JP2008543911A - Benzofuranone derivatives as non-steroidal progesterone receptor modulators - Google Patents

Abstract

The present invention relates to non-steroidal progesterone receptor modulators of general formula (I), methods for their production, use of progesterone receptor modulators for the production of pharmaceutical agents, and pharmaceutical compositions comprising these compounds. The compounds of the present invention are useful for the treatment and prevention of gynecological diseases such as endometriosis, uterine leiomyoma, dysfunctional bleeding and dysmenorrhea, and for the treatment and prevention of hormone dependent tumors and for women. Is suitable for use in birth control and hormone replacement therapy.

Description

  The present invention relates to non-steroidal progesterone receptor modulators, methods for their production, use of progesterone receptor modulators for the production of pharmaceutical agents, and pharmaceutical compositions comprising these compounds.

  The steroid hormone progesterone regulates female reproductive processes in a critical way. During the cycle and in pregnancy, progesterone is secreted in large amounts from the ovary or placenta. In response to estrogen, progesterone produces periodic changes in the uterine mucosa (endometrium) during the menstrual cycle. After ovulation, under the influence of elevated progesterone levels, the uterine mucosa is converted to a state that allows implantation of embryos (end culture germ cells). In pregnancy, progesterone regulates myometrial relaxation and retains decidual tissue function.

  Furthermore, it is known that progesterone inhibits endometrial proliferation by suppressing estrogen-mediated mitosis in uterine tissue (K. Chwalisz, RM Brenner, U. Fuhrmann, H. Hess-Stumpp, W. Elger , Steroids 65, 2000, 741-751).

  The important role of progesterone and progesterone receptors is also known in pathophysiological processes. Progesterone receptors are detected in the lesions of endometriosis and in tumors of the uterus, breast and CNS. Furthermore, it is known that uterine leiomyomas grow in a progesterone-dependent state.

  The action of progesterone in tissues of the reproductive organs and other tissues is carried out by interaction with progesterone receptors that can take charge of cellular effects.

  Progesterone receptor modulators are pure agonists or partially or completely inhibit the action of progesterone. Consequently, substances are defined as pure agonists, partial agonists (SPRMS) and pure antagonists.

  According to the ability of progesterone receptor modulators to affect the action of progesterone receptors, these compounds have considerable potential as therapeutic agents for gynecological and oncological signs, and obstetrics and birth control.

  Pure progesterone receptor antagonists completely inhibit the action of progesterone at the progesterone receptor. They have anti-ovulatory properties and the ability to inhibit estrogenic effects in the endometrium until sufficient atrophy. Thus, they impede implantation, in the female reproductive process, for example in post-ovulation; to increase uterine responsiveness to prostaglandins or oxytocin, or to open and harden the neck ("maturation") It is particularly suitable for intervention in pregnancy to ensure and to produce myometrium that is highly prepared for parturition.

  In endometriosis or tumor tissue lesions supplied with a progesterone receptor, favorable effects of the disease process are expected after application of a pure progesterone receptor antagonist. Next, certain advantages for pathological conditions such as endometriosis or uterine leiomyoma are further obtained if inhibition of ovulation can be achieved by progesterone receptor antagonists. If ovulation is inhibited, part of the ovarian hormone production and thus the stimulating effect by this part is also due to pathologically altered tissue.

  Following the numerous analogs with varying degrees of progesterone receptor-antagonist activity, there is the first described progesterone receptor antagonist RU486 (also mifepristone). In addition to the progesterone receptor-antagonist action, RU486 also exhibits an anti-gluticocorticoid action, but the compounds synthesized later are distinguished primarily by a more selective action than the progesterone receptor antagonist.

  In addition to steroidal compounds such as onapristone or lilopristone, which are distinguished from the progesterone-receptor-antagonist action against the anti-glucocorticoid action on RU486 by a good dissociation of the action from the literature, antagonist action on the progesterone receptor Various non-steroidal structures are also known (also known as 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, the compounds known so far have slightly moderate antagonist activity compared to known steroid structures. The most effective non-steroidal compounds are described as having an in vitro activity of 10% of the activity of RU486.

  Antiglucocorticoid activity is not advantageous for therapeutic applications where inhibition of progesterone receptors is the main focus of treatment. Anti-glucocorticoid activity causes unwanted side effects when administered therapeutically. This prevents the application of a therapeutically useful dose or leads to the end of treatment.

  Thus, partial or complete reduction in anti-glucocorticoid properties is an important requirement for treatment with progesterone receptor antagonists, especially for those indications that require treatment lasting weeks or months .

  Compared to pure antagonists, progesterone receptor partial agonists (SPRMs) exhibit residual agonist properties that can be strongly asserted to be different. This leads to the fact that these substances show substantial antagonism of the progesterone receptor in certain functional 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 dissociated effects can be therapeutically usable effects for the described symptoms.

  Accordingly, it is an object of the present invention to produce additional non-steroidal progesterone receptor modulators that can be utilized. These compounds should have a reduced anti-glucocorticoid action and are therefore suitable for the treatment and prevention of gynecological diseases such as endometriosis, uterine leiomyoma, dysfunctional bleeding and dysmenorrhea It is. Furthermore, the compounds of the present invention are suitable for the treatment and prevention of hormone dependent tumors such as breast cancer, endometrial cancer, ovarian cancer and prostate cancer. Furthermore, the compounds are suitable for use in female birth control and for female hormone replacement therapy.

The purpose is to have the following general formula I:

[In the formula, R ¹ and R ² independently of one another represent a hydrogen atom, a linear or non-linear, branched or unbranched C ₁ -C ₅ -alkyl group, and C in the chain. With the atoms form a ring with a total of 3-7 members;
R ³ means the group C≡C1-R ^a , where
R ^a is substituted with hydrogen, or optionally K, in one or more positions, in the same way or differently, C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ Means -alkynyl, C ₃ -C ₁₀ -cycloalkyl or heterocycloalkyl, or aryl or heteroaryl, optionally substituted by L, in one or more positions, in the same way or differently;

K is cyano, halogen, hydroxy, nitro, -C (O) R ^b , CO ₂ R ^b , -OR ^b , -SR ^b , SO ₂ NR ^b R ^d , -C (O) -NR ^c R ^d , -OC (O) -NR ^c R ^d , or optionally substituted by M, in one or more positions, in the same way or differently -C = NOR ^b -NR ^c R ^d or C ₃ -C _10- Cycloalkyl, heterocycloalkyl, or aryl or heteroaryl optionally substituted by L in the same means or differently 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 ) pNO 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 C0NR ^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 ^c ,-(CH ₂ ) _p -C = NOR ^b , -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH- or - (CH _{2) n + 2} - means, wherein, n is 1 or 2 and the terminal oxygen atoms and / or carbon atoms adjacent ring - is directly attached to a carbon atom,

M means C ₁ -C ₆ -alkyl or the group -COR ^b , CO ₂ R ^b , -OR ^b or -NR ^c R ^d , where
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 Means -C ₃ -perfluoroalkyl, and
R ^c and R ^d are independently of each other hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl, C _6- Means C ₁₂ -aryl, C (O) R ^b or a hydroxy group,

here
When R ^c is a hydroxy group, R ^d is only one hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl or Can be C ₆ -C ₁₂ -aryl, and vice versa, and
R ^c represents hydrogen, 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 p can be a number from 0 to 6;

R ³ is a group C = CR ^g R ^h , whereby
R ^g and R ^h, independently of one another, hydrogen, or optionally one or more places, in the same way or differently, C ₁ -C substituted by X ₈ - alkyl, C ₂ -C ₈ - Alkenyl or C ₂ -C ₈ -alkynyl, wherein 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 , and with respect to R ^b , R ^c and R ^d already have the meanings mentioned above; and

R ^4a and R ^4b each independently represent a hydrogen atom, C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, or together with the ring carbon atom, forms a 3- to 6-membered ring. ;

A means a monocyclic or bicyclic, carbocyclic or heterocyclic aromatic ring, which is in one or more positions C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₃ - 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 ) pNO 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 C0NR ^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 ^c ,-(CH ₂ ) _p -C = NOR ^b , -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH- or-(CH ₂ ) _{n + 2-} Optionally substituted, whereby n is 1 or 2, and the terminal oxygen atom and / or carbon atom is directly bonded to the adjacent ring-carbon atom; or

A means the group --CO ₂ R ^b , C (O) NR ^c R ^d , COR ^b , or
A means an alkenyl group -CR ⁵ = CR ⁶ R ⁷ where:
R ⁵ , R ⁶ and R ⁷ may be the same or different and, independently of one another, a hydrogen atom, a halogen atom, an aryl group or unsubstituted or partially or fully fluorinated. Means a C ₁ -C ₅ -alkyl group; or

A means an alkyl group —C≡CR ⁵ , and for R ⁵ , has the meaning cited above, and
B means carbonyl group or CH ₂ group] and is achieved according to the present invention by the preparation of non-steroidal compounds represented by: and pharmaceutically acceptable salts thereof.

  The compounds of general formula I according to the invention can exist as different stereoisomers due to the presence of asymmetric centers. Both racemates and separately present stereoisomers are part of the subject of the present invention.

Furthermore, the present invention encompasses novel compounds as pharmaceutically active ingredients, their production, their therapeutic application, and pharmaceutical dispersions containing said novel substances.
The compounds of general formula (I) or their pharmaceutically acceptable salts of the present invention are useful for the treatment and prevention of gynecological diseases such as endometriosis, uterine leiomyoma, dysfunctional bleeding and dysmenorrhea. Can be used for the manufacture of drugs. Furthermore, the compounds of 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) according to the invention or their pharmaceutically acceptable salts are suitable for use in female birth control or female hormone replacement therapy.
Furthermore, the process for producing the compounds of general formula (I) is also an object of the present invention. The substituent R ³ is introduced into the keto group by a selective addition reaction of an organometallic compound such as lithium alkynylene or magnesium haloalkynylene. This results in the compounds of general formula (I) of the present invention, either directly or after performing additional modifications:

The production of the compounds of the present invention is carried out by selective addition of organometallic compounds to ketoamides as described in published WO2003 / 75915 and WO98 / 54159. The organometallic compound can be, for example, a lithium alkynyl compound or a magnesium haloalkynyl compound. The latter compound is produced, for example, by reaction of its corresponding alkyne with a butyllithium or Grignard compound. Analogously to this, the corresponding organometallic alkenyl compounds can also be produced. Compared to amidocarbonyl or phthalide, the reactivity of the keto group is in this case significantly higher so that selective addition is achieved by appropriate selection of reaction conditions. On the other hand, the alkynyl or alkenyl group introduced as R ³ can also be further modified later. For those modifications, reactions known to those skilled in the art are suitable, for example oxidation, reduction, substitution, alkylation or palladium-catalyzed reactions. Optionally, any protecting groups present are degraded at the appropriate time.

  The non-steroidal compounds of general formula I according to the invention have a strong antagonist or strong partial agonistic action on the progesterone receptor. They exhibit a strong dissociation of action on progesterone and glucocorticoid receptors with respect to their binding strength. Known progesterone receptor antagonists, such as Mifepristone (RU486), exhibit high affinity for the glucocorticoid receptor in addition to the desired high binding affinity for the progesterone receptor, but the compounds of the invention are present at the same time Along with progesterone receptor affinity, it is distinguished by very low glucocorticoid receptor binding.

The substituents of the compounds of the general formula I according to the invention, defined as groups, in each case have the following meanings:
A C ₁ -C _5- , C ₁ -C ₆ -or C ₁ -C ₈ -alkyl group is defined as a linear or non-linear, branched or unbranched alkyl group. In this case, for example, this is methyl, ethyl, n-propyl, iso-propyl, n-, iso-, tert-butyl, n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl, hexyl, heptyl or octyl It is a group.

Regarding ^Ra , in this case, methyl, ethyl, n-propyl or n-butyl and n-pentyl are preferred.
For R ¹ and R ² , methyl or ethyl is preferred.
According to the invention, hydrogen is preferred for R ^4a and R ^4b .

Alkenyl is defined as a linear or non-linear, branched or unbranched alkenyl group. For the present invention, C ₂ -C ₈ - alkenyl group, for example, are defined as follows: vinyl, allyl, 3-buten-1-yl -, or 2,3-dimethyl-2-propenyl. If the aromatic compound A is substituted by a C ₂ -C ₈ -alkenyl group, this is preferably a vinyl group.

Alkynyl is defined as a linear or non-linear, branched or unbranched alkynyl group. For example, an ethynyl, propynyl, butynyl, pentynyl, hexynyl or octynyl group, preferably an ethynyl or propynyl group represents a C ₂ -C ₈ -alkynyl group.
With respect to C ₃ -C ₁₀ -cycloalkyl, for example, cyclopropane, cyclobutane, cyclopentane and cyclohexane may be mentioned. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.

With respect to R ^a , K or L, heterocycloalkyl is defined as a 3-8 membered heterocycloalkyl group. Examples of heterocycloalkyl are morpholine, tetrahydrofuran, pyran, piperazine, piperidine, pyrrolidine, oxirane, oxetane, aziridine, dioxolane and dioxane. In this case, the position of the heteroatom with respect to the point of attachment can be any chemically possible position.

For example, methoxymethoxy, ethoxymethoxy or 2-methoxyethoxy can represent a C ₁ -C ₆ -alkoxyl-C ₁ -C ₆ -alkoxy group.
In the context of the present invention, the group OR ^b is a hydroxy, methoxy, ethoxy, n-propyl, iso-propoxy, n-, iso- or tert-butoxy group, or a 2,2-dimethylpropoxy or 3-methylbutoxy group. . Hydroxy, methoxy and ethoxy are preferred.

With regard to partially or fully fluorinated C ₁ -C ₅ -alkyl groups, the perfluorinated alkyl groups mentioned above are considered. Of the latter, mainly trifluoromethyl groups or pentafluoroethyl groups, and partially fluorinated alkyl groups such as 5,5,4,4-pentafluoropentyl groups or 5,5,5,4,4 A 3,3-heptafluoropentyl group is preferred.

A fluorine, chlorine, bromine or iodine atom can represent a halogen atom. Fluorine, chlorine or bromine is preferred.
If R ¹ and R ² together with the C atom of the chain form a 3-7 membered ring, this is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. A cyclopropyl ring and a cyclopentyl ring are preferred.

A monocyclic or bicyclic carbocyclic aromatic ring A, which may be substituted at several positions, is a carbocyclic or heterocyclic aryl group.
In the first case it is for example a phenyl or naphthyl group, preferably a phenyl group.
As the heterocyclic group, for example, a monocyclic heterocyclic group such as chenyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, Thiazolyl or tetrazolyl groups and in particular all possible isomers for the heteroatom position can be used.

For R ³ , the aryl group is an optionally substituted phenyl, 1- or 2-naphthyl group, whereby the phenyl group is preferred. Examples of heteroaryl groups are 2-, 3- or 4-pyridinyl Group, 2- or 3-furyl group, 2- or 3-thienyl group, 2- or 3-pyrrolyl group, 2-, 4- or 5-imidazolyl group, pyrazinyl group, 2-, 4- or 5-pyrimidinyl group Or a 3- or 4-pyridazinyl group.

P about (CH _{2) p} group, 0-6, preferably can be a number from 0 to 2. A “group” is defined according to the invention as all functional groups represented with respect to (CH ₂ ) _p .
When the compound of general formula I (B = —CH ₂ —) is present as a salt, this is for example the hydrochloride, sulphate, nitrate, tartaric acid, citrate, fumarate, oxalate or benzoate Can exist in form.

When the compounds of the present invention are present as racemic mixtures, they can be separated into pure optically active forms according to racemic separation methods known to those skilled in the art. For example, racemic mixtures can be separated into pure isomers by chromatography based on engineered active carrier materials (CHIRALPAK AD ™). The free hydroxy group in the racemic compound of the general formula is esterified with an optically active acid, and the diastereomeric esters obtained by fractional crystallization or by chromatographic treatment are separated, and the optically pure isomer is obtained. It is also possible to saponify the separated ester in each case to form. As optically active acid, for example, mandelic acid, camphor sulfonic acid or tartaric acid can be used.
The compounds mentioned below and their use are preferred according to the invention:

Biological characterization of the compounds of the invention :
Identification of progesterone receptor modulators can be performed using simple methods, test programs known to those skilled in the art. To do this, for example, the compound to be tested is incubated with a gestagen in a test system for the progesterone receptor and it is used to determine whether the progesterone-mediated action in this test system is altered in the presence of a modulator. Can be tested.

In the present invention, substances of general formula I were tested in the following model:
Progesterone receptor binding test:
Measurement of receptor binding affinity:
Receptor binding affinity was determined by competitive binding of ³ H-labeled hormone (tracer) that specifically binds and compounds tested against the receptor in the cytosol from animal target organs. In this case, receptor saturation and reaction equilibration were investigated.

The tracer and increasing concentrations of the compound to be tested (competitor) were co-incubated with the receptor-containing cytosol fraction for 18 hours at 0-4 ° C. After separation of the end-bound tracer with a carbon-dextran suspension, the receptor-bound tracer moiety was measured for each concentration and the IC ₅₀ was determined from its concentration sequence. Relative molar binding affinity (RBA) was calculated as the ratio of the IC ₅₀ values of the control substance and the compound to be tested (× 100%) (control substance RBA = 100%).

For the receptor type, the following incubation conditions were selected:
Progesterone receptor:
Estradiol-sensitized rabbit uterine cytosol homogenized in TED buffer (20 mmol Tris / HCl, pH 7.4; 1 mmol ethylenediaminetetraacetic acid, 2 mmol dithiothreitol), and 250 mmol Of sucrose was stored at -30 ° C. Tracer: ³ H-ORG2058, 5 nmol; control substance: progesterone.

Glucocorticoid receptor:
Adrenalectomized rat thymic cytosol was stored at -30 ° C; buffer: TED. Tracer: ³ H-dexamethasone, 20 nmol; control substance: texamethasone.
The relative receptor binding affinity (RBA value) of the compounds of general formula (I) according to the invention for the progesterone receptor is 23-100% for progesterone. For glucocorticoid receptors, RBA values range from 3 to 30% for dexamethasone.

Thus, the compounds of the present invention have a high affinity for the progesterone receptor, but a low affinity for the glucocorticoid receptor.
Antagonism of the progesterone receptor PR-B:
The transactivation assay is performed as described in WO02 / 054064.

Action of progesterone receptor PR-B:
Transactivation assays are described in Fuhrmann et al. (Fuhrmann, U .; Hess-Stump, H .; Cleve, A .; Neef, G .; Schwede, W .; Hoffmann, J .; Fritzemeier, K.-H., Chwalisz, K .; Journal of Medicinal Chem., 43, 26, 2000, 5010-5016.

dose:
For use in accordance with the present invention, the progesterone receptor modulator can be administered orally, enterally, parenterally or transdermally.
Generally satisfactory results can be expected in the treatment of the above mentioned symptoms if the daily dose contains 1 μg to 500 mg of a compound of the invention.

Suitable doses of the compounds of the invention in humans for the treatment of endometriosis, uterine leiomyoma, dysfunctional bleeding, and for use in birth control, and for hormone replacement therapy are determined by the age of the patient. And depending on the configuration, it is 50 μg to 500 mg per day, whereby the required daily dose can be administered one or more times.
For the treatment of breast cancer, the dose range for the compounds of the invention is 10 mg to 100 mg per day.

  Formulations of pharmaceutical formulations based on novel compounds are usually used in crude drugs and converted to the desired dosage form, vehicles, fillers, substances that affect degradation, binders, humectants, lubricants, absorbents, It is carried out by means known in the art by means of active ingredients processed together with diluents, flavor correctors, pigments, etc. In this case, see 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, formulations for injection and infusion are possible.
For intra-articular injection, correspondingly prepared crystalline suspensions can be used.
For intramuscular injection, aqueous and oily injection solutions or suspensions and corresponding depot formulations can be used.

For rectal administration, the new compounds can be used in the form of suppositories, capsules, solutions (eg, enema forms), and ointments for systemic and local treatment.
Furthermore, agents for vaginal application can also be mentioned as formulations.
For pulmonary administration of a new compound, the new compound can be used in the form of aerosols and inhalants.

  For transdermal administration, patches are possible, or for topical application, gels, ointments, fat ointments, creams, pastes, powders, milk and tinctures are possible. The dosage of the compounds of general formula I should be 0.01-20% in these formulations in order to achieve an appropriate pharmacological action.

  Corresponding tablets are for example active ingredients and known adjuvants such as inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, explosives such as corn starch or alginic acid, binders such as starch or gelatin, lubricants, For example, it is obtained by mixing magnesium stearate or talc and / or an agent for achieving a depot effect, such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. A tablet can also consist of several layers.

  Thus, coated tablets are obtained by coating a core produced similar to tablets with agents usually used for tablet coating, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide, or sugar. Can be generated. In this case, the coated tablet shell also consists of several layers, so that the adjuvants mentioned above in the tablets can be used.

  Solutions or suspensions of the compounds of general formula I according to the invention may contain additional taste modifiers such as saccharin, cyclamate or sugar, and flavor substances such as vanilla or organic extracts. In addition, they can contain suspending adjuvants such as sodium, carboxymethylcellulose or preservatives such as p-hydroxybenzoates.

Capsules containing the compound of general formula I can be produced by mixing the compound of general formula I with an inert vehicle such as lactose or sorbitol and encapsulating in a gelatin capsule.
Suitable suppositories can be made, for example, by mixing with vehicles provided for this purpose, such as neutral fats or polyethylene glycols, or derivatives thereof.

  The compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts are particularly useful for the production of pharmaceutical agents, especially for gynecological diseases such as endometriosis, uterine leiomyoma, dysfunctional bleeding and menstruation. For the treatment and prevention of dysfunction, they can be used based on their antagonistic or partial agonistic effects. Furthermore, they can be used to neutralize hormonal irregularities, to induce menstruation, and alone or in combination with prostaglandins and / or oxytocin to induce childbirth.

Furthermore, the compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts are suitable for the production of formulations for female contraception (also WO 93/23020, WO 93/21927). (See issue number.)
Furthermore, the compounds of the present invention or their pharmaceutically acceptable salts can be used alone or in combination with selective estrogen receptor modulators (SERMs) for female hormone replacement therapy.

Furthermore, the compound exhibits an antiproliferative action in hormone-dependent tumors. They are therefore suitable for the treatment of hormone-dependent cancers such as breast cancer, prostate cancer or endometrial cancer.
The compounds of the invention or their pharmaceutically acceptable salts can be used for the treatment of hormone-dependent cancers after primary and secondary treatment, especially after tamoxifen failure.

  The compounds of general formula (I) according to the invention or their pharmaceutically acceptable salts with antagonistic or partial agonistic action are also used for the production of pharmaceutical formulations for treating hormone-dependent tumors. It can be used in combination with a compound having an action (an estrogen receptor antagonist or an aromatase inhibitor) or a selective estrogen receptor modulator (SERM). For the treatment of endometriosis or uterine leiomyoma, the compounds of 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, a progesterone receptor modulator and an anti-estrogen (estrogen receptor antagonist or aromatase inhibitor) or SERM can be supplied for simultaneous or sequential administration. In sequential administration, preferably an anti-estrogen (estrogen receptor antagonist or aromatase inhibitor) or SERM is administered first, and then a progesterone receptor modulator is administered.

  In this case, in combination with the non-steroidal progesterone receptor modulators of the invention, for example, the following antiestrogens (estrogen receptor antagonists or aromatase inhibitors) or SERMs are considered:

  Tamoxifen, 5- (4- {5-[(RS)-(4,4,5,5,5-pentafluoropentyl) sulfinyl] -pentyloxy} phenyl) -6-phenyl-8,9-dihydro-7H -Benzocycloheptan-2-ol (WO 00/03979), ICI 182 780 (7α- [9- (4,4,5,5-pentafluoropentylsulfinyl) nonyl] estra-1,3,5 (10 ) -Triene-3,17-β-diol), 1lβ-fluoro-7α- [5- (methyl {3-[(4,4,5,5,5-pentafluoropentyl) sulfanyl] propyl} amino) pentyl ] Estra-1,3,5 (10) -triene-3, 17β-diol (WO98 / 07740), 1 lβ-fluoro-7α- {5- [methyl (7,7,8,8,9,9 , 10,10,10-nonafluorodecyl) amino] pentyl} estra-1,3,5 (10) -triene-3,17β-diol (WO 99/33855), 1 lβ-fluoro-17α-methyl- 7α- {5- [Methyl (8,8,9,9,9-pentafluorononyl) amino] pentyl} estra-1,3,5 (10) -triene-3,17β-diol (WO 03/045972 No.), clomiphene, raloxifene and other antiestrogenic active compounds, and aromatase inhibitors such as fadrozole, formestane, letrozole, anastrozole or atamestane.

Finally, the invention also relates to the use of compounds of general formula I, and optionally antiestrogens or SERMs, for the production of pharmaceutical agents.
The present invention also relates to at least one of the present invention in the form of a pharmaceutically / pharmacologically compatible salt, optionally with or without pharmaceutically compatible adjuvants and / or vehicles. It also relates to a pharmaceutical composition comprising the compound.

These pharmaceutical compositions and pharmaceutical agents can be supplied for oral, rectal, vaginal, subcutaneous, transdermal, intravenous or intramuscular administration. In addition to commonly used vehicles and / or diluents, they contain at least one compound of the invention.
The pharmaceutical agents of the present invention are produced in a known manner by commonly used solid or liquid vehicles or diluents and commonly used pharmaceutical-technical adjuvants corresponding to the desired dosage form at the appropriate dose. Preferred formulations exist in a dispersion that is suitable for oral administration. Such dispersion forms are, for example, tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions, or depot forms.

A pharmaceutical composition comprising at least one compound of the invention is preferably administered orally.
Parenteral preparations such as injection solutions are also contemplated.
Furthermore, agents for eg suppositories and vaginal applications can also be mentioned as formulations.
The following examples are used for a more detailed explanation of the subject of the invention and are not intended to limit the invention.

  The formation of the starting compound 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxypropionylamino} -phthalide is described in WO2003 / 75915 and 4- The production of {3- [1-phenyl-cyclopropyl] -2-oxypropionylamino} phthalide is described in WO 98/54159.

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

  Ethynylmagnesium bromide (6 ml, 0.5 M in tetrahydrofuran) was added to 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxypropionyl in THF (4 ml). To an ice-cooled solution consisting of amino} -phthalide (632 mg). The reaction solution under argon was brought to room temperature within 3 hours. The reaction mixture was then poured into ice-cooled 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 resulting crude product was chromatographed on silica gel. 2.2 g of product was obtained.

¹ H-NMR (ppm, CDCl ₃ , 400 MHz): 0.83 (IH), 0.92-1.10 (2H), 2.37 (IH), 2.56 (IH), 2.59 (IH), 3.10 (IH), 5.28 (2H) , 7.02 (IH), 7.31 (IH), 7.37 (IH), 7.58 (IH), 7.86 (IH), 7.94 (1H), 8.70 (1H).

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

Analogously to Example 1, 145 mg of the product was mixed with 1-propynylmagnesium bromide (2 ml of a 0.5M solution in tetrahydrofuran) and 210 mg of 6- [4- (2-chloro-4-fluorophenyl) -4-methyl- 2-Oxovaleroylamino] -4-methyl-2,3-benzoxazin-1-one.
¹ H-NMR (ppm, CDCl ₃ , 400 MHz): 0.86 (IH), 0.90-1.05 (3H), 1.72 (3H), 2.35 (IH), 2.49 (IH), 2.96 (IH), 5.27 (2H) , 7.03 (IH), 7.30 (IH), 7.36 (IH), 7.58 (IH), 7.85 (IH), 7.98 (IH), 8.73 (IH).

(+)-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenyl-propionylamino} phthalide 3a and
(−)-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (phenylethynyl) -propionylamino} phthalide 3b :

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

¹ H-NMR (ppm, CDCl ₃ , 300 MHz): 0.88 (IH), 0.95-1.11 (3H), 2.46 (IH), 2.65 (IH), 3.10 (IH), 5.27 (2H), 7.00 (IH) , 7.24-7.42 (7H), 7.61 (IH), 7.84 (IH), 7.98 (IH), 8.80 (1H).
3a: [α] ^D ₂₀ : + 12.9 ° (CHCl ₃ , 1.06 g / 100 ml; λ = 589 nM)
3b: [α] ^D ₂₀ :-14.4 ° (CHCl ₃ , 1.03 glOO ml; λ = 589 nM)

  Analogously to Example 3, compounds 4 and 5 were converted to 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxypropionylamino} -phthalide and the respective lithium Produced from aryl acetylide.

rac-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-[(4-trifluoromethylphenyl) ethynyl] propionylamino} phthalide 4 :

¹ H-NMR (ppm, CDCl ₃ , 300 MHz): 0.92 (IH), 0.99-1.16 (3H), 2.55 (IH), 2.68 (IH), 3.27 (IH), 5.30 (2H), 7.03 (IH) 7.30-7.52 (4H), 7.55-7.62 (2H), 6.67 (IH), 7.99 (IH), 8.03 (IH), 8.84 (IH).

(+)-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -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) by preparative chiral HPLC (column Chiralpak AD 250 × 10 mm).
4a: [α] ^D ₂₀ : + 6.3 ° (CHCl ₃ , 1.07 g / 100 ml; λ = 589 nM)
4b: [α] ^D ₂₀ :-5.3 ° (CHCl ₃ , 1.09 glOO ml; λ = 589 nM)

rac-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-[(4-methylphenyl) ethynyl] propionylamino} phthalide 5 :

¹ H-NMR (ppm, CDCl ₃ , 300 MHz): 0.87 (IH), 0.93-1.15 (3H), 2.38 (3H), 2.45 (IH), 2.66 (IH), 3.11 (IH), 5.25 (2H) , 6.99 (IH), 7.10 (2H), 7.18-7.38 (4H), 7.61 (IH), 7.86 (IH), 8.00 (IH), 8.80 (IH).

(+)-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-[(4-methylphenyl) ethynyl] propionylamino} phthalide 5a , as well as
(−)-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) by preparative chiral HPLC (column Chiralpak AD 250 × 10 mm).
5a: [α] ^D ₂₀ : + 14.8 ° (CHCl ₃ , 1.07 g / 100 ml; λ = 589 nM)
5b: [α] ^D ₂₀ : -16.3 ° (CHCl ₃ , 1.13 glOO ml; λ = 589 nM)

rac-5- {2-[(4-acetoxyphenyl) ethynyl] -2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -propionylamino} phthalide 6 :

A suspension of the compound described in Example 1 (104 mg), copper iodide (8.9 mg), 4-iodophenylacetate (92 mg), palladium acetate (5.3 mg) in THF (5 ml) and triethylamine (5 ml). The reaction was allowed to proceed for 1 hour in an ultrasonic bath at 25 ° C under argon. It was then poured into a saturated aqueous ammonium chloride solution. It was extracted with ethyl acetate and washed with water and saturated sodium chloride solution. The combined organic phase was dried over sodium sulfate. After column chromatography of the crude product on silica gel, 55 mg of product was obtained.
¹ H-NMR (ppm, CDCl ₃ , 400 MHz): 0.88 (IH), 0.95-1.10 (3H), 2.29 (3H), 2.45 (IH), 2.63 (IH), 3.17 (IH), 5.29 (2H) , 6.97-7 '.07 (3H), 7.28-7.37 (4H), 7.60 (IH), 7.84 (IH), 7.98 (IH), 8.80 (IH).

rac-5- {2-hydroxy-2-[(4-hydroxyphenyl) ethynyl] -3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -propionylamino} phthalide 7 :

A solution of the compound described under 6 (45 mg) in 5 ml of methanol was mixed with sodium bicarbonate (130 mg). Stirring was continued at 23 ° C. for more than 2 hours. The reaction mixture was then diluted with ethyl acetate. It was then washed twice with saturated sodium chloride solution. After drying over sodium sulfate, the crude product was purified on silica gel by column chromatography. 38 mg of product was obtained.
¹ H-NMR (ppm, CDCl ₃ , 300 MHz): 0.87 (IH), 0.92-1.1 1 (3H), 2.43 (IH), 2.64 (IH), 3.11 (IH), 5.27 (2H), 5.67 (IH ), 6.73 (2H), 6.98 (IH), 7.14 (2H), 7.28-7.38 (2H), 7.60 (IH), 7.85 (IH), 7.97 (IH), 8.84 (IH).

rac-5- {2-[(4-Carboxyphenyl) ethynyl] -2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -propionylamino} phthalide 8 :

Analogously to Example 6, compound 8 was generated from the compound described under Example 1 and 4-iodobenzoic acid.
¹ H-NMR (ppm, CDCl ₃ / MeOD (5%), 400 MHz): 0.82 (IH), 0.89-1.05 (3H), 2.37 (IH), 2.65 (IH), 5.24 (2H), 6.97 (IH ), 7.35 (IH), 7.44 (2H), 7.50-7.65 (2H), 7.72 (IH), 7.80 (IH), 7.92 (2H).

rac-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (pentyn-1-yl) -propionylamino} phthalide 9 :

A solution consisting of 1-pentyne (0.94 ml) in THF (9 ml) was mixed at −78 ° C. with nBuLi (0.6 ml, 1.6 M in hexane). It is stirred at −78 ° C. for 30 minutes and then 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxypropionyl in 3 ml of tetrahydrofuran. A solution of amino} -phthalide was added. It was then brought to 23 ° C. for about 3 hours and then stirred for a further 10 hours. The reaction mixture was then poured into ice-cooled saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic layers 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.
¹ H-NMR (ppm, CDCl ₃ , 400 MHz): 0.82 (IH), 0.92-1.07 (6H), 1.45 (2H), 2.08 (2H), 2.30 (IH), 2.53 (IH), 2.83 (IH) , 5.27 (2H), 7.02 (IH), 7.29 (IH), 7.36 (IH), 7.57 (IH), 7.84 (IH), 7.96 (IH), 8.72 (IH).

(+)-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (pentyn-1-yl) -propionylamino} phthalide 9a , and
(−)-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (pentyn-1-yl) -propionylamino} phthalide 9b
The racemic mixture described in Example 9 (120 mg) was separated into enantiomers 9a (46 mg) and 9b (47 mg) by preparative chiral HPLC (column Chiralpak AD 250 × 10 mm).
9a: [α] ^D ₂₀ : + 10.9 ° (CHCl ₃ , 1.01 g / 100 ml; λ = 589 nM)
9b: [α] ^D ₂₀ : -10.6 ° (CHCl ₃ , 1.08 glOO ml; λ = 589 nM)

rac-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (hexyn-1-yl) -propionylamino} phthalide 10 :

Compound 10 was synthesized analogously to Example 9.
¹ H-NMR (ppm, CDCl ₃ , 400 MHz): 0.80-1.06 (7H), 1.30-1.50 (2H), 1.59 (2H), 2.10 (2H), 2.30 (IH), 2.52 (IH), 2.82 ( IH), 5.28 (2H), 7.02 (IH), 7.30 (IH), 7.36 (IH), 7.57 (IH), 7.84 (IH), 7.95 (IH), 8.72 (IH).

rac-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-[(4-hydroxy) butyn-1-yl] -propionylamino} phthalide 11 :

  Step A: Analogous to the method described below in Example 9, 4- (tert-butyldimethylsilyloxo) but-1-yne (175 mg), nBuLi (0.59 ml, 1.6 M in hexane) in tetrahydrofuran, Reaction of 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxypropionylamino} -phthalide (200 mg) gave 164 mg of product.

Step B: The product obtained under Step A (160 mg) was dissolved in 5 ml of tetrahydrofuran. At 0 ° C., 270 μl of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran was added and stirred for 1 hour at 0 ° C. and a further 2 hours at 23 ° C. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate 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.
¹ H-NMR (ppm, CDCl ₃ , 400 MHz): 0.83 (IH), 0.90-1.03 (3H), 2.20-2.40 (3H), 2.50 (IH), 3.39 (IH), 3.68 (2H), 5.25 ( 2H), 7.01 (IH), 7.32 (2H), 7.57 (IH), 7.82 (IH), 7.93 (IH), 8.91 (IH).

Analogously to Example 11, compounds 12 and 13 were generated from 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxypropionylamino} -phthalide:
rac-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-[(5-hydroxy) pentin-1-yl] -propionylamino} phthalide 12 :

¹ H-NMR (ppm, CDCl ₃ , 400 MHz): 0.83 (IH), 0.90-1.03 (3H), 1.70 (2H), 2.24 (2H), 2.33 (IH), 2.50 (IH), 3.09 (IH) , 3.71 (2H), 5.26 (2H), 7.02 (IH), 7.35 (2H), 7.57 (IH), 7.83 (IH), 7.97 (IH), 8.82 (IH).

rac-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-[(3-hydroxy) propin-1-yl] -propionylamino} phthalide 13 :

¹ H-NMR (ppm, CDCl ₃ , 400 MHz): 0.84 (IH), 0.90-1.03 (3H), 2.37 (IH), 2.52 (IH), 3.25 (IH), 4.17 (2H), 5.27 (2H) , 7.02 (IH), 7.30-7.40 (2H), 7.58 (IH), 7.83 (IH), 7.91 (IH), 8.77 (IH).

(+)-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-[(3-hydroxy) propin-1-yl] -propionylamino } Phthalide 13a , and
(−)-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-[(3-hydroxy) propin-1-yl] -propionylamino } Phthalide 13b
The racemic mixture described in Example 13 (80 mg) was separated into enantiomers 13a (35 mg) and 13b (37 mg) by preparative chiral HPLC (column Chiralpak AD 250 × 10 mm).
13a: [α] ^D ₂₀ : + 28.3 ° (CHCl ₃ , 1.01 g / 100 ml; λ = 589 nM)
_{^{13b: [α] D 20:}} -29.3 ° (CHCl 3, 1.08 glOO ml; λ = 589 nM)

rac-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-[(4-hydroxy-3-methyl) butyn-1-yl]- Propionylamino} phthalide 14 :

Step A: Analogously to Example 11, 300 mg of 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxypropionylamino} -phthalide and 282 mg of tert- Butyl- (1,1-dimethylprop-2-ynyl-oxy) -dimethylsilane was reacted. 15 mg of product A was obtained.
Step B: 70 mg of the compound obtained under A was dissolved in 1 ml of dichloromethane. 640 μl of trifluoroacetic acid (20% in dichloromethane) was added at 0 ° C. and it was stirred at 0 ° C. for 3.5 hours. It was then evaporated to dryness under vacuum and the residue was purified by column chromatography on silica gel. 27 mg of product was obtained.
¹ H-NMR (ppm, CDCl ₃ , 400 MHz): 0.82 (IH), 0.90-1.00 (2H), 1.04 (IH), 1.47 (6H), 2.28 (IH), 2.58 (IH), 3.08 (IH) 5,27 (2H), 7.03 (IH), 7.30 (IH), 7.36 (IH), 7.59 (IH), 7.83 (IH), 7.91 (IH), 8.78 (IH).

rac-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (2- (tert-butylcarbonyl) ethyn-1-yl) -propionyl Amino} phthalide 15 :

Compound 15 was produced analogously to Example 9.
¹ H-NMR (ppm, CDCl ₃ , 400 MHz): 0.87 (IH), 0.93-1.05 (3H), 1.46 (9H), 2.42 (IH), 2.59 (IH), 3.39 (IH), 5.28 (2H) , 7.03 (IH), 7.30-7.42 (2H), 7.57 (IH), 7.85 (IH), 7.92 (IH), 8.68 (IH).

rac-5- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (2-carboxyethin-1-yl) -propionylamino} phthalide 16 :

Example 15 50 mg of the compound described below was dissolved in 5 ml of dichloromethane. 100 μl of trifluoroacetic acid was added and it was stirred at 23 ° C. for over 12 hours. It was then evaporated to dryness under vacuum and the residue was purified by column chromatography on silica gel. 36 mg of product was obtained.
¹ H-NMR (ppm, DMSO-D ₆ , 300 MHz): 0.48 (IH), 0.78 (IH), 0.86 (IH), 1.09 (IH), 1.73 (IH), 2.89 (IH), 5.27 (2H) 6.62 (IH), 7.13 (IH), 7.31 (IH), 7.41 (IH), 7.53 (IH), 7.62 (IH), 7.68 (IH), 9.85 (IH).

Analogously to Example 3, compound 17 was generated from 5- {3- [1-phenyl-cyclopropyl] -2-oxopropioamino} phthalide:
rac-5- {2-hydroxy-3- [1-phenyl-cyclopropyl] -2- (phenyl-ethynyl) -propionylamino} phthalide 17 :

¹ H-NMR (ppm, CDCl ₃ , 400 MHz): 0.78 (IH), 0.90 (IH), 1.10-1.21 (2H), 2.38 (IH), 2.72 (IH), 2.77 (IH), 5.28 (2H) , 7.18 (IH), 7.25-7.42 (6H), 7.41-7.52 (4H), 7.82 (IH), 8.06 (IH), 8.79 (IH).

Claims (25)

The following general formula I:

[Wherein, R ¹ and R ² independently of one another represent a hydrogen atom, a linear or non-linear, branched or unbranched C ₁ -C ₅ -alkyl group, With the atoms form a ring with a total of 3-7 members;
R ³ means the group C≡C1-R ^a , where
R ^a is substituted with hydrogen, or optionally K, in one or more positions, in the same way or differently, C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ Means -alkynyl, C ₃ -C ₁₀ -cycloalkyl or heterocycloalkyl, or aryl or heteroaryl, optionally substituted by L, in one or more positions, in the same way or differently;
K is cyano, halogen, hydroxy, nitro, -C (O) R ^b , CO ₂ R ^b , -OR ^b , -SR ^b , SO ₂ NR ^b R ^d , -C (O) -NR ^c R ^d , -OC (O) -NR ^c R ^d , or optionally substituted by M, in one or more positions, in the same way or differently -C = NOR ^b -NR ^c R ^d or C ₃ -C _10- Cycloalkyl, heterocycloalkyl, or aryl or heteroaryl optionally substituted by L in the same means or differently 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 ) pNO 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 C0NR ^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 ^c ,-(CH ₂ ) _p -C = NOR ^b , -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH- or - (CH _{2) n + 2} - means, wherein, n is 1 or 2 and the terminal oxygen atoms and / or carbon atoms adjacent ring - is directly attached to a carbon atom,
M means C ₁ -C ₆ -alkyl or the group -COR ^b , CO ₂ R ^b , -OR ^b or -NR ^c R ^d , where
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 Means -C ₃ -perfluoroalkyl, and
R ^c and R ^d are independently of each other hydrogen, 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 means a C (O) R ^b or a hydroxy group, wherein
When R ^c is a hydroxy group, R ^d is only one hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ -alkynyl, C ₃ -C ₁₀ -cycloalkyl or Can be C ₆ -C ₁₂ -aryl, and vice versa, and
R ^c represents hydrogen, 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 p can be a number from 0 to 6;
R ³ is a group C = CR ^g R ^h , where
R ^g and R ^h, independently of one another, hydrogen, or optionally one or more places, in the same way or differently, C ₁ -C substituted by X ₈ - alkyl, C ₂ -C ₈ - Alkenyl or C ₂ -C ₈ -alkynyl, wherein 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 , and with respect to R ^b , R ^c and R ^d already have the meanings mentioned above; and
R ^4a and R ^4b each independently represent a hydrogen atom, C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, or together with the ring carbon atom, forms a 3- to 6-membered ring. ;
A means a monocyclic or bicyclic, carbocyclic or heterocyclic aromatic ring, which is in one or more positions C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₃ - 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 ) pNO 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 C0NR ^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 ^c ,-(CH ₂ ) _p -C = NOR ^b , -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -0-CH = CH- or-(CH ₂ ) _{n + 2-} Optionally substituted, wherein n is 1 or 2, and the terminal oxygen atom and / or carbon atom is directly bonded to the adjacent ring-carbon atom; or
A means the group —CO ₂ R ^b , C (O) NR ^c R ^d , COR ^b ; or
A means an alkenyl group -CR ⁵ = CR ⁶ R ⁷ where:
R ⁵ , R ⁶ and R ⁷ may be the same or different and, independently of one another, a hydrogen atom, a halogen atom, an aryl group, or unsubstituted or partially or completely fluorine A substituted C ₁ -C ₅ -alkyl group; or
A means an alkyl group —C≡CR ⁵ , and for R ⁵ , has the meaning cited above; and
B represents a carbonyl group or a CH ₂ group]
And pharmaceutically acceptable salts thereof. The compound according to claim 1, wherein R ¹ and R ² represent a hydrogen atom, a methyl group or an ethyl group. ^2. A compound according to claim ¹ wherein R <1> and R <2> preferably form a ring with a total of 3-7 bonds together with the C atoms of the chain. R ³ is alkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, compounds of any one of claims 1 to 3 means a cycloalkyl alkynyl or heterocycloalkyl alkynyl. R ³ is vinyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, hydroxypropynyl, hydroxybutynyl, 3-hydroxy-3-methylbutynyl, hydroxypentynyl, carboxypropynyl, t-butylcarboxypropynyl, phenylethynyl , (Hydroxyphenyl) ethynyl, (methoxyphenyl) ethynyl, (dimethylaminophenyl) ethynyl, (methylphenyl) ethynyl, (cyanophenyl) ethynyl, (trifluoromethyl) ethynyl, (diphenyl) ethynyl, (nitrophenyl) ethynyl, The compound according to any one of claims 1 to 5, which means a (tert-butylphenyl) ethynyl, (acetylphenyl) ethynyl, (acetoxyphenyl) ethynyl, (carboxyphenyl) ethynyl or benzylethynyl group.   A is an aromatic ring, The compound of any one of Claims 1-5.   A is a phenyl or naphthyl group, The compound of any one of Claims 1-6.   8. A compound according to claim 7, wherein A is an unsubstituted phenyl group, or optionally a phenyl group substituted at one or more positions.   The compound according to claim 8, wherein the phenyl group is substituted by 1 or 2 halogen atoms or a trifluoromethyl group.   The compound according to claim 9, wherein the halogen atom is chlorine and / or fluorine. A is a phenyl ring substituted by -0- (CH ₂ ) _n -O- or -O- (CH ₂ ) _n -CH _2- , wherein each said directly adjacent ring-carbon atom is 9. A compound according to any one of claims 1 to 8 which is bound. The compound according to any one of claims 1 to 11, wherein R ^4a and R ^4b independently of each other are each a hydrogen atom. Compounds according to any one of claims 1 to 12, i.e. compounds represented by the following formula and table:

  14. A pharmaceutical composition comprising at least one compound of general formula I according to any one of claims 1 to 13 and optionally at least one additional active ingredient and a pharmaceutically compatible adjuvant and / or vehicle.   15. The composition of claim 14, wherein the additional active ingredient is SERM (selective estrogen receptor modulator), an aromatase inhibitor, an anti-estrogen or a prostaglandin.   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 (7α- [9- (4,4,5,5-pentafluoropentylsulfinyl) nonyl] estradiol 1,3,5 (10) -Triene-3,17-β-diol), 1lβ-fluoro-7α- [5- (methyl {3-[(4,4,5,5,5-pentafluoropentyl) sulfanyl] propyl} amino) pentyl] Estra-1,3,5 (10) -triene-3, 17β-diol, 1 lβ-fluoro-7α- {5- [methyl (7,7,8,8,9,9, 10,10,10 Nonafluorodecyl) amino] pentyl} estra-1,3,5 (10) -triene-3,17β-diol, 1 lβ-fluoro-17α-methyl-7α- {5- [methyl (8,8,9, 9,9-pentafluorononyl) amino] pentyl} estra-1,3,5 (10) -triene-3,17β-diol, clomiphene, raloxy 15. The composition of claim 14, which can be phen, fadrozole, formestane, letrozole, anastrozole or atamestan.   Use of a compound according to any one of claims 1 to 13 for the manufacture of a pharmaceutical agent.   14. 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 leiomyoma, dysfunctional bleeding and dysmenorrhea. use.   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 hormone-dependent tumors.   Use of a compound according to any one of claims 1 to 13 for the manufacture of a pharmaceutical agent 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 medicament for the treatment and prevention of endometriosis.   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 ovarian cancer.   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 prostate cancer.   14. Use of a compound according to any one of claims 1 to 13 for the manufacture of a pharmaceutical agent for female hormone replacement therapy.   Use of a compound according to any one of claims 1 to 13 for the regulation of female birth.