KR20080018275A - Benzofuranone derivatives as nonsteroidal progesterone receptor modulators - Google Patents

Abstract

This invention relates to nonsteroidal progesterone receptor modulators of general formula (I), a process for their production, the use of progesterone receptor modulators for the production of pharmaceutical agents as well as pharmaceutical compositions that contain these compounds. The compounds according to the invention are suitable for therapy and prophylaxis of gynecological diseases, such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhea, as well as for the therapy and prophylaxis of hormone-dependent tumors and for use for female birth control as well as for hormone replacement therapy.

Description

Benzofuranone derivatives as nonsteroidal progesterone receptor modulators {BENZOFURANONE DERIVATIVES AS NONSTEROIDAL PROGESTERONE RECEPTOR MODULATORS}

The present invention relates to nonsteroidal progesterone receptor modulators, methods for their preparation, the use of progesterone receptor modulators for the manufacture of pharmaceutical formulations, and pharmaceutical compositions containing these compounds.

The steroid hormone progesterone plays a critical role in regulating the female reproductive process. During the reproductive cycle and during pregnancy, progesterone is secreted from the ovary or placenta. The interaction of estrogen with progesterone results in periodic changes in the uterine mucosa (endometrium) in the menstrual cycle. After ovulation, the effects of elevated progesterone levels change the uterine mucosa into a state where embryos (blastocysts) can implant. During pregnancy, progesterone regulates the relaxation of the myometrium and maintains the function of the decidual tissue.

In addition, it is known that progesterone inhibits proliferation of the endometrium by inhibiting estrogen-mediated mitosis in uterine tissue (K. Chwalisz, RM Brenner, U. Fuhrmann, H. Hess-Stumpp, W). Elger, Steroids 65, 2000, 741-751).

It is also known that progesterone and progesterone receptors play an important role in pathophysiological progression. Progesterone receptors are found in tumors of the uterus, breast and CNS as well as in lesions of endometriosis. In addition, it is known that fibroids proliferate in a progesterone-dependent manner.

The action of progesterone in the tissues of the reproductive organs and other tissues is carried out by interaction with progesterone receptors, which manifests itself as cellular effects.

Progesterone receptor modulators are pure agonists or partially or wholly inhibit the action of progesterone. Thus, such substances are defined as pure agonists, partial agonists (SPRMs) and pure antagonists.

Depending on the ability of the progesterone receptor modulators to influence the action of the progesterone receptors, these compounds have significant potential as therapeutic agents for obstetrics diseases and contraception as well as for gynecological diseases and tumor indications.

Pure progesterone receptor antagonists completely inhibit the action of progesterone at the progesterone receptor. In addition to antiovulation, it has the ability to inhibit the effects of estrogen until the endometrium is completely contracted. Thus, it may intervene during the female reproductive process, for example to prevent implantation after ovulation; It is suitable to increase the responsiveness of the uterus to prostaglandins or oxytocin during pregnancy or to achieve opening and softening of the cervix ("maturation") and to ensure maximum preparation of the myometrium for delivery.

In lesions of endometriosis or tumor tissue with progesterone receptors, a beneficial effect on the progression of the disease after application of pure progesterone receptor antagonists is expected. In addition, if inhibition of ovulation can be achieved by progesterone receptor antagonists, particular advantages may be given that affect pathological diseases such as endometriosis or myoma. When ovulation is suppressed, the stimulating effects on some ovarian hormone production and pathologically altered tissues caused by some hormones are also unnecessary.

The first described progesterone receptor antagonist RU 486 (also called mifepristone) followed by a number of analogs with varying degrees of progesterone receptor-antagonistic activity. While RU 486 also exhibits antiglucocorticoid action in addition to progesterone receptor-antagonistic action, later synthesized compounds are distinguished by more selective action than progesterone receptor antagonists.

In addition to steroid compounds, such as onapristone or lilopriston, which are distinguished by a relatively better segregation action against RU 486 in progesterone-receptor-antagonism and antiglucocorticoid action, various nonsteroidal studies have been studied. Sex constructs are known from the literature (see, eg, SA Leonhardt and DP Edwards, Exp. Biol. Med. 227: 969-980 (2002)) and R. Winneker, A. Fensome, JE Wrobel, Z. Zhang, P. Zhang, Seminars in Reproductive Medicine, Volume 23: 46-57 (2005)). However, previously known compounds have only moderate antagonistic activity compared to known steroid constructs. The most effective nonsteroidal compounds are described as having in vitro activity of 10% of the activity of RU 486.

Antiglucocorticoid activity is disadvantageous for therapeutic applications where the inhibition of progesterone receptors is the focus of therapy. Antiglucocorticoid activity causes undesirable side effects in the case of therapeutically necessary dosages. This may prevent the application of a therapeutically useful dosage or lead to termination of treatment.

Thus, partial or complete reduction in antiglucocorticoid properties is an important prerequisite for treatment with progesterone receptor antagonists, especially indications requiring treatment lasting weeks or months.

In contrast to pure antagonists, progesterone receptor partial agonists (SPRMs) exhibit residual efficacy, which can be strongly expressed to varying degrees. This has led to the discovery that these substances exhibit the potential potent action of progesterone receptors in certain organ systems (D. DeManno, W. Elger, R. Garg, R. Lee, B. Schneider, H. Hess- Stumpp, G. Schuber, K. Chwalisz, Steroids 68, 2003, 1019-1032). Such organ-specific and dissociative action may be therapeutically useful for the indications described above.

Accordingly, it is an object of the present invention to make additional nonsteroidal progesterone receptor modulators available. Such compounds will have reduced antiglucocorticoid activity and will therefore be suitable for the treatment and prevention of gynecological diseases such as endometriosis, uterine myoma, dysfunctional uterine bleeding and dysmenorrhea. In addition, the compounds according to the invention will be suitable for the treatment and prevention of hormone-dependent tumors such as breast cancer, endometrial cancer, ovarian cancer and prostate cancer. In addition, the compounds will be suitable for use in female contraception and female hormone replacement therapy.

According to the present invention the object of the present invention is achieved by preparing the nonsteroidal compounds of the general formula (I) and their pharmaceutically acceptable salts.

Where

R ¹ and R ² , independently of one another, are hydrogen atoms or are straight or non-chain, branched or unbranched C ₁ -C ₅ -alkyl groups, and together with the C atoms of the chain form a total of 3-7 membered rings; ,

R ³ is the radical C≡CR ^a [here,

R ^a is hydrogen or, the same way or in different ways in one or more positions with one or more optionally substituted with K C ₁ -C ₈ - alkyl, C ₂ -C ₈ - alkenyl, C ₂ -C ₈ - alkynyl, C ₃ -C ₁₀ -cycloalkyl or heterocycloalkyl, or aryl or heteroaryl, optionally substituted by L in one or more positions in the same or different ways,

K is cyano, halogen, hydroxy, nitro, -C (O) R ^b , CO ₂ R ^b , -OR ^b , -SR ^b , SO ₂ NR ^c R ^d , -C (O) -NR ^c R ^d , -OC (O) -NR ^c R ^d or -C = NOR ^b -NR ^c R ^d , or C ₃ -C ₁₀ -cycloalkyl optionally substituted by M in one or more positions in the same or different ways, or Heterocycloalkyl or aryl or heteroaryl substituted with L at one or more positions,

L is C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₁ -C ₆ -perfluoroalkyl, C ₁ -C ₆ -perfluoroalkoxy, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - _{alkoxy, (CH 2) p -C 3} -C 10 - cycloalkyl, (CH _{2) p} - _{heterocycloalkyl, (CH 2) p CN,} (CH ₂ ) _p Hal, (CH ₂ ) _p NO ₂ , (CH ₂ ) _p -C ₆ -C ₁₂ -aryl, (CH ₂ ) _p -heteroaryl,-(CH ₂ ) _p PO ₃ (R ^b ) ₂ , -(CH ₂ ) _p NR ^c R ^d ,-(CH ₂ ) _p NR ^e COR ^b ,-(CH ₂ ) _p NR ^e CSR ^b ,-(CH ₂ ) _p NR ^e S (O) R ^b ,-( CH ₂ ) _p NR ^e S (O) ₂ R ^b ,-(CH ₂ ) _p NR ^e CONR ^c R ^d ,-(CH ₂ ) _p NR ^e COOR ^b ,-(CH ₂ ) _p NR ^e C (NH) NR ^c R ^d ,-(CH ₂ ) _p NR ^e CSNR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) NR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) ₂ NR ^c R ^d ,-(CH ₂ ) _p COR ^b ,-(CH ₂ ) _p CSR ^b ,-(CH ₂ ) _p S (O) R ^b ,-(CH ₂ ) _p S (O) (NH) R ^b , -(CH ₂ ) _p S (O) ₂ R ^b ,-(CH ₂ ) _p S (O) ₂ NR ^c R ^d ,-(CH ₂ ) _p SO ₂ OR ^b ,-(CH ₂ ) _p CO ₂ R ^b ,-(CH ₂ ) _p CONR ^c R ^d ,-(CH ₂ ) _p CSNR ^c R ^d ,-(CH ₂ ) _p OR ^b ,-(CH ₂ ) _p SR ^b ,-(CH ₂ ) _p CR ^b (OH) -R ^e ,-(CH ₂ ) _p -C = NOR ^b , -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -O-CH = CH- or-(CH ₂ ) _{n + 2-} , where n = 1 or 2, the terminal oxygen atoms and / or carbon atoms are directly connected to adjacent ring-carbon atoms,

M is C ₁ -C ₆ -alkyl or -COR ^b , CO ₂ R ^b , -OR ^b , or -NR ^c R ^d ,

R ^b is hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl, C ₆ -C ₁₂ -aryl or C ₁ -C ₃ -perfluoroalkyl,

R ^c and R ^d are each independently hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl, C _6- C ₁₂ -aryl, C (O) R ^b or a hydroxy group wherein if R ^c is a hydroxy group, R ^d is only hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl or C ₆ -C ₁₂ -aryl, and vice versa,

R ^e is hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl or C ₆ -C ₁₂ -aryl,

p may be a number from 0 to 6], or

R ³ is a radical C = CR ^g R ^h wherein

R ^g and R ^h are independently of each other hydrogen or C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₈ optionally substituted with X at one or more positions in the same or different ways -Alkynyl,

X is cyano, halogen, hydroxy, nitro, -C (O) R ^b , CO ₂ R ^b , -OR ^b , -C (O) -NR ^c R ^d , -NR ^c R ^d , where R ^b , R ^c and R ^d are as defined above;

R ^4a and R ^4b are independently of each other a hydrogen atom, C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, or together with a ring-carbon atom form a 3- to 6-membered ring,

A is a monocyclic or bicyclic, carbocyclic or heterocyclic aromatic ring (which is at least one position C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₁ -C ₆ -perfluoroalkyl, C ₁ -C ₆ -perfluoroalkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkoxy, (CH ₂ ) _p -C ₃ -C ₁₀ -cycloalkyl, (CH ₂ ) _p -heterocycloalkyl, (CH ₂ ) _p CN, (CH ₂ ) _p Hal, (CH ₂ ) _p NO ₂ , (CH ₂ ) _p -C ₆ -C ₁₂ -aryl, (CH ₂ ) _p -heteroaryl,-(CH ₂ ) _p PO ₃ (R ^b ) ₂ ,-(CH ₂ ) _p NR ^c R ^d ,- (CH ₂ ) _p NR ^e COR ^b ,-(CH ₂ ) _p NR ^e CSR ^b ,-(CH ₂ ) _p NR ^e S (O) R ^b ,-(CH ₂ ) _p NR ^e S (O) ₂ R ^b ,-(CH ₂ ) _p NR ^e CONR ^c R ^d ,-(CH ₂ ) _p NR ^e COOR ^b ,-(CH ₂ ) _p NR ^e C (NH) NR ^c R ^d ,-(CH ₂ ) _p NR ^e CSNR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) NR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) ₂ NR ^c R ^d ,-(CH ₂ ) _p COR ^b , -(CH ₂ ) _p CSR ^b ,-(CH ₂ ) _p S (O) R ^b ,-(CH ₂ ) _p S (O) (NH) R ^b ,-(CH ₂ ) _p S (O) ₂ R ^b ,-(CH ₂ ) _p S (O) ₂ NR ^c R ^d ,- (CH ₂ ) _p SO ₂ OR ^b ,-(CH ₂ ) _p CO ₂ R ^b ,-(CH ₂ ) _p CONR ^c R ^d ,-(CH ₂ ) _p CSNR ^c R ^d ,-(CH ₂ ) _p OR ^b ,-(CH ₂ ) _p SR ^b ,-(CH ₂ ) _p CR ^b (OH) -R ^d ,-(CH ₂ ) _p -C = NOR ^b , Optionally substituted with -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -O-CH = CH- or-(CH ₂ ) _{n + 2-} n = 1 or 2 and the terminal oxygen atom and / or carbon atom is directly connected to an adjacent ring-carbon atom), or

A is a radical —CO ₂ R ^b , C (O) NR ^c R ^d , COR ^b, or

A represents an alkenyl group -CR ⁵ = CR ⁶ R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are the same or different and independently of one another represent a hydrogen atom, a halogen atom, an aryl radical, or an unsubstituted or partially Or a fully fluorinated C ₁ -C ₅ -alkyl group), or

A is an alkynyl group —C≡CR ⁵ , wherein R ⁵ has the meanings mentioned above,

B is a carbonyl group or a CH ₂ group.

The compounds of the general formula (I) according to the invention may exist in other stereoisomers because they have an asymmetric center. Both racemates and individual stereoisomers belong to the subject of the invention.

In addition, the present invention includes pharmaceutical dosage forms comprising new compounds as pharmaceutical active ingredients, their preparation, their therapeutic applications and new substances.

The compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts can in particular be used for the preparation of pharmaceutical preparations for the treatment and prevention of gynecological diseases such as endometriosis, uterine myoma, dysfunctional uterine bleeding and dysmenorrhea. have. In addition, the compounds according to the invention can be used for the treatment and prevention of hormone-dependent tumors such as breast cancer, prostate cancer and endometrial cancer.

The compounds of general formula (I) or pharmaceutically acceptable salts thereof according to the invention are suitable for use for female contraception or female hormone replacement therapy.

Processes for preparing compounds of general formula (I) are also subject of the present invention. The substituent R ³ is introduced into the keto group by selective addition reaction of organometallic compounds such as lithium alkynylene or magnesium haloalkynylene. This gives a compound of the general formula (I) according to the invention either directly or after further modifications.

The preparation of the compounds according to the invention is carried out by selective addition reactions of organometallic compounds to ketoamides, which are disclosed, for example, in the published applications WO 200375915 and WO 9854159. The organometallic compound may be, for example, a lithium alkynyl compound or a magnesium haloalkynyl compound. It can be prepared, for example, by reacting a suitable alkyne with a butyl lithium or Grignard compound. Similarly, corresponding organometallic alkenyl compounds can also be prepared. Compared to amidocarbonyl or phthalide, the reactivity of the keto groups in this case is quite high, and with the appropriate choice of reaction conditions a selective addition reaction is achieved. Alternatively, the alkynyl or alkenyl radicals introduced as R ³ can also be further modified afterwards. For this modification, reactions known to those skilled in the art are suitable, such as oxidation, reduction, substitution, alkylation, or palladium-catalyzed reactions. Optionally present protecting groups are removed when appropriate.

Nonsteroidal compounds of the general formula (I) according to the invention have a strong antagonistic action or a strong partial agonistic action on progesterone receptors. They exhibit a strong dissociation action with respect to their binding strength to progesterone receptors and glucocorticoid receptors. Although known progesterone receptor antagonists such as mifepristone (RU 486) exhibit the desired high binding affinity for progesterone receptors, the compounds according to the invention exhibit a high affinity for glucocorticoid receptors, but exhibit a high progesterone receptor affinity. At the same time it is distinguished in that it exhibits very low glucocorticoid receptor binding capacity.

Substituents of the compounds of the general formula (I) according to the invention, defined as groups, may in each case have the following meanings.

C ₁ -C _5- , C ₁ -C ₆ -or C ₁ -C ₈ -alkyl groups are defined as straight or non-chain, branched or unbranched alkyl radicals. Examples thereof include methyl, ethyl, n-propyl, iso-propyl, n-, iso-, tert-butyl, n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl, hexyl, heptyl or octyl groups.

With respect to R ^a , methyl, ethyl, n-propyl or n-butyl groups and n-pentyl groups are preferred in this case.

Regarding R ¹ and R ² , methyl or ethyl is preferable.

According to the invention, hydrogen is preferred as R ^4a and R ^4b .

Alkenyl is defined as a straight or non-chain, branched or unbranched alkenyl radical. In the context of the present invention, C ₂ -C ₈ -alkenyl groups are defined, for example, by the following groups: vinyl, allyl, 3-buten-1-yl- or 2,3-dimethyl-2-propenyl. When aromatic compound A is substituted with a C ₂ -C ₈ -alkenyl radical, it is preferably a vinyl group.

Alkynyl is defined as straight or non-chain, branched or unbranched alkynyl radical. For example, there are ethynyl, propynyl, butynyl, pentynyl, hexynyl or octinyl groups, but preferably the ethynyl or propynyl groups represent C ₂ -C ₈ -alkynyl radicals.

For C ₃ -C ₁₀ -cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl can be mentioned. Preference is given to cyclopropyl, cyclopentyl and cyclohexyl.

With respect to R ^a , K or L, heterocycloalkyl is defined as a 3- to 8-membered heterocycloalkyl radical. Examples of heterocycloalkyl are morpholinyl, tetrahydrofuranyl, pyranyl, piperazinyl, piperidinyl, pyrrolidinyl, oxiranyl, oxetanyl, aziridinyl, dioxolanyl and dioxanyl . In this case the position of the heteroatom relative to the position of the linkage can be any chemically possible position.

For example, a methoxymethoxy, ethoxy, methoxy or 2-methoxyethoxy is C ₁ -C ₆ - may represent an alkoxy group-alkoxyl, -C ₁ -C _6.

In the context of the present invention, the radical OR ^b is a hydroxy, methoxy, ethoxy, n-propoxy, iso-propoxy, n-, iso-, or tert-butoxy group, or n-pentoxy, 2,2 -Dimethylpropoxy or 3-methylbutoxy group. Preference is given to hydroxy, methoxy and ethoxy.

Partially or fully fluorinated C ₁ -C ₅ -alkyl groups are considered such perfluorinated alkyl groups. Fully fluorinated groups are mainly trifluoromethyl groups or pentafluoroethyl groups, and partially fluorinated alkyl groups are, for example, 5,5,5,4,4-pentafluoropentyl groups or 5,5 Preference is given to, 5,4,4,3,3-heptafluoropentyl groups.

Fluorine, chlorine, bromine or iodine atoms may represent halogen atoms.

Preference is given here to fluorine, chlorine or bromine.

When R ¹ and R ² together with the C atoms of the chain form a 3- to 7-membered ring it is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. Preference is given to cyclopropyl rings and cyclopentyl rings.

Monocyclic or bicyclic carbocyclic aromatic rings A, which may be substituted at several positions, are carbocyclic or heterocyclic aryl radicals.

In the former case it is, for example, a phenyl or naphthyl radical, preferably a phenyl radical.

As heterocyclic radicals, for example, monocyclic heterocyclic radicals such as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyri Daginyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, or tetrazolyl radicals, and especially all possible isomers related to the position of the heteroatoms, are to be used. Can be.

With respect to R ³ , the aryl radical is an optionally substituted phenyl, 1- or 2-naphthyl radical, wherein the phenyl radical is preferred. Examples of heteroaryl radicals include 2-, 3- or 4-pyridinyl radicals, 2- or 3-furyl radicals, 2- or 3-thienyl radicals, 2- or 3-pyrrolyl radicals, 2-, 4- or 5-imidazolyl radicals, pyrazinyl radicals, 2-, 4- or 5-pyrimidinyl radicals or 3- or 4-pyridazinyl radicals.

The number p for the (CH ₂ ) _p radical may be a number from 0 to 6, preferably 0 to 2. "Radial" is defined as all functional groups linked with (CH ₂ ) _p in accordance with the invention.

If a compound of the general formula (I) (B = -CH _2- ) is present as a salt, it may be in the form of, for example, hydrochloride, sulfate, nitrate, tartrate, citrate, fumarate, succinate or benzoate have.

If the compounds according to the invention are present as racemic mixtures, they can be separated in optically active pure form according to the racemic separation methods familiar to those skilled in the art. For example, the racemic mixture can be separated into pure isomers by chromatography on an optically active carrier material (CHIRALPAK AD®). The free hydroxy groups in the racemic compound of general formula (I) are esterified with an optically active acid and the diastereomeric esters obtained by fractional crystallization or chromatography are separated and the separated esters in each case are optically pure. It is also possible to form isomers. As optically active acids, for example, mandelic acid, camphorsulfonic acid or tartaric acid can be used.

The compounds mentioned below and their uses are preferred according to the invention.

Biological Properties of the Compounds According to the Invention

Identification of progesterone receptor modulators can be performed using simple methods, test programs known to those skilled in the art. For this purpose, for example, the compound to be tested can be incubated with gestagen in a test system for progesterone receptors and tested in this test system whether the progesterone-mediated effect is changed in the presence of a modulator.

The materials of general formula (I) according to the invention were tested in the following models.

Progesterone receptor binding test

Receptor binding affinity measurement:

Receptor binding affinity was determined by competitive binding of ³ H-labeled hormones (tracers) that specifically bind on receptors in the cytoplasm from animal target organs and the compounds to be tested. In this case, receptor saturation and reaction equilibrium were investigated.

The tracer and increasing concentrations of compound to be tested (competitors) were co-incubated with the receptor-containing cytoplasmic fraction at 0-4 ° C. over 18 hours. After separating the unbound tracer with a carbon-dextran suspension, the receptor-bound tracer portion was measured at each concentration and the IC ₅₀ was determined from the concentration sequence. The relative molecular binding affinity (RBA) was calculated as the ratio of the IC ₅₀ value of the reference material and the test compound (x 100%) (RBA = 100% of the reference material).

Depending on the receptor type, the following incubation conditions were selected.

Progesterone Receptor:

Uterine cytoplasm of estradiol-infused rabbit homogenized in TED buffer (tris / HCl 20 mmol, pH 7.4; 1 mmol ethylenediamine tetraacetate, 2 mmol dithiothritol) with 250 mmol of saccharose; Store at -30 ° C. Tracer: ³ H-ORG 2058, 5 nmol; Reference substance: progesterone.

Glucocorticoid Receptor:

Thymic cytoplasm of adrenal isolated rats, thymus stored at −30 ° C .; Buffer: TED. Tracer: ³ H-dexamethasone, 20 nmol; Reference substance: Dexamethasone.

The relative receptor binding affinity (RBA value) of the compounds of general formula (I) according to the invention for progesterone receptors is 3 to 100% for progesterone. The RBA value for the glucocorticoid receptor is 3-30% for dexamethasone.

Thus, the compounds according to the invention have a high affinity for the progesterone receptor but a low affinity for the glucocorticoid receptor.

Progesterone receptor PR Antagonism of -B

Transactivation assays are performed as described in WO 02/054064.

Progesterone receptor PR Efficacy of -B

Fuhrmann, U .; described by Fuhrmann et al .; Hess-Stump, H .; Cleve, A .; Neef, G .; Schwede, W .; Hoffmann, J .; Fritzemeier, K.-H., Chwalisz, K .; Transition activity assays are performed according to the Journal of Medicinal Chem., 43, 26, 2000, 5010-5016.

number Antagonist activity Efficacy Activity IC ₅₀ [nM] validity EC ₅₀ [nM] validity 9 3 96 n.b. 3 13 3 92 n.b. 7 3b 0.4 97 n.b. 2 7 4 82 2 11

Dosage

For use according to the invention, progesterone receptor modulators can be administered orally, enterally, parenterally or transdermally.

In general, satisfactory results can be expected in the treatment of the indications if the daily dose comprises 1 μg to 500 mg of the compound according to the invention.

In humans, the dosage of the compound according to the invention suitable for the treatment of endometriosis, fibroids and dysfunctional uterine bleeding, as well as for contraceptive use and hormone replacement therapy is between 50 μg and 500 mg per day, which is the age of the patient. Depending on the constitution and the required daily dosage may be administered more than once.

The dosage range of the compound according to the invention for the treatment of breast cancer is 10 mg to 1000 mg per day.

Formulation of pharmaceutical formulations based on new compounds is carried out in a manner known in the art, in which the active ingredient is a carrier, filler, wetting agent, binder, wetting agent, lubricant, absorbent, diluent, flavor enhancer, commonly used in herbal medicines. It is carried out by processing with colorants, etc. and converting it into the desired dosage form. In this case, Remington's Pharmaceutical Science, 15 ^th Ed. Mack Publishing Company, East Pennsylvania (1980).

For oral administration in particular tablets, film tablets, coated tablets, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions are suitable.

For parenteral administration, injection and infusion preparations are possible.

For intraarticular injection, correspondingly prepared crystal suspensions can be used.

For intramuscular injection, aqueous and oily injection solutions or suspensions and the corresponding depot preparations can be used.

For rectal administration, the new compounds can be used for systemic and topical treatment in the form of suppositories, capsules, solutions (eg in the form of enema) and ointments.

In addition, agents for vaginal application may also be referred to as preparations.

For pulmonary administration of the new compounds, they can be used in the form of aerosols and inhalants.

For transdermal administration, patches are possible, or for topical administration gels, ointments, fatty ointments, creams, pastes, powders, tonsilles and tinctures are possible. In order to achieve adequate pharmacological action, the dosage of the compound of general formula (I) in these preparations should be 0.01% to 20%.

Corresponding tablets may be prepared by, for example, the active ingredient with known excipients, for example inert diluents such as dextrose, sugars, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch Or gelatin, lubricants such as magnesium stearate or talc and / or agents that achieve the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also consist of several layers.

Thus, coated tablets may be prepared using coating cores prepared similarly to tablets and agents commonly used in coating tablets, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugars. Can be. In this case, the coated tablet shell may consist of several layers, and the aforementioned excipients may be used in the tablet.

Solutions or suspensions of the compounds of general formula (I) according to the invention may further comprise taste-enhancing agents such as saccharin, cyclates or sugars and eg flavoring substances such as vanilla or orange extracts. In addition, they may include suspending excipients such as sodium carboxy methyl cellulose or preservatives such as p-hydroxybenzoate.

Capsules comprising a compound of general formula (I) can be prepared, for example, by mixing the compound (s) of general formula (I) with an inert carrier such as lactose or sorbitol and encapsulating in gelatin capsules.

Suitable suppositories can be prepared, for example, by mixing with a carrier provided for this purpose, such as triglycerides or polyethylene glycols or derivatives thereof.

The compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts are particularly suitable for the preparation of pharmaceutical preparations for the treatment and prevention of gynecological diseases such as endometriosis, uterine myoma, dysfunctional uterine bleeding and dysmenorrhea. It can be used based on antagonism or partial agonistic action. In addition, they can be used to correct hormonal irregularities, induce menstruation and induce delivery alone or in combination with prostaglandins and / or oxytocin.

In addition, the compounds of the general formula (I) or pharmaceutically acceptable salts thereof according to the invention are suitable for the preparation of contraceptive preparations for women (see also WO 93/23020, WO 93/21927).

In addition, the compounds according to the invention or pharmaceutically acceptable salts thereof can be used in female hormone replacement therapy alone or in combination with a selective estrogen receptor modulator (SERM).

In addition, the aforementioned compounds exhibit antiproliferative action in hormone-dependent tumors. Thus, the compounds are suitable for the treatment of hormone-dependent cancers such as breast cancer, prostate cancer or endometrial cancer.

The compounds according to the invention or their pharmaceutically acceptable salts can be used for the treatment of hormone-dependent cancers in primary and secondary therapies, in particular after tamoxifen therapy failure.

Compounds of the general formula (I) or pharmaceutically acceptable salts thereof according to the invention having an antagonistic or partial agonistic action are also compounds having estrogen action for the preparation of pharmaceutical preparations for the treatment of hormone-dependent tumors (estrogen receptor antagonists) Or in combination with an aromatase inhibitor) or a selective estrogen receptor modulator (SERM). For the treatment of endometriosis or fibroids, the compounds according to the invention can also be used in combination with SERMs or antiestrogens (estrogen receptor antagonists or aromatase inhibitors). In the treatment of hormone-dependent tumors, progesterone receptor modulators and antiestrogens (estrogen receptor antagonists or aromatase inhibitors) or SERMs may be provided for simultaneous or sequential administration. In sequential administration, an anti-estrogen (estrogen receptor antagonist or aromatase inhibitor) or SERM is preferably administered first, followed by a progesterone receptor modulator.

In combination with the nonsteroidal progesterone receptor modulator according to the invention, for example, the following antiestrogens (estrogen receptor antagonists or aromatase inhibitors) or SERMs are contemplated.

Tamoxifen, 5- (4- {5-[(RS)-(4,4,5,5,5-pentafluoropentyl) sulfinyl] -pentyloxy} phenyl) -6-phenyl-8,9-di Hydro-7H-benzocyclohepten-2-ol (WO 00/03979), ICI 182 780 (7alpha- [9- (4,4,5,5-pentafluoropentylsulfinyl) nonyl] estra-1, 3,5 (10) -triene-3,17-beta-diol), 11beta-fluoro-7alpha- [5- (methyl {3-[(4,4,5,5,5-pentafluoro) Lofentyl) sulfanyl] propyl} amino) pentyl] estra-1,3,5 (10) -triene-3,17beta-diol (WO98 / 07740), 11beta-fluoro-7alpha- {5- [Methyl (7,7,8,8,9,9,10,10,10-nonafluorodecyl) amino] pentyl} estra-1,3,5 (10) -triene-3,17beta-diol (WO 99/33855), 11beta-fluoro-17alpha-methyl-7alpha- {5- [methyl (8,8,9,9,9-pentafluorononyl) amino] pentyl} estra-1, 3,5 (10) -triene-3,17beta-diol (WO 03/045972), clomiphene, raloxifene as well as other antiestrogens active compounds, and aromatase inhibitors such as padrazole, formemstan, letrozole , Or Straw sol or methoxy Atta Stan.

Finally, the present invention also relates to the use of the compounds of general formula (I), optionally in combination with antiestrogens or SERMs, for the preparation of pharmaceutical preparations.

The invention also relates to pharmaceutical compositions which contain one or more compounds according to the invention, optionally in the form of pharmaceutically / pharmacologically compatible salts, with or without pharmaceutically compatible excipients and / or carriers.

The pharmaceutical compositions and pharmaceutical formulations may be provided for oral, rectal, vaginal, subcutaneous, transdermal, intravenous or intramuscular administration. The compositions and preparations contain one or more compounds according to the invention in addition to the carriers and / or diluents commonly used.

Pharmaceutical formulations of the present invention may be prepared in a known manner using conventionally used solid or liquid carriers or diluents and commonly used pharmaceutical-technical excipients which correspond to the desired type of administration at suitable dosages. Preferred formulations are in dosage forms suitable for oral administration. Such dosage forms include, for example, tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions, or depots.

Pharmaceutical compositions containing at least one compound according to the invention are preferably administered orally.

Parenteral preparations such as injection solutions are also contemplated.

In addition, suppositories and vaginal application agents may also be referred to as preparations, for example.

The following examples are used to illustrate the subject matter of the present invention in more detail, but are not intended to be limited to these examples.

The preparation of the starting compound 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionylamino} phthalide is described in patent WO 200375915, 5- The preparation of {3- [1-phenyl-cyclopropyl] -2-oxopropionylamino} phthalide is described in WO 9854159.

rac-5- {2-ethynyl-2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -propionylamino} phthalide One

Ethinyl magnesium bromide (6 ml, 0.5 M in tetrahydrofuran) was added 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- in THF (4 ml). It was added to an ice cold solution consisting of oxopropionylamino} phthalide (632 mg). Under argon the reaction solution was allowed to reach room temperature in 3 hours. The reaction mixture was then poured into ice cold saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. The crude product obtained was chromatographed on silica gel. 2.2 g of product was obtained.

rac -5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl ) -Cyclo Pro Phil] -2- Propynyl - Propionylamino } Phthalide 2

Similar to Example 1, 145 mg of product was prepared with 1-propynylmagnesium bromide (2 ml of 0.5 M solution in tetrahydrofuran) and 6- [4- (2-chloro-4-fluorophenyl) -4-methyl- Obtained from 210 mg of 2-oxovaleroylamino] -4-methyl-2,3-benzoxazin-1-one.

(+)-5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl ) -Cyclo Pro Phil] -2- Phenyl - Propionylamino } Phthalide 3a  And

(-)-5- {2-hydroxy-3- [1- (2-fluoro-5-triple Uromethylphenyl ) -Cyclo Pro Phil] -2- ( Phenylethynyl )- Propionylamino } Phthalide 3b

n-butyllithium (625 μl, 1.6 M in hexane) was added to a solution of 110 μl of phenylacetylene in tetrahydrofuran at −78 ° C. Stirring was continued for 30 minutes at this temperature and then 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionylamino in 5 ml of tetrahydrofuran. } A solution of phthalide (210 mg) was added dropwise. It was then allowed to reach 23 ° C. over about 3 hours and then stirred for an additional 10 hours. The reaction mixture was then poured into ice cold saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. The crude product was chromatographed on silica gel. The racemic mixture obtained was then separated into enantiomers 3a (46 mg) and 3b (47 mg) using preparative chiral HPLC (Chiralpak AD column, 250 × 10 mm).

3a and 3b :

Similar to Example 3, compound 4 and compound 5 were selected from 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionylamino} phthalide and Was prepared from lithium aryl acetylide.

rac -5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl )- Cyclopropyl ] -2-[(4- Trifluoromethylphenyl ) Ethynyl ] Propionylamino } Phthalide 4

(+)-5- {2-hydroxy-3- [1- (2- Fluoro -5-trifluoro Methylphenyl ) -Cyclo Pro Phil] -2-[(4- Trifluoromethylphenyl ) Ethynyl ] Propionylamino } Phthalide 4a  And

(-)-5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl )- Cyclopropyl ] -2-[(4- Trifluoromethylphenyl ) Ethynyl ] Propionylamino } Phthalide 4b

The racemic mixture (150 mg) described in Example 4 was separated into enantiomers 4a (51 mg) and 4b (62 mg) using preparative chiral HPLC (Column Chiralpak AD 250x10 mm).

rac -5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl )- Cyclopropyl ] -2-[(4- Methylphenyl ) Ethynyl ] Propionylamino } Phthalide 5

(+)-5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl ) -Cyclo Pro Phil] -2-[(4- Methylphenyl ) Ethynyl ] Propionylamino } Phthalide 5a  And

(-)-5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl )- Cyclopropyl ] -2-[(4- Methylphenyl ) Ethynyl ] Propionylamino } Phthalide 5b

The racemic mixture (109 mg) described in Example 5 was separated into enantiomers 5a (41 mg) and 5b (28 mg) using preparative chiral HPLC (Column Chiralpak AD 250x10 mm).

rac -5- {2-[(4- Acetoxyphenyl ) Ethynyl ] -2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl )- Cyclopropyl ]- Propionylamino } Phthalide 6

Compound described in Example 1 in THF (5 ml) and triethylamine (5 ml) (104 mg), triphenylphosphine (12.2 mg), copper iodide (8.9 mg), 4-iodophenyl acetate (92 mg), a suspension of palladium acetate (5.3 mg) was reacted under argon at 25 ° C. in an ultrasonic bath for 1 hour. This was then poured into saturated aqueous ammonium chloride solution. It was extracted with ethyl acetate and washed with water and saturated sodium chloride solution. The combined organic phases were dried over sodium sulfate. After column chromatography on silica, the crude product is obtained 55 mg.

rac -5- {2-hydroxy-2-[(4- Hydroxyphenyl ) Ethynyl ] -3- [1- (2- Fluoro -5- Trifluoromethylphenyl )- Cyclopropyl ]- Propionylamino } Phthalide 7

A solution of the compound described in Example 6 (45 mg) in 5 ml of methanol was mixed with sodium hydrogen carbonate (130 mg). Stirring was continued for an additional 2 hours at 23 ° C. The reaction mixture was then diluted with ethyl acetate. Then it was washed twice with saturated sodium chloride solution. After drying over sodium sulfate, the crude product was purified by column chromatography on silica gel. 38 mg of product was obtained.

rac -5- {2-[(4-carboxy Phenyl ) Ethynyl] -2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl)- Cyclopropyl ]- Propionylamino } Phthalide 8

Similar to Example 6, compound 8 was prepared from the compound described in Example 1 and 4-iodobenzoic acid.

rac -5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl )- Cyclopropyl ]-2-( Pentin -1 day)- Propionylamino } Phthalide 9

A solution consisting of 1-pentine (0.94 ml) in THF (9 ml) was mixed with nBuLi (0.6 ml, 1.6 M in hexane) at -78 ° C. Stir at −78 ° C. for 30 min, then 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionylamino} in 3 ml tetrahydrofuran A solution of phthalide (200 mg) was added. It was then allowed to reach 23 ° C. over about 3 hours and stirred at this temperature for an additional 10 hours. The reaction mixture was then poured into ice cold saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. The crude product was chromatographed on silica gel. 130 mg of product was obtained.

(+)-5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl )- Cyclopropyl ]-2-( Pentin -1 day)- Propionylamino } Phthalide 9a  And

(-)-5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl ) -Cyclo Pro Phil] -2- ( Pentin -1 day)- Propionylamino } Phthalide 9b

The racemic mixture (120 mg) described in Example 9 was separated into enantiomers 9a (46 mg) and 9b (47 mg) using preparative chiral HPLC (Column Chiral Pack AD 250x10 mm).

rac -5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl )- Cyclopropyl ]-2-( Hexin -1 day)- Propionylamino } Phthalide 10

Compound 10 was synthesized similar to Example 9.

rac -5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl )- Cyclopropyl ] -2-[(4-hydroxy) butyn-1-yl]- Propionylamino } Phthalide 11

Step A: Similar to the method described in Example 9, 4- (tert-butyldimethylsilyloxo) but-1-yne (175 mg), nBuLi (0.59 ml, 1.6 M in hexane), 5- in tetrahydrofuran {3- [1- (2-Fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionylamino} -phthalide (200 mg) was reacted to give 165 mg of product.

Step B: The product obtained in Step A (160 mg) was dissolved in 5 ml of tetrahydrofuran. At 0 ° C., 270 μl of tetrabutylammonium fluoride 1 M solution in tetrahydrofuran were added, stirred at 0 ° C. for 1 h, and further at 23 ° C. for 2 h. The reaction mixture was then poured into saturated aqueous sodium hydrogen carbonate solution. It was extracted several times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After column chromatography on silica gel, 77 mg of product was obtained.

Similar to Example 11, compound 12 and compound 13 were prepared from 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionylamino} phthalide It was.

rac -5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl )- Cyclopropyl ] -2-[(5-hydroxy) Pentin -1 day]- Propionylamino } Phthalide 12

rac -5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl )- Cyclopropyl ] -2-[(3-hydroxy) Propine -1 day]- Propionylamino } Phthalide 13

(+)-5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl ) -Cyclo Pro Phil] -2-[(3-hydroxy) Propine -1 day]- Propionylamino } Phthalide  One 3a  And

(-)-5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl )- Cyclopropyl ] -2-[(3-hydroxy) Propine -1 day]- Propionylamino } Phthalide 13b

The racemic mixture (80 mg) described in Example 13 was separated into enantiomers 13a (35 mg) and 13b (37 mg) using preparative chiral HPLC (column chiralpak AD 250x10 mm).

rac -5- {2-hydroxy-3- [1- (2-fluoro-5-triple Uromethylphenyl ) -Cyclo Pro Phil] -2-[(4-hydroxy-3- methyl ) Butyn-1-yl]- Propionylamino } Phthalide 14

Step A: Similar to Example 11, 300 mg of 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionylamino} phthalide and tert- 282 mg of butyl- (1,1-dimethylprop-2-ynyl-oxy) -dimethylsilane were reacted. 15 mg of product A was obtained.

Step B: 70 mg of the compound obtained in Step A was dissolved in 1 ml of dichloromethane. 650 μl of trifluoroacetic acid (20% in dichloromethane) was added at 0 ° C. and stirred at 0 ° C. for 3.5 h. It was then evaporated to dryness in vacuo and the residue was purified by column chromatography on silica gel. 27 mg of product was obtained.

rac -5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl ) -Cyclo Pro Phil] -2- (2- ( tert - Butyl Carboxy ) Etin -1 day)- Propionylamino } Phthalide 15

Compound 15 was synthesized similar to Example 9.

rac -5- {2-hydroxy-3- [1- (2- Fluoro -5- Trifluoromethylphenyl )- Cyclopropyl ] -2- (2- Carboxytine -1 day)- Propionylamino } Phthalide 16

50 mg of the compound described in Example 15 was dissolved in 5 ml of dichloromethane. 100 μl of trifluoroacetic acid was added and stirred at 23 ° C. for an additional 12 h. It was then evaporated to dryness in vacuo and the residue was purified by column chromatography on silica gel. 36 mg of product was obtained.

Similar to Example 3, compound 17 was prepared from 5- {3- [1-phenyl-cyclopropyl] -2-oxopropionylamino} phthalide.

rac-5- {2-hydroxy-3- [1-phenyl-cyclopropyl] -2- (phenyl-ethynyl) propionylamino} -phthalide 17

Claims (25)

The following general formula (I) and pharmaceutically acceptable salts thereof. <Formula I>

Where R ¹ and R ² independently of one another are hydrogen atoms or are straight or non-chain, branched or unbranched C ₁ -C ₅ -alkyl groups, and together with the C atoms of the chain form a total of 3 to 7 membered rings; , R ³ is a radical C≡CR ^a [where R ^a is hydrogen or, the same way or in different ways in one or more positions with one or more optionally substituted with K C ₁ -C ₈ - alkyl, C ₂ -C ₈ - alkenyl, C ₂ -C ₈ - alkynyl, C ₃ -C ₁₀ -cycloalkyl or heterocycloalkyl, or aryl or heteroaryl, optionally substituted by L in one or more positions in the same or different ways, K is cyano, halogen, hydroxy, nitro, -C (O) R ^b , CO ₂ R ^b , -OR ^b , -SR ^b , SO ₂ NR ^c R ^d , -C (O) -NR ^c R ^d , -OC (O) -NR ^c R ^d or -C = NOR ^b -NR ^c R ^d , or C ₃ -C ₁₀ -cycloalkyl optionally substituted by M in one or more positions in the same or different ways, or Heterocycloalkyl or aryl or heteroaryl substituted with L at one or more positions, L is C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₁ -C ₆ -perfluoroalkyl, C ₁ -C ₆ -perfluoroalkoxy, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - _{alkoxy, (CH 2) p -C 3} -C 10 - cycloalkyl, (CH _{2) p} - _{heterocycloalkyl, (CH 2) p CN,} (CH ₂ ) _p Hal, (CH ₂ ) _p NO ₂ , (CH ₂ ) _p -C ₆ -C ₁₂ -aryl, (CH ₂ ) _p -heteroaryl,-(CH ₂ ) _p PO ₃ (R ^b ) ₂ , -(CH ₂ ) _p NR ^c R ^d ,-(CH ₂ ) _p NR ^e COR ^b ,-(CH ₂ ) _p NR ^e CSR ^b ,-(CH ₂ ) _p NR ^e S (O) R ^b ,-( CH ₂ ) _p NR ^e S (O) ₂ R ^b ,-(CH ₂ ) _p NR ^e CONR ^c R ^d ,-(CH ₂ ) _p NR ^e COOR ^b ,-(CH ₂ ) _p NR ^e C (NH) NR ^c R ^d ,-(CH ₂ ) _p NR ^e CSNR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) NR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) ₂ NR ^c R ^d ,-(CH ₂ ) _p COR ^b ,-(CH ₂ ) _p CSR ^b ,-(CH ₂ ) _p S (O) R ^b ,-(CH ₂ ) _p S (O) (NH) R ^b , -(CH ₂ ) _p S (O) ₂ R ^b ,-(CH ₂ ) _p S (O) ₂ NR ^c R ^d ,-(CH ₂ ) _p SO ₂ OR ^b ,-(CH ₂ ) _p CO ₂ R ^b ,-(CH ₂ ) _p CONR ^c R ^d ,-(CH ₂ ) _p CSNR ^c R ^d ,-(CH ₂ ) _p OR ^b ,-(CH ₂ ) _p SR ^b ,-(CH ₂ ) _p CR ^b (OH) -R ^e ,-(CH ₂ ) _p -C = NOR ^b , -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -O-CH = CH- or-(CH ₂ ) _{n + 2-} , where n = 1 or 2, the terminal oxygen atom and / or carbon atom is directly connected to the adjacent ring-carbon atom, M is C ₁ -C ₆ -alkyl or -COR ^b , CO ₂ R ^b , -OR ^b , or -NR ^c R ^d , R ^b is hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl, C ₆ -C ₁₂ -aryl or C ₁ -C ₃ -perfluoroalkyl, R ^c and R ^d are each independently hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl, C _6- C ₁₂ -aryl, C (O) R ^b or a hydroxy group wherein if R ^c is a hydroxy group, R ^d is only hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl or C ₆ -C ₁₂ -aryl, and vice versa, R ^e is hydrogen or C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl or C ₆ -C ₁₂ -aryl, p may be a number from 0 to 6], or R ³ is a radical C = CR ^g R ^h wherein R ^g and R ^h are independently of each other hydrogen or C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₈ optionally substituted with X at one or more positions in the same or different ways -Alkynyl, X is cyano, halogen, hydroxy, nitro, -C (O) R ^b , CO ₂ R ^b , -OR ^b , -C (O) -NR ^c R ^d , -NR ^c R ^d , where R ^b , R ^c and R ^d are as defined above; R ^4a and R ^4b are independently of each other a hydrogen atom, C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, or together with a ring-carbon atom form a 3- to 6-membered ring, A is a monocyclic or bicyclic, carbocyclic or heterocyclic aromatic ring (which is at least one position C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₁ -C ₆ -perfluoroalkyl, C ₁ -C ₆ -perfluoroalkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkoxy, (CH ₂ ) _p -C ₃ -C ₁₀ -cycloalkyl, (CH ₂ ) _p -heterocycloalkyl, (CH ₂ ) _p CN, (CH ₂ ) _p Hal, (CH ₂ ) _p NO ₂ , (CH ₂ ) _p -C ₆ -C ₁₂ -aryl, (CH ₂ ) _p -heteroaryl,-(CH ₂ ) _p PO ₃ (R ^b ) ₂ ,-(CH ₂ ) _p NR ^c R ^d ,- (CH ₂ ) _p NR ^e COR ^b ,-(CH ₂ ) _p NR ^e CSR ^b ,-(CH ₂ ) _p NR ^e S (O) R ^b ,-(CH ₂ ) _p NR ^e S (O) ₂ R ^b ,-(CH ₂ ) _p NR ^e CONR ^c R ^d ,-(CH ₂ ) _p NR ^e COOR ^b ,-(CH ₂ ) _p NR ^e C (NH) NR ^c R ^d ,-(CH ₂ ) _p NR ^e CSNR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) NR ^c R ^d ,-(CH ₂ ) _p NR ^e S (O) ₂ NR ^c R ^d ,-(CH ₂ ) _p COR ^b , -(CH ₂ ) _p CSR ^b ,-(CH ₂ ) _p S (O) R ^b ,-(CH ₂ ) _p S (O) (NH) R ^b ,-(CH ₂ ) _p S (O) ₂ R ^b ,-(CH ₂ ) _p S (O) ₂ NR ^c R ^d ,- (CH ₂ ) _p SO ₂ OR ^b ,-(CH ₂ ) _p CO ₂ R ^b ,-(CH ₂ ) _p CONR ^c R ^d ,-(CH ₂ ) _p CSNR ^c R ^d ,-(CH ₂ ) _p OR ^b ,-(CH ₂ ) _p SR ^b ,-(CH ₂ ) _p CR ^b (OH) -R ^d ,-(CH ₂ ) _p -C = NOR ^b , Optionally substituted with -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -O-CH = CH- or-(CH ₂ ) _{n + 2-} n = 1 or 2 and the terminal oxygen atom and / or carbon atom is directly connected to an adjacent ring-carbon atom), or A is a radical —CO ₂ R ^b , C (O) NR ^c R ^d , COR ^b, or A represents an alkenyl group -CR ⁵ = CR ⁶ R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are the same or different and independently of one another represent a hydrogen atom, a halogen atom, an aryl radical, or an unsubstituted or partially Or a fully fluorinated C ₁ -C ₅ -alkyl group), or A is an alkynyl group —C≡CR ⁵ , wherein R ⁵ has the meanings mentioned above, B is a carbonyl group or a CH ₂ group. The compound of claim 1, wherein R ¹ and R ² are hydrogen atoms, methyl groups or ethyl groups. The compound of claim 1, wherein R ¹ and R ² together with the C atoms of the chain form a total of 3 to 7 membered rings. The compound of any one of claims 1-3, wherein R ³ is alkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, cycloalkylalkynyl or heterocycloalkylalkynyl. 5. The compound of claim 1, wherein R ³ is vinyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, hydroxypropynyl, hydroxybutynyl, 3-hydroxy-3-methylbutynyl, hydroxypentynyl, carboxypropynyl, t-butylcarboxypropynyl, phenylethynyl, (hydroxyphenyl) ethynyl, (methoxyphenyl) ethynyl, (dimethylamino Phenyl) ethynyl, (methylphenyl) ethynyl, (cyanophenyl) ethynyl, (trifluoromethyl) ethynyl, (diphenyl) ethynyl, (nitrophenyl) ethynyl, (tert-butylphenyl) ethynyl , (Acetylphenyl) ethynyl, (acetoxyphenyl) ethynyl, (carboxyphenyl) ethynyl or benzylethynyl group. The compound of any one of claims 1-5, wherein A is an aromatic ring. The compound according to any one of claims 1 to 6, wherein A is preferably a phenyl or naphthyl radical. 8. A compound according to claim 7, wherein A is an unsubstituted phenyl radical or an optionally substituted phenyl radical at one or more positions. The compound of claim 8, wherein the phenyl radical is substituted with one or two halogen atoms or trifluoromethyl groups. The compound of claim 9, wherein the halogen atoms are chlorine and / or fluorine. 9. The compound of claim 1, wherein A is —O— (CH ₂ ) _n —O— or —O— (CH ₂ ) _n —CH ₂ —substituted phenyl rings, wherein each is directly adjacent A compound in which ring-carbon atoms are connected. The compound of any one of claims 1-11, wherein R ^4a and R ^4b are each, independently of one another, a hydrogen atom. The compound according to any one of claims 1 to 12, wherein:

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A pharmaceutical composition comprising at least one compound of the general formula (I) according to any one of claims 1 to 13 and optionally at least one further active ingredient together with pharmaceutically compatible excipients and / or carriers. The pharmaceutical composition of claim 14, wherein the additional active ingredient is SERM (selective estrogen receptor modulator), aromatase inhibitor, antiestrogens or prostaglandins. The active ingredient according to claim 14, wherein the active ingredient is tamoxifen, 5- (4- {5-[(RS)-(4,4,5,5,5-pentafluoropentyl) sulfinyl] -pentyloxy} phenyl)- 6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol, ICI 182 780 (7alpha- [9- (4,4,5,5-pentafluoropentylsulfinyl) nonyl] estra -1,3,5 (10) -triene-3,17-beta-diol), 11beta-fluoro-7alpha- [5- (methyl {3-[(4,4,5,5,5 -Pentafluoropentyl) sulfanyl] propyl} amino) pentyl] estra-1,3,5 (10) -triene-3,17beta-diol, 11beta-fluoro-7alpha- {5- [methyl (7,7,8,8,9,9,10,10,10-nonafluorodecyl) amino] pentyl} estra-1,3,5 (10) -triene-3,17beta-diol, 11 Beta-fluoro-17alpha-methyl-7alpha- {5- [methyl (8,8,9,9,9-pentafluorononyl) amino] pentyl} estra-1,3,5 (10) -tri Pharmaceutical composition, which may be en-3,17beta-diol, clomiphene, raloxifene, padrosol, formestan, letrozole, anastrozole or atamestane. A compound according to any one of claims 1 to 13 for the manufacture of a medicament. Use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment and prevention of gynecological diseases such as endometriosis, uterine fibroids, dysfunctional uterine bleeding and dysmenorrhea. Use of a compound according to any one of claims 1 to 13 for the manufacture of a pharmaceutical formulation for the treatment and prevention of hormone-dependent tumors. Use of a compound according to any one of claims 1 to 13 for the manufacture of a pharmaceutical formulation for the treatment and prevention of breast cancer. Use of a compound according to any one of claims 1 to 13 for the manufacture of a pharmaceutical formulation for the treatment and prevention of endometrial cancer. Use of a compound according to any one of claims 1 to 13 for the manufacture of a pharmaceutical formulation for the treatment and prophylaxis of ovarian cancer. Use of a compound according to any one of claims 1 to 13 for the manufacture of a pharmaceutical formulation for the treatment and prophylaxis of prostate cancer. Use of a compound according to any one of claims 1 to 13 for the manufacture of a pharmaceutical formulation for female hormone replacement therapy. Use of a compound according to any one of claims 1 to 13 for female contraception.