated for 7 days with test substance or vehicle (administration: transdermal or oral, 6 times a day). Seven days after the first dose, the animals are choked, uterine weights are measured, and oxytocin-, oxytocin receptor- or vasopressin-mRNA levels are studied by in situ hybridization of appropriate brain secretion. ED ₅₀ values are measured for stimulation of uterine enlargement and for induction of oxytocin receptor mRNA.

Another possibility for confirming the isolated estrogen action of a substance according to the invention in vivo is to assess the expression of 5HT2a-receptor and serotonin transporter protein and mRNA levels in ERβ-rich brain regions after a single dose of the substance in rats. The effect can be measured. Compared to the effect on serotonin receptor and vehicle expression, the effect on LH-secretion is measured. Substances with higher binding to the rat prostate compared to the rat uterine estrogen receptor are more potent in increasing the expression of serotonin receptors and transporters compared to the positive effect on LH release. The density of serotonin receptors and transporters is measured in the brain region using radioactive ligands, and the corresponding mRNAs are measured using in situ hybridization. The method is described in G.Fink & B.E.R.H. Sumner 1996 Nature 383: 306; B.E.H.Sumner et al. 1999 Molecular Brain Reserch, in press.

Depending on the stronger binding to the rat prostate than the rat uterine estrogen receptor, the substances A, B, C, D and E according to the invention result in increased expression of serotonin receptors and transporters.

Preparation of the compounds according to the invention

Compounds of formula (I) (or I ') according to the invention are prepared as described in the Examples. Further compounds of formula (I ′) can be obtained by similar processes using reagents homogenous to the reagents described in the examples.

Etherification and / or esterification of the free hydroxy groups is carried out according to methods customary to those skilled in the art.

The compounds according to the invention may exist as α, β-stereoisomers at the carbon atoms 6, 7, 11, 15, 16 and 17. In the preparation of the compounds according to the described process, the compounds in most cases accumulate in a mixture of the corresponding α, β-isomers. The mixture can be separated by, for example, chromatographic methods.

According to formula (I), possible substituents may be present in the form of precursors, even in the final form, or even starting products, substituted estrone that already corresponds to the desired end product.

Thus, it is possible to introduce substituents on carbon atoms 7 or substituents on reactive precursors or 6-vinylsulfone by nucleophilic addition reactions (DE 42 18 743 A1). In this case, 7α- and 7β-substituted compounds, which can be separated by, for example, chromatographic methods, are obtained in different fractions based on the reactants and the selected reaction conditions.

17-substituents are also introduced according to known methods and further optionally constituted by nucleophilic addition of the desired substituents or reactive precursors thereof.

The 8β-substituted estradione-carboxylic acids according to the invention are prepared from the corresponding hydroxy steroids in analogy to known processes (see, for example, Pharmazeutische Wirkstoffe, Synthesen, Patente, Anwendungen [Pharmaceutical Active Ingredients, Syntheses, Patents, Applications; A. Kleemann, J. Engel, Georg Thieme Verlag Stuttgart 1978, Arzneimittel, Fortschritte [Pharmaceutical Agents, Improvements] 1972 to 1985; A. Kleemann, E. Lindur, J. Engel (Editors), VCH 1987, pp. 773-814).

Estratriene-sulfamate according to the invention is available from the corresponding hydroxy steroids by a method known in the art by esterification with sulfamoyl chloride in the presence of a base (Z. Chem. 15, 270-272 (1975); Steroids 61, 710-717 (1996)).

Subsequent acylation of the sulfamide group affords the (N-acyl) sulfamate according to the invention, with the pharmacokinetic benefits already absent in the absence of 8-substituents (see DE 195 40 233 A1).

Regioselective esterification of polyhydroxylated steroids with N-substituted and N-unsubstituted sulfamoyl chlorides is carried out in accordance with partially protecting the hydroxyl groups from being esterified. The silyl ethers are stable under sulfamate forming conditions, and the silyl ethers remain intact when the silyl ethers are decomposed for the reformation of residual hydroxyl groups still contained in the molecule. It has been found to conjugate to this purpose (Steroids 61, 710-717 (1996)). The preparation of sulfamates according to the invention with one or more additional hydroxyl groups in the molecule is also possible when the starting material is a suitable hydroxy-steroid ketone. First, as desired, one or more hydroxyl groups present are sulfamoylated. The sulfamate group can then be converted to the desired acyl chloride and the present (N-acyl) sulfate, optionally in the presence of a base. The oxosulfate or oxo- (N-acyl) sulfate now present is converted to the corresponding hydroxysulfate or hydroxy- (N-acyl) sulfate by reduction (Steroids 61, 710-717 (1996). )). Sodium borohydride and borane-dimethyl sulfide complexes are suitable as suitable reducing agents.

Functionalization of carbon atom 2 is, for example, prior deprotection of the 2-position with the corresponding base of 3- (2-tetrahydropyranyl)-or 3-methyl ether (eg methyllithium, butyllithium) By electrophilic substitution. Thus, for example, fluorine atoms can be introduced by reaction of C-H activated substrates with fluorination reagents such as N-fluoromethane sulfonimide (WO 94/24098).

The introduction of the variable substituents in the rings B, C and D of the estradione backbone can be carried out basically according to chemical teachings known to those skilled in the art, whereby the corresponding estritriene derivatives which are not substituted at the 8-position are prepared. (Steroide [Steroids], LF, Fieser, M. Fieser, Verlag Chemie, Weinheim / Bergstr., 1961; Organic Reactions in Steroid Chemistry, J. Fried, JA Edwards, Van Nostrand Reinhold Company, New York, Cincinnati, Toronto, London , Melbourne, 1972; Medicinal Chemistry of Steroids, FJZeelen, Elsevier, Amsterdam, Oxford, New York, Tokyo, 1990). This relates to the introduction of substituents such as, for example, hydroxyl or alkoxy groups, alkyl, alkenyl or alkynyl groups or halogens, in particular fluorine.

However, substituents according to formula (I) can also be introduced into estradione in the state already substituted at the 8-position. This may be particularly useful or necessary in the case of multiple substituents of the desired final compound.

The following examples were used to illustrate the invention in more detail.

General synthetic routes for these examples are shown in Schemes 1-3.

As starting material of the synthesis, 11-keto-estratene of type 1 or 2 (US 3491089, Tetrahedron Letters, 1967, 37, 3603), which stereoselectively substituted 8β-position in reaction with diethylaluminum cyanide Derivatives are used. 8β-substituted estra-1,3,5 (10), 9 (11, which in turn can be 8β-aldehyde converted by subsequent reduction of the carbonyl functional group of C (11) and removal of the resulting hydroxyl groups ) -Tetraene is obtained. Functionalization by, for example, the Wittig reaction, for example using subsequent removal of protecting groups, yields 8β-steroids according to the invention.

The first 11-oxidized estradiol derivative obtained in this sequence can be further reacted with many substitution patterns on steroid-like double bonds C (9) -C (11) according to methods known to those skilled in the art. For example, an 11α-hydroxy group can be converted to an 11β-fluorine atom according to the process described by Borbrueggen et al.

For the preparation of derivatives of 8β-substituted estra-1,3,5 (10) -triene-3,16ξ-diol according to the invention without 17-substituents, the following synthetic strategy is mainly used. In this respect, the 8β-carbonyl functional group is protected with acetal. After subsequent oxidation, the 17-ketosteroid can be converted to the sulfonylhydra zone in the simplest case by reaction with phenylsulfonyl hydrazide. By the decomposition reaction, formation of C (16) -C (17) olefins is carried out (Z. Chem. 1970, 10, 221-2; Liebigs Ann. Chem. 1981, 1973-81), where hypobromide is located Stored in a controlled manner. Reductive dehalogenation and removal of the acetal protecting group of 8β result in modification of the compound according to the invention. 16β-alcohols obtainable according to this method can be converted to 16α-epimer by known methods (Synthesis 1980, 1).

Another variant for the introduction of hydroxyl groups of carbon atoms 16 consists of boron hydride addition using stericly constrained boranes of 16 (17) double bonds. It is known that the reaction produces a 16-oxidized product (Indian J. Chem. 1971, 9, 287-8). Thus, the reaction of 9-vorabicyclo [3.3.1] nonane of estra-1,3,5 (10), 16-tetraene 17 after oxidation with alkaline hydrogen peroxide resulted in 16α-hydroxyestritriene. Create Epimeric 16β-hydroxy steroids are less formed in this reaction. Subsequent modifications to the 8β-substituent then give the compounds of formula (I) according to the invention.

Characteristic but non-limiting synthetic processes useful for providing representative substitution patterns on estrone bone fractures with multiple substituents are found, for example, in C (1) J. Chem. Soc. (C) 1968, 2915; C (7) Steroids 54, 1989, 71; C (8α) Tetrahedron Letters 1991, 743; C (8β) Tetrahedron Letters 1964, 1763; J. Org. Chem. 1970, 35, 468; C (11) J. Steroid Biochem. 31, 1988, 549; Tetrahedron 33, 1977, 609 and J. Org. Chem. 60, 1995, 5316; C (9) DE-OS 2035879; J. Chem. Soc. Perk. 1 1973, 2095; C (15) J. Chem. Soc. Perk. 1 1996, 1269; C (13α) Mendeleev Commun. 1994, 187; C (14β) Z. Chem. 25, 1983, 410.

In the examples and schemes the following abbreviations apply:

THF = tetrahydrofuran; THP = tetrahydropyran-2-yl; DHP = dihydropyran; DMSO = dimethyl sulfoxide; MTBE = methyl-tert-butyl ether; DIBAH = diisobutyl-aluminum hydride; LTBAH = lithium-tri-tert-butoxyaluminum hydride.

Example 1

3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10), 8-tetraen-11-one (2)

47 ml of dihydropyran and 0.96 g of pyridine toluenesulfonate were added to 15.29 g of 11-keto-3-methoxy-estra-1,3,5 (10), 8-tetraene in 35 ml of dichloromethane at room temperature. Was added to -17βol and stirred for 2 hours. The reaction solution was then shaken several times with saturated sodium bicarbonate solution, washed with water and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified on silica gel (solvent mixture: cyclohexane / ethyl acetate = 8/2). 16.8 g (83%) of a light yellow viscous oil were obtained.

8β-cyano-3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-11-one (3)

195 ml of diethylaluminum cyanide (1.0 M in toluene) was added dropwise to a solution of 24.5 g of 11-ketosteroid 2 in 330 ml of toluene at −5 ° C. under argon and stirred for 1.5 hours with continuous cooling. . The mixture was then poured into 470 ml of ice cold 1 N sodium hydroxide solution, stirred for 1 hour, extracted several times with ethyl acetate, and the collected organic phases washed with water and brine and dried over magnesium sulfate. The evaporation residue was chromatographed on silica gel (solvent mixture: cyclohexane / ethyl acetate = 4/1) to give 3 as a foam in a total yield of 12.0 g (37%).

8β-cyano-3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-11-ol (4)

A solution of 33.1 g of steroid 3 in 400 ml of THF was cooled to 0 ° C., partly mixed with 51.0 g of LTBAH, stirred for 1 hour with continuous cooling and for 1 hour at room temperature. 25 ml of saturated sodium bicarbonate solution was added dropwise to the reaction solution at 0 ° C., the resulting precipitate was separated by filtration in celite and the filtrate was concentrated in very large amounts by evaporation. The residue was extracted several times with ethyl acetate and the collected organic phases were washed with brine, dried over magnesium sulfate and the solvent removed in vacuo. In this method, 327.6 g (97%) of foam 4 was obtained and used in the next step without further purification.

8β-cyano-3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10), 9 (11) -tetraene (5)

27.6 ml of phosphorus oxychloride was added dropwise to a solution of 27.6 g of 4 in 275 ml of pyridine at a temperature of 0-5 ° C. and stirred at this temperature for an additional 1.5 hours. The mixture was then transferred to a dropping funnel and added dropwise to ice cold saturated sodium bicarbonate solution. Extracted with dichloromethane, the collected organic phases were extracted with brine, dried over magnesium sulphate and the solvent removed in vacuo. In this method, 23.5 g (89%) of almost colorless foam 5 was obtained, which was used in the next step without further purification.

8β-carbonyl-3-methoxy-estra-1,3,5 (10), 9 (11) -tetraen-17β-ol (6)

A solution of 41 ml DIBAH in 100 ml toluene was added dropwise to 11.4 g 8β-cyano-steroid 5 in 70 ml toluene at 0 ° C. and stirred at this temperature for 1.5 hours. The solution was mixed successively at 0 ° C. with 33 ml of ethanol, 33 ml of ethanol-water mixture (v / v = 1/1) and 120 ml of semiconcentrated hydrochloric acid and then refluxed for 2 hours. The mixture was extracted several times with ethyl acetate and the collected organic phases were washed with water, dried over magnesium sulfate and evaporated in vacuo to dryness. The residue was chromatographed on silica gel (solvent mixture: cyclohexane / ethyl acetate = 3/2) to give 3.21 g (35%) of foamy 6 .

3-methoxy-8β-methyl-estra-1,3,5 (10), 9 (11) -tetraen-17β-ol (7a)

0.18 ml of hydrazinium hydroxide (80% with water) and 50 mg of 8β-carbonyl-3-methoxy-estra-1,3,5 (10), 9 (11) in 6.5 ml of triethylene glycol -Tetraen-17β-ol ( 6 ) was added to a solution of 225 mg potassium hydroxide in 3.5 ml of triethylene glycol at room temperature and heated at 200 ° C. for 2 hours. After cooling, it was continuously mixed with 10 ml of water and 3 ml of 10% sulfuric acid. The mixture was extracted several times with ether and the collected organic phases were washed with water, dried over magnesium sulfate and evaporated to rotary evaporation to dryness. The residue was chromatographed on silica gel (solvent mixture: cyclohexane / ethyl acetate = 8/2) 3-methoxy-8β-methyl-estra-1,3,5 (10), 9 (11) at a melting point of 168 ° C. 36 mg (79%) of -tetraen-17β-ol were obtained.

Example 2

The synthesis of material 7a is described in Examples 1, 1.1-1.6.

3-methoxy-8β-methyl-estra-1,3,5 (10) -triene-17β-ol (8a)

A solvent consisting of 75 mg 3-methoxy-8β-methyl-estra-1,3,5 (10), 9 (11) -tetraen-17β-ol ( 7a ) consisting of 3.5 ml of THF and 1.5 ml of methanol It was dissolved in the mixture and stirred with 75 mg of palladium (on magnesium carbonate, 10%) under hydrogen atmosphere at room temperature for 3.75 hours. The reaction solution was then filtered through celite and the filtrate was dried by evaporation in a vacuum evaporator and the resulting TLC-uniform foamy product (74 mg, 98%) was used in the next step without further purification.

8β-methyl-estra-1,3,5 (10) -triene-3,17β-diol (8b)

74 mg of 3-methoxy-8β-methyl-estra-1,3,5 (10) -triene-17β-ol were dissolved in 3 ml of anhydrous toluene, cooled to 0 ° C. and 0.6 ml of under argon. Carefully mix with DIBAH. The reaction mixture was slowly refluxed and maintained at this temperature for 3.5 hours. It was again cooled to 0 ° C. and the solution was successively mixed with 2 ml of ethanol, 2 ml of ethanol-water mixture (v / v = 1/1) and 2 ml of semi concentrated hydrochloric acid and extracted several times with ethyl acetate. It was. The collected organic phases were neutralized washed with water, dried over magnesium sulfate and evaporated in vacuo to dryness. 70 mg (99%) of colorless crystals (melting point 168-170 ° C) were obtained.

Example 3

The synthesis of substance 6 is described in Examples 1, 1.1-1.5.

8β-carbonyl-3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10), 9 (11) -tetraene (9)

A 500 mg solution of 6 in 10 ml dichloromethane was mixed with 1.45 ml 3,4-dihydro-2H-pyran and 28 mg (0.11 mmol) pyridine toluene sulfonate and stirred at room temperature for 16 hours. The mixture was washed successively with saturated sodium bicarbonate solution and water, and the organic phase was dried over magnesium sulfate and then evaporated in vacuo to dryness. Product 9 accumulated in the foam in a yield of 527 mg (86%).

3-methoxy-17β- (tetrahydropyran-2-yloxy) -8β-vinyl-estra-1,3,5 (10), 9 (11) -tetraene (10a)

Of 585 mg of 8β-carbonyl-3-methoxy-17β- (tetrahydropyran-2-oloxy) -estra-1,3,5 (10), 9 (11) -tetraene in 25 ml DMSO The solution was first mixed under argon with 4.92 g of methyltriphenylphosphonium bromide, then carefully 394 mg of sodium hydride (80% in paraffin oil) and then slowly heated to an internal temperature of 55 ° C. for 2 hours. After cooling, 25 ml of water were added dropwise, washed several times with diethyl ether, washed with water and the collected organic phases were dried over magnesium sulfate. After removal of the solvent, the residue was purified by chromatography on silica gel (solvent mixture: cyclohexane / MTBE = 30/1). 520 mg (89%) of 8β-vinyl steroid were obtained in the form of a colorless foam.

8β-vinyl-estra-1,3,5 (10), 9 (11) -tetraene-3,17β-diol (11a)

550 mg of 3-methoxy-17β- (tetrahydropyran-2-yloxy) -8β-vinyl-estri-1,3,5 (10), 9 (11) -tetraene were added to General Operation Instructions 19. Therefore, it was reacted. The yield of colorless crystals at melting point 149-150 ° C. was 315 mg (76%).

8β- (2,2-difluorovinyl-3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10), 9 (11) -tetraene (10b )

A solution of 0.22 ml of diethyl (difluoromethyl) phosphonate and 2 ml of 1,2-dimethoxyethane in 0.4 ml of n-pentane was cooled under argon at −78 ° C., and 0.82 ml of tert-butyl Mix with lithium solution (1.7 M, in n-pentane) and stir at this temperature for 0.25 h. At the same temperature, 220 mg 8β-carbonyl-3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10 in 3.5 ml 1,2-dimethoxyethane) ), 9 (11) -tetraene and a solution of 0.58 ml of n-pentane were added dropwise and stirred for 0.5 h with continuous cooling. It was then first heated to room temperature and then diluted with n-pentane while heating to an internal temperature of 84 ° C. for 1 hour. After cooling, the batch was poured into 20 ml of cold water, the light brown precipitate was filtered off, extracted with dichloromethane, and the collected oil phase was dried over magnesium sulfate. After removal of the solvent, the residue was purified by chromatography on silica gel (solvent mixture: cyclohexane / MTBE = 30/1). The yield of oily, almost colorless steroid was 108 mg (46%).

8β- (2,2-difluorovinyl) -estra-1,3,5 (10), 9 (11) -tetraene-3,17β-diol (11b)

105 mg of 8β- (2,2-difluorovinyl) -3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10), 9 (11)- Tetraene was reacted for ether degradation with DIBAH / acid according to General Operation Instruction 19. The yield of colorless crystals at melting point 103-106 ° C. was 75 mg (93%).

Example 4

The synthesis of substance 9 is described in Examples 3, 3.1.

8β-carbonyl-3-methoxy-17β- (tetrahydropyran-2-yloxy) -estri-1,3,5 (10) -triene (12)

1.73 g of 9 is dissolved in 75 ml of a solvent mixture consisting of THF and methanol (v / v = 7/3), and 1.0 g of palladium (10% on magnesium carbonate) under hydrogen atmosphere at room temperature for 3.75 hours. It was kovaba. The reaction solution was then filtered through celite, the filtrate was evaporated in a rotary evaporator to dryness, and the resulting TLC-uniform bright oil was used in another reaction without further purification.

3-methoxy-17β- (tetrahydropyran-2-yloxy) -8β-vinyl-estra-1,3,5 (10) -triene (13a)

2.47 g of 8β-carbonyl-3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10), 9 (11) -tetraene in 100 ml DMSO The solution was first mixed with 19.80 g of methyltriphenylphosphonium bromide under argon and then with 1.58 g of sodium hydride (80% in paraffin oil) and slowly heated to an internal temperature of 55 ° C. for 2 hours. After cooling, 100 ml of water were added dropwise, extracted several times with diethyl ether, washed with water and the collected organic phases were dried over magnesium sulfate. After removal of the solvent, the residue was purified by chromatography on silica gel (solvent mixture: cyclohexane / MTBE = 30/1). 1.91 g (78%) of 8β-vinyl steroid was obtained as a colorless foam.

8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (14a)

1.86 g of 3-methoxy-17β- (tetrahydropyran-2-yloxy) -8β-vinyl-estra-1,3,5 (10) -triene were reacted according to general operation instructions 19. Crude 8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol was purified on silica gel (solvent mixture: cyclohexane / ethyl acetate = 7/3) and colorless at a melting point of 163-165 ° C. Obtained in crystal form with a yield of 1.02 g (86%).

8β- (2,2-difluorovinyl) -3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene (13b)

A solution of 0.6 ml of diethyl (difluoromethyl) phosphonate in 1.0 ml of n-pentane and 5.6 ml of 1,2-dimethoxyethane were cooled under argon at −78 ° C. and 2.2 ml of tert-butyl It was mixed with a lithium solution (1.7 M in n-pentane) and stirred at this temperature for 0.25 hours. At the same temperature, 600 mg of 8β-carbonyl-3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10 in 9.2 ml of 1,2-dimethoxyethane) ), A solution of 9 (11) -tetraene and 1.6 ml of n-pentane were added dropwise and stirred for 0.5 h with continuous cooling. It was then first heated to room temperature and then heated to an internal temperature of 84 ° C. with dilution with n-pentane for 1 hour. After cooling, the batch was poured into 40 ml of cold water, the light brown precipitate was filtered off, extracted with dichloromethane and the collected organic phases were dried over magnesium sulfate. After removal of the solvent, the residue was purified by chromatography on silica gel (solvent mixture: cyclohexane / MTBE = 30/1). The yield of oily, almost colorless steroid was 75 mg (12%).

8β- (2,2-difluorovinyl) -estra-1,3,5 (10) -triene-3,17β-diol (14b)

78 mg of 3-methoxy-8β- (2,2-difluorovinyl) -17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10 according to general operating instructions 19) Triene was reacted. The yield of colorless crystals at melting point 154-156 ° C. was 56 mg (90%).

Example 5

The synthesis of material 13a is described in Examples 4, 4.2.

8β-ethyl-3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene

0.50 g 13a is dissolved in 25 ml solvent mixture consisting of THF and methanol (v / v = 7/3) and stirred with 0.30 g of palladium (10% on magnesium carbonate) under hydrogen atmosphere at room temperature for 3.75 hours It was. The reaction solution was then filtered through celite, the filtrate was evaporated in a rotary evaporator to dryness and the resulting clear foam used in the next step without further purification.

8β-ethyl-estra-1,3,5 (10) -triene-3,17β-diol (15a, 15b)

330 mg of crude 8β-ethyl-3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene obtained from the last step were subjected to general tissue instructions 6.1 and 6.2 It reacted accordingly. Chromatography on silica gel allowed 161 mg or 20 mg yields of epimeric estradione diols 15a and 15b to be isolated from the accumulated crude product. The melting point of 15a was about 149-152 ° C, and the melting point of 15b was 185-187 ° C.

Example 6

3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17-one

A solution of 700 mg 3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17β-ol in 30 ml dichloromethane is mixed with 740 mg pyridinium chlorochromate and room temperature Stirred for 3 h. 680 mg (98%) of 3-methoxy-8β-vinyl-estra by filtration on silica gel of the reaction mixture (solvent mixture: cyclohexane / ethyl acetate = 7/3) and subsequent concentration in a rotary evaporator of the filtrate. -1,3,5 (10) -trien-17-one was obtained as a nearly colorless foam which was used in the next step without further purification.

3-hydroxy-8β-vinyl-estra-1,3,5 (10) -trien-17-one

460 mg of 3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17-one are added to 9.2 g pyridinium hydrochloride at 180 ° C. and at the same temperature for 3 hours Stirred. It was then poured on ice and the deposited precipitate was filtered off, washed with water and dried. The yield of 2-hydroxy-8β-vinyl-estra-1,3,5 (10) -trien-17-one having a melting point of 239-242 ° C. was 400 mg (90%).

Example 7

3-Sulfamoyloxy-8β-vinyl-estra-1,3,5 (10) -trien-17-one

76 mg of 3-hydroxy-8β-vinyl-estra-1,3,5 (10) -trien-17-one are dissolved in 7 ml of dichloromethane and 0.26 ml of 2,6-di-tert- It was mixed with butylpyridine and 221 mg of sulfamoyl chloride and stirred for 1.5 hours at room temperature. The reaction mixture was then added to water and extracted several times with dichloromethane. The collected organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, evaporated in vacuo and concentrated as much as possible. Chromatography on silica gel of the obtained residue (solvent mixture: cyclohexane / ethyl acetate = 7/3) of 46 mg (48%) of 17-oxo-8β-vinyl-estra-1,3,5 (10)- Trien-3-yl-amidosulfonate was obtained.

3-Sulfamoyloxy-8β-vinyl-estra-1,3,5 (10) -trien-17β-ol

46 mg of 17-oxo-8β-vinyl-estra-1,3,5 (10) -trien-3-yl-amidosulfonate is dissolved in 1.5 ml of THF and 1.5 ml of methanol and 33 mg of It was mixed with sodium borohydride at 0 ° C. and stirred at 0 ° C. for 1 hour. 0.2 ml of concentrated acetic acid were then added, which was concentrated by evaporation in vacuo. The residue was taken up in ethyl acetate and water, the organic phase was separated and the aqueous phase was extracted several times with ethyl acetate. The collected organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. The crude product was purified by chromatography on silica gel (solvent mixture: cyclohexane / ethyl acetate = 6/4) and had a fine needle-like 17β-hydroxy-8β-vinyl-estra-1,3 at melting point 82-86 ° C. 45 mg of 5 (10) -trien-3-yl-amidosulfonate was obtained.

Example 8

3-methoxy-8β-prop-1- (Z) -enyl-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene

A solution of 100 mg 8β-formyl-3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene in 5 ml of DMSO was first placed under argon. It was mixed with 830 mg of ethyltriphenyl phosphonium bromide and then carefully mixed with 64 mg of sodium hydride (80% in paraffin oil) and slowly heated to an internal temperature of 60 ° C. for 2 hours. After cooling, 10 ml of water was added dropwise, extracted several times with ethyl acetate, and the collected organic phases were washed with water and dried over magnesium sulfate. After removal of the solvent, the residue was purified by chromatography on silica gel (solvent mixture: cyclohexane / ethyl acetate = 30/1). 24 mg (23%) of 8β-propenyl steroid in the form of colorless foam were obtained.

8β-prop-1- (Z) -enyl-estra-1,3,5 (10) -triene-3,17β-diol

24 mg of 3-methoxy-8β- (prop-1- (Z) -enyl) -17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene The reaction was carried out according to the general operation instructions for the decomposition of THP and 3-methyl ether. Purification of crude 8β-prop-1- (Z) -enyl-estra-1,3,5 (10) -triene-3,17β-diol on silica gel (solvent mixture: cyclohexane / ethyl acetate = 7 / 3) A yield of 10 mg (66%) was obtained in the form of colorless crystals having a melting point of 119-125 ° C.

Example 9

3-methoxy-17α-ethynyl-8β-vinyl-estra-1,3,5 (10) -trien-17β-ol

Under argon, 85 mg of 3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17-one in 8 ml of THF was dissolved, cooled to -78 ° C, 5.5 ml Was mixed with an ethynyl magnesium bromide solution (0.5 M in THF) and 100 ml of lithium acetylide-ethylene diamine complex. While heating to room temperature, the reaction mixture was stirred for 3 hours, then cooled to 0 ° C. and mixed with 10 ml of saturated ammonium chloride solution. The mixture was extracted several times with ethyl acetate and the collected organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. The residue was chromatographed on silica gel (solvent mixture: cyclohexane / ethyl acetate = 9/1) to give 30 mg (33%) of oily 17α-ethynyl-3-methoxy-8β-vinyl-estra-1,3, 5 (10) -triene-17β-ol was obtained.

17α-ethynyl-8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

15 mg 17α-ethynyl-3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17β-ol and 82 mg tetrabutylammonium iodide in 2 ml dichloromethane The solution of was cooled to −78 ° C. under argon, mixed with 0.3 ml of boron trichloride solution (1 M in dichloromethane) and stirred at 0 ° C. for 24 h. The reaction solution was then added dropwise to a saturated ammonium chloride solution cooled to 5 ° C., the mixture was extracted several times with diethyl ether, and the collected organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. Concentrated by. The residue was chromatographed on silica gel (solvent mixture: cyclohexane / ethyl acetate = 7/3) with 17α-ethynyl-8β-vinyl-estra-1,3,5 (10) -triene having a melting point of 156 ° C. 5 mg (35%) of -3,17β-diol were obtained.

Example 10

3-methoxy-17α-methyl-8β-vinyl-estra-1,3,5 (10) -triene-17β-diol

1 ml of methyl, cooled in a solution of 50 mg of 3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17-one in 2 ml of dry THF to −78 ° C. under argon. To the lithium solution (1.6 M in diethyl ether) was added dropwise, then 0.5 ml of anhydrous dimethylformamide was added and stirred for 1.5 hours while heating to room temperature. The mixture was mixed with saturated sodium bicarbonate solution, extracted several times with ethyl acetate, and the collected organic phases were washed with water and dried over magnesium sulfate. The organic phase was concentrated by evaporation to give 42 mg (80%) of crude 3-methoxy-17α-methyl-8β-vinyl-estra-1,3,5 (10) -trien-17β-ol. It was used in the next step without further purification.

17α-methyl-8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

40 mg of 3-methoxy-17α-methyl-8β-vinyl-estra-1,3,5 (10) -trien-17α-ol were reacted according to the general operating instructions for 3-methyl ether degradation. Purification on silica gel (solvent mixture: cyclohexane / ethyl acetate = 7/3) followed by 17α-methyl-8β-vinyl-estra-1,3,5 (10) -triene-3,17β at melting point 129-130 ° C. Diol was obtained in a yield of 30 mg (78%).

Example 11

3-methoxy-8β-vinyl-estra-1,3,5 (10) -triene-17α- (4'-nitro) -benzoate

0.48 ml of a 40% solution of diethylazodicarboxylate in toluene was added to 100 mg of 3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17β-ol, 277 mg of triphenyl. To the mixture consisting of phosphine, 175 mg of 4-nitrobenzoic acid and 5 ml of toluene was added dropwise, which was stirred at 60 ° C. for 3 hours. After cooling, it was extracted several times with ethyl acetate and the collected organic phases were washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. 84 mg (57%) of yellow oily 3-methoxy-8β-vinyl-estra-1,3,5 (10) -tree by chromatography on silica gel (solvent mixture: n-hexane / ethyl acetate = 25/1) En-17α- (4'-nitro) -benzoate was obtained.

3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17α-ol

A solution of 80 mg 3-methoxy-8β-vinyl-estra-1,3,5 (10) -triene-17α- (4′-nitro) -benzoate in 12 ml methanol and 0.4 ml water Mix with 480 mg potassium carbonate and stir for 24 hours at room temperature. It was then concentrated as much as possible by evaporation in vacuo and the residue was taken up in water and extracted several times with ethyl acetate. The collected organic phases were washed with saturated sodium chloride, dried over magnesium sulfate and concentrated by evaporation in rotary evaporation. 40 mg (54%) of 3-methoxy-8β-vinyl-estra-1,3,5 (10) -triene-17α-ol was obtained by the above method.

8β-vinyl-estra-1,3,5 (10) -trien-3,17α-ol

40 mg (0.13 mmol) of 3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17α-ol were reacted according to the general operating instructions for 3-methyl ether degradation. 8β-Vinyl-Estra-1,3,5 (10) -triene-3,17α-diol obtained by the above method was purified on silver silica gel (solvent mixture: cyclohexane / ethyl acetate = 7/3), melting point 149 The yield was -151 ° C and 9 mg (24%).

Example 12

16-dimethyl-3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17-one

A solution of 150 mg of 3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17β-ol in 6 ml of dry THF cooled to -40 ° C. under 1.2 ml of lithium. Mix with diisopropylamide solution (2 M in THF / n-hexane / ethylbenzene) and stir at this temperature for 1 hour. 0.24 ml of methyl iodide was then added at the same temperature and stirred for an additional hour while heating to room temperature. It was then cooled to -5 ° C, 4 ml of 2N sodium hydroxide solution was added and the mixture was extracted several times with ethyl acetate. The collected organic phases were washed with water, dried over MgSO ₄ and concentrated by evaporation in vacuo.

The obtained product was used again under the same reaction conditions.                 

130 mg (80%) of tan oily 16-dimethyl-3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17-ol was obtained as crude.

16-dimethyl-8β-vinyl-estra-1,3,5 (10) -triene-3,17β-ol

130 mg of crude 16-dimethyl-3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17-one were reacted according to the general operating instructions for the decomposition of 3-methyl ether. . The resulting crude product was purified by chromatography on silica gel (solvent mixture: cyclohexane / ethyl acetate = 85/15). In this method, 50 mg (40%) of colorless crystalline 16-dimethyl-8β-vinyl-estra-1,3,5 (10) -triene-3,17β-ol having a melting point of 113-123 ° C. (decomposition) was added. Got it.

Example 13

3-methoxy-8β- (prop-1- (E) -enyl) -17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene

A mixture of 4 ml of pentane, 20 ml of 1,2-dimethoxyethane and 2 ml of diethylethylphosphonate cooled to -78 [deg.] C. in a 1.7 M solution of tert-butyllinium (in pentane) under argon. Mix with 8 ml and stir at this temperature for 15 minutes. Then 500 mg of 8β-formyl-3-methoxy-17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10)-in 8 ml of 1,2-dimethoxyethane. A solution consisting of triene and 1.5 ml of pentane was added dropwise, stirred for 30 minutes while exposed to continuous cooling, and stirred for 1.5 hours while heating to room temperature. The pentane was then distilled off and the residual reaction solution was refluxed for 3 hours.                 

The mixture was poured into crushed ice and the fine white precipitate was filtered off and dried. Chromatographic purification on silica gel (solvent mixture: cyclohexane / ethyl acetate = 20/1) followed by 275 mg (54%) of 3-methoxy-8β- (prop-1- (E) -enyl) -17β- (Tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene was obtained in the form of a colorless foam.

8β-prop-1- (E) -enyl-estra-1,3,5 (10) -triene-3,17β-diol

275 mg of 3-methoxy-8β- (prop-1- (E) -enyl) -17β- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene The reaction was carried out according to the general operation instructions for THP and 3-methyl ether degradation. Purify crude 8β-prop-1- (E) -enyl-estra-1,3,5 (10) -triene-3,17β-diol with silica gel (solvent mixture: cyclohexane / ethyl acetate = 8/1) The melting point was 110-125 ° C., yield was 108 mg (52%).

Example 14

3-methoxy-17α-trifluoromethyl-17β-trimethylsilyloxy-8β-vinyl-estra-1,3,5 (10) -triene

A solution of 80 mg of 3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17-one in 2 ml of THF cooled to 0 ° C. under 0.2 ml of trifluoro under argon. It was mixed with methyltrimethyl-silane and 5 mg of tetrabutylammonium fluoride trihydrate, which was stirred for 24 hours at room temperature. The dark reaction solution was poured into cold water, extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. The obtained crude product was purified by flash chromatography on silica gel (solvent mixture: cyclohexane / ethyl acetate = 9/1). 63 mg (54%) of 3-methoxy-17α-trifluoromethyl-17β-trimethylsilyloxy-8β-vinyl-estra-1,3,5 (10) -triene was obtained as a dark oil.

17α-trifluoromethyl-8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

1.26 g of tetrabutylammonium fluoride trihydrate was added to 60 mg of 3-methoxy-17α-trifluoromethyl-17β-trimethylsilyloxy-8β-vinyl-estra-1,3,5 in 6 ml of THF. 10) -triene was added to the solution, which was stirred for 2 hours at room temperature. Then saturated sodium chloride solution was added, extracted several times with ethyl acetate, and the collected organic phases were dried over magnesium sulfate and concentrated by evaporation in vacuo. The oily yellow residue (50 mg) was used in the next step without further purification.

Of 50 mg of crude 3-methoxy-17α-trifluoromethyl-8β-vinyl-estra-1,3,5 (10) -trien-17β-ol in 3 ml of dichloromethane cooled to -78 ° C. The solution was mixed successively under argon with 243 mg of tetrabutylammonium iodide and 0.7 ml of a 1M boron trichloride solution in dichloromethane and stirred for 2 hours while heating to 0 ° C. The reaction mixture was then added dropwise to 5 ° C. saturated ammonium chloride solution and extracted several times with ethyl acetate. The collected organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. The crude product (90 mg) was purified by chromatography on silica gel (solvent mixture: cyclohexane / ethyl acetate = 7/3). 25 mg (52%) of powdery 17α-trifluoromethyl-8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (melting point 76-79 ° C.) were obtained.                 

Example 15

2-fluoro-3,17β-bis (tetrahydropyran-2-yloxy) -8β-vinyl-estra-1,3,5 (10) -triene

3 ml of 1.3 M s-butyllithium solution in 120 ml of 3,17β-bis- (tetrahydropyran-2-yloxy) -8β-vinyl-estra- in 4 ml of THF cooled to -78 ° C under argon. Add to a solution of 1,3,5 (10) -triene, stir for 30 minutes, and then continuously expose the solution consisting of 650 mg of N-fluorobenzenesulfonimide in 4 ml of THF to cooling While dropping. The reaction mixture was first stirred at −78 ° C. for 1 hour and then stirred for an additional 16 hours while heating to room temperature. The reaction solution was poured into cold water, extracted several times with ethyl acetate, and the collected organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. Dark oily crude product (330 mg) was used in the next step without further purification.

2-fluoro-8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol

The final crude oily product was dissolved in 10 ml of methanol, mixed with 1 ml of water and 250 mg of oxalic acid dihydrate and heated at 60 ° C. for 1 hour.

For work-up, it was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. The resulting crude product was purified by chromatography on silica gel (solvent mixture: cyclohexane / ethyl acetate = 8/2). The 2-fluoro-8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol (15 mg, 18%) obtained had a melting point of 67-73 ° C.

Example 16

3,17β-bis- (tetrahydropyran-2-yloxy) -8β-vinyl-estra-1,3,5 (10) -trien-2-ol

3 ml of 1.3 M s-butyllithium solution in 120 ml of 3,17β-bis- (tetrahydropyran-2-yloxy) -8β-vinyl-estra- in 4 ml of THF cooled to -78 ° C under argon. To the solution of 1,3,5 (10) -triene was added dropwise, it was stirred for 30 minutes, and 0.5 ml of trimethyl borate was added in one portion. While heating to 0 ° C., it was stirred for 2 hours, 2 ml of 3 N sodium hydroxide solution and 1 ml of 30% hydrogen peroxide were added and finally stirred at room temperature for an additional 4 hours.

The mixture was diluted with water, saturated sodium hydrogen sulfite solution was added, extracted several times with methyl-tert-butyl ether, and the collected organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. Concentrated by. The residue was chromatographed on silica gel (solvent mixture; n-hexane / ethyl acetate = 9: 1) to 65 mg (52%) of colorless oily 3,17β-bis- (tetrahydropyran-2-yloxy)- 8β-vinyl-estra-1,3,5 (10) -trien-2-ol was obtained.

8β-vinyl-estra-1,3,5 (10) -triene-2,3,17β-triol

The final oily product was dissolved in 3 ml of methanol, mixed with 0.3 ml of water and 50 mg of oxalic acid dihydrate, and heated at 60 ° C. for 1 hour.                 

For work-up, it was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. The obtained yellow powdery 8β-vinyl-estra-1,3,5 (10) -triene-2,3,17β-triol (38 mg, 95%) had a melting point of 82-85 ° C. (decomposition).

General operating instructions for the decomposition of 3-methoxy-17- (tetrahydropyran-2-yloxy) -estratriene and -tetraene to the corresponding 17-alcohols by acid

1.0 mmol of steroid is dissolved in 22 ml of acetone and stirred with 1.5 ml of 4N hydrochloric acid for 3 hours at room temperature. If the conversion is not complete during this time, the solution is heated to 50 ° C. for an additional 1.5 hours. It is then diluted with 20 ml of water, extracted several times with dichloromethane, the collected organic phases are dried over magnesium sulfate and the solvent is distilled off on a rotary evaporator. The crude 17-hydroxyl compound prepared in this way accumulates in the foam and immediately proceeds to the next procedure.

General Operation Instructions for the Degradation of 3-methoxy-17- (tetrahydropyran-2-yloxy) -estratriene and -tetraene to the corresponding 3,17-diol using acid and DIBAH

1.0 mmol of steroid is dissolved in 15-20 ml of anhydrous toluene, cooled to 0 ° C. and carefully mixed with 3.0 ml of DIBAH under argon. The reaction mixture is slowly refluxed and maintained at this temperature for 3.5 hours. Subsequently, 10 ml of ethanol, 10 ml of ethanol-water mixture (v / v = 1/1) and 10 ml of semi-concentrated hydrochloric acid are added coarsely to the solution cooled to 0 ° C., which is then added with ethyl acetate. Extract several times. The collected organic phases are neutralized and washed with water, dried over magnesium sulfate, evaporated in a rotary evaporator to dryness. The yield is 90 to 99%.

A description of the synthesis of 1 is described in RP Stein, GC Buxby, RC Smith and H. Smith, "11-Oxygenated Steroids and Process for Their Preparation," US Patent No. 3,491,089, January 20, 1970.

Claims (47)

8β-substituted estra-1,3,5 (10) -triene derivative of formula I '. <Formula I '>

Where R ² is a hydrogen atom, a halogen atom, a R ¹⁸ -or R ¹⁸ -O- radical, where R ¹⁸ is a hydrogen atom or a straight or branched chain saturated or unsaturated hydrocarbon radical having up to 6 carbon atoms, a trifluoromethyl group ), R ¹⁹ SO ₂ -O- group, wherein R ¹⁹ is a R ²⁰ R ²¹ N group, R ²⁰ and R ²¹ are independently of each other a hydrogen atom, a C ₁ -C ₅ -alkyl radical, C (O) R ²² group and, R ²² is a carbon atom number of 10 or less and a straight chain or branched and saturated or unsaturated 3 and where less hydrocarbon radical which may be halogenated, C ₃ -C ₇ - cycloalkyl radical, C ₄ -C ₁₅ - A cycloalkylalkyl radical or an aryl, heteroaryl or aralkyl radical, or a polymethyleneimino radical or morpholino radical having 4 to 6 carbon atoms with N-atoms, Wherein aryl is a phenyl or 1- or 2-naphthyl radical and heteroaryl is 2-, 3- or 4-pyridinyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3- Pyrrolyl, 2-, 4- or 5-imidazolyl, pyrazinyl, 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radicals, wherein the aryl and heteroaryl are methyl, ethyl , Trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen, hydroxy, amino, mono (C _1-8 -alkyl) _-or di (C _{1 -8} -alkyl) amino, di (aralkyl) amino, and Aralkyl is benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl or pyridylpropyl radicals, and the ring of arylalkyl is halogen, OH, O-alkyl, CO ₂ H, CO ₂ − May be substituted by an alkyl, —NO ₂ , —N ₃ , —CN, C ₁ -C ₂₀ -alkyl, C ₁ -C ₂₀ -acyl or C ₁ -C ₂₀ -acyloxy group, Alkyl and hydrocarbon radicals may be substituted by 1-5 halogen atoms, hydroxy groups or C ₁ -C ₄ -alkoxy groups; R ³ is an R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -OC (O) R ²² group (R ¹⁸ , R ¹⁹ and R ²² in each case have the same meaning as indicated for R ² , R ¹⁸ is phenyl or 1- or 2-naphthyl, 2-, 3- or 4-pyridinyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 2- 4- or 5-imidazolyl, pyrazinyl, 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, Thienylethyl or pyridylpropyl radicals); R ⁶ and R ⁷ are each a hydrogen atom or together represent a double bond; R ^{6 '} and R ^7' are independently of each other a hydrogen atom, a halogen atom, R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² groups (R ¹⁸ , R ¹⁹ and R ²² in each case are R Meaning as indicated in ² ); R ⁸ is a straight or branched chain alkyl or alkenyl radical, ethynyl or prop-1-ynyl radical having up to 5 carbon atoms and which may be halogenated; R ⁹ is a hydrogen atom, a straight or branched chain, saturated or unsaturated hydrocarbon radical having up to 5 carbon atoms or a double bond with R ¹¹ ; R ¹¹ is a hydrogen atom or represents a double bond together with R ⁹ or together with R ¹² ; R ^{11 '} is a saturated or unsaturated hydrocarbon radical which may be halogenated by a hydrogen atom, a halogen atom, or F or Cl (the hydrocarbon radical has a maximum straight chain length of 4 carbon atoms), or a -XR ^18' group Wherein X is an oxygen or sulfur atom and R ^{18 '} is an alkyl radical of 1 to 3 carbon atoms; R ¹² is a hydrogen atom or represents a double bond with R ¹¹ ; R ¹⁴ is a hydrogen atom or represents a double bond with R ¹⁵ ; R ¹⁵ is a hydrogen atom or represents a double bond together with R ¹⁴ or together with R ¹⁶ ; R ¹⁶ is a hydrogen atom or represents a double bond with R ¹⁵ ; R ^{15 '} and R ^16' are independently of each other a hydrogen atom, a halogen atom, R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or -R ²² groups (R ¹⁸ , R ¹⁹ and R ²² in each case are R Meaning as indicated in ² ); R ¹⁷ and R ^{17 '} are hydrogen atoms; Hydrogen atom and halogen atom; Hydrogen atom and benzyloxy group; Hydrogen atom and R ¹⁹ SO ₂ —O— group; R ¹⁸ groups and —C (O) R ²² or —OC (O) R ²² groups; R ¹⁸ -O- and R ¹⁸ -groups; R ¹⁸ —O— and —OC (O) —R ²² groups (in all cases R ¹⁸ , R ¹⁹ and R ²² in each case have the meaning as indicated for R ² ); or R ¹⁷ and R ^{17 '} together are a = CR ²³ R ²⁴ group, wherein R ²³ and R ²⁴ are independently of each other a hydrogen atom and a halogen atom or together are an oxygen atom; Where R ³ is a hydroxy, methoxy or acetyl group and at the same time R ² is a hydrogen atom, R ⁶ , R ^{6 '} , R ⁷ and R ^7' in each case are hydrogen atoms, R ⁸ is a methyl group, R ⁹ is a hydrogen atom, or R ⁹ and R ¹¹ together represent a double bond, R ^{11 '} and R ¹² are in each case a hydrogen atom, R ¹⁴ , R ¹⁵ , R ^{15 '} , R ¹⁶ and R ^16' are in each case a hydrogen atom, R ¹⁷ and R ^{17 '} are a β-hydroxy group and a hydrogen atom; β- (2-bromoacetyl) oxy group and hydrogen atom; β-acetyl group and hydrogen atom; β-carboxyl group and hydrogen atom, or Excludes compounds of formula I, wherein R ¹⁷ and R ^{17 '} together are an oxygen atom. The method of claim 1, R ² is hydrogen or a halogen atom or a hydroxy group; R ³ represents an R ¹⁸ —O—, R ¹⁹ SO ₂ —O— or —OC (O) R ²² group (R ¹⁸ , R ¹⁹ and R ²² in each case have the meaning as indicated in R ² of claim 1). And further R ¹⁸ may be phenyl or 1- or 2-naphthyl, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl or pyridylpropyl radicals); R ⁶ and R ⁷ are each a hydrogen atom; R ^{6 '} is a hydrogen atom, a hydroxy group, a R ²² group (R ²² group has the same meaning as indicated in R ² ); R ^{7 ′} is a hydrogen atom, a halogen atom, R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or a R ²² group (R ¹⁸ , R ¹⁹ and R ²² in each case have the meaning as indicated for R ² )ego; R ⁸ is a straight or branched chain alkyl or alkenyl radical, ethynyl- or prop-1-ynyl radical having up to 5 carbon atoms and which may be halogenated; R ⁹ is a hydrogen atom or represents a double bond with R ¹¹ ; R ¹¹ is a hydrogen atom or represents a double bond with R ⁹ ; R ^{11 '} is a saturated or unsaturated hydrocarbon radical which may be halogenated by a hydrogen atom, a halogen atom, or F or Cl (the hydrocarbon radical has a maximum straight chain length of 4 carbon atoms), or a -XR ^18' group Wherein X is a sulfur atom and R ^{18 '} is an alkyl radical of 1 to 3 carbon atoms; R ¹² , R ¹⁴ , R ¹⁵ and R ¹⁶ in each case represent a hydrogen atom; R ^{16 '} is a hydrogen atom, a halogen atom, R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or a R ²² group (R ¹⁸ , R ¹⁹ and R ²² in each case have the meaning as indicated for R ² )ego; R ¹⁷ and R ^{17 '} are at each occurrence a hydrogen atom; Hydrogen atom and halogen atom; Hydrogen atom and benzyloxy group; Hydrogen atom and R ¹⁹ SO ₂ —O— group; R ¹⁸ groups and —C (O) R ²² or —OC (O) R ²² groups; R ¹⁸ -O- and R ¹⁸ -groups; R ¹⁸ —O— and —OC (O) —R ²² groups (in all cases R ¹⁸ , R ¹⁹ and R ²² in each case have the meaning as indicated for R ² ); or R ¹⁷ and R ^{17 '} together are a = CR ²³ R ²⁴ group, wherein R ²³ and R ²⁴ are independently of each other a hydrogen atom and a halogen atom or together are an oxygen atom. The method of claim 1, R ² is hydrogen or a fluorine atom or a hydroxyl group; R ³ represents an R ¹⁸ —O—, R ¹⁹ SO ₂ —O— or —OC (O) R ²² group (R ¹⁸ , R ¹⁹ and R ²² in each case have the meaning as indicated in R ² of claim 1). And further R ¹⁸ may be phenyl or 1- or 2-naphthyl, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl or pyridylpropyl radicals); R ⁶ and R ⁷ are at each occurrence a hydrogen atom; R ^{6 '} is a hydrogen atom or a hydroxy group; R ^{7 '} is a hydrogen atom, a fluorine or chlorine atom, R ¹⁸ -O-, R ¹⁹ SO ₂ -O- or a R ²² group (R ¹⁸ , R ¹⁹ and R ²² in each case are as defined for R ² Has; R ⁸ is 5 or fewer carbon atoms and is a straight or branched chain alkyl or alkenyl radical, ethynyl radical or prop-1-ynyl radical which may be halogenated; R ⁹ is a hydrogen atom or represents a double bond with R ¹¹ ; R ^{11 '} is a hydrogen atom, a fluorine or chlorine atom, a saturated straight or branched C ₁ -C ₄ -alkyl group, a -XR ^18' group where X is a sulfur atom and R ^{18 '} is a saturated straight or branched chain C ₁ -C ₃ -alkyl group, chloromethyl or chloroethyl group; R ¹² , R ¹⁴ , R ¹⁵ and R ¹⁶ are in each case a hydrogen atom; R ^{16 '} is a hydrogen atom, a fluorine or chlorine atom, a R ¹⁸ -O- or R ²² group (R ¹⁸ and R ²² in each case have the meaning as indicated for R ² ); R ¹⁷ and R ^{17 '} are at each occurrence a hydrogen atom; Hydrogen atom and halogen atom; Hydrogen atom and benzyloxy group; Hydrogen atom and R ¹⁹ SO ₂ —O— group; R ¹⁸ groups and —C (O) R ²² or —OC (O) R ²² groups; R ¹⁸ -O- and R ¹⁸ -groups; R ¹⁸ —O— and —OC (O) —R ²² groups (in all cases R ¹⁸ , R ¹⁹ and R ²² in each case have the meaning as indicated for R ² ); or R ¹⁷ and R ^{17 '} together are a = CR ²³ R ²⁴ group, wherein R ²³ and R ²⁴ are independently of each other a hydrogen atom and a halogen atom or together are an oxygen atom. The compound of claim 1, wherein R ^{6 ′} , R ^{7 ′} , R ⁹ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ^{15 ′} and R ¹⁶ are each hydrogen atoms, or R ^{6 ′} , R ^{7 ′} , R ¹⁴ , Estratriene of formula I, wherein R ¹⁵ , R ^{15 ′} and R ¹⁶ are each hydrogen atoms and R ⁹ and R ¹¹ together represent a double bond and all other substituents have the meanings as indicated in claim 1. The method of claim 1, having one double bond in positions 9 (11), 14 (15) or 15 (16), or two double bonds in positions 9 (11) and 14 (15) or 15 (16). Estratriene of Formula (I). The compound of claim 1, wherein R ¹⁷ and R ^{17 ′} are selected from the group consisting of R ¹⁸ -O- and R ^18- ; Estratriene of formula I, wherein R ¹⁸ -and —OC (O) R ^{22 are the} groups, and R ¹⁸ and R ²² each have the same meaning as indicated for R ² . Estratriene of formula I according to claim 6, wherein R ¹⁷ and R ^{17 '} are a hydroxy group and a hydrogen atom, a C ₁ -C ₄ -alkyl group or a C ₂ -C ₄ -alkynyl group. 8. Estratriene of formula I according to claim 7, wherein R ¹⁷ and R ^{17 '} are a hydroxy group and a hydrogen atom, methyl, ethynyl or prop-1-ynyl group. The compound of claim 1, wherein R ^{16 ′} is an R ¹⁸ —O— or R ¹⁹ SO ₂ —O group (R ¹⁸ and R ¹⁹ in each case have the meaning as indicated in R ² of claim 1), and R ¹⁷ and R ^{17 '} are each a hydrogen atom and all other substituents may have the meanings shown in formula (I). The method of claim 1, 8β-vinyl-estra-1,3,5 (10), 9 (11) -tetraene-3,17β-diol 3-methoxy-8β-vinyl-estra-1,3,5 (10), 9 (11) -tetraen-17β-ol 8β- (2 ', 2'-difluorovinyl) -estra-1,3,5 (10), 9 (11) -tetraene-3,17β-diol 8β- (2'2'-difluorovinyl) -3-methoxy-estra-1,3,5 (10), 9 (11) -tetraen-17β-ol 8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol 3-methoxy-8β-vinyl-estra-1,3,5 (10) -trien-17β-ol 8β- (2 ', 2'-difluorovinyl) -estra-1,3,5 (10) -triene-3,17β-diol 8β- (2 ', 2'-difluorovinyl) -3-methoxy-estra-1,3,5 (10) -trien-17β-ol 8β-ethyl-estra-1,3,5 (10) -triene-3,17β-diol 8β-ethyl-3-methoxy-estra-1,3,5 (10) -trien-17β-ol 8β-vinyl-estradiol-3-sulfate 8β-vinyl-estradiol-3,17-disulfamate 8β-vinyl-estradiol-3- (N-acetyl) -sulfate 8β-vinyl-estrone-3-sulfate 8β-vinyl-estrone-3-acetate 8β-vinyl-estriol 8β-vinyl-estriol-3-sulfate 8β-methyl-estrone-3-sulfate 8β-methyl-estriol 8β- (prop- (Z) -enyl) -estradiol 8β- (n-propyl) -estradiol 8β-ethynyl-estradiol 17α-ethynyl-8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol 17α-methyl-8β-vinyl-estra-1,3,5 (10) -triene-3,17β-diol 16α-fluoro-8β-methyl-estra-1,3,5 (10) -triene-3,17β-diol 8β-vinyl-estra-1,3,5 (10) -triene-3,17α-diol 8β-methyl-estra-1,3,5 (10) -triene-3,17α-diol 8β-vinyl-estradiol-diacetate 8β-methyl-estradiol-diacetate 8β-vinyl-estradiol-17-valerate 17β-acetoxy-8β-vinyl-estra-1,3,5 (10) -trien-3-ol 8β-vinyl-9β-estra-1,3,5 (10) -triene-3,17β-diol Estratriene of formula I, which is 8β-ethyl-9β-estra-1,3,5 (10) -triene-3,17β-diol. Postmenopausal and postmenopausal symptoms, premenopausal and postmenopausal symptoms of men, comprising at least one 8β-substituted estra-1,3,5 (10) -triene derivative of Formula I 'and a pharmaceutically suitable vehicle Treatment, hot flashes, sleep disorders, irritability, mood swings, incontinence, vaginal atrophy, emotional disorders caused by hormonal deficiency, prevention or treatment of genitourinary diseases, prevention or treatment of diseases of the gastrointestinal tract, prevention of gastrointestinal ulcers and hemorrhagic predispositions Or treatment, prevention or treatment of neoplasms, in vitro or in vivo treatment of male infertility, in vitro or in vivo treatment of female infertility, hormone replacement therapy (HRT), loss of bone mass caused by hormone deficiency , Osteoporosis, cardiovascular disease, vascular disease, atherosclerosis, neointimal hyperplasias, neurodegenerative diseases caused by hormone deficiency, Alzheimer's disease, hormone deficiency Prevention or treatment of damage caused memory and learning ability, inflammatory disease, and pharmaceutical compositions for the prevention or treatment of immune diseases, benign prostatic hyperplasia (BPH) in. <Formula I '>

Where R ² , R ⁶ , R ⁷ , R ^{6 '} , R ^7' , R ⁹ , R ^{11 '} , R ¹² , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ^15' , R ^{16 '} are hydrogen; R ³ is a hydroxy group; R ⁸ is a straight or branched chain alkyl or alkenyl radical, ethynyl or prop-1-ynyl radical having up to 5 carbon atoms and which may be halogenated; R ¹¹ is a hydrogen atom or represents a double bond with R ⁹ ; R ¹⁷ and R ^{17 '} are hydrogen atoms; Hydrogen atom and halogen atom; A hydrogen atom and a hydroxyl group; Where R ³ is hydroxy R ² is a hydrogen atom, R ⁶ , R ^{6 '} , R ⁷ and R ^7' in each case are hydrogen atoms, R ⁸ is a methyl group, R ⁹ is a hydrogen atom, or R ⁹ and R ¹¹ together represent a double bond, R ^{11 '} and R ¹² are in each case a hydrogen atom, R ¹⁴ , R ¹⁵ , R ^{15 '} , R ¹⁶ and R ^16' in each case are hydrogen atoms, Excludes compounds of formula I, wherein R ¹⁷ and R ^{17 '} are a β-hydroxy group and a hydrogen atom. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete