BRPI0612305A2 - non-steroidal progesterone receptor modulators - Google Patents

Abstract

NON-STEROID PROGESTERONE RECEPTOR MODULATORS. This invention relates to non-steroidal progesterone receptor modulators of formula 1. A process for their production is the use of progesterone receptor modulators for the production of pharmaceutical agents as well as pharmaceutical compositions containing these compounds. The compounds according to the invention are suitable for therapy and prophylaxis of gynecological diseases such as endometriosis, uterine fibroids, dysfunctional bleeding and dysmenorrhea, as well as for the therapy and prophylaxis of hormone-dependent tumors and for use in controlling the disease. female birth as well as for hormone replacement therapy.

Description

Patent Descriptive Report for "NON-STEROID PROGESTERONE RECEPTOR MODULATORS".

This invention relates to non-steroidal progesterone receptor modulators, a process for their production, the use of progesterone receptor modulators for the production of pharmaceutical agents as well as pharmaceutical compositions containing these compounds.

The steroid hormone progesterone regulates the reproductive process in the female organism in a decisive way. During the cycle and in pregnancy, progesterone is secreted in large quantities from the ovary or placates. By interaction with estrogens, progesterone produces cyclic changes in the uterine mucous membrane (endometrium) in the menstrual cycle. Under the influence of elevated progesterone levels after ovulation, the uterine membranous membrane is converted into a state that allows the nesting of an embryo (blastocyte). In pregnancy, progesterone controls domiometric relaxation and retains the function of decidual tissue.

In addition, progesterone is known to inhibit endometrial proliferation by suppressing estrogen-mediated mitosis in the douterium tissue (K. Chwalisz, RM Brenner, U. Fuhrmann, H. Hess-Stumpp1. Elger, Steroids 65, 2000 , 741-751).

An important role of progesterone and progesterone receptors is also known in pathophysiological processes. Progesterone receptors are detected in endometriosis foci, but also in uterine, breast and CNS tumors. In addition, it is known that uterine fibroids develop in a progesterone-dependent manner.

Progesterone actions on the tissues of genital organs and other tissues are performed by interactions with progesterone receptors, which are responsible for cellular effects.

Progesterone receptor modulators are either pure agonists or partially or completely inhibit progesterone action. Consequently, substances are defined as pure agonists, partial agonists (SPRMS) and pure antagonists. According to the ability of deprogesterone receptor modulators to influence progesterone receptor action, these compounds have considerable potential as therapeutic agents for indi -gynecological and oncological actions as well as for obstetric and birth control.

Pure progesterone receptor antagonists completely inhibit the action of progesterone on the progesterone receptor. They have antiovulatory properties as well as the ability to inhibit the effects of estrogen on the endometrium until complete atrophy. They are therefore especially suitable for mediating the female reproductive process, for example post-ovulation, to prevent nesting; in pregnancy, to increase uterine responsiveness to prostaglandins or oxytocin or to ensure opening and softening ("maturation") of the cervix as well as to make the myometrium highly prepared for labor pains.

In endometriosis outbreaks or in tumor tissue, which is equipped with progesterone receptors, an advantageous influence of the disease process is expected after progesteronapur receptor application. Special advantages for influencing pathological conditions, such as endometriosis or uterus lymphomas, can then be given if in addition an ovulation inhibition can be obtained by deprogesterone receptor antagonists. When ovulation is inhibited, a portion of the ovarian hormone production and thus the stimulatory effect that is due to this portion is also due to the factually altered tissue.

A large number of analogues with varying degrees of progesterone receptor antagonistic activity followed the first progesterone receptor antagonist described in RU 486 (also mifepristone). While RU 486, in addition to the progesterone receptor antagonistic action, also shows an anti-glucocorticoid action, later synthesized compounds are distinguished primarily by a more selective action of the progesterone receptor quagantagonist.

From the literature, in addition to the steroidal compounds such asonapristone or lilopristone, which are distinguished from progesterone receptor antagonist action for antiglorticoid action with respect to RU486 by a better dissociation of action, various non-steroidal structures whose antagonistic action on the receptor of progesterone is examined, are also known [see, for example, SA Leonhardt and DP Edwards, Exp. Biol. Med. 227: 969-980 (2002) and R. Winneker, A. Fensome, J. E. Wro-bel, Z. Zhang, P. Zhang, Seminars in Reproductive Medicine, Volume 23: 46-57 (2005)]. Previously known compounds, however, have antagonistic activity only moderately compared to known steroidal structures. Effective non-steroidal compounds are described as having in vitro activities of 10% of RU 486 activity.

Antiglycorticoid activity is disadvantageous for a therapeutic application where progesterone receptor inhibition is a primary focus of therapy. An anti-glucocorticoid activity causes unwanted side effects in the case of therapeutically required dosages. This may prevent the application of a therapeutically useful dose or induce termination of treatment.

Partial or complete reduction of anti-glucocorticoid properties is therefore an important requirement for progesterone receptor antagonist therapy, in particular for those indications requiring treatment that takes weeks or months.

In contrast to pure antagonists, partial deprogesterone receptor agonists (SPRMs) show a residual dual agonistic property, which can be strongly pronounced to varying degrees. This induces the fact that these substances show potential progesterone receptor agonistic actions in specific organ systems (D. DeManno, W. Elger, R. Garg, R. Lee, B. Schneider, H. Hess-Stumpp, G. Schuber, K. Ch-walisz, Steroids 68, 2003, 1019-1032). Such dissociated and organ-specific action may be of therapeutic use for the indications described.

It is therefore the object of this invention to form available additional non-steroidal progesterone receptor modulators. These compounds should have a reduced anti-glucocorticoid action and are therefore suitable for the therapy and prophylaxis of gynecological diseases such as endometriasis, uterus lymphomas, dysfunctional bleeding and dysmenorrhea.

In addition, the compounds according to the invention should be suitable for the therapy and prophylaxis of hormone dependent tumors, for example breast, endometrial, ovarian and prostate cancers. In addition, the compounds should be suitable for use in female birth control and for female hormone replacement therapy.

The objective is achieved according to this invention by the preparation of non-steroidal compounds of formula I

<formula> formula see original document page 5 </formula>

on what

R 1 and R 21 independently of each other means a hydrogen atom, a straight or non-branched, branched or unbranched C1 -C5 alkyl group, also together with a chain C atom having a total of 3 to 7 members,

R3 means a radical O = C-Ra, whereby

Ra means a hydrogen or a C1 -C8 alkyl, C2 -C8 alkenyl, C2 -C8 alkynyl, C3 -C10 cycloalkyl, or heterocycloalkyl which is optionally substituted in one or more places, in the same manner or differently with K1 or an aryl or heteroaryl which is optionally substituted in one or more places, in the same way or differently with L,

K is a cyano, halogen, hydroxy, nitro, -C (O) Rb, CO2Rb, -O-Rb, -S-Rb, SO2NRcRd, -C (O) -NRcRd, -OC (O) -NRcRd,

or -C = NORb -NR c R d or a C 3 -C 10 -cycloalkyl which is optionally substituted in one or more places, in the same or different manner, with M, heterocycloalkyl, or aryl or heteroaryl which is optionally substituted on one or more places with L,

L means 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, (CH2) pCN1 (CH2) fa1 (CH2) pNO2, (CH2) p-C6 -C12 riIa, (CH2) p-heteroaryl, - (CH2) pPO3 (Rb) 2, - (CH2) pNRcRd1 - (CH2) pNReCORb1- (CH2) pNReCSRb, - (CH2) pNReS (O) Rb, - (CH2) pNReS (O) 2Rb1 - (CH2) pNReCONRcRd1- (CH2) pNReCOORb1 - (CH2) pNR nRe (CH2) pNReCSNRcRd1 - (CH2) pNReS (O) NRcRd, - (CH2) pNReS (O) 2NRcRd1- (CH2) pCORb - (CH2) pS (O) Rb, - (CH2) pS O) (NH) Rb1 - (CH2) pS (O) 2Rb, - (CH2) pS (O) 2NRcRd, - (CH2) pSO2ORb1- (CH2) pCO2Rb, - (CH2) pCONRcRd, - (CH2) pCSNRcRd1 - ( CH2) pORb1 - (CH2) pSRb1- (CH2) pCRb (OH) -Re, - (CH2) pC = NORb1-O- (CH2) nO-, -O- (CH2) n-CH2-, -O-CH = CH-or - (CH2) n + 2-, whereby η = 1 or 2, and the oxygen atoms and / or terminal carbon atoms are attached to directly adjacent ring carbon atoms,

M means C1 -C6 alkyl or a group -CORb, CO2Rb, -O-Rb, or -NRcRd, by which

Rb is hydrogen or C 1 -C 6 alkyl, C 2 -C 8 alkynyl, C 2 -C 8 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C 12 aryl or C 1 -C 3 perfluoroalkyl, and

Rc and Rd independently of one another are hydrogen, C1 -C6 alkyl, C2 -C8 alkenyl, C2 -C8 alkynyl, C3 -C10 cycloalkyl, C6 -C12 aryl, C (O) Rb or a hydroxy at which one

Rc is a hydroxy group, Rd may be just hydrogen, C1-C6-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3-C10-cycloalkyl or C6-C12-aryl and vice versa, and

Re means 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 r may be a number from 0-6,

or

R3 is a radical C = C-R9Rh1 whereby

R9 and Rh1 independently of each other are hydrogen or a C1-C8-alkyl, C2-C8-alkenyl or C2-C-e-alkynyl which optionally is substituted by a

or more places, in the same way or differently, with X, where

X is a cyano, halogen, hydroxy, nitro, -C (O) Rb, CO2Rb, -O-Rb, -C (O) -NRcRd, -NRcRd with the meanings mentioned above for Rb, Rc and Rd, and

R4a and R4b independently of one another are hydrogen, C1 -C6 alkyl,

a C 2 -C 4 -alkenyl or together as a forward carbon atom forming a 3 to 6 membered ring,

A means a monocyclic or bicyclic, carbo-cyclic or heterocyclic aromatic ring, which may optionally be substituted in one or more places with C1 -C8 alkyl, C2 -C8 alkenyl, C2 -C8 alkynyl, C1 -C6 perfluoroalkyl, C1 -C6 -fluoroalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy, (CH2) p-C3-Cycloalkyl, (CH2) p-heterocycloalkyl, (CH2) pCN, (CH2) p1, (CH2) pNO2, (CH2) p-C6-C12-aryl, (CH2) p-heteroaryl, - (CH2) pPO3 (Rb) 2, - (CH2) pNRcRd, - (CH2) pNReCORb1 - (CH2) pNReCSRb, - (CH2) pNReS (O) Rb, - (CH2) pNReS (O) 2Rb, - (CH2) pNReCONRcRd, - (CH2) pNReCOORb, - (CH2) pNReC (NH) NRcRd, - (CH2) ) pNReCSNRcRd, - (CH2) pNReS (O) NR0Rd, - (CH2) pNReS (O) 2NRcRd, - (CH2) pCORb1- (CH2) pCSRb, - (CH2) pS (O) (NH) Rb, - (CH2) pS (O) 2Rb, - (CH2) pS (O) 2NRcRd, - (CH2) pSO2ORb, - (CH2) pCO2Rb, - (CH2) pCONRcRd, - (CH2) pCSNRcRd, - (CH2) pORb, - (CH2) pSRb, - (CH2) pCRb (OH) -Rd, - (CH2) pC = NORb, -O- (CH2) nO-, -O- (CH2) n- CH2 -, - O-CH = CH- or

- (CH2) n + 2-, where η = 1 or 2, and oxygen atoms and / or terminal carbon atoms are attached to ring carbon atoms directly adjacent, or A means a radical -CO2Rb, C ( O) NRcRd1 CORb, or

A means an alkenyl group -CR5 = CR6 R7, whereby

R5 R6 and R7 are the same or different, independently of one another, mean hydrogen atoms, halogen atoms, radicaysaryl or an unsubstituted or partially or fully fluorinated C1-C5-alkyl group, or

A means an alkynyl group -C = CR5, with the meaning given above for R5, and

B means a carbonyl group or a CH 2 group as well as pharmaceutically acceptable salts thereof.

The compounds of formula I according to the invention may be present as different stereoisomers because of the presence of asymmetry centers. Both racemates and separately present stereoisomers are part of the object of this invention.

Further, this invention comprises the novel compounds as pharmaceutical active ingredients, their production, their therapeutic application and pharmaceutical dispensing forms containing the novel substances.

The compounds of formula (I) according to the invention or their pharmaceutically acceptable salts may be used for the production of a pharmaceutical agent, especially for the treatment and prophylaxis of gynecological disorders, such as endometriosis, uterine lymphomas, dysfunctional bleeding and dysmenorrhea. . In addition, the compounds according to the invention may be used for the treatment and prophylaxis of hormone dependent tumors such as, for example, breast, prostate and endometrial cancers.

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

A process for producing the compounds of formula (I), furthermore, is also an object of this invention. The R3 substituent is introduced into a keto group by selective addition of organometallic compounds such as lithiumalkylene or magnesium haloalkylene. This results either directly or upon implementation of further modifications in the compounds of formula (I) according to the invention.

The production of the compounds according to the invention is carried out by selective addition of organometallic compounds to ketoamides, which have been described, for example, in specifications open to the public WO200375915 and WO 9854159. Organometallic compounds may be, for example, lithium alkynyl compounds. haloalkyl and magnesium compounds. The latter are produced, for example, by reacting the corresponding alkynes with butyllithium or Grignard compounds. Similarly to this, the corresponding organometallic alkenyl compounds may also be produced. The reactivity of the keto group compared to amidocarbyl nyl or phthalide is significantly higher in this case, such that with proper selection of reaction conditions, a selective addition is obtained. Alternatively, alkynyl or alkenyl radicals which may be introduced as R 3 may also be further modified later. For these modifications, reactions which have become known to one of skill in the art, such as oxidation, reduction, substitution, alkylation, or palladium catalyzed reaction are suitable. Optionally present the protecting groups present are cleaved at an appropriate time.

The non-steroidal compounds of formula I according to the invention have a strongly antagonistic or strongly partially agonistic action on the receptor progesterone receptor. They exhibit a strong dissociation of action with respect to their binding intensity on progesterone receptor and glucocorticoid receptor. As progesterone receptor antagonist such as Mifepristone (RU 486), in addition to the desired high binding affinity for progesterone receptor also shows high affinity for glucocorticoid receptor, the compounds according to the invention are distinguished. by a very low glucocorticoid receptor binding with high progesterone receptor simultaneously present.

The substituents of the compounds of formula I according to the invention which are defined as groups may have the meanings below in each case:

C1-C5-, C1-C6- or C1 -C8 -alkyl groups are defined as linear or non-linear branched or unbranched alkyl radicals. In this case, for example, this is a methyl, ethyl, n-propyl, iso-propyl, n-, iso-, tert-butyl group, an n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl, hexyl, heptyl or octyl. .

In terms of Ra, in this case the methyl, ethyl, n-propyl oun-butyl group as well as an n-pentyl group is preferred.

In terms of R1 and R2, methyl or ethyl is preferred.

According to the invention a hydrogen is preferred for R4a and R4b.

Alkenyl is defined as branched or unbranched alkenyl radicals, linear or nonlinear. In terms of the invention, a C2 -C8 alkenyl group is defined, for example, as follows: vinyl, allyl, 3-buten-1-yl or 2,3-dimethyl-2-propenyl. If aromatic compound A is substituted with a C 2 -C 8 alkenyl radical, this is preferably a vinyl group.

Alkynyl is defined as linear or non-linear, branched or unbranched alkynyl radicals. For example, an ethinyl, propynyl, butynyl, pentinyl, hexinyl or octinyl group, but preferably an ethinyl or propynyl group, should mean a C2 -C8 -Alkynyl radical.

For C 3 -C 10 -cycloalkyl, for example, cyclopropane, cyclobutane, cyclopentane and cyclohexane may be mentioned. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.

In terms of Ra, K or L, heterocycloalkyl is defined as 3 to 8 membered heterocycloalkyl radicals. Examples of heterocycloalkyl are morpholine, tetrahydrofuran, pyran, piperazine, piperidine, pyrrolidine, oxirane, oxetane, aziridine, dioxolane and dioxario. In this case, the position of the heteroatom relative to the point of attachment may be any chemically possible position.

For example, methoxymethoxy, ethoxymethoxy or 2-methoxyethoxy may mean a C1-C6-alkoxy-C1-C6-alkoxy group.

In terms of the invention, an ORb radical is a hydroxy, methoxy, ethoxy, n-propoxy, iso-propoxy, n-, iso-, or tert-butoxy group, or an n-pentoxy, 2,2-dimethylpropoxy group or 3-methylbutoxy. Preferred hydroxy, methoxy and ethoxy.

For a partially or fully fluorinated C1 -C5 alkyl group, the perfluorinated alkyl groups appearing above are considered. Lastly, primarily the trifluoromethyl group or the pen-tafluoroethyl group as well as partially fluorinated alkyl groups, for example the 5,5,4,4-pentafluoropentyl group or the 5,5,5,4,4,3,3-heptafluoropentyl group. , are preferred.

A fluorine, chlorine, bromine or iodine atom may mean a halogen atom.

Preferred here is fluorine, chlorine or bromine.

If R 1 and R 2 together with the chain C atom form a 3 to 7 membered ring, that is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. The cyclopropyl ring as well as the cyclopentyl ring are preferred.

The monocyclic or bicyclic carbocyclic ring A, which may be substituted at various sites, is a carbocyclic or heterocyclic aryl radical.

In the first case, that is, for example, a phenyl radical or naphthyl, preferably a phenyl radical.

As a heterocyclic radical, for example, a monocyclic heterocyclic radical, for example, a thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolol, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, outetrazolyl, and specifically all possible isomers with respect to heteroatom positions can be used.

In terms of R 31 an aryl radical is an optionally substituted phenyl, 1- or 2-naphthyl radical, whereby the phenyl radical is preferred. Examples of the heteroaryl radical are 2-, 3- or 4-pyridinyl radical, 2- or 3-furyl radical, 2- or 3-thienyl radical, 2- or 3-pyrrolyl radical, 2-, 4- or 5-imidazolyl, the pyrazinyl radical, 2-, 4- or 5-pyrimidinyl radical or the 3- or 4-pyridazinyl radical.

The number ρ for the radical (CH2) p may be a number from 0 to 6, preferably O to 2. "Radicals" are defined according to the invention as all functional groups which are presented with respect to (CH2) p.

Where the compounds of formula I (B = -CH 2 -) are present as salts, they may be, for example, in the form of hydrochloride, sulfate, nitrate, tartrate, citrate, fumarate, succinate or benzoate.

If the compounds according to the invention are present as racemic mixtures, they may be separated into pure, reactive forms according to racemate separation methods which are familiar to those skilled in the art. For example, racemic mixtures may be separated into pure isomers by chromatography on a still optically active carrier material (CHIRALPAK AD0). It is also possible to esterify the free hydroxy group into a racemic compound of general formula I with an optically active acid and to separate diastereomeric esters which are obtained by fractional crystallization or chromatography and to saponify the separate esters in each case to form the optically pure isomers. As an optically active acid, for example, mandelic acid, camphorsulfonic acid or tartaric acid may be used. The compounds which are mentioned below as well as the latter are preferred according to the invention:

<formula> formula see original document page 13 </formula> Continued

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Continuation

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Biological characterization of the compounds according to the invention

Identification of progesterone receptor modulators can be accomplished using simple methods, testing programs that are well known to one skilled in the art. For this purpose, for example, a compound to be tested may be incubated together with a gestagen in a progesterone receptor test system, and it may be examined whether the progesterone-mediated action in this test system is altered in the presence of modulators.

The substances of formula I according to the invention were tested on the following models:

Progesterone Binding Test Receptor

Receiver Binding Affinity Rating:

Receptor binding affinity was determined by competitive binding of a specific binding 3 H-labeled hormone (tracer) and the compound to be tested at receptors on the cytosol of animal target organs. In this case, receptor saturation and reaction equilibrium were sought.

Tracers and increasing concentrations of the compounds to be tested (competitor) were co-incubated with the 0-4 ° C receptor-containing cytosol fraction for 18 hours. After separation of the unconnected tracer with carbon-dextran suspension, the receptor-bound tracer portion was evaluated for each concentration concentration, and the IC50 was determined from the concentration sequence. As a quotient of the IC 50 values of the reference substance and the compound to be tested (x 100%), the relative molar binding affinity (RBA) was calculated (RBA of the reference substance = 100%).

For receiver types, the following incubation conditions have been selected:

Progesterone Receptor:

Rabbit utero cytosol prepared with estradiol, homogenized in TED buffer (20 mmol Tris / HCl, pH 7.4; 1 mmol ethylenediamine tetraacetate, 2 mmol dithiothreitol) with 250 mmol sucrose; stored at -305C. Tracer: 3H-ORG 2058, 5 nmol; reference substance: progesterone.

Glucocorticoid Receptor:

Adrenalectomized rat thymus cytosol, thymus stored at -30 ° C; buffer: TED. Tracer: 3H-Dexamethasone, 20 nmol; Reference substance: dexamethasone.

The relative receptor binding affinities (RBA values) of the compounds of formula (I) according to the invention at the deprogesterone receptor are between 3 and 100% with respect to progesterone. In glucocorticoid receptor, RBA values are in the range of 3 to 30% with respect to dexamethasone.

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

PR-B progesterone receptor antagonism

The transactivation assay is performed as described in WO02 / 054064.

PR-B progesterone receptor agonism

The transactivation assay is performed as described in Fuhr-mann et al. (Fuhrmann1;.; 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).

<table> table see original document page 84 </column> </row> <table> Dosage

For use in accordance with the invention, progesterone receptor modulators may be administered orally, enterally, parenterally or transdermally.

In general, satisfactory results may be expected in the treatment of the above indications if daily doses range from 1 pg to 500 mg of the compound according to the invention.

Suitable dosages of the compounds according to the invention in humans for the treatment of endometriosis, uterine dysfunctional bleeding and for birth control as well as hormone replacement therapy are 50 pg to 500 mg per day. depending on the age and constitution of the patient, whereby the required medical record may be administered one or more times.

For the treatment of breast cancer, the dosage range for the compounds according to the invention comprises from 10 mg to 1000 mg daily.

The formulation of pharmaceutical preparations based on the new compounds is carried out in a manner known in the art by the active ingredient being processed with vehicles, fillers, substances that influence decomposition, binding agents, humectants, lubricants, absorbents, diluents, flavoring concealers, dyes, etc., which are commonly used in galenics and are converted to the desired form of administration. In this case, reference is made to Remington's Pharmaceutical Science, 15th 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 intraarticulate injection, correspondingly prepared crystal suspensions may be used. For intramuscular injection, aqueous and oily injection solutions or suspensions and corresponding depot preparations may be used.

For rectal administration, the novel compounds may be used in the form of suppositories, capsules, solutions (e.g., in the form of enema) and ointments for both systemic and local therapy.

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

For pulmonary administration of the new compounds, the latter may be used as aerosols and inhalants.

For transdermal administration, plasters are possible, or for topical application, formulations of gels, ointments, fatty ointments, creams, pastes, powders, milk and tinctures are possible. The dosage of the compounds of formula I should be

0.01% - 20% in these preparations to obtain adequate pharmacological action.

Corresponding tablets may be obtained, for example, by mixing the active ingredient with known adjuvants by inert examples such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, explosives such as cornstarch or alginic acid, agglutinates such as starch. or gelatin, lubricants such as magnesium stearate or talc and / or agents for obtaining a depot effect such as carboxypo-limethylene, carboxyl methyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also consist of several layers.

Accordingly, coated tablets may be produced by coating cores, produced analogously to tablets, which are commonly used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. In this case, the coated tablet shell may also consist of several, whereby adjuvants which are mentioned as compressed tablets may be used. Solutions or suspensions of the compounds of formula I according to the invention may contain additional taste enhancing agents such as: as saccharin, cyclamate or sugar, as well as, for example, flavoring substances, such as vanilla or orange extract. In addition, they may contain suspension adjuvants such as carboxymethylcellulosesodium or preservatives such as p-hydroxybenzoates.

Capsules which may contain compounds of formula I may be produced, for example, by the compound (s) of Isendo mixed with an inert carrier such as lactose or sorbitol and encapsulated in gelatin capsules.

Suitable suppositories may be produced, for example, by mixing with carriers which are provided for this purpose, such as neutral fat or polyethylene glycol, or derivatives thereof.

The compounds of formula (I) according to the invention or their pharmaceutically acceptable salts may be used based on their antagonistic or partial agonistic action for the production of a pharmaceutical agent, in particular for the treatment and prophylaxis of gynecological disorders, such as endometriosis, uteriomyoma, dysfunctional bleeding and dysmenorrhea. In addition, they can be used to counteract hormonal irregularities, to trigger menstruation and alone or in combination with prostaglandins and / or oxytocin to induce childbirth.

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

In addition, the above compounds exert antiproliferative action on hormone dependent tumors. They are therefore suitable for the therapy of hormone dependent carcinomas, such as, for example, breast, prostate or endometrial carcinomas.

The compounds according to the invention or their pharmaceutically acceptable salts may be used for the treatment of hormone-dependent carcinomas in both first-line therapy and second-line therapy, in particular following tamoxifen failure.

The compounds of formula (I) according to the invention which have partial antagonistic or agonistic action or their pharmaceutically acceptable salts may also be used in combination with compounds having an antiestrogenic action (estrogen receptor antagonists or aromatase inhibitors). ) or selective estrogen receptor modulator (SERM) for the production of pharmaceutical preparations for the treatment of hormone-dependent tumors, for the treatment of endometriosis or uterine leiomyomas, the compounds according to the invention may also be used in combination with SERMs or a antiestrogen (estrogen receptor antagonists or aromatase inhibitors). In the treatment of hormone dependent tumors, the progesteronamodulator receptor and antiestrogen (estrogen receptor antagonists or aromatase inhibitors) or SERM may be provided for simultaneous administration or if not for sequential administration. In sequential administration, preferably first the antiestrogen (estrogen receptor antagonists or aromatase inhibitor) or SERM is administered, and then the progesterone modulator receptor is administered.

In this case, the combination with the non-steroidal deprogesterone receptor modulators according to 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] pentyl-loxy} phenyl) -6-phenyl-8,9-dihydro-7H- benzocycloepten-2-ol (WO 00/03979), ICI 182780 (7alpha- [9- (4,4,5,5-pentafluoropentylsulfinyl) nonyl] estra-1,3,5 (10) -triene-3,17- beta-diol), 11 beta-fluoro-7alpha- [5- (methyl {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} amino) pentyl] estra-1,3, 5 (10) -trieno-3,17beta-diol (WO98 / 07740), 11beta-fluoro-7alpha- {5- [methyl (7,7,8,8,9,9,10,10-nonafluorodecyl) amino] pen-til} estra-1,3,5 (10) -trieno-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 antiestrogenically active compounds, and inhibitors of aromatase, such as, for example, fadrozole, formestane, letrozole, anastrozole or atamestane.

Finally, this invention also relates to the use of the compounds of formula I, optionally together with an antiestrogen or SERM, for the production of a pharmaceutical agent.

This invention also relates to pharmaceutical compositions containing at least one compound according to the invention, optionally in the form of a pharmaceutically / pharmaceutically compatible salt, without or together with pharmaceutically compatible adjuvants and / or vehicles.

These pharmaceutical compositions and pharmaceutical agents may be provided for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular administration. In addition to commonly used vehicles and / or diluents, they contain at least one compound according to the invention.

The pharmaceutical agents of the invention are produced in a known manner with solid or liquid or diluent carriers or diluents and the commonly used pharmaceutical-technical adjuvants corresponding to the type of administration desired at a suitable dosage. Preferred preparations may exist in a dispensing form that is suitable for oral administration. Such dispensing forms are, for example, tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions or depot forms.

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

Parenteral preparations, such as injection solutions, are also considered. In addition, for example, suppositories and agents for vaginal application may also be mentioned as preparations.

The following examples are used for a more detailed explanation of the object of the invention, without intending to limit it to these examples.

The production of 5- {3- [1- (2-fluoro-5-trifluoro-methylphenyl) -cyclopropyl] -2-oxopropionylamino} -phthalide starting compound is described in WO200375915, and the production of 5- {3- [ 1-phenyl-cyclopropyl] -2-oxopropionylamino} phthalide is described in WO 9854159.

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

<formula> formula see original document page 90 </formula>

Ethinyl magnesium bromide (6 ml, 0.5 M in tetrahydrofuran) was added to an ice solution consisting of 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionylamino} phthalide (632 mg) in THF (4 ml). The reaction solution under argon was allowed to come to room temperature within 3 hours. Then the reaction mixture was 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 were obtained.

1H-NMR (ppm, CDCl3, 400 MHz): 0.83 (1H), 0.92-1.10 (2H), 2.37 (1H), 2.56 (1H), 2.59 (1H) , 3.10 (1H), 5.28 (2H), 7.02 (1H), 7.31 (1H), 7.37 (1H), 7.58 (1H), 7.86 (1H), 7.94 (1H), 8.70 (1H).

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

<formula> formula see original document page 90 </formula> Similarly to Example 1, 145 mg of product was obtained with 1-propynylmagnesium bromide (2 ml of 0.5 M tetrahydrofuran solution) and 210 mg of 6- [4- (2-chloro-4-fluorophenyl) -4-methyl-2-oxovaleroylamino] -4-methyl-2,3-benzoxazin-1-one.

1H-NMR (ppm, CDCl3, 400 MHz): 0.86 (1H), 0.90 - 1.05 (3H), 1.72 (3H), 2.35 (1H), 2.49 (1H) , 2.96 (1H), 5.27 (2H), 7.03 (1H), 7.30 (1H), 7.36 (1H), 7.58 (1H), 7.85 (1H), 7.98 (1H), 8.73 (1H). (+) - 5- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-phenylpropionylamino} phthalide 3rd and

(-) - 5- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2- (phenyltinyl) propionylamino} phthalide 3b

<formula> formula see original document page 91 </formula>

n-Butyllithium (625 μΙ, 1.6 M in hexane) was added at -78 ° C to a 110 μΙ solution of phenylacetylene in tetrahydrofuran. Stirring was continued at this temperature for 30 minutes, and then a solution of 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionylamino} phthalide (210 mg) in 5 ml of tetrahydrofuran was added dropwise. Then it was allowed to come to 23 ° C for about 3 hours and then stirred for a further 10 hours. Then the reaction mixture was 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 obtained racemic mixture was then separated by preparative chiral HPLC (Chiralpak AD Column, 250x10 mm) into enantiomers 3a (46 mg) and 3b (47 mg) .3a and 3b:

1H-NMR (ppm, CDCl3, 300 MHz): 0.88 (1H), 0.95 - 1.11 (3H), 2.46 (1H), 2.65 (1H), 3.10 (1H) , 5.27 (2H), 7.00 (1H), 7.24 - 7.42 (7H), 7.61 (1 H), 7.84 (1H) 1 7.98 (1 H), 8, 80 (1).

3a: [α] D20: + 12.9 ° (CHCl3, 1.06 g / 100 mL; λ = 589 ηΜ) 3b: [α] 20 °: - 14.4 ° (CHCl3, 1.03 g100 mL; λ = 589 ηΜ)

Analogously to Example 3, compounds 4 and 5 were produced from 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionylamino} phthalide and its lithium aryl acetylide.

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

<formula> formula see original document page 92 </formula>

1H-NMR (ppm, CDCl3, 300 MHz): 0.92 (1H), 0.99 - 1.16 (3H), 2.55 (1H), 2.68 (1H), 3.27 (1H) , 5.30 (2H), 7.03 (1H), 7.30 - 7.52 (4H), 7.55-7.62 (2H), 6.67 (1H), 7.99 (1H) 8.03 (1H), 8.84 (1H).

(+) - 5- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2 - [(4-trifluoromethylphenyl) ethynyl] propionylamino} phthalate 4a and (-) - 5- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2 - [(4-trifluoromethylphenyl) ethynyl] propionylamino} phthalide 4b

The racemic mixture (150 mg) that was described in example 4 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the 4a (51 mg) and 4b (62 mg) enantiomers.

4a: [Otf 20: + 6.3 ° (CHCl3, 1.07 g / 100 mL; λ = 589 ηΜ) 4b: [α] 20 °: 5.3 ° (CHCl3, 1.09 g / 100 mL; λ = 589 ηΜ)

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

<formula> formula see original document page 92 </formula> 1H-NMR (ppm, CDCl3, 300 MHz): 0.87 (1 Η), 0.93 - 1.15 (3Η), 2.38 (3Η) , 2.45 (1H), 2.66 (1H) 1 3.11 (1H) t 5.25 (2Η), 6.99 (1Η), 7.10 (2Η), 7.18 - 7, 38 (4Η), 7.61 (1Η), 7.86 (1Η), 8.00 (1H), 8.80 (1Η).

(+) - 5- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -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) that was described in example 5 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the 5a (41 mg) and 5b (28 mg) enantiomers.

5a: [α] D20: + 14.8 ° (CHCl3, 1.07 g / 100 mL; λ = 589 nM)

5b: [Otf 20: - 16.3 ° (CHCl3, 1.13 g100 ml; λ = 589 nM)

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

<formula> formula see original document page 93 </formula>

A suspension of the compound (104 mg) described under Example 1, triphenylphosphine (12.2 mg), copper iodide (8.9 mg), 4-iodophenyl acetate (92 mg), palladium acetate (5.3 mg) in THF (5 ml) and triethylamine (5 ml) was stirred for 1 hour in an ultrasonic bath at 25 ° C under argon. Then it was 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 of the crude product on silica gel, 55 mg of product was obtained.

1H-NMR (ppm, CDCl3, 400 MHz): 0.88 (1H), 0.95 - 1.10 (3H), 2.29 (3H), 2.45 (1H), 2.63 (1H) 3.17 (1H), 5.29 (2H), 6.97 - 7.07 (3H), 7.28 -7.37 (4H), 7.60 (1H), 7.84 (1H) 7.98 (1H), 8.80 (1H) .rac-5- {2-Hydroxy-2 - [(4-hydroxyphenyl) ethynyl] -3- [1- (2-fluoro-5-trifluoromethylphenyl ) - cyclopropyl] propionylamino} phthalide 7

<formula> formula see original document page 94 </formula>

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 for a further 2 hours at 23 ° C. Then, the reaction mixture was diluted with ethyl acetate. Then it was 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 were obtained.

1H-NMR (ppm, CDCl3, 300 MHz): 0.87 (1H), 0.92 - 1.11 (3H), 2.43 (1H), 2.64 (1H), 3.11 (1H) , 5.27 (2H), 5.67 (1H), 6.73 (2H), 6.98 (1H), 7.14 (2H), 7.28 - 7.38 (2H), 7.60 (1H), 7.85 (1H), 7.97 (1H), 8.84 (1H).

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

<formula> formula see original document page 94 </formula>

Similarly to Example 6, compound 8 was produced as a compound described under Example 1 and 4-iodobenzoic acid.

1H-NMR (ppm, CDCls / MeOD (5%), 400 MHz): 0.82 (1H), 0.89 -1.05 (3H), 2.37 (1H), 2.65 (1H), 5.24 (2H), 6.97 (1H), 7.35 (1H), 7.44 (2H), 7.50 - 7.65 (2H), 7.72 (1H), 7.80 ( 1H), 7.92 (2H).

rac-5- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2- (pen-tin-1-yl) propionylamino} phthalide 9 <formula> formula see original document page 95 </formula>

A solution consisting of 1-pentine (0.94 mL) in THF (9 mL) was mixed at -78 ° C with nBuLi (0.6 mL, 1.6 M in hexane). It was allowed to stir for 30 minutes at -78 ° C, and then a solution of 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionylamino} phthalide (200 mg) in 3 ml of tetrahydrofuran was added. Then it was allowed to come to 23 ° C for about 3 hours, and was stirred for a further 10 hours at this temperature. Then, the reaction mixture was 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 were obtained.

1H-NMR (ppm, CDCl3, 400 MHz): 0.82 (1H), 0.92-1.07 (6H), 1.45 (2H), 2.08 (2H), 2.30 (1H) 2.53 (1H), 2.83 (1H), 5.27 (2H), 7.02 (1H), 7.29 (1H), 7.36 (1H), 7.57 (1H), 7.84 (1H), 7.96 (1H), 8.72 (1H).

(+) - 5- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2- (pentin-1-yl) propionylamino} phthalide 9a and

(-) - 5- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2- (pentin-1-yl) propionylamino} phthalide 9b

The racemic mixture (120 mg) that was described in example 9 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into enantiomers 9a (46 mg) and 9b (47 mg).

9a: [α] 20 °: + 10.9 ° (CHCl3, 1.01 g / 100 ml; λ = 589 nM)

9b: [α] 20 ° -10.6 ° (CHCl 3, 1.08 g100 ml; λ = 589 nM)

rac-5- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2- (hexin-1-yl) propionylamino} phthalide 10 <formula> formula see original document page 96 </formula>

Compound 10 was synthesized analogously to Example 9.1H-NMR (ppm, CDCl3, 400 MHz): 0.80 - 1.06 (7H), 1.30 - 1.50 (2H), 1.59 (2H), 2.10 (2H), 2.30 (1H), 2.52 (1H), 2.82 (1H), 5.28 (2H), 7.02 (1H), 7.30 (1H), 7 , 36 (1H), 7.57 (1H), 7.84 (1H), 7.95 (1H), 8.72 (1H).

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

<formula> formula see original document page 96 </formula>

Stage A: Reaction of 4- (tert-Butyldimethylsilyloxy) but-1-yl (175mg), nBuLi (0.59 ml, 1.6 M in hexane) 5- {3- [1- (2-Fluoro-5- trifluoromethylphenyl) cyclopropyl] -2-oxopropionylamino} phthalide (200 mg) in tetrahydrofuran analogously to the procedure described under Example 9 yielded 165 mg of product.

Stage Β: The product obtained under Stage A (160 mg) was dissolved in 5 ml of tetrahydrofuran. 9C, 270 μΙ of a 1 molar solution of tetrabutylammonium defluoride in tetrahydrofuran were added and stirred for one hour at 0 ° C and for a further 2 hours at 23 ° C. Then the reaction mixture was poured into 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 silica gel column chromatography, 77 mg of product were obtained.

1H-NMR (ppm, CDCl3, 400 MHz): 0.83 (1H), 0.90-1.03 (3H), 2.20-2.40 (3H), 2.50 (1H), 3, 39 (1H), 3.68 (2H), 5.25 (2H), 7.01 (1H), 7.32 (2H), 7.57 (1H), 7.82 (1H), 7.93 (1H), 8.91 (1H).

Similarly to Example 11, compounds 12 and 13 were produced from 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionyl-minojthalide:

rac-5- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2 - [(5-hydroxy) pentin-1-j] propionylamino} phthalide 12

<formula> formula see original document page 97 </formula>

1H-NMR (ppm, CDCl3, 400 MHz): 0.83 (1H), 0.90 - 1.03 (3H), 1.70 (2H), 2.24 (2H), 2.33 (1H) 2.50 (1H), 3.09 (1H), 3.71 (2H), 5.26 (2H), 7.02 (1H), 7.35 (2H), 7.57 (1H), 7.83 (1H), 7.97 (1H), 8.82 (1H).

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

2.37 (1H), 2.52 (1H), 3.25 (1H), 4.17 (2H), 5.27 (2H), 7.02 (1H), 7.30 - 7.40 ( 2H), 7.58 (1H), 7.83 (1H), 7.91 (1H), 8.77 (1H).

(+) - 5- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2 - [(3-hydroxy) propin-1-yl] propionylamino} phthalate 13a and

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

The racemic mixture (80 mg) that was described in example 13 was separated by preparative chiral HPLC (Chiralpak AD 250x10 mm column) at the 13a (35 mg) and 13b (37 mg) enantiomers.

13a: [α] D20: + 28.3 ° (CHCl3, 1.01 g / 100 ml; λ = 589 nM)

13b: [α] 20 °: - 29.3 ° (CHCl3, 1.08 g100 ml; λ = 589 nM)

rac-5- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2 - [(4-hydroxy-3-methyl) butin-1-yl] -propionylamino} phthalide 14

<formula> formula see original document page 97 </formula>

1H-NMR (ppm, CDCl3, 400 MHz): 0.84 (1H), 0.90 - 1.03 (3H) <formula> formula see original document page 98 </formula>

Stage A: Similarly to Example 11, 300 mg of 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionylamino} phthalide and 282 mg of tert-butyl- (1,1-dimethylprop) -2-ynyloxy) dimethylsilane are reacted. 15 mg of product A is obtained.

Stage B: 70 mg of the compound obtained under A was dissolved in 1 ml of dichloromethane. 650 μΙ trifluoroacetic acid (20% in dichloromethane) was added at 0 ° C, and stirred for 3.5 hours at 0 ° C. It was then evaporated to dryness under vacuum and the residue was purified by silica gel column chromatography. 27 mg of product were obtained.

1H-NMR (ppm, CDCl3, 400 MHz): 0.82 (1H), 0.90 - 1.00 (2H), 1.04 (1H), 1.47 (6H), 2.28 (1H) 2.58 (1H), 3.08 (1H), 5.27 (2H), 7.03 (1H), 7.30 (1H), 7.36 (1H), 7.59 (1H), 7.83 (1H), 7.91 (1H), 8.78 (1H).

rac-5- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2- (2- (tert-butylcarboxy) ethin-1-yl) propionylamino} phthalide 15

<formula> formula see original document page 98 </formula>

Compound 15 was synthesized analogously to Example 9.1H-NMR (ppm, CDCl3, 400 MHz): 0.87 (1H), 0.93 - 1.05 (3H), 1.46 (9H), 2.42 (1H ), 2.59 (1H), 3.39 (1H), 5.28 (2H), 7.03 (1H), 7.30 - 7.42 (2H), 7.57 (1H), 7, 85 (1H), 7.92 (1H), 8.68 (1H).

rac-5- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2- (2-carboxyethyn-1-yl) propionylamino} phthalide 16 <formula> formula see original document page 99 </formula>

50 mg of the compound which is described under Example 15 was dissolved in 5 ml of dichloromethane. 100 μΙ of formalin-added trifluoroacetic acid was stirred for a further 12 hours at 23 ° C. It was then evaporated to dryness in a vacuum, and the residue was purified by silica gel column chromatography. 36 mg of product were obtained.

1H-NMR (ppm, DMSO-D6, 300 MHz): 0.48 (1H), 0.78 (1H), 0.86 (1H), 1.09 (1H), 1.73 (1H), 2 89 (1H), 5.27 (2H), 6.62 (1H), 7.13 (1H), 7.31 (1H), 7.41 (1H), 7.53 (1H), 7, 62 (1H), 7.68 (1H), 9.85 (1H).

Similarly to Example 3, compound 17 was produced from 5- {3- [1-phenyl-cyclopropyl] -2-oxopropionylamino} phthalide:

rac-5- {2-Hydroxy-3- [1-phenyl-cyclopropyl] -2- (phenylethynyl) propionylamino-phthalide 17

<formula> formula see original document page 99 </formula>

1H-NMR (ppm, CDCl3, 400 MHz): 0.78 (1H), 0.90 (1H), 1.10 -1.21 (2H), 2.38 (1H), 2.72 (1H) , 2.77 (1H), 5.28 (2H), 7.18 (1H), 7.25 - 7.42 (6H), 7.41-7.52 (4H), 7.82 (1H) 8.06 (1H), 8.79 (1H).

Claims (26)

1. Compounds of formula I wherein R 1 and R 2 independently of one another are hydrogen, straight or non-linear, branched or unbranched C1-C5-alkyl group , also together with the C atom of the chain forming a 3- to 7-membered total ring, R3 means a radical C = C-Ra, whereby Ra is hydrogen or C1 -C8 alkyl, C2 -C8 alkenyl, C2- C8-alkynyl, C3-Cycloalkyl, or heterocycloalkyl which is optionally substituted in one or more places, in the same manner or differently with K, or an aryl or heteroaryl which is optionally substituted in one or more places, in the same or unlike with L, K is a cyano, halogen, hydroxy, nitro, -C (O) Rb, COaRb, -O-Rb, -S-Rb, SO2NRcRd, -C (O) -NRcRd, -OC (O) -NRcRd, or -C = NORb -NRcRd or a C3 -C10 cycloalkyl which is optionally substituted in one or more places, in the same or different manner, with M, heterocyclo alkyl, or aryl or heteroaryl which is optionally substituted in one or more places with L, L means C1 -C8 alkyl, C2 -C8 alkenyl, C2 -C8 alkynyl, C1 -C6 perfluoroalkyl, C1 -C6 perfluoroalkoxy, C1-6. C6-C6-alkoxy-alkoxy, (CH2) p-C3-C10-cycloalkyl, (CH2) p-heterocycloalkyl, (CH2) pCN, (CH2) fa1, (CH2) pNO2, (CH2) p-C6- C12-aryl, (CH2) p-heteroaryl, - (CH2) pPO3 (Rb) 2, - (CH2) pNRcRd, - (CH2) pNReCORb, - (CH2) pNReCSRb, - (CH2) pNReS (O) Rb, - (CH2) pNReS (O) 2Rb, - (CH2) pNReCRNRd, - (CH2) pNReC (NH) NRcRd, - (CH2) pNReCSNRcRd, - (CH2) pNReS (O) NRcR ) pNReS (O) 2NRcRd, - (CH2) pCORb1 - (CH2) pCSRb1 - (CH2) pS (O) Rb, - (CH2) pS (O) (NH) Rb1- (CH2) pS (O) 2Rb1 - ( CH2) pS (O) 2NRcRd1 - (CH2) pSO2ORb, - (CH2) pCO2Rb1- (CH2) pCONRcRd1 - (CH2) pCSNRcRd1 - (CH2) pSRb1- (CH2) pCRb (OH) -Re1 CH2) pC = NORb1 -O- (CH2) nO-, -O- (CH2) n-CH2 -, -O-CH = CH-or - (CH2) n + 2-, whereby η = 1 or 2, and the terminal oxygen atoms and / or carbon atoms are attached to directly adjacent ring carbon atoms, M means Cr C6-alkyl or a group -CORb, CO2Rb, -O-Rb, or -NRcRd1 by which Rb means a hydrogen or a C1 -C6 alkyl, C2 -C8 -alkyl, C2-C8-alkynyl, C3-C10-cycloalkyl, C 6 -C 12 aryl or C 1 -C 3 perfluoroalkyl and R c and R d independently of one another mean a hydrogen group, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 C 10 cycloalkyl, C 6 -C12-aryl, C (O) Rb or a hydroxy, whereby seRc for a hydroxy group, Rd may be just a hydrogen, a C1-C6-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3- C10-cycloalkyl or C6-C12-aryl and vice versa, eRe means a hydrogen, C1 -C6-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3-Cyclo-alkyl or C6-C12-aryl, and r can be a O-6, or R3 is a C = C-R9Rh radical, whereby R9 and Rh independently of one another are hydrogen or a C1 -C8-alkyl, C2-C8-alkenyl or C2-C8-alkynyl which is optionally substituted by one or more places, in the same way or differently, with X, where X is a cyano, halogen, hydroxy, n it, -C (O) Rb, CO2Rb, -O-Rb, -C (O) -NRcRd1 -NRcRd with the meanings already mentioned above, for Rb, Rc and Rd, eR4a and R4b1 independently of one another, mean one. hydrogen atom, C1 -C4 alkyl, a C2 -C4 alkenyl or together as a ring carbon atom forming a 3 to 6 membered ring, A means a monocyclic or bicyclic aromatic ring, carbocyclic or heterocyclic, which may optionally be substituted in one or more places with 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 C6-C1 -C6 alkoxy-alkoxy, (CH2) p-C3 -C10 cycloalkyl, (CH2) p-heterocycloalkyl, (CH2) pCN1 (CH2) fa1 (CH2) pNO2, (CH2) p-C6 -C12- aryl, (CH2) p-heteroaryl, - (CH2) pPO3 (Rb) 2, - (CH2) pNRcRd1 - (CH2) pNReCORb, - (CH2) pNReCSRb1- (CH2) pNReS (O) Rb, - (CH2) pNReS (O) 2Rb, - (CH2) pNReCONRcRd, - (CH2) pNReCOORb1 - (CH2) pNReC (NH) NRcRd1- (CH2) pNReCSNRcRd1- (CH2) pNReS (O) NRcRd1 - (CH2) pN CH2) pCORb1- (CH2) pCSRb1 - (CH2) p S (O) Rb1 - (CH2) pS (O) (NH) Rb, - (CH2) pS (O) 2Rb, - (CH2) pS (O) 2NRcRd1 - (CH2) pSO2ORb1 - (CH2) pCO2Rb1- (CH2) pCONRcRd1- ( CH2) pCSNRcRd1 - (CH2) pORb, - (CH2) pSRb1 - (CH2) pCRb (OH) -Rd1- (CH2) pC = NORb, -O- (CH2) nO-, -O- (CH2) n-CH2 -, -O-CH = CH- or- (CH2) n + 2-, where η = 1 or 2, and the terminal oxygen atoms and / or carbon atoms are attached to directly adjacent ring carbon atoms , orA means a radical -CO2Rb1 C (O) NRcRd1 CORb, orA means an alkenyl-CR5 = CR6R7 group, whereby R51 R6 and R7 are the same or different, independently of one another, hydrogen atoms, halogen atoms, aryl radicals or one unsubstituted or partially or fully fluorinated C1 -C5 alkyl group, or A means a -C = CR alkynyl group, with the meaning given above for R, eB means a carbonyl group or a CH2 group as well as pharmaceutically acceptable salts thereof. Compounds according to claim 1, wherein R1 and R2 preferably mean a hydrogen atom, a methyl group or an ethyl group. Compounds according to claim 1, wherein R 1 and R 2 preferably together with the C atom of the chain form a ring having a total of 3 to 7 bonds. Compounds according to claims 1 to 3, wherein R 3 preferably means alkenyl, alkynyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl. Compounds according to one of the preceding claims, wherein R3 preferably means a vinyl, ethinyl, propynyl, butynyl, pentinyl, hexinyl, heptinyl, octinyl, hydroxypropynyl, hydroxybutynyl, 3-hydroxy-3-methylbutinyl, hydroxypentinyl group; carboxypropynyl, t-butylcarboxypro-pinyl, phenylethynyl, (hydroxyphenyl) ethinyl, (methoxyphenyl) ethinyl, (methylphenyl) ethinyl, (cyanophenyl) ethinyl, (trifluoromethyl) ethinyl, (diphenyl) ethinyl, ethenyl, (tert-butylphenyl) ethinyl, (acetylphenyl) ethinyl, (acetoxyphenyl) ethinyl, (carboxyphenyl) ethinyl or a benzylethynyl. Compounds according to one of the preceding claims, wherein A is preferably an aromatic ring. Compounds according to one of the preceding claims, wherein A is preferably a phenyl or naphthyl radical. Compounds according to claim 7, wherein A is preferably an unsubstituted phenyl radical or optionally a phenylphenyl radical which is substituted in one or more places. Compounds according to claim 8, wherein the radi-phenyl phenyl is preferably substituted with one or two halogen atoms or a trifluoromethyl group. Compounds according to claim 9, wherein the halogen atoms are preferably chlorine and / or fluorine. A compound according to any of claims 1 to 8, wherein it is preferably a phenyl ring substituted by -O- (CH 2) n O- or -O- (CH 2) n -CH 2 -, whereby the carbon ring atoms respectively Directly adjacent carbon ring atoms are bonded. Compounds according to one of the preceding claims, wherein R4a and R4b independently of each other are in each case a hydrogen atom. Compounds according to claims 1 to 12, namely: <table> table see original document page 104 </column> </row> <table> <table> table see original document page 105 </column> </ row> <table> <table> table see original document page 106 </column> </row> <table> <table> table see original document page 107 </column> </row> <table> <table> table see original document page 108 </column> </row> <table> <table> table see original document page 109 </column> </row> <table> <table> table see original document page 110 </column> </ row> <table> <table> table see original document page 111 </column> </row> <table> <table> table see original document page 112 </column> </row> <table> <table> table see original document page 113 </column> </row> <table> <table> table see original document page 114 </column> </row> <table> <table> table see original document page 115 </column> </ row> <table> <table> table see original document page 116 </column> </row> <table> <table> table see original document page 117 </column> </row> <table> <table> table see original document page 118 </column> </row> <table> <table> table see original document page 119 </column> </row> <table> <table> table see original document page 120 </column> </ row > <table> <table> table see original document page 121 </column> </row> <table> <table> table see original document page 122 </column> </row> <table> <table> table see original document page 123 </column> </row> <table> <table> table see original document page 124 </column> </row> <table> <table> table see original document page 125 </column> </ row > <table> <table> table see original document page 126 </column> </row> <table> <table> table see original document page 28 </column> </row> <table> <table> table see original document page 128 </column> </row> <table> <table> table see original document page 30 </column> </row> <table> <table> table see original document page 130 </column> </ row > <table> <table> table see original document page 131 </column> </row> <table> <table> table see original document page 132 </column> </row> <table> <table> table see original document page 133 </column> </row><table> <table> table see original document page 134 </column> </row> <table> <table> table see original document page 135 </column> </row> <table> <table> table see original document page 136 </column> </row> <table> <table> table see original document page 137 </column> </row> <table> table see original document page 138 </column> </row><table> <table> table see original document page 139 </column> </row> <table> <table> table see original document page 140 </column> </row> <table> <table> table see original document page 141 </column> </row> <table> <table> table see original document page 142 </column> </row> <table> <table> table see original document page 143 </column> </row><table> <table> table see original document page 144 </column> </row> <table> <table> table see original document page 145 </column> </row> <table> <table> table see original document page 146 </column> </row> <table> <table> table see original document page 48 </column> </row> <table> <table> table see original document page 148 </column> </row><table> <table> table see original document page 149 </column> </row> <table> <table> table see original document page 51 </column> </row> <table> table see original document page 151 </column> < / row> <table> <table> table see original document page 53 </column> </row> <table> <table> table see original document page 153 </column> </row> <table> <table> table see original document page 154 </column> </row> <table> <table> table see original document page 56 </column> </row> <table> table see original document page 156 </column> < / row> <table> <table> table see original document page 157 </column> </row> <table> <table> table see original document page 158 </column> </row> <table> <table> table see original document page 159 </column> </row> <table> <table> table see original document page 160 </column> </row> <table> table see original document page 161 </column> < / row> <table> <table> table see original document page 162 </column> </row> <table> <table> table see original document page 163 </column> </row> <table> <table> table see original document page 1 64 </column> </row> <table> <table> table see original document page 165 </column> </row> <table> <table> table see original document page 166 </column> </row> < table> <table> table see original document page 68 </column> </row> <table> <table> table see original document page 168 </column> </row> <table> <table> table see original document page 169 </column> </row> <table> <table> table see original document page 170 </column> </row> <table> <table> table see original document page 171 </column> </row> < table> <table> table see original document page 172 </column> </row> <table> A pharmaceutical composition containing at least one compound of formula I according to one of claims 1 to 13, and optionally at least one additional active ingredient together with pharmaceutically compatible adjuvants and / or vehicles. The pharmaceutical composition of claim 14, wherein the additional active ingredient is a SERM (selective estrogen receptor modulator), an aromatase inhibitor, an antiestrogen, or a prostaglandin. The pharmaceutical composition of claim 14, wherein the active ingredients may be tamoxifen, 5- (4- {5 - [(RS) - (4,4,5,5,5-5-pentafluoropentyl) sulfinyl] - pentyloxy} phenyl) -6-phenyl-8,9-dihydro-7H-benzocycloep-ten-2-ol, ICI 182 780 (7alfa- [9- (4,4,5,5-pentafluoropentylsulfinyl) nonyl] estra-- 1,3,5 (10) -thieno-3,17-beta-diol), 11beta-fluoro-7alpha- [5- (methyl {3 - [(4,4,5,5,5-pen-tafluoropentyl) sulfanyl] propyl} amino) pentyl] estra-1,3,5 (10) -trieno-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) -trieno-3,17beta-diol, 11 beta-fluoro-17alpha-methyl-7alpha- {5- [methyl (8 8,9,9,9-pentafluorononyl) amino] pentyl} estra-1,3,5 (10) -trieno-3,17beta-diol, clomiphene, raloxifene, fadrozole, formestane, letrozole, anastrozole or ataestane. Use of compounds according to one of claims 1 to 13 for the production of a pharmaceutical agent. Use of compounds according to claim 17 for the manufacture of a pharmaceutical agent for the therapy and prophylaxis of gynecological diseases such as endometriosis, uterine lymphomas, dysfunctional bleeding and dysmenorrhea. Use of compounds according to claim 17 for the manufacture of a pharmaceutical agent for therapy and prophylaxis of hormone dependent tumors. Use of compounds according to claim 17 for the manufacture of a pharmaceutical agent for breast cancer therapy and prophylaxis. Use of compounds according to claim 17, for the manufacture of a pharmaceutical agent for endometrial carcinoma therapy and prophylaxis. Use of compounds according to claim 17 for the manufacture of a pharmaceutical agent for ovarian cancer therapy and prophylaxis. Use of compounds according to claim 17 for the manufacture of a pharmaceutical agent for prostate cancer therapy and prophylaxis. Use of compounds according to claim 17 for the manufacture of a pharmaceutical agent for female hormone replacement therapy. Use of compounds according to claim 17, female birth control. 26. Process for the selective addition of lithium alkynyl compounds and magnesium haloalkyl compounds to ketoamide.