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WO2009007396A1 - Nonsteroidal progesterone receptor modulators - Google Patents

Nonsteroidal progesterone receptor modulators Download PDF

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Publication number
WO2009007396A1
WO2009007396A1 PCT/EP2008/058921 EP2008058921W WO2009007396A1 WO 2009007396 A1 WO2009007396 A1 WO 2009007396A1 EP 2008058921 W EP2008058921 W EP 2008058921W WO 2009007396 A1 WO2009007396 A1 WO 2009007396A1
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alkyl
compounds according
trifluoromethylphenyl
aryl
hydroxy
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German (de)
French (fr)
Inventor
Wolfgang Schwede
Carsten Moeller
Anja Schmidt
Ulrike Fuhrmann
Andrea Rotgeri
Thomas Andrew Kirkland
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Bayer Pharma AG
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Bayer Schering Pharma AG
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61P15/18—Feminine contraceptives
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    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
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    • C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • Nonsteroidal progesterone receptor modulators are provided.
  • the present invention relates to nonsteroidal progesterone receptor modulators, a process for their preparation, the use of the progesterone receptor modulators for the production of medicaments, and pharmaceutical compositions containing these compounds.
  • progesterone regulates decisively the reproductive process in the female organism.
  • Progesterone is secreted by the ovary or placenta in large quantities during the cycle and during pregnancy.
  • progesterone causes cyclic changes of the uterine lining (endometrium) in the menstrual cycle.
  • the uterine mucosa is transferred to a state that allows the implantation of an embryo (blastocyst).
  • progesterone controls the immobilization of the myometrium and maintains the function of the decidual tissue.
  • progesterone inhibits endometrial proliferation by suppression of estrogen-mediated mitosis in the uterine tissue (K. Chwalisz, RM Brenner, U. Fuhrmann, H. Hess-Stumpp, W. Elger, Steroids 65, 2000, 741- 751).
  • Progesterone and progesterone receptors are also known in pathophysiological processes. Progesterone receptors are detected in endometriosis, but also in tumors of the uterus, the breast and the CNS. Furthermore, it is known that leiomyomas of the uterus grow progesterone dependent.
  • progesterone in the tissues of the genital organs and in other tissues are through interactions with progesterone receptors responsible for the cellular effects.
  • Progesterone receptor modulators are either pure agonists or partially or completely inhibit the action of progesterone. Accordingly, become Substances as pure agonists, partial agonists (Selective
  • Progesterone receptor modulators SPRM
  • pure antagonists SPRM
  • progesterone receptor modulators According to the ability of progesterone receptor modulators to exert their action via the progesterone receptor, these compounds have considerable potential as therapeutic agents for gynecological and oncologic indications as well as for obstetrics and fertility control.
  • progesterone receptor antagonists completely inhibit the action of progesterone on the progesterone receptor. They have antiovulatory properties as well as the ability to inhibit estrogen effects in the endometrium to complete atrophy. They are therefore particularly suitable to intervene in the reproductive process of the woman, for.
  • Postovulatory in order to prevent the nidation of a fertilized egg, in pregnancy, to increase the reactivity of the uterus for prostaglandins or oxytocin or to achieve opening and softening ("maturation") of the cervix, as well as a high labor readiness of the myometrium In endometrial or tumor tissues, which are equipped with progesterone receptors, one expects after application of pure progesterone receptor antagonists a favorable influence on the disease process.
  • Present advantages for influencing disease states such as endometriosis or leiomyomas of the uterus could be given if by The inhibition of ovulation also eliminates part of the ovarian hormone production and thus the stimulating effect on the pathologically altered tissue that is attributable to this proportion.
  • RU 486 also called mifepristone
  • the first described progesterone receptor antagonist, RU 486 was followed by the synthesis and characterization of a large number of analogs with varying levels of progesterone receptor antagonist activity. While RU 486 also shows an antiglucocorticoid effect in addition to the progesterone receptor antagonistic effect, later synthesized compounds are characterized in particular by a more selective action as progesterone receptor antagonists.
  • Progesterone receptor antagonistic to antiglucocorticoid effect Also known are various non-steroidal structures whose antagonistic activity is investigated on the progesterone receptor [see, for example, 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)].
  • previously known non-steroidal compounds have only modest antagonistic activity compared to the activity of known steroidal structures. The most potent non-steroidal compounds are described with in vitro activities of 10% of the activity of RU 486.
  • Antiglucocorticoid activity is detrimental to a therapeutic application in which inhibition of progesterone receptors is at the forefront of therapy. Antiglucocorticoid activity causes undesirable side effects at the therapeutically required dosages. This may prevent the application of a therapeutically useful dose or lead to discontinuation of treatment.
  • the partial or complete reduction of the anti-glucocorticoid properties is therefore an important prerequisite for the treatment with progesterone receptor antagonists, in particular for those indications which require treatment lasting over weeks or months.
  • progesterone receptor partial agonists show a residual agonistic property, which can be of varying severity.
  • SPRMs progesterone receptor partial agonists
  • these substances exhibit agonistic effects on the progesterone receptor in certain organ systems (D. DeManno, W. Elger, R. Garg, R. Lee, B. Schneider, H. Hess-Stumpp, G. Schuber, K. Chwalisz, Steroids 68, 2003, 1019-1032).
  • organ specific and dissociated effect may be of therapeutic use for the described indications.
  • the object of the present invention is therefore to provide further nonsteroidal progesterone receptor modulators. These compounds are said to have a reduced anti-glucocorticoid effect and therefore be suitable for the
  • the compounds according to the invention should be suitable for the therapy and prophylaxis of hormone-dependent tumors, for example breast,
  • R 1 and R 2 are independently a hydrogen atom, a branched or unbranched -C 5 - alkyl group, further forming a ring together with the C-atom of the chain with a total of 3-7 members
  • R 3 is a radical C ⁇ CR a, wherein R a a hydrogen or an optionally mono- or polysubstituted, identically or differently, with K C 1 - C 8 -alkyl, C 2 -C 8 alkenyl, C 2 -C 8 -alkyl kiny I, C 3 -C 10 cycloalkyl, 3-8 membered heterocycloalkyl or optionally substituted one or more times, identically or differently, with L C 6 -C 2 signifies aryl or 3-8-membered heteroaryl or silicon,
  • Heteroaryl is, L d -C ⁇ -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, Ci-C 6 -
  • n 1 or 2 and the terminal oxygen atoms and / or carbon atoms are linked to directly adjacent ring carbon atoms,
  • R b is a hydrogen or a C 1 -C 6 -alkyl
  • R c and R d independently represent a hydrogen, d-Ce-alkyl, C 2 -C 8 alkenyl, C 2 - C 8 -alkyl kinyl, C 3 -d 0 cycloalkyl, C 6 -C 2 -
  • Ci-C 6 alkyl, C 2 -C 8 - alkenyl, C 2 -C 8 alkynyl, C 3 -C 0 - cycloalkyl or C 6 -C 2 aryl may be, and vice versa, and
  • R ⁇ is a hydrogen, C 1 -C 6 -alkyl, C 2 -C 8 -
  • Alkenyl, C 2 -C 8 alkynyl, C 3 -C 0 -CyCIo- alkyl or C 6 -C 2 represents aryl, and p can be a number from 0- 6,
  • R 9 and R h independently of one another a hydrogen or an optionally mono- or polysubstituted, identically or differently, with X-substituted C 8 alkyl, C 2 -C 8 - alkenyl or C 2 -C 8 alkynyl, where X is a Cyano, halogen, hydroxy, nitro, -C (O) R b , CO 2 R b , -OR b , -C (O) -NR c R d , -NR c R d with the meanings given above for R b , R c and R d is and
  • R 4 may be an unsubstituted or optionally substituted with 1-3 radicals 3-8-membered aromatic or heteroaromatic mono- or bicyclic or one of the following groups:
  • R ba and R '6b independently of one another form a hydrogen atom, a C 1 -C 4 -alkyl, a C 2 -C 4 -alkenyl or together with the ring carbon atom form a 3-membered 6-membered ring,
  • a mono- or bicyclic carbocyclic or heterocyclic aromatic ring which may optionally be mono or polysubstituted by C r C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, 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 ) pC 3 -cio-cycloalkyl, (CH 2 ) P -
  • Heterocycloalkyl (CH 2) p CN, (CH 2) p Hal, (CH 2) p NO 2, (CH 2) P -C 6 -C 2 aryl, (CH 2) P -heteroaryl,
  • A is a radical -CO 2 R b , C (O) NR c R d , COR b ,
  • R, R and R are the same or different and independently of one another represent hydrogen atoms, halogen atoms, aryl radicals or an unsubstituted or partially or completely fluorinated C 1 -C 4 -alkyl group, or
  • A is an alkynyl group -C ⁇ CR, with the above R listed
  • B is a carbonyl or a CH 2 group
  • the compounds of the general formula (I) according to the invention can be present as different stereoisomers due to the presence of asymmetric centers. Both the racemates and the separately present stereoisomers are the subject of the present invention.
  • the present invention comprises the novel compounds as pharmaceutical active ingredients, their preparation, their therapeutic application and pharmaceutical dosage forms containing the new substances.
  • the compounds of the general formula (I) or their pharmaceutically acceptable salts according to the invention can be used for the preparation of a medicament, in particular for the treatment and prophylaxis of gynecological diseases such as endometriosis, uterine leiomyomas, dysfunctional bleeding and dysmenorrhea.
  • the compounds according to the invention can be used for the treatment and prophylaxis of hormone-dependent tumors such as, for example, breast, prostate and endometrial carcinoma.
  • the compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts are suitable for use in female fertility control or in female hormone replacement therapy.
  • the nonsteroidal compounds of the general formula I according to the invention have a strong antagonistic or partial agonistic action on the progesterone receptor. They show a strong dissociation of activity with regard to their binding strength at the progesterone and glucocorticoid receptors. While known progesterone receptor antagonists such as mifepristone (RU 486) in addition to the desired high binding affinity for progesterone receptor also show a high affinity for glucocorticoid receptor, the compounds of the invention are characterized by a very low glucocorticoid receptor binding at the same time present high progesterone receptor affinity.
  • CrC 5 -, CrC 6 - or CrC 8 alkyl group are meant straight or odd, branched or unbranched alkyl radicals. These are, for example, a methyl, ethyl, n-propyl, iso-propyl, n, iso, tert-butyl, n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl -, hexyl, heptyl or octyl group. In the context of R a , the methyl, ethyl, n-propyl or n-butyl group and an n-pentyl group are preferred.
  • R4 R4 a and b is preferably a hydrogen.
  • Alkenyl is understood to mean branched or unbranched alkenyl radicals.
  • C 2 -C 6 -alkenyl group is understood to mean, for example, the following: Vinyl, allyl, 3-buten-1-yl or 2,3-dimethyl-2-propenyl. If the aromatic A is substituted by a C 2 -C 6 -alkenyl radical, it is preferably a vinyl group.
  • Alkynyl is understood as meaning branched or unbranched alkynyl radicals.
  • a C 2 -C 8 -alkynyl radical should be, for example, an ethynyl, propynyl, butynyl, pentynyl, hexynyl and octynyl group, but preferably an ethynyl or propynyl group.
  • 3-10-membered cycloalkyl or heterocycloalkyl is meant both monocyclic and bicyclic radicals.
  • C 3 -C 10 -cycloalkyl in the sense of R 3 , K, L, R b , R c , R d , R 4 , R 6a and R 6b , mention may be made, for example, of cyclopropane, cyclobutane, cyclopentane and cyclohexane. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.
  • Heterocycloalkyl in the sense of R a , K or L is to be understood as meaning 3-8-membered monocyclic heterocycloalkyl radicals.
  • heterocycloalkyl are morpholine, tetrahydrofuran, pyran, piperazine, piperidine, pyrrolidine, oxirane, oxetane, aziridine, dioxolane and dioxane, it being possible to use any chemically meaningful isomers with respect to the positions of the heteroatoms.
  • methoxymethoxy, ethoxymethoxy or 2-methoxyethoxy may be C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy.
  • a radical OR b in the context of the invention is a hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n, iso, tert-butoxy or n-pentoxy radical, 2,2-dimethylpropoxy or 3-methylbutoxy group. Hydroxy, methoxy and ethoxy are preferred.
  • the perfluorinated above-mentioned alkyl groups come into consideration.
  • the trifluoromethyl or pentafluoroethyl group and, for example, the 5,5,4,4-pentafluoropentyl or 5,5,5,4,4,3,3-heptafluoropentyl group are preferred as partially fluorinated alkyl groups.
  • CrC 3 - or CrC 6 Perfluoralkyl phenomenon are also especially trifluoromethyl or the pentafluoroethyl group into consideration.
  • C 1 -C 3 or C 1 -C 6 perfluoroalkoxy groups preference is given to the trifluoromethoxy or pentafluoroethoxy radical.
  • a halogen atom may be a fluorine, chlorine, bromine or iodine atom. Preference is given here to fluorine, chlorine or bromine.
  • 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, butyl, pentyl or hexyl ring.
  • the cyclopropyl as well as the cyclopentyl ring are preferred.
  • the mono- or bicyclic carbocyclic aromatic ring A which may be multiply substituted is a carbocyclic or heterocyclic aryl group.
  • it is for example a phenyl or naphthyl radical, preferably a phenyl radical.
  • heterocyclic radical for example, a monocyclic heterocyclic radical, for example the thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl , Pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl, all possible isomers with respect to the positions of the heteroatoms are used.
  • a monocyclic heterocyclic radical for example the thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, fur
  • R 3 are in a C 6 -C 2 aryl to an optionally substituted phenyl, 1- or 2-naphthyl, wherein the phenyl radical is preferred.
  • a heteroaryl radical are 2-, 3- or 4-pyridinyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 2-, 4- or 5 -imidazolyl, the pyrazinyl, 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl.
  • the number p for (CH 2 ) P radical may be an integer from 0 to 6, preferably 0, 1 or 2.
  • radical is meant according to the invention all functional groups which are listed in connection with (CH 2 ) P under L and A.
  • the compounds according to the invention are present as racemic mixtures, they can be separated into the pure optically active forms by methods of racemate resolution which are familiar to the person skilled in the art. For example, the racemic mixtures can be separated into the pure isomers by chromatography on an even optically active carrier material (CHIRALPAK AD ®).
  • optically active acid for example, mandelic acid, camphorsulfonic acid or tartaric acid can be used.
  • Preferred according to the present invention are compounds of the general formula (I) in which:
  • R 1 and R 2 are each independently a hydrogen atom, a methyl or an ethyl radical, or together with the C atom of the chain form a ring having a total of 3-7 members. Particular preference is given to compounds in which R 1 and R 2 are simultaneously a hydrogen atom, a methyl or cyclopropyl radical, particularly preferably a methyl or cyclopropyl radical.
  • R 3 is an alkynyl group of formula C ⁇ CR a, wherein R a optionally substituted with C 1 -C 4 K -A ⁇ YI, C 3 -C 10 cycloalkyl, 3- 8 is a heterocycloalkyl radical or optionally an L-substituted C 6 -C 12 aryl or 3-8-membered heteroaryl radical, and
  • K is a cyano, halogen, hydroxy, -OR b , SO 2 NR c R d , -C (O) -NR c R d , -NR c R d or a 3 optionally substituted one or more times, identically or differently with M -8- is a heterocycloalkyl or an optionally multiply L-substituted aryl or heteroaryl radical, and L is a C 1 -C 4 -A ⁇ yI, Ci-C 4 perfluoroalkyl, (CH 2 ) p-C3-C 10 -cycloalkyl, (CH 2 ) p -Heterocyclo- alkyl radical, (CH 2 ) p CN, (CH 2 ) p Hal, (CH 2 ) P NO 2 , (CH 2 ) P -C 6 -C 12 aryl , (CH 2 ) p -heteroaryl, - (CH 2 ) p
  • R a is an optionally substituted with K dC 4 alkyl or optionally substituted with L phenyl or hetaryl, wherein L is preferably a methyl, trifluoromethyl, methoxy, acetoxy, hydroxy, carboxyl or carboxyalkyl.
  • R 4 is a phenyl ring, more preferably a 1-3-substituted phenyl ring.
  • Preferred substituents on the phenyl ring are nitro, trifluoromethyl, pentafluoroethyl, cyano, chlorine, fluorine, methyl.
  • R 4 is one of the following groups:
  • A is preferably substituted by the following radicals: C 1 -C 6 -alkyl, C 1 -C 6 -perfluoroalkyl, C 1 -C 6 -fluoroalkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 6 -alkoxy, (CH 2 ) p -C 3 -do-cycloalkyl, (CH 2 ) p -heterocycloalkyl, (CH 2 ) p CN, (CH 2 ) p Hal, (CH 2 ) p NO 2 , (CH 2 ) P -C 6 -Ci 2 - aryl, (CH 2 ) p -heteroaryl, - (CH 2 ) p NR c R d , - (CH 2 ) p NR ⁇ C
  • A is C 1 -C 4 alkyl, dC 2 perfluoroalkyl, d-Cz-perfluoroalkoxy, (CH 2) p CN, (CH 2) p Hal, - (CH 2) p NR c R d , - (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 OR b or - (CH 2 ) p SR b is substituted and p and R b , R c and R d have the meanings already mentioned.
  • A is either an unsubstituted phenyl ring or a phenyl ring which is monosubstituted or disubstituted by identical or different fluorine, chlorine, bromine, methyl, trifluoromethyl or methoxy.
  • B is a carbonyl group or a group -CH 2 -.
  • progesterone receptor modulators can be carried out with the aid of simple methods, test programs known to the person skilled in the art.
  • a compound to be tested can be incubated together with a gestagen in a test system for progesterone receptor ligands and it can be tested whether the action mediated by progesterone is changed in the presence of the modulator in this test system.
  • Receptor binding affinity was determined by competitive binding of a specific binding 3 H-labeled hormone (tracer) and the compound to be tested to receptors in the cytosol from animal target organs. The aim was receptor saturation and reaction equilibrium.
  • Glucocorticoid receptor thymus cytosol of the adrenalectom striv rat, thymi stored at -30 0 C; Buffer: TED. Tracer: 3 H-Dexamethasone, 20 nM; Reference substance: dexamethasone.
  • the competition factors (KF values) of the compounds of general formula (I) according to the invention on the progesterone receptor are between 0.2 and 35 with respect to progesterone. At the glucocorticoid receptor, KF values are in the range of 3 to 35 based on dexamethasone.
  • the compounds according to the invention have a high affinity for the progesterone receptor but only a low affinity for the glucocorticoid receptor.
  • the transactivation assay is carried out as described in WO 02/054064.
  • the IC 50 values are in the range of 0.1 to 150 nM.
  • the transactivation assay is carried out as 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 Chemistry, 43, 26, 2000 , 5010-5016).
  • the EC 50 values are in the range from 0.01 to 150 nM.
  • the progesterone receptor modulators can be administered orally, enterally, parenterally or transdermally.
  • satisfactory results in the treatment of the above-mentioned indications are to be expected if the daily doses range from 1 ⁇ g to 1000 mg of the compound of the invention for gynecological indications such as treatment of endometriosis, uterine leiomyomas and dysfunctional bleeding and for use in fertility control and hormone replacement therapy.
  • daily dosages ranging from 1 ⁇ g to 2000 mg of the compound of the invention are to be administered.
  • Hormone replacement therapy is 50 ⁇ g to 500 mg per day, depending on the age and Constitution of the patient, whereby the necessary daily dose can be administered by single or multiple delivery.
  • the dosage range for the compounds of the invention comprises 10 mg to 2000 mg daily.
  • the formulation of the pharmaceutical preparations based on the new compounds is carried out in a conventional manner, by processing the active ingredient with the commonly used in galenics carriers, fillers, Zerfallbeeinpoundern, binders, humectants, lubricants, absorbents, diluents, flavoring agents, colorants, etc., and in the desired
  • crystal suspensions For intraarticular injection, appropriately prepared crystal suspensions may be used.
  • aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.
  • the new compounds may be used in the form of suppositories, capsules, solutions (e.g., in the form of enemas) and ointments for both systemic and local therapy. Furthermore, may be mentioned as a preparation and agents for vaginal use.
  • these can be used in the form of aerosols and inhalants.
  • Corresponding tablets can be prepared, for example, by mixing the active compound with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or Achieve a depot effect such as carboxyl polymethylene, carboxyl methyl cellulose, cellulose acetate phthalate or polyvinyl acetate.
  • the tablets can also consist of several layers.
  • Coated tablets can accordingly be prepared by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar.
  • the dragee wrapper can also consist of several layers, wherein the auxiliaries mentioned above in the case of the tablets can be used.
  • Solutions or suspensions of the compounds of general formula I according to the invention may additionally taste-improving agents such as saccharin, cyclamate or sugar and z.
  • B. flavorings such as vanillin or orange extract. They may also contain suspending aids such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.
  • the capsules containing the compounds of the general formula I can be prepared, for example, by mixing the compound (s) of the general formula I with an inert carrier such as lactose or sorbitol and encapsulating it in gelatine capsules.
  • an inert carrier such as lactose or sorbitol
  • Suitable suppositories can be prepared, for example, by mixing with suitable carriers such as neutral fats or polyethylene glycol or derivatives thereof.
  • suitable carriers such as neutral fats or polyethylene glycol or derivatives thereof.
  • the compounds of the general formula (I) or their pharmaceutically acceptable salts according to the invention can, because of their antagonistic or partial agonist activity, be used for the preparation of a medicament, in particular for the treatment and prophylaxis of gynecological diseases such as endometriosis, uterine leiomyomas, dysfunctional bleeding and dysmenorrhoea. Furthermore, they can be used against hormonal irregularities, menstruation release and alone or in combination with prostaglandins and / or oxytocin to induce labor.
  • the compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts are furthermore suitable for the preparation of preparations for contraception for women (see also WO 93/23020, WO 93/21927).
  • the compounds according to the invention or their pharmaceutically acceptable salts can also be used alone or in combination with estrogens, estrogen derivatives, estrogen-active substances or with a Selective E estrogen receptor modulators (SERM) for female hormone replacement therapy.
  • SERM Selective E estrogen receptor modulators
  • the compounds mentioned exert an antiproliferative effect in hormone-dependent tumors. They are therefore suitable for the therapy of hormone-dependent carcinomas, such as, for example, breast, prostate and endometrial carcinomas.
  • the compounds according to the invention or their pharmaceutically acceptable salts can be used for the treatment of hormone-dependent carcinomas both in first-line therapy and in second-line therapy, in particular after tamoxifen failure.
  • antagonistic or partially agonistic effective compounds of general formula (I) or their pharmaceutically acceptable salts may also be used in combination with active compounds antiestrogen (estrogen receptor antagonists or aromatase inhibitors) or Selective E ⁇ strogen- receptor modulators (SERM) for the preparation of pharmaceutical preparations for the treatment of hormone-dependent tumors are used.
  • active compounds antiestrogen estrogen receptor antagonists or aromatase inhibitors
  • SERM Selective E ⁇ strogen- receptor modulators
  • the compounds of the invention may also be used in combination with SERM's or an antiestrogen (estrogen receptor antagonist or aromatase inhibitor)
  • SERM's or an antiestrogen estrogen receptor antagonist or aromatase inhibitor
  • the following antiestrogens (estrogen receptor antagonists or aromatase inhibitors) or SERMs are suitable for combination with the nonsteroidal progesterone receptor modulators according to the invention: tamoxifen, 5- (4- ⁇ 5 - [(RS) - (4,4, 5,5,5-pentafluoropentyl) sulfinyl] pentyloxy ⁇ phenyl) -6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol (WO 00/03979), ICI 182 780 (7alpha [9- (4 , 4,5,5-pentafluoropentylsulfinyl) nonyl] estra-1, 3,5 (10) -
  • estrogen-3-alkyl sulfonates such as 17 ⁇ -estradiol-3-alkyl sulfonate and 17 ⁇ -ethinylestradiol-3-alkyl sulfonate
  • saturated, branched or unbranched C 1 -C 5 -alkyl groups are particularly suitable for the alkyl sulfonate.
  • Ci-Cs-alkyl the meanings given in the definitions on page 9 apply.
  • the present invention also relates to the use of the compounds of the general formula I, optionally together with an antiestrogen, an estrogen or estrogen derivative or an estrogen-active substance or a SERM, for the production of a medicament. Furthermore, the present invention relates to pharmaceutical compositions containing at least one compound of the invention, optionally in the form of a pharmaceutically / pharmacologically acceptable salt.
  • compositions and pharmaceutical compositions may be for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular administration.
  • conventional carriers and / or diluents they contain at least one compound of the invention.
  • compositions of the invention are prepared in a known manner with the usual solid or liquid carriers or diluents and the pharmaceutical excipients customarily used according to the desired mode of administration with a suitable dosage.
  • the preferred formulations consist of a dosage form which is suitable for oral administration.
  • dosage forms are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions, optionally as depot form.
  • compositions containing at least one of the compounds of the invention are preferably administered orally.
  • parenteral preparations such as injection solutions into consideration.
  • Further examples of preparations which may be mentioned are suppositories and vaginal administration agents.
  • the compounds of general formula I can be synthesized as shown in Scheme 1.
  • Carboxylic acids of the general formula II have, for example, been described in WO 199854159, WO 200375915 and WO 9854159 already described.
  • the amides of the general formula III are prepared, for example, via the formation of the acid chlorides and subsequent reaction with the corresponding amines. Alternatively, depending on the amine to be introduced, other methods for amide formation can also be used. From the amides of general formula III, the compounds of general formula I are then prepared by addition of Grignard or lithium-organic compounds. However, steps 1 and 2 can also be carried out in the reverse order.
  • the substituents A, R 1 , R 2 , R 3 and R 4 can optionally be further modified even after the introduction.
  • Butyllithium (314 ul, 1, 6 M in hexane) added. The mixture was stirred for 30 minutes at this temperature and then dripped a solution of the described under 1 a) Add compound (100 mg) in 4 ml of tetrahydrofuran. The mixture was then allowed to come to 23 ° C over about 3 h and then stirred for 10 h. Thereafter, the reaction mixture was poured onto 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. 93 mg of product were obtained.
  • the racemic mixture obtained in Example 1b was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 1c and 1d.
  • Example 2 The compound described in Example 2 was prepared analogously to the process described under Example 1 b) from the compound described under 1 a), 4-methylphenylacetylene and n-butyllithium.
  • Example 3a The compound described in Example 3a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionic acid and 4-amino-2-trifluoromethyl-benzonitrile.
  • 1 H NMR (ppm, CDCl 3 , 300 MHz): 1.02 (4H), 3.30 (2H), 7.08 (1H), 7.49 (1H), 7.70 (1H), 7.82 (1H), 7.93 (1 H), 8.08 (1 H), 8.94 (1 H).
  • Example 3b The compound described under Example 3b) was prepared from 3a) analogously to Example 1 b).
  • Example 3b The racemic mixture obtained in Example 3b was separated by preparative chiral HPLC (column Chiralpak AD 250 ⁇ 10 mm) into the enantiomers 3c and 3d.
  • Example 4 The compound described under Example 4 was prepared from 3a) analogously to Example 2.
  • Example 4 The racemic mixture obtained in Example 4 was separated by preparative chiral HPLC (column Chiralpak AD 250 ⁇ 10 mm) into the enantiomers 4a and 4b.
  • Example 5a The compound described under Example 5a) was prepared analogously to the method described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and 4-nitro-3-trifluoromethylphenylamine.
  • Example 5b The compound described under Example 5b) was prepared from 5a) analogously to Example 1 b).
  • 1 H NMR ppm, CDCl 3 , 400 MHz: 0.87 (1H), 0.95-1.12 (3H), 2.40 (1H), 2.73 (1H), 3.01 (1H), 7.00 (1H), 7.23-7.40 (6H), 7.60 (1H), 7.82-7.99 (3H), 8.90 (1H).
  • Example 5c and 5d (+) - ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methylphenylethynyl)] propionic acid ⁇ (4-nitro-3-trifluoromethylphenyl ) amide 5a and (-) - ⁇ 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methylphenylethynyl)] propionic acid ⁇ (4-nitro-3-trifluoromethylphenyl) amide 5b
  • the racemic mixture obtained in Example 5b was separated by preparative chiral HPLC (column Chiralpak AD 250 ⁇ 10 mm) into the enantiomers 5c and 5d.
  • Example 6 The compound described in Example 6 was prepared from 5a) analogously to Example 2.
  • Example 7 rac- ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methylphenyl) -ethynyl)] -propionic acid ⁇ (1-oxo-1 H-1 ⁇ 4- benzo [b] thiophen-5-yl) amide
  • Example 7c The compound described under Example 7c) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and the compound described under 7b).
  • 1 H NMR ppm, CDCl 3 , 300 MHz: 1.01 (4H), 3.35 (2H), 7.09 (1H), 7.30 (1H), 7.40 (1H), 7.48 (2H), 7.73 (1H ), 7.82 (1 H), 8.24 (1 H), 8.74 (1 H).
  • Example 7d The compound described under Example 7d) was prepared from 7c) analogously to Example 2.
  • Example 8 Rac- ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methyl-phenyl) -ethynyl)] -propionic acid ⁇ (1,1-dioxo) 2,3-dihydro-1H-1 ⁇ 6 -benzo [b] thiophen-5-yl) amide
  • Example 8a The compound described under Example 8a) was analogous to the method described under Example 1a) of 3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionic acid and 1, 1-dioxo-2,3-dihydro -1 H-1 ⁇ 6 -benzo [b] thiophen-5-ylamine.
  • Example 8b The compound described under Example 8b) was prepared from 8a) analogously to Example 2.
  • Example 8 The racemic mixture obtained in Example 8 was separated by preparative chiral HPLC (column Chiralpak AD 250 ⁇ 10 mm) into the enantiomers 9a and 9b.
  • Example 1oa The compound described under Example 1oa) was prepared in analogy to the process described in Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxo-propionic acid and 1, 1-Dioxo-1H-1 ⁇ 6 benzo [b] thiophen-5-ylamine.
  • 1 H-NMR (ppm, DMSO-D 6 , 300 MHz): 0.92 (4H), 3.24 (2H), 7.28-7.38 (2H), 7.48 (2H), 7.74 (2H), 7.86 (1H), 8.01 ( 1H), 10.78 (1H).
  • Example 10 The compound described under Example 10) was prepared from 10a) analogously to Example 2.
  • Example 11 Rac- ⁇ 2-Hydroxy-3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-phenylethynyl)] - propionic acid ⁇ (4-cyano-3-trifluoromethyl) amide
  • Example 11 a The compound described under Example 11 a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-chloro-6-fluorophenyl) dimethyl] -2-oxopropionic acid and 4-amino-2-trifluoromethyl-benzonitrile ,
  • Example 11 b) The compound described in Example 11 b) was prepared from 1 1a) analogously to Example 1 b).
  • Example 12a The compound described under Example 12a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-oxopropionic acid and 4-amino-2-chlorobenzonitrile.
  • Example 12b The compound described under Example 12b) was prepared from 12a) analogously to Example 1 b).
  • 1 H-NMR ppm, CDCl 3 , 400 MHz: 1.72 (3H), 1.80 (3H), 2.92 (2H), 3.04 (1H), 6.81 (1H), 6.94 (1H), 7.03 (1 H), 7.26-7.43 (6H), 7.58 (1H), 7.82 (1H), 8.72 (1H).
  • Example 12b The racemic mixture obtained in Example 12b was separated by preparative chiral HPLC (column Chiralpak AD 250 ⁇ 10 mm) into the enantiomers 12c and 12d.
  • Example 13 Rac- ⁇ 2-Hydroxy-3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-phenylethynyl)] - propionic acid ⁇ (4-nitro-3-trifluoromethylphenyl) amide
  • Example 12a The compound described under Example 12a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-oxopropionic acid and 4-nitro-3-trifluoromethylanilines.
  • Example 13b The compound described under Example 13b) was prepared from 13a) analogously to Example 1 b).
  • Example 14 Rac- ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenyl-ethynyl) -propionic acid ⁇ (4-cyanophenyl) -amide
  • Example 14a The compound described under Example 14a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionic acid and 4-aminobenzonitrile.
  • Example 14b The compound described under Example 14b) was prepared from 14a) analogously to Example 1 b).
  • Example 15a The compound described under Example 15a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and aniline.
  • 1 H NMR (ppm, CDCl 3 , 300 MHz): 1.00 (4H), 3.33 (2H), 7.09 (1H), 7.16 (1H), 7.35 (2H), 7.48 (1H), 7.58 (2H) , 7.73 (1H), 8.61 (1H).
  • Example 16 Rac- ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3-hydroxypropynyl)] - propionic acid ⁇ (4-cyano-3-trifluoromethylphenyl) amide
  • Example 16a The compound described under Example 16a) was prepared analogously to the process described under Example 1 b) from ⁇ 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid ⁇ (4-cyano-3-trifluoromethylphenyl) amide (see Example 3a) and 3-tert-butylsilyloxypropyne.
  • Examples 16c and 16d (+) - ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3-hydroxy-propynyl)] -propionic acid ⁇ (4-cyano-3 -trifluoromethylphenyl) amide 16c and (-) - ⁇ 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2- (3-hydroxypropynyl)] propionic acid ⁇ (4-cyano) 3-trifluoromethylphenyl) amide 16d
  • the racemic mixture obtained in Example 16b was separated by preparative chiral HPLC (column Chiralpak AD 250 ⁇ 10 mm) into the enantiomers 16c and 16d.
  • Example 17 rac- ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (1-pentynyl)] - propionic acid ⁇ (4-cyano-3-trifluoromethylphenyl) amide
  • Example 17 The compound described in Example 17 was analogous to the method described in Example 1 b) of ⁇ 3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropion Acid ⁇ (4-cyano-3-trifluoromethylphenyl) amide and 1-penty.
  • Example 18a The compound described under Example 18a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and 3-trifluoromethylaniline.
  • Example 18b The compound described in Example 18b) was prepared from 18a) analogously to Example 1 b).
  • 1 H NMR ppm, CDCl 3 , 400 MHz: 0.87-0.94 (1H), 1.01-1.13 (3H), 2.49 (1H), 2.70 (1H), 3.14 (1H), 7.04 (1H ), 7.32-7.51 (8H), 7.68 (2H), 7.82 (1H), 8.61 (1H).
  • Example 19 Rac- ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-hydroxyphenylethynyl)] - propionic acid ⁇ (4-cyano-3-trifluoromethylphenyl) amide
  • Example 19a The compound described in Example 19a was prepared from ⁇ 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid ⁇ (4-cyano-3-trifluoromethylphenyl) amide and trimethylsilylacetylene in analogy to Example 1b ) produced.
  • Example 19b The compound described in Example 19b) was prepared from 19a) analogously to Example 16b).
  • Example 20a The compound described under Example 20a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-chlorophenyl) -cyclopropyl] -2-oxopropionic acid and 4-amino-2-trifluoromethylbenzonitrile.
  • Example 20b The compound described under Example 20b) was prepared from 20a) analogously to Example 1 b).
  • 1 H-NMR ppm, CDCl 3 , 400 MHz: 0.80-0.88 (1H), 0.96-1.03 (1H), 1.09-1.28 (2H), 2.94 (2H), 7.04-7.14 (2H), 7.27- 7.48 (8H), 7.79 (2H), 7.93 (1H), 8.80 (1H).
  • Example 20b The racemic mixture obtained in Example 20b was purified by preparative chiral
  • Example 21 Rac- ⁇ 2-Hydroxy-3- [1- (2-chlorophenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid ⁇ (4-cyano-3-chlorophenyl) amide 21 a) ⁇ 3- [1- (2-chlorophenyl) -cyclopropyl] -2-oxopropionic acid ⁇ (4-cyano-3-chlorophenyl) amide
  • Example 21 a The compound described in Example 21 a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-chlorophenyl) -cyclopropyl] -2-oxopropionic acid and 4-amino-2-chlorobenzonitrile.
  • Example 21 b The compound described in Example 21 b) was prepared from 21a) analogously to Example 1 b).
  • 1 H NMR ppm, CDCl 3 , 400 MHz: 0.83 (1H), 1.00 (1H), 1.08-1.20 (2H), 2.89 (1H), 7.07-7.15 (2H), 7.29-7.49 (8H ), 7.59 (1 H), 7.81 (1 H), 8.86 (1 H).
  • Example 21 b The racemic mixture obtained in Example 21 b was purified by preparative chiral
  • Example 22a The compound described in Example 22a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-chlorophenyl) -cyclopropyl] -2-oxopropionic acid and 4-nitro-3-trifluoromethylaniline.
  • Example 22b The compound described under Example 22b) was prepared from 22a) analogously to Example 1 b).
  • 1 H-NMR ppm, CDCl 3 , 400 MHz: 0.85 (1H), 1.01 (1H), 1.12-1.20 (2H), 2.93 (2H), 7.06- 7.14 (2H), 7.28-7.48 (7H) , 7.87-7.97 (3H), 8.84 (1H).
  • Example 23 Rac- ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-dimethyl-aminopropine-propionic acid ⁇ (4-cyano-3-trifluoromethyl-phenyl) -amide
  • Example 23 The compound described in Example 23 was prepared from ⁇ 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid ⁇ (4-cyano-3-trifluoromethylphenyl) amide and 3- (N, N-dimethylamino ) propyne in analogy to Example 1 b).
  • Example 24 Rac- ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (1-methyl-1H-imidazol-5-ylethynyl)] - propionic acid ⁇ (4 cyano-3-trifluoromethylphenyl) amide
  • Example 24 The compound described in Example 24 was prepared from ⁇ 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid ⁇ (4-cyano-3-trifluoromethylphenyl) amide and 1-methyl-1-imidazole 5-ylethine analogously to Example 1 b).
  • Examples 24a and 24b (+) - ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (1-methyl-1H-imidazol-5-ylethynyl)] - propionic acid ⁇ (4-cyano-3-trifluoromethylphenyl) amide 24a and (-) ⁇ 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (1-methyl-1 H- imidazol-5-ylethynyl)] - propionic acid ⁇ (4-cyano-3-trifluoromethylphenyl) amide 24b
  • the racemic mixture obtained in Example 24 was separated into the enantiomers 24a and 24b by preparative chiral HPLC (Chiralpak AD column 250 ⁇ 10 mm).
  • Example 25 Rac- ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (2-pyridylethynyl)] - propionic acid ⁇ (4-cyano-3-trifluoromethylphenyl) amide
  • Example 25 The compound described in Example 25 was prepared from ⁇ 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid ⁇ (4-cyano-3-trifluoromethylphenyl) amide and 2-pyridinylethine analogously to Example 1b ) produced.
  • Example 26 Rac- ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-carboxyethynyl)] - propionic acid ⁇ (4-cyano-3-trifluoromethylphenyl) amide
  • Example 26a The compound described under Example 26a) was prepared from 19b) and methyl 4-iodobenzoate analogously to Example 19c).
  • Example 26b The racemic mixture obtained in Example 26b was separated by preparative chiral HPLC (column Chiralpak AD 250 ⁇ 10 mm) into the enantiomers 26c and 26d.
  • Example 27 rac-2- ⁇ hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-phenyl)] - propionic acid ⁇ (3,4-dichlorophenyl) amide
  • the compound described under example 27a) was prepared analogously to the process described under example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and 3,4-dichloroaniline.
  • Example 27b The compound described under Example 27b) was prepared from 27a) analogously to Example 1 b).
  • 1 H NMR ppm, CDCl 3 , 400 MHz: 0.90-0.94 (1H), 1.02-1.13 (3H), 2.49 (1H), 2.65 (1H), 3.06 (1H), 7.05 (1H ), 7.32-7.43 (8H), 7.67 (1H), 7.77 (1H), 8.52 (1H).
  • Example 27b The racemic mixture obtained in Example 27b was purified by preparative chiral
  • Example 28 rac- ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3- (1-piperidenyl) propynyl)] - propionic acid ⁇ (4-cyano-3 trifluoromethylphenyl) amide
  • Example 29 Rac- ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3- (4-methyl-1-piperazinyl) propyne)] - propionic acid ⁇ (4 cyano-3-trifluoromethylphenyl) amide
  • Example 29 The compound described in Example 29 was prepared from rac - ⁇ 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3-bromopropinyl)] - propionic acid ⁇ (4-cyano-3 - trifluoromethylphenyl) amide (see Example 28a) and 1-methylpiperazine prepared in analogy to Example 28b).
  • Example 30 Rac- ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3- (4-carboxy-piperidin-1-yl) -propynyl)] -propionic acid ⁇ (4-cyano-3-trifluoromethylphenyl) amide
  • Example 30a The compound described in Example 30a was prepared from rac - ⁇ 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3-bromopropinyl)] - propionic acid ⁇ (4-cyano-3 -trifluoromethylphenyl) amide and piperidine-4-carboxylate in analogy to Example 28b).
  • Example 30b The compound described under Example 30b) was prepared from 30a) analogously to Example 26b).
  • Example 31 rac-2- ⁇ hydroxy-3- [1- (2-fluoro-5-trifluoromethyl-phenyl) -cyclopropyl] -2-phenyl-ethynyl) -propionic acid ⁇ (5-indanyl) -amide
  • Example 31 a The compound described in Example 31 a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and 5-aminoindan.
  • Example 31 b) The compound described in Example 31 b) was prepared from 31a) analogously to Example 1 b).
  • Example 32 rac-2- ⁇ hydroxy-3- [1- (2-fluoro-5-trifluoromethyl-phenyl) -cyclopropyl] -2-phenyl-ethynyl) -propionic acid ⁇ (3,4-dimethyl-phenyl) -amide
  • Example 32a The compound described under Example 32a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and 3,4-dimethylaniline.
  • 1 H NMR (ppm, CDCl 3 , 300 MHz): 0.99 (4H), 2.23 (3H), 2.25 (3H), 3.32 (2H), 7.06-7.11 (2H), 7.31 (1H), 7.36 (1H ), 7.48 (1H), 7.73 (1H), 8.53 (1H).
  • Example 32b The compound described under Example 32b) was prepared from 32a) analogously to Example 1 b).
  • Example 33 rac-2- ⁇ hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenyl-ethynyl) -propionic acid ⁇ (6-quinonyl-linyl) -amide
  • Example 33a The compound described in Example 33a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and 6-aminoquinoline.
  • Example 33b The compound described under Example 33b) was prepared from 33a) analogously to Example 1 b).
  • Example 34 rac- ⁇ 2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3-amino-propynyl)] - propionic acid ⁇ (4-cyano-3-trifluoromethylphenyl) amide

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Abstract

The present invention relates to nonsteroidal progesterone receptor modulators of the general formula (I), to the use of the progesterone receptor modulators for the preparation of medicaments, and to pharmaceutical compositions which comprise these compounds. The compounds according to the invention are suitable for the therapy and prophylaxis of gynecological diseases such as endometriosis, uterus leiomyomas, dysfunctional bleeding and dysmenorrhea and for the therapy and prophylaxis of hormone-dependent tumors and for use for female contraception and for hormone replacement therapy.

Description

Nichtsteroidale Progesteronrezeptor-Modulatoren Nonsteroidal progesterone receptor modulators

Die vorliegende Erfindung betrifft nichtsteroidale Progesteronrezeptor-Modulatoren, ein Verfahren zu deren Herstellung, die Verwendung der Progesteronrezeptor-Modulatoren zur Herstellung von Arzneimitteln sowie pharmazeutische Zusammensetzungen, die diese Verbindungen enthalten.The present invention relates to nonsteroidal progesterone receptor modulators, a process for their preparation, the use of the progesterone receptor modulators for the production of medicaments, and pharmaceutical compositions containing these compounds.

Das Steroidhormon Progesteron reguliert in entscheidender Weise das Fortpflanzungsgeschehen im weiblichen Organismus. Progesteron wird während des Zyklus und in der Gravidität in großen Mengen vom Ovar bzw. der Plazenta sezerniert. Im Zusammenwirken mit Estrogenen bewirkt Progesteron zyklische Veränderungen der Uterusschleimhaut (Endometrium) im Menstruationszyklus. Unter dem Einfluss erhöhter Progesteronspiegel nach der Ovulation wird die Uterusschleimhaut in einen Zustand überführt, der die Einnistung eines Embryos (Blastozyste) zulässt. In der Gravidität kontrolliert Progesteron die Ruhigstellung des Myometriums und erhält die Funktion des dezidualen Gewebes.The steroid hormone progesterone regulates decisively the reproductive process in the female organism. Progesterone is secreted by the ovary or placenta in large quantities during the cycle and during pregnancy. In conjunction with estrogens, progesterone causes cyclic changes of the uterine lining (endometrium) in the menstrual cycle. Under the influence of increased progesterone levels after ovulation, the uterine mucosa is transferred to a state that allows the implantation of an embryo (blastocyst). In pregnancy, progesterone controls the immobilization of the myometrium and maintains the function of the decidual tissue.

Es ist weiterhin bekannt, dass Progesteron durch die Unterdrückung der estrogen- vermittelten Mitose im Uterusgewebe die endometriale Proliferation hemmt (K. Chwalisz, R.M. Brenner, U. Fuhrmann, H. Hess-Stumpp, W. Elger, Steroids 65, 2000, 741-751 ).It is furthermore known that progesterone inhibits endometrial proliferation by suppression of estrogen-mediated mitosis in the uterine tissue (K. Chwalisz, RM Brenner, U. Fuhrmann, H. Hess-Stumpp, W. Elger, Steroids 65, 2000, 741- 751).

Eine bedeutende Rolle des Progesterons und der Progesteronrezeptoren ist auch in pathophysiologischen Prozessen bekannt. Progesteronrezeptoren sind in Endometrioseherden, aber auch in Tumoren des Uterus, der Mamma und des ZNS nachgewiesen. Weiterhin ist bekannt, dass Leiomyome des Uterus Progesteron- abhängig wachsen.An important role of progesterone and progesterone receptors is also known in pathophysiological processes. Progesterone receptors are detected in endometriosis, but also in tumors of the uterus, the breast and the CNS. Furthermore, it is known that leiomyomas of the uterus grow progesterone dependent.

Die Wirkungen von Progesteron in den Geweben der Genitalorgane und in anderen Geweben erfolgen durch Interaktionen mit Progesteronrezeptoren, die für die zellulären Effekte verantwortlich sind.The effects of progesterone in the tissues of the genital organs and in other tissues are through interactions with progesterone receptors responsible for the cellular effects.

Progesteronrezeptor-Modulatoren sind entweder reine Agonisten oder hemmen die Wirkung von Progesteron teilweise oder vollständig. Dementsprechend werden Substanzen als reine Agonisten, Partialagonisten (SelektiveProgesterone receptor modulators are either pure agonists or partially or completely inhibit the action of progesterone. Accordingly, become Substances as pure agonists, partial agonists (Selective

Progesteronrezeptorrnodulatoren = SPRM) und reine Antagonisten definiert.Progesterone receptor modulators = SPRM) and pure antagonists.

Entsprechend der Fähigkeit von Progesteronrezeptor-Modulatoren, ihre Wirkung über den Progesteronrezeptor zu entfalten, besitzen diese Verbindungen ein beträchtliches Potential als Therapeutika für gynäkologische und onkologfsche Indikationen sowie für die Geburtshilfe und die Fertilitätskontrolle.According to the ability of progesterone receptor modulators to exert their action via the progesterone receptor, these compounds have considerable potential as therapeutic agents for gynecological and oncologic indications as well as for obstetrics and fertility control.

Reine Progesteronrezeptor-Antagonisten hemmen die Wirkung von Progesteron am Progesteronrezeptor komplett. Sie haben antiovulatorische Eigenschaften sowie die Fähigkeit, Estrogeneffekte im Endometrium bis zur völligen Atrophie zu hemmen. Sie sind daher besonders geeignet, in den Reproduktionsprozess der Frau einzugreifen, z. B. postovulatorisch, um die Nidation einer befruchteten Eizelle zu verhindern, in der Gravidität, um die Reaktionsbereitschaft des Uterus für Prostaglandine oder Oxytocin zu erhöhen oder um eine Eröffnung und Erweichung („Reifung") der Cervix zu erreichen sowie um eine hohe Wehenbereitschaft des Myometriums auszulösen. In Endometrioseherden bzw. in Tumorgeweben, welche mit Progesteronrezeptoren ausgestattet sind, erwartet man nach Applikation von reinen Progesteronrezeptor- Antagonisten eine günstige Beeinflussung des Krankheitsgeschehens. Besondere Vorteile für die Beeinflussung von Krankheitszuständen wie Endometriose oder Leiomyome des Uterus könnten dann gegeben sein, wenn durch die Progesteronrezeptor-Antagonisten zusätzlich eine Hemmung der Ovulation erreicht werden kann. Mit der Hemmung der Ovulation entfällt auch ein Teil der ovariellen Hormonproduktion und damit der auf diesen Anteil entfallenden Stimulationseffekt auf das pathologisch veränderte Gewebe.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 estrogen effects in the endometrium to complete atrophy. They are therefore particularly suitable to intervene in the reproductive process of the woman, for. Postovulatory, in order to prevent the nidation of a fertilized egg, in pregnancy, to increase the reactivity of the uterus for prostaglandins or oxytocin or to achieve opening and softening ("maturation") of the cervix, as well as a high labor readiness of the myometrium In endometrial or tumor tissues, which are equipped with progesterone receptors, one expects after application of pure progesterone receptor antagonists a favorable influence on the disease process.Present advantages for influencing disease states such as endometriosis or leiomyomas of the uterus could be given if by The inhibition of ovulation also eliminates part of the ovarian hormone production and thus the stimulating effect on the pathologically altered tissue that is attributable to this proportion.

Dem ersten beschriebenen Progesteronrezeptor-Antagonisten, RU 486 (auch Mifepristone) folgte die Synthese und Charakterisierung einer großen Zahl Analoga mit variierender Stärke der Progesteronrezeptor-antagonistischen Aktivität. Während RU 486 neben der Progesteronrezeptor-antagonistischen Wirkung auch eine antiglukokortikoide Wirkung zeigt, zeichnen sich später synthetisierte Verbindungen vor allem durch eine selektivere Wirkung als Progesteronrezeptor-Antagonisten aus.The first described progesterone receptor antagonist, RU 486 (also called mifepristone), was followed by the synthesis and characterization of a large number of analogs with varying levels of progesterone receptor antagonist activity. While RU 486 also shows an antiglucocorticoid effect in addition to the progesterone receptor antagonistic effect, later synthesized compounds are characterized in particular by a more selective action as progesterone receptor antagonists.

Aus der Literatur sind neben steroidalen Verbindungen wie Onapriston oder Lilopriston, die sich gegenüber RU 486 durch eine bessere Wirkungsdissoziation vonIn addition to steroidal compounds such as onapristone or lilopristone, which are distinguished from RU 486 by a better dissociation of activity from the literature

Progesteronrezeptor-antagonistischer zu antiglukokortikoider Wirkung auszeichnen, auch verschiedene nicht-steroidale Strukturen bekannt, deren antagonistische Wirkung am Progesteronrezeptor untersucht wird [siehe z.B. S. A. Leonhardt und D. P. Edwards, Exp. Biol. Med. 227: 969-980 (2002) und R. Winneker, A. Fensome, J. E. Wrobel, Z. Zhang, P. Zhang, Seminars in Reproductive Medicine, Volume 23: 46-57 (2005)]. Bisher bekannte nicht-steroidale Verbindungen besitzen jedoch nur mäßige antagonistische Aktivität verglichen mit der Aktivität bekannter steroidaler Strukturen. Die wirksamsten nicht-steroidalen Verbindungen werden mit in vitro Aktivitäten von 10 % der Aktivität von RU 486 beschrieben.Progesterone receptor antagonistic to antiglucocorticoid effect, Also known are various non-steroidal structures whose antagonistic activity is investigated on the progesterone receptor [see, for example, SA Leonhardt and DP Edwards, Exp. Biol. Med. 227: 969-980 (2002) and R. Winneker, A. Fensome, JE Wrobel, Z. Zhang, P. Zhang, Seminars in Reproductive Medicine, Volume 23: 46-57 (2005)]. However, previously known non-steroidal compounds have only modest antagonistic activity compared to the activity of known steroidal structures. The most potent non-steroidal compounds are described with in vitro activities of 10% of the activity of RU 486.

Die antiglukokortikoide Aktivität ist nachteilig für eine therapeutische Anwendung, bei der die Hemmung der Progesteronrezeptoren im Vordergrund der Therapie steht. Eine antiglukokortikoide Wirksamkeit verursacht unerwünschte Nebenwirkungen bei den therapeutisch erforderlichen Dosierungen. Dies kann die Applikation einer therapeutisch sinnvollen Dosis verhindern oder zum Abbruch der Behandlung führen. Die teilweise oder vollständige Reduktion der antiglukokortikoiden Eigenschaften ist deshalb eine wichtige Voraussetzung für die Therapie mit Progesteronrezeptor- Antagonisten, insbesondere für diejenigen Indikationen, die eine über Wochen oder Monate andauernde Behandlung erfordern.Antiglucocorticoid activity is detrimental to a therapeutic application in which inhibition of progesterone receptors is at the forefront of therapy. Antiglucocorticoid activity causes undesirable side effects at the therapeutically required dosages. This may prevent the application of a therapeutically useful dose or lead to discontinuation of treatment. The partial or complete reduction of the anti-glucocorticoid properties is therefore an important prerequisite for the treatment with progesterone receptor antagonists, in particular for those indications which require treatment lasting over weeks or months.

Im Gegensatz zu den reinen Antagonisten zeigen Progesteronrezeptor-Partialagonisten (SPRMs) eine residuelle agonistische Eigenschaft, welche unterschiedlich stark ausgeprägt sein kann. Dies führt dazu, dass diese Substanzen in bestimmten Organsystemen agonistische Wirkungen am Progesteronrezeptor zeigen (D. DeManno, W. Elger, R. Garg, R. Lee, b. Schneider, H. Hess-Stumpp, G. Schuber, K. Chwalisz, Steroids 68, 2003, 1019-1032). Eine solche organspezifische und dissoziierte Wirkung kann für die beschriebenen Indikationen von therapeutischem Nutzen sein.In contrast to the pure antagonists, progesterone receptor partial agonists (SPRMs) show a residual agonistic property, which can be of varying severity. As a result, these substances exhibit agonistic effects on the progesterone receptor in certain organ systems (D. DeManno, W. Elger, R. Garg, R. Lee, B. Schneider, H. Hess-Stumpp, G. Schuber, K. Chwalisz, Steroids 68, 2003, 1019-1032). Such organ specific and dissociated effect may be of therapeutic use for the described indications.

Aufgabe vorliegender Erfindung ist es daher, weitere nichtsteroidale Progesteron- rezeptor-Modulatoren zur Verfügung zu stellen. Diese Verbindungen sollen eine reduzierte antiglukokortikoide Wirkung besitzen und daher geeignet sein für dieThe object of the present invention is therefore to provide further nonsteroidal progesterone receptor modulators. These compounds are said to have a reduced anti-glucocorticoid effect and therefore be suitable for the

Therapie und Prophylaxe von gynäkologischen Erkrankungen wie Endometriose,Therapy and prophylaxis of gynecological diseases such as endometriosis,

Leiomyomen des Uterus, dysfunktionelle Blutungen und der Dysmenorrhoe. Außerdem sollen die erfindungsgemäßen Verbindungen geeignet sein für die Therapie und Prophylaxe von hormonabhängigen Tumoren, beispielsweise von Mamma-,Leiomyomas of the uterus, 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,

Endometriums-, Ovar- sowie Prostatakarzinomen. Die Verbindungen sollen weiterhin geeignet sein für die Verwendung in der weiblichen Fertilitätskontrolle als auch für die weibliche Hormonersatztherapie.Endometrial, ovarian and prostate cancers. The connections should continue be suitable for use in female fertility control as well as for female hormone replacement therapy.

Die Aufgabe wird gemäß vorliegender Erfindung durch die Bereitstellung nichtsteroidaler Verbindungen der allgemeinen Formel I gelöstThe object is achieved according to the present invention by the provision of non-steroidal compounds of general formula I.

worin

Figure imgf000005_0001
wherein
Figure imgf000005_0001

R1 und R2 unabhängig voneinander ein Wasserstoffatom, eine verzweigte oder unverzweigte CrC5- Alkylgruppe, ferner gemeinsam mit dem C-Atom der Kette einen Ring mit insgesamt 3-7 Gliedern bildend, R3 ein Rest C≡C-Ra, wobei Ra ein Wasserstoff oder ein gegebenenfalls ein- oder mehrfach, gleich oder verschieden mit K substituiertes C1- C8-AIkVl, C2-C8-Alkenyl, C2-C8-Al kiny I, C3-C10-Cycloalkyl, 3-8-gliedriges Heterocycloalkyl oder ein gegebenenfalls ein- oder mehrfach, gleich oder verschieden mit L substituiertes C6-Ci2-Aryl oder 3-8-gliedriges Heteroaryl oder Silicium bedeutet,R 1 and R 2 are independently a hydrogen atom, a branched or unbranched -C 5 - alkyl group, further forming a ring together with the C-atom of the chain with a total of 3-7 members, R 3 is a radical C≡CR a, wherein R a a hydrogen or an optionally mono- or polysubstituted, identically or differently, with K C 1 - C 8 -alkyl, C 2 -C 8 alkenyl, C 2 -C 8 -alkyl kiny I, C 3 -C 10 cycloalkyl, 3-8 membered heterocycloalkyl or optionally substituted one or more times, identically or differently, with L C 6 -C 2 signifies aryl or 3-8-membered heteroaryl or silicon,

K ein Cyano, Halogen, Hydroxy, Nitro, Azido, - C(O)Rb, CO2Rb, -O-Rb, -OSiRbRcRd -S-Rb, SO2NRcRd, -C(O)-NRcRd, -OC(O)-NRcRd, -C=NORb -NRcRd oder ein gegebenenfalls ein- oder mehrfach, gleich oder verschieden mit M substituiertes C3-Ci0-Cycloalkyl, 3-8-gliedriges Heterocycloalkyl oder gegebenenfalls ein- oder mehrfach, gleich oder verschieden mit L substituiertes C6-Ci2-Aryl oder 3-8-gliedrigesK is cyano, halogen, hydroxy, nitro, azido, - C (O) R b , CO 2 R b , -OR b , -OSiR b R c R d -SR b , SO 2 NR c R d , -C ( O) -NR c R d, -OC (O) -NR c R d, -C = NOR b -NR c R d, or an optionally mono- or polysubstituted, identically or differently, with M C 0 -C 3 cycloalkyl , 3-8 membered heterocycloalkyl or optionally substituted one or more times, identically or differently, with L-substituted C 6 -C 2 aryl or 3-8-membered

Heteroaryl ist, L d-Cβ-Alkyl, C2-C8-Alkenyl, C2-C8-Alkinyl, Ci-C6-Heteroaryl is, L d -Cβ-alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, Ci-C 6 -

Perfluoralkyl, d-C6-Perfluoralkoxy, Ci-C6-Alkoxy- Ci-Ce-alkoxy, (CH2)P-C3-Ci0-Cycloalkyl, (CH2)P- Heterocycloalkyl, (CH2)PCN, (CH2)pHal, (CH2)PNO2,Perfluoroalkyl, dC 6 perfluoroalkoxy, Ci-C 6 alkoxy Ci-Ce-alkoxy, (CH 2) P -C 3 -C 0 cycloalkyl, (CH 2) P - heterocycloalkyl, (CH 2) p CN, ( CH 2 ) p Hal, (CH 2 ) P NO 2 ,

5 (CH2)p-C6-Ci2-Aryl, (CH2)P-Heteroaryl,5 (CH 2 ) pC 6 -Ci 2 -aryl, (CH 2 ) p -heteroaryl,

-(CH2)pPO3(Rb)2,- (CH 2 ) p PO 3 (R b ) 2 ,

-(CH2)PNRcRd, -(CH2)pNRΘCORb, -(CH2)pNRΘCSRb, -(CH2)pNRΘS(O)Rb, -(CH2)pNRΘS(O)2Rb, -(CH2)PNR6CONR0R0,- (CH 2 ) P NR c R d , - (CH 2 ) p NR Θ COR b , - (CH 2 ) p NR Θ CSR b , - (CH 2 ) p NR Θ S (O) R b , - ( CH 2 ) p NR Θ S (O) 2 R b , - (CH 2 ) P NR 6 CONR 0 R 0 ,

10 -(CH2)pNRΘCOORb, -(CH2)pNRΘC(NH)NRcRd,10 - (CH 2 ) p NR Θ COOR b , - (CH 2 ) p NR Θ C (NH) NR c R d ,

-(CH2)pNRΘCSNRcRd, -(CH2)pNRΘS(O)NRcRd, -(CH2)pNRΘS(O)2NRcRd, -(CH2)pCORb, -(CH2)pCSRb, -(CH2)pS(O)Rb, -(CH2)pS(O)(NH)Rb, -(CH2)pS(O)2Rb,- (CH 2 ) p NR Θ CSNR c R d , - (CH 2 ) p NR Θ S (O) NR c R d , - (CH 2 ) p NR Θ 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 ,

15 -(CH2)pS(O)2NRcRd, -(CH2)pSO2ORb,15 - (CH 2 ) p S (O) 2 NR c R d , - (CH 2 ) p SO 2 OR b ,

-(CH2)pCO2Rb, -(CH2)pCONRcRd, -(CH2)pCSNRcRd, -(CH2)pORb, -(CH2)pOCORb, -(CH2)pSRb, -(CH2)pCRb(OH)-RΘ, -(CH2)P- C=NORb,- (CH 2 ) p CO 2 R b , - (CH 2 ) p CONR c R d , - (CH 2 ) p CSNR c R d , - (CH 2 ) p OR b , - (CH 2 ) p OCOR b , - (CH 2 ) p SR b , - (CH 2 ) p CR b (OH) -R Θ , - (CH 2 ) P - C = NOR b ,

20 -O-(CH2)n-O-, -O-(CH2)n-CH2-, -0-CH=CH- oder -(CH2)n+2-, wobei n=1 oder 2 ist und die endständigen Sauerstoffatome und/ oder Kohlenstoffatome mit direkt benachbarten Ringkohlenstoffatomen verknüpft sind,20 is -O- (CH 2 ) n -O-, -O- (CH 2 ) n -CH 2 -, -O-CH = CH- or - (CH 2 ) n + 2 -, where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms are linked to directly adjacent ring carbon atoms,

25 M d-Cβ-Alkyl oder eine Gruppe -CORb, CO2Rb,25 M d-Cβ-alkyl or a group -COR b , CO 2 R b ,

-O-Rb oder -NRcRd bedeutet, wobei-OR b or -NR c R d , where

Rb ein Wasserstoff oder eine Ci-C6-Alkyl,R b is a hydrogen or a C 1 -C 6 -alkyl,

C2-C8-Alkenyl, C2-C8-Alkinyl, C3-C10-C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 10 -

30 Cycloalkyl, C6-C12-Aryl oder C1-C3-30 cycloalkyl, C 6 -C 12 -aryl or C 1 -C 3 -

Perfluoralkyl undPerfluoroalkyl and

Rc und Rd unabhängig voneinander ein Wasserstoff, d-Ce-Alkyl, C2-C8-Alkenyl, C2- C8-Al kinyl, C3-d0-Cycloalkyl, C6-Ci2-R c and R d independently represent a hydrogen, d-Ce-alkyl, C 2 -C 8 alkenyl, C 2 - C 8 -alkyl kinyl, C 3 -d 0 cycloalkyl, C 6 -C 2 -

35 Aryl, C(O)Rb oder eine Hydroxygruppe bedeuten, wobei wenn Rc eine Hydroxygruppe ist, Rd nur ein35 aryl, C (O) R b or a hydroxy group, where if R c is a hydroxy group, R d is only one

Wasserstoff, ein Ci-C6-Alkyl, C2-C8- Alkenyl, C2-C8-Alkinyl, C3-Ci0- Cycloalkyl oder C6-Ci2-Aryl sein kann und umgekehrt sowieHydrogen, a Ci-C 6 alkyl, C 2 -C 8 - alkenyl, C 2 -C 8 alkynyl, C 3 -C 0 - cycloalkyl or C 6 -C 2 aryl may be, and vice versa, and

RΘ ein Wasserstoff, Ci-Ce-Alkyl, C2-C8-R Θ is a hydrogen, C 1 -C 6 -alkyl, C 2 -C 8 -

Alkenyl, C2-C8-Alkinyl, C3-Ci0-CyCIo- alkyl oder C6-Ci2-Aryl bedeutet und p eine Zahl von 0- 6 sein kann,Alkenyl, C 2 -C 8 alkynyl, C 3 -C 0 -CyCIo- alkyl or C 6 -C 2 represents aryl, and p can be a number from 0- 6,

oder R3 ein Rest C=C-R9Rh, wobeior R 3 is a radical C = CR 9 R h , where

R9 und Rh unabhängig voneinander ein Wasserstoff oder ein gegebenenfalls ein- oder mehrfach, gleich oder verschieden mit X substituiertes Ci-C8-Alkyl, C2-C8- Alkenyl oder C2-C8-Alkinyl ist, worin X ein Cyano, Halogen, Hydroxy, Nitro, -C(O)Rb, CO2Rb, -O-Rb, -C(O)-NRcRd, -NRcRdmit den bereits weiter oben genannten Bedeutungen für Rb, Rc und Rd ist undR 9 and R h independently of one another a hydrogen or an optionally mono- or polysubstituted, identically or differently, with X-substituted C 8 alkyl, C 2 -C 8 - alkenyl or C 2 -C 8 alkynyl, where X is a Cyano, halogen, hydroxy, nitro, -C (O) R b , CO 2 R b , -OR b , -C (O) -NR c R d , -NR c R d with the meanings given above for R b , R c and R d is and

R4 ein unsubstituierter oder gegebenenfalls mit 1-3 Resten substituierter 3-8-gliedriger aromatischer oder heteroaromatischer Mono- oder Bicyclus sein kann oder eine der folgenden Gruppen:R 4 may be an unsubstituted or optionally substituted with 1-3 radicals 3-8-membered aromatic or heteroaromatic mono- or bicyclic or one of the following groups:

A: 6-Ring/6-Ring-Systeme:A: 6-ring / 6-ring systems:

Figure imgf000007_0001
Figure imgf000007_0001

Verknüpfung an Position 5,6,7 oder 8 B: 6-Ring/5-Ring-Systeme:Link at positions 5, 6, 7 or 8 B: 6-ring / 5-ring systems:

Figure imgf000008_0001
Figure imgf000008_0001

Verknüpfung an Position 4,5,6 oder 7Link at position 4,5,6 or 7

Wasserstoff oder C1-C4 Alkyl, oder C1-C4 Perfluoralkyl sein kannMay be hydrogen or C 1 -C 4 alkyl, or C 1 -C 4 perfluoroalkyl

Rba und R' 6b unabhängig voneinander ein Wasserstoffatom, eine C1-C4-AIkYl, eine C2-C4-Alkenyl oder gemeinsam mit dem Ringkohlenstoffatom einen 3- 6-gliedrigen Ring bildend,R ba and R '6b independently of one another form a hydrogen atom, a C 1 -C 4 -alkyl, a C 2 -C 4 -alkenyl or together with the ring carbon atom form a 3-membered 6-membered ring,

ein mono- oder bicyclischer carbocyclischer oder heterocyclischer aromatischer Ring, der gegebenenfalls ein oder mehrfach substituiert sein kann mit CrC8-Alkyl, C2-C8-Alkenyl, C2-C8-Alkinyl, Ci-C6- Perfluoralkyl, Ci-C6-Perfluoralkoxy, Ci-C6-Alkoxy-Ci-C6-alkyl, Ci-C6- Alkoxy-Ci-Ce-alkoxy, (CH2)p-C3-Cio-Cycloalkyl, (CH2)P-a mono- or bicyclic carbocyclic or heterocyclic aromatic ring, which may optionally be mono or polysubstituted by C r C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, 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 ) pC 3 -cio-cycloalkyl, (CH 2 ) P -

Heterocycloalkyl, (CH2)PCN, (CH2)pHal, (CH2)PNO2, (CH2)P-C6-Ci2-Aryl, (CH2)P-Heteroaryl,Heterocycloalkyl, (CH 2) p CN, (CH 2) p Hal, (CH 2) p NO 2, (CH 2) P -C 6 -C 2 aryl, (CH 2) P -heteroaryl,

-(CH2)pPO3(Rb)2, -(CH2)pNRcRd, -(CH2)pNRΘCORb, -(CH2)pNRΘCSRb, -(CH2)pNRΘS(O)Rb, -(CH2)pNRΘS(O)2Rb, -(CH2)PNR6CONR0R0,- (CH 2 ) p PO 3 (R b ) 2 , - (CH 2 ) p NR c R d , - (CH 2 ) p NR Θ COR b , - (CH 2 ) p NR Θ CSR b , - (CH 2 ) p NR Θ S (O) R b , - (CH 2 ) p NR Θ S (O) 2 R b , - (CH 2 ) P NR 6 CONR 0 R 0 ,

-(CH2)PNRΘCOORD, -(CH2)pNRΘC(NH)NRcRα, -(CH2)PNR6CSNR0R0, -(CH2)PNRΘS(O)NRcRd, -(CH2)PNReS(O)2NRcRd, -(CH2)PCORb, -(CH2)pCSRb, -(CH2)p S(O)Rb, -(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)p-C=NORb, -O-(CH2)n-O-, -O-(CH2)n-CH2-, -0-CH=CH- oder -(CH2)n+2-, wobei n=1 oder 2 ist und die endständigen Sauerstoffatome und/oder Kohlenstoffatome mit direkt benachbarten Ringkohlenstoffatomen verknüpft sind oder- (CH 2 ) P NR Θ COOR D , - (CH 2 ) p NR Θ C (NH) NR c R α , - (CH 2 ) P NR 6 CSNR 0 R 0 , - (CH 2 ) P NR Θ S (O) NR c R d , - (CH 2 ) P NR e S (O) 2 NR c R d , - (CH 2 ) P COR b , - (CH 2 ) p CSR b , - (CH 2 ) p S (O) R b , - (CH 2 ) p S (O) (NH) R b , - (CH 2 ) p S (O) 2 R b , - (CH 2 ) p S (O) 2 NR c R d , - (CH 2 ) p SO 2 OR b , - (CH 2 ) p CO 2 R b , - (CH 2 ) p CONR c R d , - (CH 2 ) p CSNR c R d , - (CH 2 ) p OR b , - (CH 2 ) p SR b , - (CH 2 ) p CR b (OH) -R d , - (CH 2 ) p -C = NOR b , -O- (CH 2 ) n -O-, -O- (CH 2 ) n -CH 2 -, -O-CH = CH- or - (CH 2 ) n + 2 -, where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms are linked to directly adjacent ring carbon atoms or

A ein Rest -CO2Rb, C(O)NRcRd, CORb,A is a radical -CO 2 R b , C (O) NR c R d , COR b ,

oderor

A eine Alkenylgruppe -CR =CR R , wobeiA is an alkenyl group -CR = CR R, where

R , R und R gleich oder verschieden sind und unabhängig voneinander Wasserstoffatome, Halogenatome, Arylreste oder eine unsubstituierte oder teilweise oder vollständig fluorierte C^C^Alkylgruppe bedeuten oderR, R and R are the same or different and independently of one another represent hydrogen atoms, halogen atoms, aryl radicals or an unsubstituted or partially or completely fluorinated C 1 -C 4 -alkyl group, or

A eine Alkinylgruppe -C≡CR , mit der für R oben angeführtenA is an alkynyl group -C≡CR, with the above R listed

Bedeutung undMeaning and

B eine Carbonyl- oder eine CH2-GruppeB is a carbonyl or a CH 2 group

bedeuten sowie ihre pharmazeutisch annehmbaren Salze.and their pharmaceutically acceptable salts.

Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) können durch das Vorhandensein von Asymmetriezentren als unterschiedliche Stereoisomere vorliegen. Sowohl die Racemate als auch die getrennt vorliegenden Stereoisomere gehören zum Gegenstand der vorliegenden Erfindung.The compounds of the general formula (I) according to the invention can be present as different stereoisomers due to the presence of asymmetric centers. Both the racemates and the separately present stereoisomers are the subject of the present invention.

Weiterhin umfasst die vorliegende Erfindung die neuen Verbindungen als pharmazeutische Wirkstoffe, deren Herstellung, ihre therapeutische Anwendung und pharma- zeutische Darreichungsformen, die die neuen Substanzen enthalten. Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) oder deren pharmazeutisch annehmbare Salze können für die Herstellung eines Arzneimittels, insbesondere zur Behandlung und Prophylaxe von gynäkologischen Erkrankungen wie Endometriose, Leiomyomen des Uterus, dysfunktionelle Blutungen und der Dysmenorrhoe verwendet werden. Weiterhin können die erfindungsgemäßen Verbindungen für die Behandlung und Prophylaxe von hormonabhängigen Tumoren wie beispielsweise für Mamma-, Prostata- und Endometriumskarzinom verwendet werden.Furthermore, the present invention comprises the novel compounds as pharmaceutical active ingredients, their preparation, their therapeutic application and pharmaceutical dosage forms containing the new substances. The compounds of the general formula (I) or their pharmaceutically acceptable salts according to the invention can be used for the preparation of a medicament, in particular for the treatment and prophylaxis of gynecological diseases such as endometriosis, uterine leiomyomas, dysfunctional bleeding and dysmenorrhea. Furthermore, the compounds according to the invention can be used for the treatment and prophylaxis of hormone-dependent tumors such as, for example, breast, prostate and endometrial carcinoma.

Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) oder deren pharma- zeutisch annehmbare Salze sind geeignet zur Verwendung für die weibliche Fertilitäts- kontrolle oder für die weibliche Hormonersatztherapie.The compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts are suitable for use in female fertility control or in female hormone replacement therapy.

Die erfindungsgemäßen nichtsteroidalen Verbindungen der allgemeinen Formel I wirken stark antagonistisch oder partialagonistisch am Progesteronrezeptor. Sie weisen eine starke Wirkungsdissoziation hinsichtlich ihrer Bindungsstärke am Progesteron- und am Glukokortikoidrezeptor auf. Während bekannte Progesteronrezeptor-Antagonisten wie Mifepristone (RU 486) neben der erwünschten hohen Bindungsaffinität zum Progesteronrezeptor gleichfalls eine hohe Affinität zum Glukokortikoidrezeptor zeigen, zeichnen sich die erfindungsgemäßen Verbindungen durch eine sehr geringe Glukokortikoidrezeptorbindung bei gleichzeitig vorhandener hoher Progesteronrezeptoraffinität aus.The nonsteroidal compounds of the general formula I according to the invention have a strong antagonistic or partial agonistic action on the progesterone receptor. They show a strong dissociation of activity with regard to their binding strength at the progesterone and glucocorticoid receptors. While known progesterone receptor antagonists such as mifepristone (RU 486) in addition to the desired high binding affinity for progesterone receptor also show a high affinity for glucocorticoid receptor, the compounds of the invention are characterized by a very low glucocorticoid receptor binding at the same time present high progesterone receptor affinity.

Die als Gruppen definierten Substituenten der erfindungsgemäßen Verbindungen der allgemeinen Formel I können jeweils die nachfolgenden Bedeutungen haben:The substituents of the compounds of the general formula I defined as groups may each have the following meanings:

Unter CrC5-, CrC6- bzw. CrC8-Alkylgruppe werden gerade oder ungerade, verzweigte oder unverzweigte Alkylreste verstanden. Dabei handelt es sich beispielsweise um eine Methyl-, Ethyl-, n-Propyl-, iso-Propyl-, n-, iso-, tert.-Butyl-, eine n-Pentyl-, 2,2- Dimethylpropyl- 3-Methylbutyl-, Hexyl-, Heptyl oder Octylgruppe. Im Sinne von Ra sind dabei die Methyl-, Ethyl-, n-Propyl- oder n-Butylgruppe sowie eine n-Pentylgruppe bevorzugt.By CrC 5 -, CrC 6 - or CrC 8 alkyl group are meant straight or odd, branched or unbranched alkyl radicals. These are, for example, a methyl, ethyl, n-propyl, iso-propyl, n, iso, tert-butyl, n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl -, hexyl, heptyl or octyl group. In the context of R a , the methyl, ethyl, n-propyl or n-butyl group and an n-pentyl group are preferred.

Im Sinne von R1 und R2 sind Methyl oder Ethyl bevorzugt. Erfindungsgemäß wird für R4a und R4b ein Wasserstoff bevorzugt.For the purposes of R 1 and R 2 , methyl or ethyl are preferred. According to the invention for R4 R4 a and b is preferably a hydrogen.

Unter Alkenyl werden verzweigte oder unverzweigte Alkenylreste verstanden. Im Sinne der Erfindung werden unter C2-Cβ-Alkenylgruppe beispielsweise folgende verstanden: Vinyl, AIIyI, 3-Buten-1-yl- oder 2,3-Dimethyl-2-propenyl. Ist der Aromat A mit einem C2- Cβ-Alkenylrest substituiert, handelt es sich vorzugsweise um eine Vinylgruppe.Alkenyl is understood to mean branched or unbranched alkenyl radicals. For the purposes of the invention, C 2 -C 6 -alkenyl group is understood to mean, for example, the following: Vinyl, allyl, 3-buten-1-yl or 2,3-dimethyl-2-propenyl. If the aromatic A is substituted by a C 2 -C 6 -alkenyl radical, it is preferably a vinyl group.

Unter Alkinyl werden verzweigte oder unverzweigte Alkinylreste verstanden. Für einen C2-C8-Alkinylrest soll beispielsweise eine Ethinyl-, Propinyl-, Butinyl-, Pentinyl-, Hexinyl- sowie Octinylgruppe, vorzugsweise jedoch eine Ethinyl- oder Propinylgruppe stehen.Alkynyl is understood as meaning branched or unbranched alkynyl radicals. A C 2 -C 8 -alkynyl radical should be, for example, an ethynyl, propynyl, butynyl, pentynyl, hexynyl and octynyl group, but preferably an ethynyl or propynyl group.

Unter 3-10-gliedrigen Cycloalkyl bzw. Heterocyckloalkyl werden sowohl monocyclische als auch bicyclische Reste verstanden.By 3-10-membered cycloalkyl or heterocycloalkyl is meant both monocyclic and bicyclic radicals.

Für monocyclische C3-C10-Cycloalkyl im Sinne von R3, K, L, Rb, Rc, Rd, R4, R6a sowie R6b seien beispielsweise Cyclopropan, Cyclobutan, Cyclopentan und Cyclohexan genannt. Cyclopropyl, Cyclopentyl und Cyclohexyl sind bevorzugt.For monocyclic C 3 -C 10 -cycloalkyl in the sense of R 3 , K, L, R b , R c , R d , R 4 , R 6a and R 6b , mention may be made, for example, of cyclopropane, cyclobutane, cyclopentane and cyclohexane. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.

Unter Heterocycloalkyl im Sinne von Ra, K bzw. L sind 3-8-gliedrige monocyclische Heterocycloalkylreste zu verstehen. Beispiele für Heterocycloalkyl sind Morpholin, Tetrahydrofuran, Pyran, Piperazin, Piperidin, Pyrrolidin, Oxiran, Oxetan, Aziridin, Dioxolan und Dioxan, wobei alle beliebigen, chemisch sinnvollen Isomeren bezüglich der Positionen der Heteroatome verwendet werden können.Heterocycloalkyl in the sense of R a , K or L is to be understood as meaning 3-8-membered monocyclic heterocycloalkyl radicals. Examples of heterocycloalkyl are morpholine, tetrahydrofuran, pyran, piperazine, piperidine, pyrrolidine, oxirane, oxetane, aziridine, dioxolane and dioxane, it being possible to use any chemically meaningful isomers with respect to the positions of the heteroatoms.

Für Ci-C6-Alkoxyl-CrC6-alkoxygruppe kann beispielsweise Methoxymethoxy, Ethoxymethoxy oder 2-Methoxyethoxy stehen.For example, methoxymethoxy, ethoxymethoxy or 2-methoxyethoxy may be C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy.

Bei einem Rest ORb handelt es sich im Sinne der Erfindung um eine Hydroxy-, Methoxy-, Ethoxy-, n-Propoxy-, iso-Propoxy-, n-, iso- , tert.-Butoxy - oder n-Pentoxy-, 2,2-Dimethylpropoxy- oder 3-Methylbutoxygruppe. Hydroxy, Methoxy und Ethoxy sind bevorzugt.A radical OR b in the context of the invention is a hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n, iso, tert-butoxy or n-pentoxy radical, 2,2-dimethylpropoxy or 3-methylbutoxy group. Hydroxy, methoxy and ethoxy are preferred.

Für eine teilweise oder vollständig fluorierte C-pCs-Alkylgruppe kommen die perfluorierten oben stehenden Alkylgruppen in Betracht. Von diesen sind vor allem die Trifluormethyl- oder die Pentafluorethylgruppe sowie als teilweise fluorierte Alkylgruppen beispielsweise die 5,5,4,4-Pentafluorpentyl- oder 5,5,5,4,4,3,3-Heptafluor- pentylgruppe bevorzugt.For a partially or completely fluorinated C-pCs-alkyl group, the perfluorinated above-mentioned alkyl groups come into consideration. Of these, especially the trifluoromethyl or pentafluoroethyl group and, for example, the 5,5,4,4-pentafluoropentyl or 5,5,5,4,4,3,3-heptafluoropentyl group are preferred as partially fluorinated alkyl groups.

Von den CrC3- bzw. CrC6-Perfluoralkylgruppen kommen ebenfalls vor allem Trifluormethyl- oder die Pentafluorethylgruppe in Betracht. Von den C1-C3- bzw. Ci-C6-Perfluoralkoxygruppen sind der Trifluormethoxy- oder Pentafluorethoxyrest bevorzugt.Of the CrC 3 - or CrC 6 Perfluoralkylgruppen are also especially trifluoromethyl or the pentafluoroethyl group into consideration. Of the C 1 -C 3 or C 1 -C 6 perfluoroalkoxy groups, preference is given to the trifluoromethoxy or pentafluoroethoxy radical.

Für ein Halogenatom kann ein Fluor-, Chlor-, Brom- oder lodatom stehen. Bevorzugt ist hier Fluor, Chlor oder Brom.A halogen atom may be a fluorine, chlorine, bromine or iodine atom. Preference is given here to fluorine, chlorine or bromine.

Wenn R1 und R2 gemeinsam mit dem C-Atom der Kette einen 3-7 gliedrigen Ring bilden, so ist dies beispielsweise ein Cyclopropyl-, -butyl-, -pentyl- oder -hexylring. Der Cyclopropyl-, sowie der Cyclopentylring sind bevorzugt.When 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, butyl, pentyl or hexyl ring. The cyclopropyl as well as the cyclopentyl ring are preferred.

Der mono- oder bicyclische carbocyclische aromatische Ring A, der mehrfach substituiert sein kann, ist ein carbocyclischer oder heterocyclischer Arylrest.The mono- or bicyclic carbocyclic aromatic ring A which may be multiply substituted is a carbocyclic or heterocyclic aryl group.

Im ersten Fall handelt es sich beispielsweise um einen Phenyl- oder Naphthylrest, vorzugsweise um einen Phenylrest.In the first case, it is for example a phenyl or naphthyl radical, preferably a phenyl radical.

Als heterocyclischer Rest kann beispielsweise ein monocyclischer heterocyclischer Rest, beispielsweise der Thienyl-, Furyl-, Pyranyl-, Pyrrolyl-, Imidazolyl-, Pyrazolyl-, Pyridyl-, Pyrazinyl-, Pyrimidinyl-, Pyridazinyl-, Thiazolyl-, Oxazolyl-, Furazanyl-, Pyrrolinyl-, Imidazolinyl-, Pyrazolinyl-, Thiazolinyl-, Triazolyl-, Tetrazolylrest, und zwar alle möglichen Isomeren bezüglich der Positionen der Heteroatome verwendet werden.As a heterocyclic radical, for example, a monocyclic heterocyclic radical, for example the thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl , Pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl, all possible isomers with respect to the positions of the heteroatoms are used.

Im Sinne von R3 handelt es sich bei einem C6-Ci2-Arylrest um einen gegebenenfalls substituierten Phenyl-, 1- oder 2-Naphthylrest, wobei der Phenylrest bevorzugt ist. Beispiele für einen Heteroarylrest sind der 2-, 3- oder 4-Pyridinyl-, der 2- oder 3-Furyl, der 2- oder 3-Thienyl, der 2- oder 3-Pyrrolyl-, der 2-, 4- oder 5-lmidazolyl-, der Pyrazinyl-, der 2-, 4- oder 5-Pyrimidinyl- oder 3- oder 4-Pyridazinylrest.In the meaning of R 3 are in a C 6 -C 2 aryl to an optionally substituted phenyl, 1- or 2-naphthyl, wherein the phenyl radical is preferred. Examples of a heteroaryl radical are 2-, 3- or 4-pyridinyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 2-, 4- or 5 -imidazolyl, the pyrazinyl, 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl.

Die Zahl p für (CH2)P-Rest kann eine ganze Zahl von 0 bis 6, bevorzugt 0, 1 oder 2 sein. Unter „Rest" werden erfindungsgemäß sämtliche funktionellen Gruppen, die in Verbindung mit (CH2)P unter L und A aufgeführt werden, verstanden.The number p for (CH 2 ) P radical may be an integer from 0 to 6, preferably 0, 1 or 2. By "radical" is meant according to the invention all functional groups which are listed in connection with (CH 2 ) P under L and A.

Im Falle, dass die Verbindungen der allgemeinen Formel I (B = -CH2-) als Salze vorliegen, kann dies beispielsweise in der Form des Hydrochlorids, Sulfats, Nitrats, Tartrats, Citrats, Fumarats, Succinats oder Benzoats sein. Wenn die erfindungsgemäßen Verbindungen als racemische Gemische vorliegen, können sie nach dem Fachmann geläufigen Methoden der Racemattrennung in die reinen, optisch aktiven Formen aufgetrennt werden. Beispielsweise lassen sich die racemischen Gemische durch Chromatographie an einem selbst optisch aktiven Trägermaterial (CHIRALPAK AD®) in die reinen Isomere trennen. Es ist auch möglich, die freie Hydroxygruppe in einer racemischen Verbindung der allgemeinen Formel I mit einer optisch aktiven Säure zu verestern und die erhaltenen diastereoisomeren Ester durch fraktionierte Kristallisation oder chromatographisch zu trennen und die getrennten Ester jeweils zu den optisch reinen Isomeren zu verseifen. Als optisch aktive Säure kann beispielsweise Mandelsäure, Camphersulfonsäure oder Weinsäure verwendet werden.In the case where the compounds of the general formula I (B = -CH 2 -) are present as salts, this may be, for example, in the form of the hydrochloride, sulfate, nitrate, tartrate, citrate, fumarate, succinate or benzoate. If the compounds according to the invention are present as racemic mixtures, they can be separated into the pure optically active forms by methods of racemate resolution which are familiar to the person skilled in the art. For example, the racemic mixtures can be separated into the pure isomers by chromatography on an even optically active carrier material (CHIRALPAK AD ®). It is also possible to esterify the free hydroxy group in a racemic compound of the general formula I with an optically active acid and to separate the resulting diastereoisomeric esters by fractional crystallization or chromatography and to saponify the separated esters respectively to the optically pure isomers. As the optically active acid, for example, mandelic acid, camphorsulfonic acid or tartaric acid can be used.

Bevorzugt gemäß vorliegender Erfindung sind Verbindungen der allgemeinen Formel (I), in denen:Preferred according to the present invention are compounds of the general formula (I) in which:

R1 und R2 jeweils unabhängig voneinander ein Wasserstoffatom, ein Methyl- oder ein Ethylrest sind oder gemeinsam mit dem C-Atom der Kette einen Ring mit insgesamt 3-7 Gliedern bilden. Besonders bevorzugt sind Verbindungen, in denen R1 und R2 gleichzeitig ein Wasserstoffatom, ein Methyl- oder Cyclopropylrest, besonders bevorzugt ein Methyl- oder Cyclopropylrest sind.R 1 and R 2 are each independently a hydrogen atom, a methyl or an ethyl radical, or together with the C atom of the chain form a ring having a total of 3-7 members. Particular preference is given to compounds in which R 1 and R 2 are simultaneously a hydrogen atom, a methyl or cyclopropyl radical, particularly preferably a methyl or cyclopropyl radical.

Bevorzugt sind weiterhin Verbindungen, in denen R3 ein Alkinylrest der Formel C≡C-Ra ist, wobei Ra ein gegebenenfalls mit K substituierter C1-C4-A^yI-, C3-C10-Cycloalkyl-, 3- 8-gliedriger Heterocycloalkylrest oder gegebenenfalls ein mit L substituierter C6-C12- Aryl- oder 3-8-gliedriger Heteroarylrest ist, undAlso preferred are compounds in which R 3 is an alkynyl group of formula C≡CR a, wherein R a optionally substituted with C 1 -C 4 K -A ^ YI, C 3 -C 10 cycloalkyl, 3- 8 is a heterocycloalkyl radical or optionally an L-substituted C 6 -C 12 aryl or 3-8-membered heteroaryl radical, and

K ein Cyano, Halogen, Hydroxy, -O-Rb, SO2NRcRd, -C(O)-NRcRd, -NRcRd oder ein gegebenenfalls ein- oder mehrfach, gleich oder verschieden mit M substituierter 3-8- gliedriger Heterocycloalkyl- oder ein gegebenenfalls mehrfach mit L substituierter Aryl- oder Heteroarylrest ist, und L ein C1-C4-A^yI-, Ci-C4-Perfluoralkyl-, (CH2)p-C3-C10-Cycloalkyl-, (CH2)P-Heterocyclo- alkylrest, (CH2)PCN, (CH2)pHal, (CH2)PNO2, (CH2)P-C6-C12-Aryl, (CH2)P-Heteroaryl, -(CH2)pNRcRd, oder -(CH2)pNRΘS(O)2Rb, -(CH2)pS(O)2NRcRd, -(CH2)pCONRcRd, -(CH2)pORb, -(CH2)pOCORb, -(CH2)pCRb(OH)-RΘ, -(CH2)pCO2Rb, und M ein CrC4-Alkylrest oder eine Gruppe -CO2Rb, -O-Rb oder -NRcRd bedeutet, wobei Rb ein Wasserstoff oder eine CrC6-Alkyl, C3-C10-Cycloalkyl, C6-C12-Aryl oder C1-C3- Perfluoralkyl und Rc und Rd unabhängig voneinander ein Wasserstoffatom, eine Ci-C6-Alkyl-, C3-Ci0- Cycloalkyl-, C6-Ci2-Aryl-, C(O)Rb- oder eine Hydroxygruppe bedeuten, wobei wenn Rc eine Hydroxygruppe ist, Rd nur ein Wasserstoff, ein d-C6-Alkyl, C2-C8-Alkenyl, C2-C8- Alkinyl, C3-Ciθ-Cycloalkyl oder C6-Ci2-Aryl sein kann und umgekehrt sowie RΘ ein Wasserstoff, Ci-C6-Alkyl, oder C6-Ci2-Aryl bedeutet und p eine Zahl 0, 1 , 2 oder 3 sein kann.K is a cyano, halogen, hydroxy, -OR b , SO 2 NR c R d , -C (O) -NR c R d , -NR c R d or a 3 optionally substituted one or more times, identically or differently with M -8- is a heterocycloalkyl or an optionally multiply L-substituted aryl or heteroaryl radical, and L is a C 1 -C 4 -A ^ yI, Ci-C 4 perfluoroalkyl, (CH 2 ) p-C3-C 10 -cycloalkyl, (CH 2 ) p -Heterocyclo- alkyl radical, (CH 2 ) p CN, (CH 2 ) p Hal, (CH 2 ) P NO 2 , (CH 2 ) P -C 6 -C 12 aryl , (CH 2 ) p -heteroaryl, - (CH 2 ) p NR c R d , or - (CH 2 ) p NR Θ S (O) 2 R b , - (CH 2 ) p S (O) 2 NR c R d , - (CH 2 ) p CONR c R d , - (CH 2 ) p OR b , - (CH 2 ) p OCOR b , - (CH 2 ) p CR b (OH) -R Θ , - (CH 2 ) p CO 2 R b , and M is a C r C 4 -alkyl radical or a group -CO 2 R b , -OR b or -NR c R d , where R b is a hydrogen or a C 1 -C 6 -alkyl, C C 3 -C 10 -cycloalkyl, C 6 -C 12 -aryl or C 1 -C 3 -perfluoroalkyl and Mean or a hydroxy group, wherein - R c and R d independently represent a hydrogen atom, a Ci-C 6 alkyl, C 3 -C 0 - cycloalkyl, C 6 -C 2 aryl, C (O) R b when R c is a hydroxy group, R d only a hydrogen, a dC 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 - alkynyl, C 3 -C θ -cycloalkyl or C 6 -C 2 aryl may be and vice versa and R Θ is a hydrogen, Ci-C 6 alkyl, or C 6 -C 2 -aryl and p may be a number 0, 1, 2 or 3.

Besonders bevorzugt sind Verbindungen, in denenParticularly preferred are compounds in which

Ra ein gegebenenfalls mit K substituierter d-C4-Alkylrest oder ein gegebenenfalls mit L substituierter Phenyl- oder Hetarylrest ist, wobei L bevorzugt ein Methyl-, Trifluormethyl- , Methoxy-, Acetoxy, Hydroxy-, Carboxyl- oder Carboxyalkylrest ist.R a is an optionally substituted with K dC 4 alkyl or optionally substituted with L phenyl or hetaryl, wherein L is preferably a methyl, trifluoromethyl, methoxy, acetoxy, hydroxy, carboxyl or carboxyalkyl.

Bevorzugt sind außerdem Verbindungen, in denenAlso preferred are compounds in which

R4 ein Phenylring, besonders bevorzugt ein mit 1-3 Resten substituierter Phenylring ist. Bevorzugte Substituenten am Phenylring sind Nitro, Trifluormethyl, Pentafluorethyl, Cyano, Chlor, Fluor, Methyl.R 4 is a phenyl ring, more preferably a 1-3-substituted phenyl ring. Preferred substituents on the phenyl ring are nitro, trifluoromethyl, pentafluoroethyl, cyano, chlorine, fluorine, methyl.

Ebenfalls bevorzugt sind Verbindungen, in denen R4 eine der folgenden Gruppen ist:Also preferred are compounds in which R 4 is one of the following groups:

A: 6-Ring/6-Ring-Systeme:A: 6-ring / 6-ring systems:

Figure imgf000014_0001
oder
Figure imgf000014_0001
or

B: 6-Ring/5-Ring-Systeme:B: 6-ring / 5-ring systems:

Figure imgf000014_0002
mit den für R sowie R und R bereits genannten Bedeutungen. A ist bevorzugt mit folgenden Resten substituiert: Ci-Cβ-Alkyl, Ci-Cβ-Perfluoralkyl, d- Ce-Perfluoralkoxy, Ci-C6-Alkoxy-Ci-C6-alkyl, Ci-C6-Alkoxy-Ci-C6-alkoxy, (CH2)p-C3-do- Cycloalkyl, (CH2)P-Heterocycloalkyl, (CH2)PCN, (CH2)pHal, (CH2)PNO2, (CH2)P-C6-Ci2- Aryl, (CH2)P-Heteroaryl, -(CH2)pNRcRd, -(CH2)pNRΘCORb, -(CH2)pNRΘS(O)2Rb, - (CH2)pNRΘCONRcRd, -(CH2)PNR6S(O)2NR0R0, -(CH2)pCORb, -(CH2)pCSRb, -(CH2)pS(O)(NH)Rb, -(CH2)pS(O)2Rb, -(CH2)pS(O)2NRcRd, -(CH2)pCO2Rb, (CH2)pCONRcRd, -(CH2)pORb, -(CH2)pSRb, -(CH2)pCRb(OH)-Rd, -(CH2)p-C=NORb, -O- (CH2)n-O-, -O-(CH2)n-CH2-, -0-CH=CH- oder -(CH2)n+2-, wobei n=1 oder 2 ist und die endständigen Sauerstoffatome und/oder Kohlenstoff atome mit direkt benachbarten Ringkohlenstoffatomen verknüpft sind.
Figure imgf000014_0002
with the meanings already given for R and R and R. A is preferably substituted by the following radicals: C 1 -C 6 -alkyl, C 1 -C 6 -perfluoroalkyl, C 1 -C 6 -fluoroalkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 6 -alkoxy, (CH 2 ) p -C 3 -do-cycloalkyl, (CH 2 ) p -heterocycloalkyl, (CH 2 ) p CN, (CH 2 ) p Hal, (CH 2 ) p NO 2 , (CH 2 ) P -C 6 -Ci 2 - aryl, (CH 2 ) p -heteroaryl, - (CH 2 ) p NR c R d , - (CH 2 ) p NR Θ COR b , - (CH 2 ) p NR Θ S (O) 2 R b , - (CH 2 ) p NR Θ CONR c R d , - (CH 2 ) P NR 6 S (O) 2 NR 0 R 0 , - (CH 2 ) p COR b , - (CH 2 ) p CSR 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 CO 2 R b , (CH 2 ) p CONR c R d , - (CH 2 ) p OR b , - (CH 2 ) p SR b , - (CH 2 ) p CR b ( OH) -R d , - (CH 2 ) p -C = NOR b , -O- (CH 2 ) n -O-, -O- (CH 2 ) n-CH 2 -, -O-CH = CH- or - (CH 2 ) n + 2 -, where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms are linked to directly adjacent ring carbon atoms.

Besonders bevorzugt sind Verbindungen, worin A mit C1-C4-Alkyl, d-C2-Perfluoralkyl, d-Cz-Perfluoralkoxy, (CH2)PCN, (CH2)pHal, -(CH2)pNRcRd, -(CH2)pS(O)(NH)Rb, -(CH2)pS(O)2Rb, -(CH2)pS(O)2NRcRd, -(CH2)pORb oder -(CH2)pSRb substituiert ist und p sowie Rb, Rc und Rd die bereits genannten Bedeutungen haben.Particularly preferred are compounds wherein A is C 1 -C 4 alkyl, dC 2 perfluoroalkyl, d-Cz-perfluoroalkoxy, (CH 2) p CN, (CH 2) p Hal, - (CH 2) p NR c R d , - (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 OR b or - (CH 2 ) p SR b is substituted and p and R b , R c and R d have the meanings already mentioned.

Ganz besonders bevorzugt sind Verbindungen, worin A entweder ein unsubstituierter Phenylring oder ein ein- oder zweifach, gleich oder verschieden mit Fluor, Chlor, Brom, Methyl, Trifluormethyl oder Methoxy substituierter Phenylring ist.Very particular preference is given to compounds in which A is either an unsubstituted phenyl ring or a phenyl ring which is monosubstituted or disubstituted by identical or different fluorine, chlorine, bromine, methyl, trifluoromethyl or methoxy.

Weiterhin bevorzugt sind Verbindungen, worin B eine Carbonylgruppe oder eine Gruppe -CH2- ist.Further preferred are compounds wherein B is a carbonyl group or a group -CH 2 -.

Ebenso sind Verbindungen bevorzugt, worin p 0 oder 1 ist. Also preferred are compounds wherein p is 0 or 1.

Die nachstehend genannten Verbindungen sowie deren Verwendung sind erfindungsgemäß bevorzugt:

Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
The compounds mentioned below and their use are preferred according to the invention:
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001

Figure imgf000020_0001
Figure imgf000020_0001

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Biologische Charakterisierung der erfindungsgemäßen VerbindungenBiological characterization of the compounds of the invention

Die Identifizierung von Progesteronrezeptor-Modulatoren kann mit Hilfe einfacher Methoden, dem Fachmann bekannten Testprogrammen vorgenommen werden. Dazu kann beispielsweise eine zu testende Verbindung zusammen mit einem Gestagen in einem Testsystem für Progesteronrezeptorliganden inkubiert werden und geprüft werden, ob in diesem Testsystem die durch Progesteron vermittelte Wirkung in Anwesenheit des Modulatoren verändert wird.The identification of progesterone receptor modulators can be carried out with the aid of simple methods, test programs known to the person skilled in the art. For this purpose, for example, a compound to be tested can be incubated together with a gestagen in a test system for progesterone receptor ligands and it can be tested whether the action mediated by progesterone is changed in the presence of the modulator in this test system.

Die erfindungsgemäßen Substanzen der allgemeinen Formel I wurden in folgenden Modellen getestet:The substances of the general formula I according to the invention were tested in the following models:

ProgesteronrezeptorbindungstestProgesterone Receptor Binding Assay

Messung der Rezeptor-Bindungsaffinität:Measurement of receptor binding affinity:

Die Rezeptorbindungsaffinität wurde bestimmt durch kompetitive Bindung eines spezifisch bindenden 3H-markierten Hormons (Tracer) und der zu testenden Verbindung an Rezeptoren im Cytosol aus tierischen Target-Organen. Dabei wurden Rezeptorsättigung und Reaktionsgleichgewicht angestrebt.Receptor binding affinity was determined by competitive binding of a specific binding 3 H-labeled hormone (tracer) and the compound to be tested to receptors in the cytosol from animal target organs. The aim was receptor saturation and reaction equilibrium.

Der Tracer und steigende Konzentrationen der zu testenden Verbindung (Competitor) wurden bei 0-40C über 18 h co-inkubiert mit der rezeptorhaltigen Cytosolfraktion. Nach Abtrennung des ungebundenen Tracers mit Kohle-Dextran-Suspension wurde für jede Konzentration der Rezeptor-gebundene Tracer-Anteil gemessen und aus der Konzentrationsreihe die IC50 bestimmt. Als Quotient der IC50-Werte von Referenzsubstanz und zu testender Verbindung (x 100%) wurde die relative molare Bindungsaffinität (RBA) errechnet (RBA der Referenzsubstanz = 100%).The tracer and increasing concentrations of the compound to be tested (Competitor) were co-incubated at 0-4 0 C for 18 h with the receptor-containing cytosol fraction. After separation of the unbound tracer with carbon-dextran suspension, the receptor-bound fraction of tracer was measured for each concentration and the IC 50 was determined from the concentration series. The quotient of the IC 50 values of the reference substance and the compound to be tested (x 100%) was calculated as the relative molar binding affinity (RBA) (RBA of the reference substance = 100%).

Für die Rezeptortypen wurden folgende Inkubationsbedingungen gewählt:The following incubation conditions were selected for the receptor types:

Progesteronrezeptor:Progesterone receptor:

Uterus-Cytosol des Estradiol-geprimten Kaninchens, homogenisiert in TED-Puffer (20 mMTris/HCI, pH 7,4; 1 mM Ethylendiamintetraacetat, 2 mM Dithiothreitol) mit 250 mM Saccharose; aufbewahrt bei -30 0C. Tracer: 3H-ORG 2058, 5 nM; Referenzsubstanz: Progesteron.Uterine cytosol of the estradiol-primed rabbit homogenized in TED buffer (20 mM Tris / HCl, pH 7.4, 1 mM ethylenediaminetetraacetate, 2 mM dithiothreitol) with 250 mM sucrose; stored at -30 0 C. Tracer: 3 H-ORG 2058, 5 nM; Reference substance: progesterone.

Glukokortikoidrezeptor: Thymus-Cytosol der adrenalectomierten Ratte, Thymi aufbewahrt bei -300C; Puffer: TED. Tracer: 3H-Dexamethason, 20 nM; Referenzsubstanz: Dexamethason. Die Kompetitionsfaktoren (KF-Werte) der erfindungsgemäßen Verbindungen der allgemeinen Formel (I) am Progesteronrezeptor liegen zwischen 0.2 und 35 bezogen auf Progesteron. Am Glukokortikoidrezeptor liegen die KF-Werte im Bereich von 3 bis 35 bezogen auf Dexamethason.Glucocorticoid receptor: thymus cytosol of the adrenalectomierten rat, thymi stored at -30 0 C; Buffer: TED. Tracer: 3 H-Dexamethasone, 20 nM; Reference substance: dexamethasone. The competition factors (KF values) of the compounds of general formula (I) according to the invention on the progesterone receptor are between 0.2 and 35 with respect to progesterone. At the glucocorticoid receptor, KF values are in the range of 3 to 35 based on dexamethasone.

Die erfindungsgemäßen Verbindungen haben demnach eine hohe Affinität zum Progesteronrezeptor, aber nur eine geringe Affinität zum Glukokortikoidrezeptor.Accordingly, the compounds according to the invention have a high affinity for the progesterone receptor but only a low affinity for the glucocorticoid receptor.

Antagonismus am Progesteronrezeptor PRAntagonism at progesterone receptor PR

Der Transaktivierungsassay wird wie in WO 02/054064 beschrieben durchgeführt. Die IC50-Werte liegen im Bereich von 0.1 bis 150 nM.The transactivation assay is carried out as described in WO 02/054064. The IC 50 values are in the range of 0.1 to 150 nM.

Agonismus am Progesteronrezeptor PRAgonism at progesterone receptor PR

Der Transaktivierungsassay wird wie in Fuhrmann et al. beschrieben durchgeführt (Fuhrmann U., Hess-Stump H., Cleve A., Neef G., Schwede W., Hoffmann J., Fritzemeier K.-H., Chwalisz K., Journal of Medicinal Chemistry, 43, 26, 2000, 5010- 5016). Die EC50-Werte liegen im Bereich von 0.01 bis 150 nM.The transactivation assay is carried out as 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 Chemistry, 43, 26, 2000 , 5010-5016). The EC 50 values are in the range from 0.01 to 150 nM.

Dosierungdosage

Zur erfindungsgemäßen Verwendung können die Progesteronrezeptor-Modulatoren oral, enteral, parenteral oder transdermal verabreicht werden. Im Allgemeinen sind zufriedenstellende Resultate bei der Behandlung der weiter oben genannten Indikationen zu erwarten, wenn die täglichen Dosen einen Bereich von 1 μg bis 1000 mg der erfindungsgemäßen Verbindung für gynäkologische Indikationen wie Behandlung von Endometriose, Leiomyome des Uterus und dysfunktionelle Blutungen sowie für die Verwendung in der Fertilitätskontrolle und für die Hormonersatztherapie umfassen. Für onkologische Indikationen sind tägliche Dosierungen im Bereich von 1 μg bis 2000 mg der erfindungsgemäßen Verbindung zu verabreichen.For use according to the invention, the progesterone receptor modulators can be administered orally, enterally, parenterally or transdermally. In general, satisfactory results in the treatment of the above-mentioned indications are to be expected if the daily doses range from 1 μg to 1000 mg of the compound of the invention for gynecological indications such as treatment of endometriosis, uterine leiomyomas and dysfunctional bleeding and for use in fertility control and hormone replacement therapy. For oncological indications, daily dosages ranging from 1 μg to 2000 mg of the compound of the invention are to be administered.

Geeignete Dosierungen der erfindungsgemäßen Verbindungen am Menschen für dieSuitable dosages of the compounds of the invention in humans for

Behandlung der Endometriose, von Leiomyomen des Uterus und dysfunktionellen Blutungen sowie für die Verwendung in der Fertilitätskontrolle sowie für dieTreatment of endometriosis, uterine leiomyomas and dysfunctional haemorrhage as well as for use in fertility control as well as for the

Hormonersatztherapie betragen 50 μg bis 500 mg pro Tag, je nach Alter und Konstitution des Patienten, wobei die notwendige Tagesdosis durch Einmal- oder Mehrfachabgabe appliziert werden kann.Hormone replacement therapy is 50 μg to 500 mg per day, depending on the age and Constitution of the patient, whereby the necessary daily dose can be administered by single or multiple delivery.

Für die Behandlung von Mammakarzinomen umfasst der Dosierungsbereich für die erfindungsgemäßen Verbindungen täglich 10 mg bis 2000 mg.For the treatment of breast cancer, the dosage range for the compounds of the invention comprises 10 mg to 2000 mg daily.

Die Formulierung der pharmazeutischen Präparate auf Basis der neuen Verbindungen erfolgt in an sich bekannter Weise, indem man den Wirkstoff mit den in der Galenik gebräuchlichen Trägersubstanzen, Füllstoffen, Zerfallsbeeinflussern, Bindemitteln, Feuchthaltemitteln, Gleitmitteln, Absorptionsmitteln, Verdünnungsmitteln, Geschmackskorrigentien, Färbemitteln usw. verarbeitet und in die gewünschteThe formulation of the pharmaceutical preparations based on the new compounds is carried out in a conventional manner, by processing the active ingredient with the commonly used in galenics carriers, fillers, Zerfallbeeinflussern, binders, humectants, lubricants, absorbents, diluents, flavoring agents, colorants, etc., and in the desired

Applikationsform überführt. Dabei ist auf Remington's Pharmaceutical Science, 15tn ed. Mack Publishing Company, East Pennsylvania (1980) hinzuweisen.Transferred application form. It is made to Remington's Pharmaceutical Science, 15 tn ed. Mack Publishing Company, pointing East Pennsylvania (1980).

Für die orale Applikation kommen insbesondere Tabletten, Filmtabletten, Dragees, Kapseln, Pillen, Pulver, Granulate, Pastillen, Suspensionen, Emulsionen oder Lösungen in Frage.For oral administration in particular tablets, film-coated tablets, dragees, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions come into question.

Für die parenterale Applikation sind Injektion- und Infusionszubereitungen möglich.For parenteral administration, injection and infusion preparations are possible.

Für die intraartikuläre Injektion können entsprechend zubereitete Kristallsuspensionen verwendet werden.For intraarticular injection, appropriately prepared crystal suspensions may be used.

Für die intramuskuläre Injektion können wässrige und ölige Injektionslösungen oder Suspensionen und entsprechende Depotpräparationen Verwendung finden.For intramuscular injection, aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.

Für die rektale Applikation können die neuen Verbindungen in Form von Suppositorien, Kapseln, Lösungen (z.B. in Form von Klysmen) und Salben sowohl zur systemischen als auch zur lokalen Therapie verwendet werden. Weiterhin seien als Zubereitung auch Mittel zur vaginalen Anwendung genannt.For rectal administration, the new compounds may be used in the form of suppositories, capsules, solutions (e.g., in the form of enemas) and ointments for both systemic and local therapy. Furthermore, may be mentioned as a preparation and agents for vaginal use.

Zur pulmonalen Applikation der neuen Verbindungen können diese in Form von Aerosolen und Inhalaten verwendet werden.For pulmonary administration of the new compounds, these can be used in the form of aerosols and inhalants.

Für die transdermale Applikation sind Pflaster bzw. für die topische Auftragung Formulierungen in Gelen, Salben, Fettsalben, Cremes, Pasten, Puder, Milch und Tinkturen möglich. Die Dosierung der Verbindungen der allgemeinen Formel I sollte in diesen Zubereitungen 0,01% - 20% betragen, um eine ausreichende pharmakologische Wirkung zu erzielen.For transdermal application are patch or for topical application formulations in gels, ointments, greases, creams, pastes, powders, milk and Tinctures possible. The dosage of the compounds of the general formula I should be 0.01% -20% in these preparations in order to achieve a sufficient pharmacological effect.

Entsprechende Tabletten können beispielsweise durch Mischen des Wirkstoffs mit bekannten Hilfsstoffen, beispielsweise inerten Verdünnungsmitteln wie Dextrose, Zucker, Sorbit, Mannit, Polyvinylpyrrolidon, Sprengmitteln wie Maisstärke oder Algin- säure, Bindemitteln wie Stärke oder Gelatine, Gleitmitteln wie Magnesiumstearat oder Talk und/oder Mitteln zur Erzielung eines Depoteffektes wie Carboxylpolymethylen, Carboxylmethylcellulose, Celluloseacetatphthalat oder Polyvinylacetat erhalten werden. Die Tabletten können auch aus mehreren Schichten bestehen.Corresponding tablets can be prepared, for example, by mixing the active compound with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or Achieve a depot effect such as carboxyl polymethylene, carboxyl methyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.

Entsprechend können Dragees durch Überziehen von analog den Tabletten hergestellten Kernen mit üblicherweise in Drageeüberzügen verwendeten Mitteln, beispielsweise Polyvinylpyrrolidon oder Schellack, Gummiarabicum, Talk, Titanoxid oder Zucker, hergestellt werden. Dabei kann auch die Drageehülle aus mehreren Schichten bestehen, wobei die oben bei den Tabletten erwähnten Hilfsstoffe verwendet werden können.Coated tablets can accordingly be prepared by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. In this case, the dragee wrapper can also consist of several layers, wherein the auxiliaries mentioned above in the case of the tablets can be used.

Lösungen oder Suspensionen der erfindungsgemäßen Verbindungen der allgemeinen Formel I können zusätzlich geschmacksverbessernde Mittel wie Saccharin, Cyclamat oder Zucker sowie z. B. Aromastoffe wie Vanillin oder Orangenextrakt enthalten. Sie können außerdem Suspendierhilfsstoffe wie Natriumcarboxymethylcellulose oder Konservierungsstoffe wie p-Hydroxybenzoate enthalten.Solutions or suspensions of the compounds of general formula I according to the invention may additionally taste-improving agents such as saccharin, cyclamate or sugar and z. B. flavorings such as vanillin or orange extract. They may also contain suspending aids such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.

Die Verbindungen der allgemeinen Formel I enthaltenden Kapseln können beispielsweise hergestellt werden, indem man die Verbindung(en) der allgemeinen Formel I mit einem inerten Träger wie Milchzucker oder Sorbit mischt und in Gelatinekapseln einkapselt.The capsules containing the compounds of the general formula I can be prepared, for example, by mixing the compound (s) of the general formula I with an inert carrier such as lactose or sorbitol and encapsulating it in gelatine capsules.

Geeignete Suppositorien lassen sich beispielsweise durch Vermischen mit dafür vorgesehenen Trägermitteln wie Neutralfetten oder Polyethylenglykol bzw. deren Derivaten herstellen. Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) oder deren pharmazeutisch annehmbare Salze können aufgrund ihrer antagonistischen oder partialagonistischen Wirksamkeit für die Herstellung eines Arzneimittels, insbesondere zur Behandlung und Prophylaxe von gynäkologischen Erkrankungen wie Endometriose, Leiomyomen des Uterus, dysfunktionelle Blutungen und der Dysmenorrhoe verwendet werden. Weiterhin können sie gegen hormonelle Unregelmäßigkeiten, zur Menstruationsauslösung und allein oder in Kombination mit Prostaglandinen und/ oder Oxytocin zur Geburtseinleitung eingesetzt werden.Suitable suppositories can be prepared, for example, by mixing with suitable carriers such as neutral fats or polyethylene glycol or derivatives thereof. The compounds of the general formula (I) or their pharmaceutically acceptable salts according to the invention can, because of their antagonistic or partial agonist activity, be used for the preparation of a medicament, in particular for the treatment and prophylaxis of gynecological diseases such as endometriosis, uterine leiomyomas, dysfunctional bleeding and dysmenorrhoea. Furthermore, they can be used against hormonal irregularities, menstruation release and alone or in combination with prostaglandins and / or oxytocin to induce labor.

Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) oder deren pharmazeutisch annehmbare Salze sind weiterhin geeignet zur Herstellung von Präparaten für die Empfängnisverhütung für die Frau (siehe auch WO 93/23020, WO 93/21927). Die erfindungsgemäßen Verbindungen oder deren pharmazeutisch annehmbare Salze können außerdem allein oder in Kombination mit Estrogenen, Estrogenderivaten, estrogen wirksamen Substanzen oder mit einem Selektiven E_strogen-Rezeptor- Modulatoren (SERM) für die weibliche Hormonersatztherapie eingesetzt werden.The compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts are furthermore suitable for the preparation of preparations for contraception for women (see also WO 93/23020, WO 93/21927). The compounds according to the invention or their pharmaceutically acceptable salts can also be used alone or in combination with estrogens, estrogen derivatives, estrogen-active substances or with a Selective E estrogen receptor modulators (SERM) for female hormone replacement therapy.

Weiterhin üben die genannten Verbindungen in hormonabhängigen Tumoren eine antiproliferative Wirkung aus. Sie sind daher für die Therapie von hormonabhängigen Karzinomen geeignet, wie beispielsweise für Mamma-, Prostata- und Endometriums- karzinome.Furthermore, the compounds mentioned exert an antiproliferative effect in hormone-dependent tumors. They are therefore suitable for the therapy of hormone-dependent carcinomas, such as, for example, breast, prostate and endometrial carcinomas.

Die erfindungsgemäßen Verbindungen oder deren pharmazeutisch annehmbare Salze können für die Behandlung hormonabhängiger Karzinome sowohl in der first-line Therapie als auch in der second-line Therapie, insbesondere nach Tamoxifen-failure, zum Einsatz kommen.The compounds according to the invention or their pharmaceutically acceptable salts can be used for the treatment of hormone-dependent carcinomas both in first-line therapy and in second-line therapy, in particular after tamoxifen failure.

Die erfindungsgemäßen, antagonistisch bzw. partialagonistisch wirksamen Verbindungen der allgemeinen Formel (I) oder deren pharmazeutisch annehmbare Salze können auch in Kombination mit antiestrogen wirksamen Verbindungen (Estrogen rezeptor-Antagonisten oder Aromatasehemmer) oder Selektiven E^strogen- Rezeptor-Modulatoren (SERM) zur Herstellung pharmazeutischer Präparate zur Behandlung hormonabhängiger Tumore verwendet werden. Für die Behandlung der Endometriose oder von Leiomyomen des Uterus können die erfindungsgemäßen Verbindungen ebenfalls in Kombination mit SERM's oder einem Antiestrogen (Estrogen rezeptor-Antagonisten oder Aromatasehemmer) verwendet werden Zur Kombination mit den erfindungsgemäßen nichtsteroidalen Progesteronrezeptor- Modulatoren kommen dabei beispielsweise die folgenden Antiestrogene (Estrogen- rezeptor-Antagonisten oder Aromatasehemmer) bzw. SERM's in Betracht: Tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-Pentafluorpentyl)sulfinyl]pentyloxy}phenyl)-6- phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol (WO 00/03979), ICI 182 780 (7alpha-[9- (4,4,5,5-Pentafluorpentylsulfinyl)nonyl]estra-1 ,3,5(10)-trien-3, 17-beta-diol), 1 1 beta-According to the invention, antagonistic or partially agonistic effective compounds of general formula (I) or their pharmaceutically acceptable salts may also be used in combination with active compounds antiestrogen (estrogen receptor antagonists or aromatase inhibitors) or Selective E ^ strogen- receptor modulators (SERM) for the preparation of pharmaceutical preparations for the treatment of hormone-dependent tumors are used. For the treatment of endometriosis or uterine leiomyomas, the compounds of the invention may also be used in combination with SERM's or an antiestrogen (estrogen receptor antagonist or aromatase inhibitor) For example, the following antiestrogens (estrogen receptor antagonists or aromatase inhibitors) or SERMs are suitable for combination with the nonsteroidal progesterone receptor modulators according to the invention: tamoxifen, 5- (4- {5 - [(RS) - (4,4, 5,5,5-pentafluoropentyl) sulfinyl] pentyloxy} phenyl) -6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol (WO 00/03979), ICI 182 780 (7alpha [9- (4 , 4,5,5-pentafluoropentylsulfinyl) nonyl] estra-1, 3,5 (10) -triene-3, 17-beta-diol), 1 liter of

Fluor-7alpha-[5-(methyl{3-[(4, 4,5,5, 5-pentafluorpentyl)sulfanyl]propyl}amino)- pentyl]estra-1 ,3,5(10)-trien-3, 17beta-diol (WO98/07740), 1 1 beta-Fluor-7alpha-{5- [methyl(7,7,8,8,9,9, 10, 10, 10-nonafluordecyl)amino]pentyl}estra-1 ,3,5(10)-trien- 3,17beta-diol (WO 99/33855), 1 1 beta-Fluor-17alpha-methyl-7alpha-{5-[methyl- (8,8,9,9,9-pentafluornonyl)amino]pentyl}estra-1 ,3,5(10)-trien-3, 17beta-diol (WOFluoro-7alpha [5- (methyl {3 - [(4, 4,5,5, 5-pentafluoropentyl) sulfanyl] propyl} amino) -pentyl] estra-1, 3,5 (10) -triene-3, 17beta-diol (WO98 / 07740), 1-1 beta-fluoro-7alpha- {5- [methyl (7,7,8,8,9,9,10,10,10-nonafluorodecyl) amino] pentyl} estra-1 , 3,5 (10) -triene-3,17beta-diol (WO 99/33855), 1 l beta-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), Clomifen, Raloxifen sowie weitere antiestrogen wirksame Verbindungen, und Aromataseinhibitoren wie beispielsweise Fadrozol, Formestan, Letrozol, Anastrozol oder Atamestan.03/045972), clomiphene, raloxifene and other antiestrogenic compounds, and aromatase inhibitors such as fadrozole, formestane, letrozole, anastrozole or atamestane.

Für eine Kombination der erfindungsgemäßen Progesteronrezeptormodulatoren mit geeigneten Estrogenen, Estrogenderivaten oder estrogen wirksamen Substanzen kommen folgende in Betracht: 17ß-Estradiol, 17ß-Ethinylestradiol, Estriol, 17ß-Estradiol- 3-alkyl-sulfonate, 17ß-Ethinylestradiol-3-alkyl-sulfonate, Estradiol-3- oder 17-ester wie Estradiol-3-benzoat oder Estradiol-17-valerat, 17ß-Ethinylestradiol-3-ether wie 17ß- Ethinylestradiol-3-methylether (Mestranol) oder konjugierte equine Estrogene (CEE = Conjugated Equine Estrogens).Suitable combinations of the progesterone receptor modulators according to the invention with suitable estrogens, estrogen derivatives or estrogen-active substances are: 17β-estradiol, 17β-ethinylestradiol, estriol, 17β-estradiol-3-alkyl-sulfonates, 17β-ethinylestradiol-3-alkyl-sulfonates, Estradiol-3 or 17-esters such as estradiol-3-benzoate or estradiol-17-valerate, 17β-ethinylestradiol-3-ether such as 17β-ethinylestradiol-3-methyl ether (mestranol) or conjugated equine estrogens (CEE = conjugated equine estrogens) ,

Im Fall der Estrogen-3-alkyl-sulfonate wie 17ß-Estradiol-3-alkyl-sulfonat und 17ß- Ethinylestradiol-3-alkyl-sulfonat kommen für das Alkylsulfonat vor allem gesättigte, verzweigte oder unverzweigte Ci-C5-Alkylgruppen in Betracht, wobei für Ci-Cs-Alkyl die in den Definitionen auf Seite 9 genannten Bedeutungen gelten. Beispielhaft, ohne Beschränkung auf diese, seien hier das 17ß-Estradiol-3-isopropyl-sulfonat sowie das 17ß-Ethinylestradiol-3-propyl-sulfonat (Turisteron) genannt.In the case of estrogen-3-alkyl sulfonates such as 17β-estradiol-3-alkyl sulfonate and 17β-ethinylestradiol-3-alkyl sulfonate, saturated, branched or unbranched C 1 -C 5 -alkyl groups are particularly suitable for the alkyl sulfonate. where for Ci-Cs-alkyl the meanings given in the definitions on page 9 apply. By way of example, but not limited to, here are the 17ß-estradiol-3-isopropyl-sulfonate and the 17ß-ethinylestradiol-3-propyl-sulfonate (Turisteron) mentioned.

Schließlich betrifft die vorliegende Erfindung auch die Verwendung der Verbindungen der allgemeinen Formel I, gegebenenfalls zusammen mit einem Antiestrogen, einem Estrogen bzw. Estrogenderivat oder einer estrogen wirksamen Substanz oder einem SERM, zur Herstellung eines Arzneimittels. Ferner betrifft die vorliegende Erfindung pharmazeutische Zusammensetzungen, die mindestens eine erfindungsgemäße Verbindung, gegebenenfalls in Form eines pharmazeutisch/ pharmakologisch verträglichen Salzes.Finally, the present invention also relates to the use of the compounds of the general formula I, optionally together with an antiestrogen, an estrogen or estrogen derivative or an estrogen-active substance or a SERM, for the production of a medicament. Furthermore, the present invention relates to pharmaceutical compositions containing at least one compound of the invention, optionally in the form of a pharmaceutically / pharmacologically acceptable salt.

Diese pharmazeutischen Zusammensetzungen und Arzneimittel können zur oralen, rektalen, vaginalen, subkutanen, perkutanen, intravenösen oder intramuskulären Applikation vorgesehen sein. Sie enthalten neben üblichen Träger- und/ oder Verdünnungsmitteln mindestens eine erfindungsgemäße Verbindung.These pharmaceutical compositions and pharmaceutical compositions may be for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular administration. In addition to conventional carriers and / or diluents they contain at least one compound of the invention.

Die Arzneimittel der Erfindung werden mit den üblichen festen oder flüssigen Trägerstoffen oder Verdünnungsmitteln und den üblicherweise verwendeten pharmazeutischtechnischen Hilfsstoffen entsprechend der gewünschten Applikationsart mit einer geeigneten Dosierung in bekannter Weise hergestellt. Die bevorzugten Zubereitungen bestehen in einer Darreichungsform, die zur oralen Applikation geeignet ist. Solche Darreichungsformen sind beispielsweise Tabletten, Filmtabletten, Dragees, Kapseln, Pillen, Pulver, Lösungen oder Suspensionen, gegebenenfalls als Depotform.The pharmaceutical compositions of the invention are prepared in a known manner with the usual solid or liquid carriers or diluents and the pharmaceutical excipients customarily used according to the desired mode of administration with a suitable dosage. The preferred formulations consist of a dosage form which is suitable for oral administration. Such dosage forms are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions, optionally as depot form.

Die pharmazeutischen Zusammensetzungen, die mindestens eine der erfindungsgemäßen Verbindungen enthalten, werden bevorzugt oral appliziert.The pharmaceutical compositions containing at least one of the compounds of the invention are preferably administered orally.

Es kommen auch parenterale Zubereitungen wie Injektionslösungen in Betracht. Weiterhin seien als Zubereitungen beispielsweise auch Suppositorien und Mittel zur vaginalen Anwendung genannt. There are also parenteral preparations such as injection solutions into consideration. Further examples of preparations which may be mentioned are suppositories and vaginal administration agents.

Herstellung der erfindunqsqemäßen Verbindungen:Preparation of the compounds according to the invention:

Figure imgf000073_0001
Die Verbindungen der allgemeinen Formel I können wie in Schema 1 gezeigt synthetisiert werden. Carbonsäuren der allgemeinen Formel Il wurden z.B. in bereits beschrieben .WO 199854159, WO 200375915 und WO 9854159 beschrieben. Die Herstellung der Amide der allgemeinen Formel III erfolgt beispielsweise über die Bildung der Säurechloride und anschließende Umsetzung mit den entsprechenden Aminen. Alternativ hierzu können je nach einzuführendem Amin aber auch andere Methoden zur Amidbildung genutzt werden. Aus den Amiden der allgemeinen Formel III werden dann durch Addition von Grignard- oder Lithium-organischen Verbindungen die Verbindungen der allgemeinen Formel I hergestellt. Die Schritte 1 und 2 können aber auch in umgekehrter Reihenfolge durchgeführt werden. Die Substituenten A, R1, R2, R3 und R4 können ggf auch nach erfolgter Einführung weiter modifiziert werden. Hierfür kommen z.B. Oxidation, Reduktion, Alkylierungen, Acylierungen, nukleophile Additionen oder besonders auch Übergangsmetall- katalysierte Kupplungsreaktionen in Frage. Funktionelle Gruppen in Verbindungen der allgemeinen Formeln II, III und IV werden ggf zwischenzeitlich mit Schutzgruppen versehen, die dann auf einer geeigneten Stufe wieder abgespalten werden.
Figure imgf000073_0001
The compounds of general formula I can be synthesized as shown in Scheme 1. Carboxylic acids of the general formula II have, for example, been described in WO 199854159, WO 200375915 and WO 9854159 already described. The amides of the general formula III are prepared, for example, via the formation of the acid chlorides and subsequent reaction with the corresponding amines. Alternatively, depending on the amine to be introduced, other methods for amide formation can also be used. From the amides of general formula III, the compounds of general formula I are then prepared by addition of Grignard or lithium-organic compounds. However, steps 1 and 2 can also be carried out in the reverse order. The substituents A, R 1 , R 2 , R 3 and R 4 can optionally be further modified even after the introduction. For this example, oxidation, reduction, alkylations, acylations, nucleophilic additions or especially transition metal-catalyzed coupling reactions in question. Functional groups in compounds of the general formulas II, III and IV are optionally provided in the meantime with protective groups, which are then cleaved off again at a suitable stage.

Die nachfolgenden Beispiele dienen der näheren Erläuterung des Erfindungsgegenstandes, ohne ihn auf diese beschränken zu wollen.The following examples serve to explain the subject matter of the invention in more detail, without wishing to restrict it to these.

Herstellung von 3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure wird in WO 200375915 beschrieben. Beispiel 1 : rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- phenylethinyl)]propionsäure} (3-chlor-4-cyanophenyl)amidPreparation of 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid is described in WO 200375915. Example 1: Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-phenylethynyl)] propionic acid} (3-chloro-4-cyanophenyl) amide

1 a) {3-[1 -(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure} (3-chlor-4-cyanophenyl)amid1 a) {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid} (3-chloro-4-cyanophenyl) amide

Figure imgf000074_0001
Figure imgf000074_0001

3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure (500 mg) wurde in 10 ml N,N-Dimetylacetamid gelöst. Man addierte bei -100C 155 μl Thionylchlorid und ließ eine Stunde bei -100C nachrühren. Anschließend wurden 368 mg 4-Amino-2-chlor- benzonitril portionsweise addiert. Danach wurde 2 Stunden nachgerührt (-100C nach 23°C). Anschließend wurde das Reaktionsgemisch auf Eiswasser gegossen. Man rührte 2 Stunden nach und saugte ab. Der erhaltene Feststoff wurde durch Säulenchromatographie an Kieselgel mit einem Gemisch aus Hexan/Ethylacetat gereinigt. Man erhielt 495 mg Produkt.3- [1- (2-Fluoro-5-trifluoromethyl-phenyl) -cyclopropyl] -2-oxo-propionic acid (500 mg) was dissolved in 10 ml of N, N-dimethylacetamide. It added 155 ul of thionyl chloride at -10 0 C and left for one hour at -10 0 C. for. Subsequently, 368 mg of 4-amino-2-chloro-benzonitrile were added in portions. The mixture was then stirred for 2 hours (-10 0 C after 23 ° C). Subsequently, the reaction mixture was poured onto ice-water. The mixture was stirred for 2 hours and sucked off. The resulting solid was purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 495 mg of product were obtained.

1H-NMR (ppm, CDCI3, 300 MHz): 1.00 (4H), 3.30 (2H), 7.08 (1 H), 7.45-7.57 (2H), 7.60- 7.75 (2H), 7.92 (1 H), 8.80 (1 H). 1 H-NMR (ppm, CDCl 3 , 300 MHz): 1.00 (4H), 3.30 (2H), 7.08 (1H), 7.45-7.57 (2H), 7.60-7.75 (2H), 7.92 (1H), 8.80 (1H).

1 b) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenylethinyl)]- propionsäure} (3-chlor-4-cyanophenyl)amid1 b) rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} (3-chloro-4-cyanophenyl) amide

Figure imgf000074_0002
Figure imgf000074_0002

Zu einer Lösung von 62 μl Phenylacetylen in Tetrahydrofuran (5 ml) wurde bei -78°C n-To a solution of 62 μl of phenylacetylene in tetrahydrofuran (5 ml) was added at -78 ° C n-

Butyllithium (314 μl, 1 ,6 M in Hexan) addiert. Man ließ 30 Minuten bei dieser Temperatur nachrühren und tropfte dann eine Lösung der unter 1 a) beschriebenen Verbindung (100 mg) in 4 ml Tetrahydrofuran hinzu. Anschließend ließ man über ca. 3 h auf 23°C kommen und rührte dann 10 h nach. Danach wurde das Reaktionsgemisch auf eiskalte gesättigte Ammoniumchloridlösung gegossen. Es wurde mit Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden mit gesättigter Natriumchloridlösung gewaschen und über Natriumsulfat getrocknet. Das Rohprodukt wurde an Kieselgel chromatographiert. Man erhielt 93 mg Produkt. 1H-NMR (ppm, CDCI3, 400 MHz): 0.88 (1 H), 0.95-1.11 (3H), 2.41 (1 H), 2.66 (1 H), 2.99 (1 H, 7.02 (1 H), 7.22-7.38 (6H), 7.40 (1 H), 7.60 (2H), 7.80 (1 H), 8.70 (1 H).Butyllithium (314 ul, 1, 6 M in hexane) added. The mixture was stirred for 30 minutes at this temperature and then dripped a solution of the described under 1 a) Add compound (100 mg) in 4 ml of tetrahydrofuran. The mixture was then allowed to come to 23 ° C over about 3 h and then stirred for 10 h. Thereafter, the reaction mixture was poured onto 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. 93 mg of product were obtained. 1 H NMR (ppm, CDCl 3 , 400 MHz): 0.88 (1H), 0.95-1.11 (3H), 2.41 (1H), 2.66 (1H), 2.99 (1H, 7.02 (1H), 7.22 -7.38 (6H), 7.40 (1H), 7.60 (2H), 7.80 (1H), 8.70 (1H).

Beispiel 1c und "Id:Example 1c and "Id:

(+)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- phenylethinyl)]propionsäure} (3-chlor-4-cyanophenyl)amid 1c und (-)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- phenylethinyl)]propionsäure} (3-chlor-4-cyanophenyl)amid 1d Das unter Beispiel 1 b erhaltene racemische Gemisch wurde durch präparative chirale HPLC (Säule Chiralpak AD 250x10 mm) in die Enantiomeren 1c und 1d getrennt. 1c: [α]D2o = +7.1 ° (CHCI3, 8.9 mg/1 ml_; λ=589 nM) 1d: [α]D 2o = -8.7° (CHCI3, 9.2 mg/1 ml_; λ=589 nM)(+) - {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenylethynyl)] propionic acid} (3-chloro-4-cyanophenyl) amide 1c and (-) - {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenylethynyl)] propionic acid} (3-chloro-4-cyanophenyl) amide 1d The racemic mixture obtained in Example 1b was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 1c and 1d. 1c: [α] D 2o = +7.1 ° (CHCl 3 , 8.9 mg / 1 ml, λ = 589 nM) 1d: [α] D 2 o = -8.7 ° (CHCl 3 , 9.2 mg / 1 ml, λ = 589 nM)

Beispiel 2: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4- methylphenyl)ethinyl)]propionsäure} (3-chlor-4-cyanophenyl)amidExample 2: Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methylphenyl) ethynyl)] propionic acid} (3-chloro-4-cyanophenyl) amide

Figure imgf000075_0001
Figure imgf000075_0001

Die unter Beispiel 2 beschriebene Verbindung wurde analog zum unter Beispiel 1 b) beschriebenen Verfahren aus der unter 1 a) beschriebenen Verbindung, 4- Methylphenylacetylen und n-Butyllithium hergestellt.The compound described in Example 2 was prepared analogously to the process described under Example 1 b) from the compound described under 1 a), 4-methylphenylacetylene and n-butyllithium.

1H-NMR (ppm, CDCI3, 300 MHz): 0.86 (1 H), 0.92-1.10 (3H), 2.33 (3H), 2.40 (1 H), 2.67 (1 H), 2.97 (1 H), 7.00 (1 H), 7.09 (2H), 7.20 (2H), 7.33 (1 H), 7.40 (1 H), 7.55-7.65 (2H), 7.79 (1 H), 8.70 (1 H). Beispiel 3: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- phenylethinyl)]- propionsäure} (4-cyano-3-trifluormethylphenyl)amid 1 H-NMR (ppm, CDCl 3 , 300 MHz): 0.86 (1H), 0.92-1.10 (3H), 2.33 (3H), 2.40 (1H), 2.67 (1H), 2.97 (1H), 7.00 (1h), 7.09 (2h), 7.20 (2h), 7.33 (1h), 7.40 (1h), 7.55-7.65 (2h), 7.79 (1h), 8.70 (1h). Example 3: Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethyl-phenyl) -cyclopropyl] -2-phenyl-ethynyl) -propionic acid} (4-cyano-3-trifluoromethyl-phenyl) -amide

3a) {3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure} (4-cyano-3-trifluormethylphenyl)amid3a) {3- [1- (2-Fluoro-5-trifluoromethyl-phenyl) -cyclopropyl] -2-oxo-propionic acid} (4-cyano-3-trifluoromethyl-phenyl) -amide

Figure imgf000076_0001
Figure imgf000076_0001

Die unter Beispiel 3a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- oxopropionsäure und 4-Amino-2-trifluormethyl-benzonitril hergestellt. 1H-NMR (ppm, CDCI3, 300 MHz): 1.02 (4H), 3.30 (2H), 7.08 (1 H), 7.49 (1 H), 7.70 (1 H), 7.82 (1 H),7.93 (1 H), 8.08 (1 H), 8.94 (1 H).The compound described in Example 3a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionic acid and 4-amino-2-trifluoromethyl-benzonitrile. 1 H NMR (ppm, CDCl 3 , 300 MHz): 1.02 (4H), 3.30 (2H), 7.08 (1H), 7.49 (1H), 7.70 (1H), 7.82 (1H), 7.93 (1 H), 8.08 (1 H), 8.94 (1 H).

3b) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenylethinyl)]- propionsäure} (4-cyano-3-trifluormethylphenyl)amid3b) rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide

Figure imgf000076_0002
Figure imgf000076_0002

Die unter Beispiel 3b) beschriebene Verbindung wurde aus 3a) analog zu Beispiel 1 b) hergestellt.The compound described under Example 3b) was prepared from 3a) analogously to Example 1 b).

1H-NMR (ppm, CDCI3, 400 MHz): 0.87 (1 H), 0.95-1.1 (3H), 2.40 (1 H), 2.72 (1 H), 3.02 (1 H), 7.00 (1 H), 7.25-7.42 (6H), 7.59 (1 H), 7.72-7.83 (2H), 7.91 (1 H), 8.87 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.87 (1H), 0.95-1.1 (3H), 2.40 (1H), 2.72 (1H), 3.02 (1H), 7.00 (1H) , 7.25-7.42 (6H), 7.59 (1H), 7.72-7.83 (2H), 7.91 (1H), 8.87 (1H).

Beispiel 3c und 3d: (+)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- phenylethinyl)]propionsäure} (4-cyano-3-trifluormethylphenyl)amid 3a undExamples 3c and 3d: (+) - {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenylethynyl)] propionic acid} (4-cyano-3-trifluoromethylphenyl) amide 3a and

(-)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- phenylethinyl)]propionsäure} (4-cyano-3-trifluormethylphenyl)amid 3b(-) - {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-phenylethynyl)] propionic acid} (4-cyano-3-trifluoromethylphenyl) amide 3b

Das unter Beispiel 3b erhaltene racemische Gemisch wurde durch präparative chirale HPLC (Säule Chiralpak AD 250x10 mm) in die Enantiomeren 3c und 3d getrennt. 3c: [α]D2o = +5.3° (CHCI3, 9.6 mg/1 ml_; λ=589 nM) 3d: [α]D2o = -5.7° (CHCI3, 9.4 mg/1 ml_; λ=589 nM)The racemic mixture obtained in Example 3b was separated by preparative chiral HPLC (column Chiralpak AD 250 × 10 mm) into the enantiomers 3c and 3d. 3c: [α] D 2o = + 5.3 ° (CHCl 3 , 9.6 mg / 1 ml, λ = 589 nM) 3d: [α] D 2o = -5.7 ° (CHCl 3 , 9.4 mg / 1 ml, λ = 589 nM)

Beispiel 4: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4- methylphenyl)ethinyl)]propionsäure} (4-cyano-3-trifluormethylphenyl)amidExample 4: Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2- (4-methylphenyl) ethynyl)] propionic acid} (4-cyano-3-trifluoromethylphenyl) amide

Figure imgf000077_0001
Figure imgf000077_0001

Die unter Beispiel 4 beschriebene Verbindung wurde aus 3a) analog zu Beispiel 2 hergestellt.The compound described under Example 4 was prepared from 3a) analogously to Example 2.

1H-NMR (ppm, CDCI3, 300 MHz): 0.83 (1 H), 0.92-1.13 (3H), 2.33 (3H), 2.39 (1 H), 2.73 (1 H); 3.00 (1 H), 7.00 (1 H), 7.09 (2H), 7.20 (2H), 7.30 (1 H), 7.57 (1 H), 7.72-7.85 (2H), 7.90 (1 H), 8.85 (1 H). 1 H-NMR (ppm, CDCl 3 , 300 MHz): 0.83 (1H), 0.92-1.13 (3H), 2.33 (3H), 2.39 (1H), 2.73 (1H); 3.00 (1 H), 7.00 (1 H), 7.09 (2H), 7.20 (2H), 7.30 (1 H), 7.57 (1 H), 7.72-7.85 (2H), 7.90 (1 H), 8.85 (1 H).

Beispiel 4a und 4b:Example 4a and 4b:

(+)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4- methylphenylethinyl)]propionsäure} (4-cyano-3-trifluormethylphenyl)amid 4a und (-)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4- methylphenylethinyl)]propionsäure} (4-cyano-3-trifluormethylphenyl)amid 4b(+) - {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methylphenylethynyl)] propionic acid} (4-cyano-3-trifluoromethylphenyl) amide 4a and ( -) - {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methylphenylethynyl)] propionic acid} (4-cyano-3-trifluoromethylphenyl) amide 4b

Das unter Beispiel 4 erhaltene racemische Gemisch wurde durch präparative chirale HPLC (Säule Chiralpak AD 250x10 mm) in die Enantiomeren 4a und 4b getrennt. 4a: [α]D 20 = +2.8° (CHCI3, 10.0 mg/1 ml_; λ=589 nM) 4b: [α]D 20 = -3.7° (CHCI3, 10.5 mg/1 ml_; λ=589 nM)The racemic mixture obtained in Example 4 was separated by preparative chiral HPLC (column Chiralpak AD 250 × 10 mm) into the enantiomers 4a and 4b. 4a: [α] D 20 = + 2.8 ° (CHCl 3 , 10.0 mg / 1 ml, λ = 589 nM) 4b: [α] D 20 = -3.7 ° (CHCl 3 , 10.5 mg / 1 ml, λ = 589 nM)

Beispiel 5: rac-6-[4,4-Dimethyl-2-hydroxy-2-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-Example 5: rac-6- [4,4-dimethyl-2-hydroxy-2-phenylpentanoylamino] -4-methyl-2,3-benzoxazine

1-on1-one

5a) {3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure} (4-nitro-3-trifluormethylphenyl)amid

Figure imgf000078_0001
5a) {3- [1- (2-Fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxo-propionic acid} (4-nitro-3-trifluoromethyl-phenyl) -amide
Figure imgf000078_0001

Die unter Beispiel 5a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- oxopropionsäure und 4-Nitro-3-trifluormethylphenylamin hergestellt.The compound described under Example 5a) was prepared analogously to the method described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and 4-nitro-3-trifluoromethylphenylamine.

1H-NMR (ppm, CDCI3, 400 MHz): 1.02 (4H), 3.31 (2H), 7.09 (1 H), 7.04 (1 H), 7.48 (1 H), 7.70 (1 H), 7.99 (2H), 8.05 1 H), 8.97 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 1.02 (4H), 3.31 (2H), 7.09 (1H), 7.04 (1H), 7.48 (1H), 7.70 (1H), 7.99 ( 2H), 8.05 1 H), 8.97 (1 H).

5b) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenylethinyl)]- propionsäure} (4-nitro-3-trifluormethylphenyl)amid5b) rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-phenylethynyl)] - propionic acid} (4-nitro-3-trifluoromethylphenyl) amide

Figure imgf000078_0002
Figure imgf000078_0002

Die unter Beispiel 5b) beschriebene Verbindung wurde aus 5a) analog zu Beispiel 1 b) hergestellt. 1H-NMR (ppm, CDCI3, 400 MHz): 0.87 (1 H), 0.95-1.12 (3H), 2.40 (1 H), 2.73 (1 H), 3.01 (1 H), 7.00 (1 H), 7.23-7.40 (6H), 7.60 (1 H), 7.82-7.99 (3H), 8.90 (1 H).The compound described under Example 5b) was prepared from 5a) analogously to Example 1 b). 1 H NMR (ppm, CDCl 3 , 400 MHz): 0.87 (1H), 0.95-1.12 (3H), 2.40 (1H), 2.73 (1H), 3.01 (1H), 7.00 (1H), 7.23-7.40 (6H), 7.60 (1H), 7.82-7.99 (3H), 8.90 (1H).

Beispiel 5c und 5d: (+)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4- methylphenylethinyl)]propionsäure} (4-nitro-3-trifluormethylphenyl)amid 5a und (-)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4- methylphenylethinyl)]propionsäure} (4-nitro-3-trifluormethylphenyl)amid 5b Das unter Beispiel 5b erhaltene racemische Gemisch wurde durch präparative chirale HPLC (Säule Chiralpak AD 250x10 mm) in die Enantiomeren 5c und 5d getrennt. 5c: [α]D 2o = +5.9° (CHCI3, 8.7 mg/1 ml_; λ=589 nM) 5d: [α]D 20 = -6.9° (CHCI3, 9.0 mg/1 ml_; λ=589 nM) Beispiel 6: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4- methylphenyl)ethinyl)]propionsäure} (4-nitro-3-trifluormethylphenyl)amidExample 5c and 5d: (+) - {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methylphenylethynyl)] propionic acid} (4-nitro-3-trifluoromethylphenyl ) amide 5a and (-) - {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methylphenylethynyl)] propionic acid} (4-nitro-3-trifluoromethylphenyl) amide 5b The racemic mixture obtained in Example 5b was separated by preparative chiral HPLC (column Chiralpak AD 250 × 10 mm) into the enantiomers 5c and 5d. 5c: [α] D 2 o = + 5.9 ° (CHCl 3 , 8.7 mg / 1 ml, λ = 589 nM) 5d: [α] D 20 = -6.9 ° (CHCl 3 , 9.0 mg / 1 ml, λ = 589 nM) Example 6: Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2- (4-methylphenyl) ethynyl)] propionic acid} (4-nitro-3-trifluoromethylphenyl) amide

Figure imgf000079_0001
Figure imgf000079_0001

Die unter Beispiel 6 beschriebene Verbindung wurde aus 5a) analog zu Beispiel 2 hergestellt.The compound described in Example 6 was prepared from 5a) analogously to Example 2.

1H-NMR (ppm, CDCI3, 400 MHz): 0.85 (1 H), 0.95-1.12 (3H), 2.32 (3H), 2.39 (1 H), 2.72 (1 H), 2.97 (1 H), 7.01 (1 H), 7.10 (2H), 7.21 (2H), 7.32 (1 H), 7.60 (1 H), 7.84-8.00 (3H), 8.90 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.85 (1H), 0.95-1.12 (3H), 2.32 (3H), 2.39 (1H), 2.72 (1H), 2.97 (1H), 7.01 (1H), 7.10 (2H), 7.21 (2H), 7.32 (1H), 7.60 (1H), 7.84-8.00 (3H), 8.90 (1H).

Beispiel 7: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4- methylphenyl)-ethinyl)]propionsäure} (1-oxo-1 H-1λ4-benzo[b]thiophen-5-yl)amidExample 7: rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methylphenyl) -ethynyl)] -propionic acid} (1-oxo-1 H-1λ 4- benzo [b] thiophen-5-yl) amide

7a) 5-Nitro-benzo[b]thiophen 1-oxid7a) 5-nitro-benzo [b] thiophene 1-oxide

Figure imgf000079_0002
Figure imgf000079_0002

Zu 4,2 ml Trifluoressigsäure wurden bei 23°C 2,15 ml Wasserstoffperoxidlösung (30%ig in Wasser) addiert. Man ließ 30 Minuten bei 23°C nachrühren und addierte dann langsam eine Lösung von 2 g 5-Nitro-benzo[b]thiophen in 15 ml Trifluoressigsäure. Man ließ eine Stunde bei 23°C nachrühren und goß danach das Reaktionsgemisch auf2.15 ml of hydrogen peroxide solution (30% strength in water) were added to 4.2 ml of trifluoroacetic acid at 23 ° C. The mixture was stirred for 30 minutes at 23 ° C and then slowly added a solution of 2 g of 5-nitro-benzo [b] thiophene in 15 ml of trifluoroacetic acid. The mixture was stirred for one hour at 23 ° C and then poured the reaction mixture

Eiswasser. Anschließend wurde 3 Stunden nachgerührt. Dann wurde der Niederschlag abgesaugt und mit Wasser gewaschen. Das erhaltene Rohprodukt wurde an Kieselgel chromatographiert. Man erhielt 1 ,08 mg Produkt.Ice water. The mixture was then stirred for 3 hours. Then the precipitate was filtered off with suction and washed with water. The resulting crude product was chromatographed on silica gel. This gave 1, 08 mg of product.

1H-NMR (ppm, CDCI3, 300 MHz): 7.32 (2H), 8.1 1 (1 H), 8.36 (2H). 7b) 1-Oxo-i H-1λ4-benzo[b]thiophen-5-ylamine

Figure imgf000080_0001
1 H-NMR (ppm, CDCl 3 , 300 MHz): 7.32 (2H), 8.1 1 (1H), 8.36 (2H). 7b) 1-Oxo-i H-1λ 4 -benzo [b] thiophen-5-ylamine
Figure imgf000080_0001

Zu 1 ,45 g der unter 7 a erhaltenen Verbindung wurden in 50 ml Ethanol suspendiert. Man addierte 8,38 g Zinn(ll)chlorid Dihydrat und ließ 10 Minuten bei 700C nachrühren. Anschließend wurde das Reaktionsgemisch auf eiskalte gesättigte Ammoniumchloridlösung gegossen. Man rührte 2 Stunden nach, verdünnte mit Ethylacetat und filtrierte über Celite die ausgefallenen Salze ab. Danach wurden die Phasen getrennt und die wässrige Phase wurde mit Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden mit gesättigter wässriger Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet und im Vakuum eingeengt. Das erhaltene Rohprodukt wurde an Kieselgel chromatographiert. Man erhielt 505 mg Produkt. 1H-NMR (ppm, DMSO-D6, 300 MHz): 5.06 (2H), 6.71 (1 H), 6.97 (1 H), 7.15 (1 H), 7.50- 7.63 (2H).To 1.45 g of the compound obtained under 7 a were suspended in 50 ml of ethanol. One added 8.38 g of tin (II) chloride dihydrate and left 10 minutes at 70 0 C stirred. Subsequently, the reaction mixture was poured onto ice-cold saturated ammonium chloride solution. The mixture was stirred for 2 hours, diluted with ethyl acetate and filtered through Celite from the precipitated salts. Thereafter, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The resulting crude product was chromatographed on silica gel. This gave 505 mg of product. 1 H-NMR (ppm, DMSO-D 6 , 300 MHz): 5.06 (2H), 6.71 (1H), 6.97 (1H), 7.15 (1H), 7.50- 7.63 (2H).

7c) {3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure}-(1-oxo-1 H-1λ4-benzo[b]thiophen-5-yl)amid7c) {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxo-propionic} - (1-oxo-1H-1λ 4 -benzo [b] thiophen-5-yl) amide

Figure imgf000080_0002
Figure imgf000080_0002

Die unter Beispiel 7c) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- oxopropionsäure und der unter 7b) beschriebenen Verbindung hergestellt. 1H-NMR (ppm, CDCI3, 300 MHz): 1.01 (4H), 3.35 (2H), 7.09 (1 H), 7.30 (1 H), 7.40 (1 H), 7.48 (2H), 7.73 (1 H), 7.82 (1 H), 8.24 (1 H), 8.74 (1 H).The compound described under Example 7c) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and the compound described under 7b). 1 H NMR (ppm, CDCl 3 , 300 MHz): 1.01 (4H), 3.35 (2H), 7.09 (1H), 7.30 (1H), 7.40 (1H), 7.48 (2H), 7.73 (1H ), 7.82 (1 H), 8.24 (1 H), 8.74 (1 H).

7d) rac-{2-Hydroxy-3-[1 -(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4-methyl- phenyl)— ethinyl)]propionsäure} (1-oxo-1 H-1λ4-benzo[b]thiophen-5-yl)amid7d) rac- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methyl-phenyl) -ethynyl)] -propionic acid} (1-oxo-1 H- 1λ 4 -benzo [b] thiophene-5-yl) amide

Figure imgf000080_0003
Die unter Beispiel 7d) beschriebene Verbindung wurde aus 7c) analog zu Beispiel 2 hergestellt.
Figure imgf000080_0003
The compound described under Example 7d) was prepared from 7c) analogously to Example 2.

1H-NMR (ppm, CDCI3, 300 MHz): 0.80-1.12 (4H), 2.33 (3H), 2.46 (1 H), 2.59 (1 H), 3.15 (1 H), 6.96 (1 H), 7.09 (2H), 7.21 (2H), 7.24-7.48 (3H), 7.48 (1 H), 7.66 (1 H), 7.80 (1 H), 8.1 1 (1 H), 8.50 (1 H). 1 H-NMR (ppm, CDCl 3 , 300 MHz): 0.80-1.12 (4H), 2.33 (3H), 2.46 (1H), 2.59 (1H), 3.15 (1H), 6.96 (1H), 7.09 (2H), 7.21 (2H), 7.24-7.48 (3H), 7.48 (1H), 7.66 (1H), 7.80 (1H), 8.1 1 (1H), 8.50 (1H).

Beispiel 8: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4-methyl- phenyl)-ethinyl)]propionsäure}(1 ,1-dioxo-2,3-dihydro-1 H-1λ6-benzo[b]thiophen-5- yl)amidExample 8 Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methyl-phenyl) -ethynyl)] -propionic acid} (1,1-dioxo) 2,3-dihydro-1H-1λ 6 -benzo [b] thiophen-5-yl) amide

8a){3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure}-(1 ,1-dioxo-8a) {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid} - (1, 1-dioxo)

2,3-dihydro-1 H-1 λ6-benzo[b]thiophen-5-yl)amid2,3-dihydro-1H-1 λ 6 -benzo [b] thiophen-5-yl) amide

Figure imgf000081_0001
Figure imgf000081_0001

Die unter Beispiel 8a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- oxopropionsäure und 1 ,1-Dioxo-2,3-dihydro-1 H-1λ6-benzo[b]thiophen-5-ylamin hergestellt.The compound described under Example 8a) was analogous to the method described under Example 1a) of 3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionic acid and 1, 1-dioxo-2,3-dihydro -1 H-1λ 6 -benzo [b] thiophen-5-ylamine.

1H-NMR (ppm, CDCI3, 400 MHz): 1.02 (4H), 3.30 (2H), 3.37 (2H), 3.50 (2H), 7.09 (1 H), 7.48 (2H), 7.71 (2H), 7.87 (1 H), 8.83 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 1.02 (4H), 3.30 (2H), 3.37 (2H), 3.50 (2H), 7.09 (1H), 7.48 (2H), 7.71 (2H), 7.87 (1H), 8.83 (1H).

8b) rac-{2-Hydroxy-3-[1 -(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4-methyl- phenyl)-ethinyl)]propionsäure}(1 , 1 -dioxo-2,3-dihydro-1 H-1 λ6-benzo[b]thiophen-5-yl)- amid8b) rac- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methyl-phenyl) -ethynyl)] -propionic acid} (1,1-dioxo-2 , 3-dihydro-1 H-1 λ 6 -benzo [b] thiophen-5-yl) - amide

Figure imgf000081_0002
Die unter Beispiel 8b) beschriebene Verbindung wurde aus 8a) analog zu Beispiel 2 hergestellt.
Figure imgf000081_0002
The compound described under Example 8b) was prepared from 8a) analogously to Example 2.

1H-NMR (ppm, CDCI3, 300 MHz): 0.87 (1 H), 0.92-1.12 (3H), 2.32 (3H), 2.43 (1 H), 2.60 (1 H), 3.04 (1 H), 3.34 (2H), 3.50 (2H), 6.98 (1 H), 7.09 (2H), 7.20 (2H), 7.34 (2H), 7.60 (1 H), 7.67 (1 H), 7.80 (1 H), 8.70 (1 H). 1 H-NMR (ppm, CDCl 3 , 300 MHz): 0.87 (1H), 0.92-1.12 (3H), 2.32 (3H), 2.43 (1H), 2.60 (1H), 3.04 (1H), 3.34 (2H), 3.50 (2H), 6.98 (1H), 7.09 (2H), 7.20 (2H), 7.34 (2H), 7.60 (1H), 7.67 (1H), 7.80 (1H), 8.70 (1H).

Beispiel 9a und 9b:Example 9a and 9b:

(+)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4- methylphenyl)-ethinyl)]propionsäure}(1 ,1-dioxo-2,3-dihydro-1 H-1λ6-benzo[b]thio- phen-5-yl)amid 9a und(+) - {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methylphenyl) -ethynyl)] -propionic acid} (1,1-dioxo-2,3 -dihydro-1H-1λ 6 -benzo [b] thiophen-5-yl) amide 9a and

(-)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4-methy)- ethinyl)]propionsäure}(1 ,1 -dioxo-2,3-dihydro-1 H-1 λ6-benzo[b]thiophen-5-yl)amid(-) - {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methy) -ethynyl)] -propionic acid} (1,1-dioxo-2,3 -dihydro-1 H-1 λ 6 -benzo [b] thiophen-5-yl) amide

9b9b

Figure imgf000082_0001
Figure imgf000082_0001

Das unter Beispiel 8 erhaltene racemische Gemisch wurde durch präparative chirale HPLC (Säule Chiralpak AD 250x10 mm) in die Enantiomeren 9a und 9b getrennt. 9a : [α]D 20: + 20.6° (CHCI3, 10,0 mg/1 ml; λ=589 nM) 9b : [α]D 20: - 20.7° (CHCI3, 9,6 mg/ 1 ml; λ=589 nM)The racemic mixture obtained in Example 8 was separated by preparative chiral HPLC (column Chiralpak AD 250 × 10 mm) into the enantiomers 9a and 9b. 9a: [α] D 20 : + 20.6 ° (CHCl 3 , 10.0 mg / 1 ml, λ = 589 nM) 9b: [α] D 20 : -20.7 ° (CHCl 3 , 9.6 mg / 1 ml λ = 589 nM)

Beispiel 10: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4-methyl- phenyl)-ethinyl)]propionsäure}(1 ,1 -dioxo-1 H-1 λ6-benzo[b]thiophen-5-yl)amidExample 10 Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methyl-phenyl) -ethynyl)] -propionic acid} (1,1-dioxo) 1 H-1 λ 6 -benzo [b] thiophen-5-yl) amide

10a) {3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure}-(1 ,1-dioxo- 1 H-1λ6-benzo[b]thiophen-5-yl)amid10a) {3- [1- (2-Fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionic acid} - (1, 1-dioxo-1H-1λ 6 -benzo [b] thiophen-5-yl) amide

Figure imgf000082_0002
Die unter Beispiel 1Oa) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- oxopropionsäure und 1 ,1-Dioxo-1 H-1λ6-benzo[b]thiophen-5-ylamin hergestellt. 1H-NMR (ppm, DMSO-D6, 300 MHz): 0.92 (4H), 3.24 (2H), 7.28-7.38 (2H), 7.48 (2H), 7.74 (2H), 7.86 (1 H), 8.01 (1 H), 10.78 (1 H).
Figure imgf000082_0002
The compound described under Example 1oa) was prepared in analogy to the process described in Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxo-propionic acid and 1, 1-Dioxo-1H-1λ 6 benzo [b] thiophen-5-ylamine. 1 H-NMR (ppm, DMSO-D 6 , 300 MHz): 0.92 (4H), 3.24 (2H), 7.28-7.38 (2H), 7.48 (2H), 7.74 (2H), 7.86 (1H), 8.01 ( 1H), 10.78 (1H).

10b) rac-{2-Hydroxy-3-[1 -(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4-methyl- phenyl)-ethinyl)]propionsäure}(1 , 1 -dioxo-1 H-1 λ6-benzo[b]thiophen-5-yl)amid10b) rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methyl-phenyl) -ethynyl)] -propionic acid} (1,1-dioxo-1 H-1 λ 6 -benzo [b] thiophen-5-yl) amide

Figure imgf000083_0001
Figure imgf000083_0001

Die unter Beispiel 10) beschriebene Verbindung wurde aus 10a) analog zu Beispiel 2 hergestellt.The compound described under Example 10) was prepared from 10a) analogously to Example 2.

1H-NMR (ppm, CDCI3, 400 MHz): 0.86 (1 H), 0.95-1.10 (3H), 2.32 (3H), 2.43 (1 H), 2.62 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.86 (1H), 0.95-1.10 (3H), 2.32 (3H), 2.43 (1H), 2.62

(1 H), 3.05 (1 H), 6.72 (1 H), 7.00 (1 H), 7.07-7.25 (5H), 7.30 (1 H), 7.48 (1 H), 7.56-7.68 (2H), 7.80 (1 H), 8.73 (1 H).(1 H), 3.05 (1 H), 6.72 (1 H), 7.00 (1 H), 7.07-7.25 (5H), 7.30 (1 H), 7.48 (1 H), 7.56-7.68 (2H), 7.80 (1H), 8.73 (1H).

Beispiel 11 : rac-{2-Hydroxy-3-[1-(2-chlor-6-fluorphenyl)-dimethyl]-2-phenylethinyl)]-propion- säure} (4-cyano-3-trifluormethyl)amidExample 11: Rac- {2-Hydroxy-3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-phenylethynyl)] - propionic acid} (4-cyano-3-trifluoromethyl) amide

11 a) {3-[1 -(2-Chlor-6-fluorphenyl)-dimethyl]-2-oxopropionsäure}(4-cyano-3-trifluor- methyl)amid11 a) {3- [1- (2-Chloro-6-fluorophenyl) -dimethyl] -2-oxopropionic acid} (4-cyano-3-trifluoromethyl) amide

Figure imgf000083_0002
Die unter Beispiel 11 a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Chlor-6-fluorphenyl)-dimethyl]-2-oxopropionsäure und 4-Amino-2-trifluormethyl-benzonitril hergestellt.
Figure imgf000083_0002
The compound described under Example 11 a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-chloro-6-fluorophenyl) dimethyl] -2-oxopropionic acid and 4-amino-2-trifluoromethyl-benzonitrile ,

1H-NMR (ppm, CDCI3, 300 MHz): 1.69 (3H), 1.71 (3H), 3.82 (2H), 6.94 (1 H), 7.09-7.16 1 H-NMR (ppm, CDCl 3 , 300 MHz): 1.69 (3H), 1.71 (3H), 3.82 (2H), 6.94 (1H), 7.09-7.16

(2H), 7.83 (1 H), 7.93 (1 H), 8.10 (1 H), 8.99 (1 H). 11 b) rac-{2-Hydroxy-3-[1-(2-chlor-6-fluorphenyl)-dimethyl]-2-phenylethinyl)]-propion- säure} (4-cyano-3-trifluormethyl)amid(2H), 7.83 (1H), 7.93 (1H), 8.10 (1H), 8.99 (1H). 11 b) rac- {2-hydroxy-3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-phenylethynyl)] - propionic acid} (4-cyano-3-trifluoromethyl) amide

Figure imgf000084_0001
Figure imgf000084_0001

Die unter Beispiel 11 b) beschriebene Verbindung wurde aus 1 1a) analog zu Beispiel 1 b) hergestellt.The compound described in Example 11 b) was prepared from 1 1a) analogously to Example 1 b).

1H-NMR (ppm, CDCI3, 400 MHz): 1.77 (3H), 1.86 (3H), 2.93-3.04 (3H), 6.86 (1 H), 6.97 (1 H), 7.06 (1 H), 7.31-7.36 (5H), 7.79-7.88 (2H), 8.02 (1 H), 8.89 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 1.77 (3H), 1.86 (3H), 2.93-3.04 (3H), 6.86 (1H), 6.97 (1H), 7.06 (1H), 7.31 -7.36 (5H), 7.79-7.88 (2H), 8.02 (1H), 8.89 (1H).

Beispiel 12: rac-{2-Hydroxy-3-[1-(2-chlor-6-fluorphenyl)-dimethyl]-2-phenylethinyl)]-propion- säure}(4-cyano-3-chlorphenyl)amidExample 12 rac- {2-Hydroxy-3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-phenylethynyl)] - propionic acid} (4-cyano-3-chlorophenyl) amide

12a) {3-[1-(2-Chlor-6-fluorphenyl)-dimethyl]-2-oxopropionsäure}(4-cyano-3-chlor- phenyl)amid12a) {3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-oxopropionic acid} (4-cyano-3-chlorophenyl) amide

Figure imgf000084_0002
Figure imgf000084_0002

Die unter Beispiel 12a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Chlor-6-fluorphenyl)-dimethyl]-2-oxopropionsäure und 4-Amino-2-chlorbenzonitril hergestellt.The compound described under Example 12a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-oxopropionic acid and 4-amino-2-chlorobenzonitrile.

1H-NMR (ppm, CDCI3, 300 MHz): 1.69 (3H), 1.71 (3H), 3.80 (2H), 6.94 (1 H), 7.07-7.17 (2H), 7.52 (1 H), 7.64 (1 H), 7.95 (1 H), 8.85 (1 H). 1 H-NMR (ppm, CDCl 3 , 300 MHz): 1.69 (3H), 1.71 (3H), 3.80 (2H), 6.94 (1H), 7.07-7.17 (2H), 7.52 (1H), 7.64 ( 1H), 7.95 (1H), 8.85 (1H).

12b) rac-{2-Hydroxy-3-[1-(2-chlor-6-fluorphenyl)-dimethyl]-2-phenylethinyl)]-propion- säure}(4-cyano-3-chlorphenyl)amid12b) rac- {2-hydroxy-3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-phenylethynyl)] - propionic acid} (4-cyano-3-chlorophenyl) amide

Figure imgf000084_0003
Die unter Beispiel 12b) beschriebene Verbindung wurde aus 12a) analog zu Beispiel 1 b) hergestellt. 1H-NMR (ppm, CDCI3, 400 MHz): 1.72 (3H), 1.80 (3H), 2.92 (2H), 3.04 (1 H), 6.81 (1 H), 6.94 (1 H), 7.03 (1 H), 7.26-7.43 (6H), 7.58 (1 H), 7.82 (1 H), 8.72 (1 H).
Figure imgf000084_0003
The compound described under Example 12b) was prepared from 12a) analogously to Example 1 b). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 1.72 (3H), 1.80 (3H), 2.92 (2H), 3.04 (1H), 6.81 (1H), 6.94 (1H), 7.03 (1 H), 7.26-7.43 (6H), 7.58 (1H), 7.82 (1H), 8.72 (1H).

Beispiel 12c und 12d: (+)-{2-Hydroxy-3-[1-(2-chlor-6-fluorphenyl)-dimethyl]-2-phenylethinyl]propion- säure} (4-cyano-3-chlorphenyl)amid 12a undExamples 12c and 12d: (+) - {2-Hydroxy-3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-phenylethynyl] propionic acid} (4-cyano-3-chlorophenyl) amide 12a and

(-)-{2-Hydroxy-3-[1-(2-chlor-6-fluorphenyl)-dimethyl]-2-phenylethinyl]propion- säure} (4-cyano-3-chlorphenyl)amid 12b(-) - {2-Hydroxy-3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-phenylethynyl] propionic acid} (4-cyano-3-chlorophenyl) amide 12b

Das unter Beispiel 12b erhaltene racemische Gemisch wurde durch präparative chirale HPLC (Säule Chiralpak AD 250x10 mm) in die Enantiomeren 12c und 12d getrennt. 12c: [α]D 20 = +13.9° (CHCI3, 10.6 mg/1 ml_; λ=589 nM) 12d: [α]D 20 = -14.0° (CHCI3, 10.8 mg/1 ml_; λ=589 nM)The racemic mixture obtained in Example 12b was separated by preparative chiral HPLC (column Chiralpak AD 250 × 10 mm) into the enantiomers 12c and 12d. 12c: [α] D 20 = + 13.9 ° (CHCl 3 , 10.6 mg / 1 ml, λ = 589 nM) 12d: [α] D 20 = -14.0 ° (CHCl 3 , 10.8 mg / 1 ml, λ = 589 nM)

Beispiel 13: rac-{2-Hydroxy-3-[1-(2-chlor-6-fluorphenyl)-dimethyl]-2-phenylethinyl)]-propion- säure}(4-nitro-3-trifluormethylphenyl)amidExample 13: Rac- {2-Hydroxy-3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-phenylethynyl)] - propionic acid} (4-nitro-3-trifluoromethylphenyl) amide

13a) {3-[1 -(2-Chlor-6-fluorphenyl)-dimethyl]-2-oxopropionsäure}(4-cyano-3-trifluor- methylphenyl)amid13a) {3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-oxopropionic acid} (4-cyano-3-trifluoromethylphenyl) amide

Figure imgf000085_0001
Figure imgf000085_0001

Die unter Beispiel 12a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Chlor-6-fluorphenyl)-dimethyl]-2-oxopropionsäure und 4-nitro-3-trifluormethylaniline hergestellt.The compound described under Example 12a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-oxopropionic acid and 4-nitro-3-trifluoromethylanilines.

1H-NMR (ppm, CDCI3, 300 MHz): 1.70 (3H), 1.71 (3H), 3.82 (2H), 6.92 (1 H), 7.08-7.17 (2H), 8.00 (2H), 8.09 (1 H), 9.01 (1 H). 1 H-NMR (ppm, CDCl 3 , 300 MHz): 1.70 (3H), 1.71 (3H), 3.82 (2H), 6.92 (1H), 7.08-7.17 (2H), 8.00 (2H), 8.09 (1 H), 9.01 (1 H).

13b) rac-{2-Hydroxy-3-[1-(2-chlor-6-fluorphenyl)-dimethyl]-2-phenylethinyl)]-propion- säure} (4-nitro-3-trifluormethylphenyl)amid13b) rac- {2-hydroxy-3- [1- (2-chloro-6-fluorophenyl) -dimethyl] -2-phenylethynyl)] - propionic acid} (4-nitro-3-trifluoromethylphenyl) amide

Figure imgf000085_0002
Die unter Beispiel 13b) beschriebene Verbindung wurde aus 13a) analog zu Beispiel 1 b) hergestellt.
Figure imgf000085_0002
The compound described under Example 13b) was prepared from 13a) analogously to Example 1 b).

1H-NMR (ppm, CDCI3, 400 MHz): 1.72 (3H), 1.81 (3H), 2.95 (2H), 3.01 (1 H), 6.78-7.03 (3H), 7.27-7.39 (5H), 7.86-7.96 (3H), 8.90 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 1.72 (3H), 1.81 (3H), 2.95 (2H), 3.01 (1H), 6.78-7.03 (3H), 7.27-7.39 (5H), 7.86 -7.96 (3H), 8.90 (1H).

Beispiel 14: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenyl- ethinyl)]-propionsäure} (4-cyanophenyl)amidExample 14: Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenyl-ethynyl) -propionic acid} (4-cyanophenyl) -amide

14a) {3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure}(4-cyano- phenyl)amid14a) {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid} (4-cyanophenyl) amide

Figure imgf000086_0001
Figure imgf000086_0001

Die unter Beispiel 14a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- oxopropionsäure und 4-aminobenzonitril hergestellt.The compound described under Example 14a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionic acid and 4-aminobenzonitrile.

1H-NMR (ppm, CDCI3, 300 MHz): 1.01 (4H), 3.31 (2H), 7.09 (1 H), 7.48 (1 H), 7.63-7.73 (5H), 8.79 (1 H). 1 H-NMR (ppm, CDCl 3 , 300 MHz): 1.01 (4H), 3.31 (2H), 7.09 (1H), 7.48 (1H), 7.63-7.73 (5H), 8.79 (1H).

14b) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenylethinyl)]- propionsäure} (4-cyanophenyl)amid14b) rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} (4-cyanophenyl) amide

Figure imgf000086_0002
Figure imgf000086_0002

Die unter Beispiel 14b) beschriebene Verbindung wurde aus 14a) analog zu Beispiel 1 b) hergestellt.The compound described under Example 14b) was prepared from 14a) analogously to Example 1 b).

1H-NMR (ppm, CDCI3, 400 MHz): 0.86-0.90 (1 H), 0.97-1.08 (3H), 2.45 (1 H), 2.64 (1 H), 3.05 (1 H), 7.00 (1 H), 7.29-7.35 (6H), 7.60-7.63 (5H), 8.68 (1 H). Beispiel 15: rac-2-{Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenyl- ethinyl)]-propionsäure} phenylamid 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.86-0.90 (1H), 0.97-1.08 (3H), 2.45 (1H), 2.64 (1H), 3.05 (1H), 7.00 (1 H), 7.29-7.35 (6H), 7.60-7.63 (5H), 8.68 (1H). Example 15: rac-2- {hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} phenylamide

15a) {3-[1 -(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure}phenylamid15a) {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid} phenylamide

Figure imgf000087_0001
Figure imgf000087_0001

Die unter Beispiel 15a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- oxopropionsäure und Anilin hergestellt. 1H-NMR (ppm, CDCI3, 300 MHz): 1.00 (4H), 3.33 (2H), 7.09 (1 H), 7.16 (1 H), 7.35 (2H), 7.48 (1 H), 7.58 (2H), 7.73 (1 H), 8.61 (1 H).The compound described under Example 15a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and aniline. 1 H NMR (ppm, CDCl 3 , 300 MHz): 1.00 (4H), 3.33 (2H), 7.09 (1H), 7.16 (1H), 7.35 (2H), 7.48 (1H), 7.58 (2H) , 7.73 (1H), 8.61 (1H).

15b) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenylethinyl)]- propionsäure} phenylamid15b) rac- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} phenylamide

Figure imgf000087_0002
Figure imgf000087_0002

Die unter Beispiel 15b) beschriebene Verbindung wurde aus 15a) analog zu BeispielThe compound described under Example 15b) became from 15a) analogous to Example

1 b) hergestellt.1 b).

1H-NMR (ppm, CDCI3, 400 MHz): 0.85-1.09 (4H), 2.47 (1 H), 2.57 (1 H), 3.17 (1 H), 6.98 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.85-1.09 (4H), 2.47 (1H), 2.57 (1H), 3.17 (1H), 6.98

(1 H), 7.14 (1 H), 7.28-7.35 (8H), 7.50 (2H), 7.64 (1 H), 8.40 (1 H).(1H), 7.14 (1H), 7.28-7.35 (8H), 7.50 (2H), 7.64 (1H), 8.40 (1H).

Beispiel 16: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3-hydroxy- propinyl)]-propionsäure}(4-cyano-3-trifluormethylphenyl)amidExample 16: Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3-hydroxypropynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide

16a) {3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3-tert-butyldimethylsilyloxy- propinyl)propionsäure} (4-cyano-3-trifluormethylphenyl)amid

Figure imgf000088_0001
16a) {3- [1- (2-Fluoro-5-trifluoromethylphenyl) cyclopropyl] -2- (3-tert-butyldimethylsilyloxypropyl) propionic acid} (4-cyano-3-trifluoromethylphenyl) amide
Figure imgf000088_0001

Die unter Beispiel 16a) beschriebene Verbindung wurde analog zum unter Beispiel 1 b) beschriebenen Verfahren aus {3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- oxopropionsäure} (4-cyano-3-trifluormethylphenyl)amid (siehe Beispiel 3a) und 3- tert.butylsilyloxypropin hergestellt.The compound described under Example 16a) was prepared analogously to the process described under Example 1 b) from {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid} (4-cyano-3-trifluoromethylphenyl) amide (see Example 3a) and 3-tert-butylsilyloxypropyne.

1H-NMR (ppm, CDCI3, 300 MHz): 0.07 (6H), 0.76-0.84 (1 H), 0.88 (9H), 1.07-0.92 (3H), 2.24 (1 H), 2.69 (1 H), 3.11 (1 H), 4.23 (2H), 7.02 (1 H), 7.31-7.36 (1 H), 7.54 (1 H), 7.76 (2H), 7.85 (1 H), 8.82 (1 H). 1 H NMR (ppm, CDCl 3 , 300 MHz): 0.07 (6H), 0.76-0.84 (1H), 0.88 (9H), 1.07-0.92 (3H), 2.24 (1H), 2.69 (1H) , 3.11 (1H), 4.23 (2H), 7.02 (1H), 7.31-7.36 (1H), 7.54 (1H), 7.76 (2H), 7.85 (1H), 8.82 (1H).

Figure imgf000088_0002
Figure imgf000088_0002

16b) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3-hydroxy- propinyl)]propionsäure} (4-cyano-3-trifluormethylphenyl)amid16b) rac- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3-hydroxypropynyl)] propionic acid} (4-cyano-3-trifluoromethylphenyl) amide

Zu einer Lösung von der unter 16a) beschriebenen Verbindung (170mg) in 5 ml_ THF wurde Tetrabutylammoniumfluorid (280 μl_, 1 M in THF) addiert. Man rührte 4h beiTo a solution of compound (170mg) described in 16a) in 5 ml of THF was added tetrabutylammonium fluoride (280 μl, 1 M in THF). It was stirred for 4h

23°C. Danach wurde das Reaktionsgemisch auf gesättigte23 ° C. Thereafter, the reaction mixture was saturated

Natriumhydrogencarbonatlösung gegossen und mit Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden mit gesättigter Natruimchloridlösung gewaschen, über Natruimsulfat getrocknet und konzentriert. Das Rohprodukt wurde an Kieselgel chromatographiert. Man enhalt 137mg Produkt.Sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was chromatographed on silica gel. One contains 137mg product.

1H-NMR (ppm, CDCI3, 400 MHz): 0.81-0.86 (1 H), 0.90-1.02 (3H), 1.25 (1 H), 2.30 (1 H), 2.64 (1 H), 4.17 (2H), 7.04 (1 H), 7.36 (1 H), 7.54 (1 H), 7.77 (2H), 7.89 (1 H), 8.87 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.81-0.86 (1H), 0.90-1.02 (3H), 1.25 (1H), 2.30 (1H), 2.64 (1H), 4.17 (2H ), 7.04 (1 H), 7.36 (1 H), 7.54 (1 H), 7.77 (2H), 7.89 (1 H), 8.87 (1 H).

Beispiel 16c und 16d: (+)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3-hydroxy- propinyl)]propionsäure}(4-cyano-3-trifluormethylphenyl)amid 16c und (-)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3-hydroxy- propinyl)]propionsäure}(4-cyano-3-trifluormethylphenyl)amid 16d Das unter Beispiel 16b erhaltene racemische Gemisch wurde durch präparative chirale HPLC (Säule Chiralpak AD 250x10 mm) in die Enantiomeren 16c und 16d getrennt. 16c: [α]D2o = +36.9° (CHCI3, 10.1 mg/1 ml_; λ=589 nM) 16d: [αf20 = -37.9° (CHCI3, 10.2 mg/1 ml_; λ=589 nM)Examples 16c and 16d: (+) - {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3-hydroxy-propynyl)] -propionic acid} (4-cyano-3 -trifluoromethylphenyl) amide 16c and (-) - {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2- (3-hydroxypropynyl)] propionic acid} (4-cyano) 3-trifluoromethylphenyl) amide 16d The racemic mixture obtained in Example 16b was separated by preparative chiral HPLC (column Chiralpak AD 250 × 10 mm) into the enantiomers 16c and 16d. 16c: [α] D 2o = + 36.9 ° (CHCl 3 , 10.1 mg / 1 ml, λ = 589 nM) 16d: [αf 20 = -37.9 ° (CHCl 3 , 10.2 mg / 1 ml, λ = 589 nM).

Beispiel 17: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(1-pentinyl)]- propionsäure}(4-cyano-3-trifluormethylphenyl)amidExample 17: rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (1-pentynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide

Figure imgf000089_0001
Figure imgf000089_0001

Die unter Beispiel 17 beschriebene Verbindung wurde analog zum unter Beispiel 1 b) beschriebenen Verfahren aus {3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- oxopropionsäure} (4-cyano-3-trifluormethylphenyl)amid und 1-pentin hergestellt.The compound described in Example 17 was analogous to the method described in Example 1 b) of {3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-oxopropionsäure} (4-cyano-3-trifluoromethylphenyl) amide and 1-penty.

1H-NMR (ppm, CDCI3, 400 MHz): 0.83-0.90 (1 H), 0.96-1.07 (6H), 1.52 (2H), 2.15 (2H), 2.29 (1 H), 2.68 (1 H), 2.83 (1 H), 7.09 (1 H), 7.41 (1 H), 7.59 (1 H), 7.81 (2H), 7.93 (1 H), 8.85 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.83-0.90 (1H), 0.96-1.07 (6H), 1.52 (2H), 2.15 (2H), 2.29 (1H), 2.68 (1H) , 2.83 (1 H), 7.09 (1 H), 7.41 (1 H), 7.59 (1 H), 7.81 (2H), 7.93 (1 H), 8.85 (1 H).

Beispiel 17a und 17b:Example 17a and 17b:

(+)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(1-pentinyl)]- propionsäure} (4-cyano-3-trifluormethylphenyl)amid 17a und(+) - {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (1-pentynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide 17a and

(-)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(1-pentinyl)]- propionsäure} (4-cyano-3-trifluormethylphenyl)amid 17b Das unter Beispiel 17 erhaltene racemische Gemisch wurde durch präparative chirale(-) - {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (1-pentynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide 17b Das obtained under Example 17 racemic mixture was prepared by preparative chiral

HPLC (Säule Chiralpak AD 250x10 mm) in die Enantiomeren 3a und 3b getrennt.HPLC (column Chiralpak AD 250x10 mm) separated into the enantiomers 3a and 3b.

3a: [α]D 2o = +27.4° (CHCI3, 21.5 mg/1 mL; λ=589 nM)3a: [α] D 2 o = + 27.4 ° (CHCl 3 , 21.5 mg / 1 mL, λ = 589 nM)

3b: [α]D 2o = -27.1 ° (CHCI3, 21.9 mg/1 mL; λ=589 nM) Beispiel 18: rac-2-{Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenyl- ethinyl)]-propionsäure} (3-trifluormethylphenyl)amid3b: [α] D 2 O = -27.1 ° (CHCl 3 , 21.9 mg / 1 mL, λ = 589 nM) Example 18: rac-2- {hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenyl-ethynyl)] - propionic acid} (3-trifluoromethyl-phenyl) -amide

18a) {3-[1 -(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure}(3-trifluor- methylphenyl)amid18a) {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid} (3-trifluoromethylphenyl) amide

Figure imgf000090_0001
Figure imgf000090_0001

Die unter Beispiel 18a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- oxopropionsäure und 3-Trifluormethylanilin hergestellt.The compound described under Example 18a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and 3-trifluoromethylaniline.

1H-NMR (ppm, CDCI3, 300 MHz): 1.01 (4H), 3.32 (2H), 7.10 (1 H), 7.33 (1 H), 7.41-7.53 (3H), 7.73 (1 H), 7.92 (1 H), 8.73 (1 H). 1 H-NMR (ppm, CDCl 3 , 300 MHz): 1.01 (4H), 3.32 (2H), 7.10 (1H), 7.33 (1H), 7.41-7.53 (3H), 7.73 (1H), 7.92 (1H), 8.73 (1H).

18b) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenylethinyl)]- propionsäure} (3-trifluoromethylphenyl)amid18b) rac- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} (3-trifluoromethylphenyl) amide

Figure imgf000090_0002
Figure imgf000090_0002

Die unter Beispiel 18b) beschriebene Verbindung wurde aus 18a) analog zu Beispiel 1 b) hergestellt. 1H-NMR (ppm, CDCI3, 400 MHz): 0.87-0.94 (1 H), 1.01-1.13 (3H), 2.49 (1 H), 2.70 (1 H), 3.14 (1 H), 7.04 (1 H), 7.32-7.51 (8H), 7.68 (2H), 7.82 (1 H), 8.61 (1 H).The compound described in Example 18b) was prepared from 18a) analogously to Example 1 b). 1 H NMR (ppm, CDCl 3 , 400 MHz): 0.87-0.94 (1H), 1.01-1.13 (3H), 2.49 (1H), 2.70 (1H), 3.14 (1H), 7.04 (1H ), 7.32-7.51 (8H), 7.68 (2H), 7.82 (1H), 8.61 (1H).

Beispiel 19: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4-hydroxy- phenylethinyl)]-propionsäure} (4-cyano-3-trifluormethylphenyl)amidExample 19: Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-hydroxyphenylethynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide

19a) rac-{2-Hydroxy-3-[1 -(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-trimethylsilyl- ethinyl]-propionsäure}(4-cyano-3-trifluormethylphenyl)amid

Figure imgf000091_0001
19a) Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-trimethylsilyl-ethynyl] -propionic acid} (4-cyano-3-trifluoromethyl-phenyl) -amide
Figure imgf000091_0001

Die unter Beispiel 19a) beschriebene Verbindung wurde aus {3-[1-(2-Fluor-5- trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure} (4-cyano-3- trifluormethylphenyl)amid und Trimethylsilylacetylen in Analogie zu Beispiel 1 b) hergestellt.The compound described in Example 19a) was prepared from {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid} (4-cyano-3-trifluoromethylphenyl) amide and trimethylsilylacetylene in analogy to Example 1b ) produced.

1H-NMR (ppm, CDCI3, 400 MHz): 0.22 (9H), 0.76-0.86 (1 H), 0.98-1.14 (3H), 2.28 (1 H), 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.22 (9H), 0.76-0.86 (1H), 0.98-1.14 (3H), 2.28 (1H),

2.74 (1 H), 2.87 (1 H), 7.08 (1 H), 7.42 (1 H), 7.61 (1 H), 7.80 (2H), 7.92 (1 H), 8.85 (1 H).2.74 (1 H), 2.87 (1 H), 7.08 (1 H), 7.42 (1 H), 7.61 (1 H), 7.80 (2H), 7.92 (1 H), 8.85 (1 H).

19b) rac-{2-Hydroxy-3-[1 -(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-ethinyl]- propionsäure} (4-cyano-3-trifluormethylphenyl)amid19b) rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-ethynyl] -propionic acid} (4-cyano-3-trifluoromethyl-phenyl) -amide

Figure imgf000091_0002
Figure imgf000091_0002

Die unter Beispiel 19b) beschriebene Verbindung wurde aus 19a) analog zu Beispiel 16b) hergestellt.The compound described in Example 19b) was prepared from 19a) analogously to Example 16b).

1H-NMR (ppm, CDCI3, 400 MHz): 0.81-0.88 (1 H), 0.92-1.06 (3H), 2.30 (1 H), 2.58 (1 H), 2.69 (1 H), 3.15 (1 H), 7.03 (1 H), 7.36 (1 H), 7.54 (1 H), 7.78 (2H), 7.88 (1 H), 8.78 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.81-0.88 (1H), 0.92-1.06 (3H), 2.30 (1H), 2.58 (1H), 2.69 (1H), 3.15 (1 H), 7.03 (1 H), 7.36 (1 H), 7.54 (1 H), 7.78 (2H), 7.88 (1 H), 8.78 (1 H).

19c) rac-{2-Hydroxy-3-[1 -(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4-acetoxy- phenylethinyl)]-propionsäure} (4-cyano-3-trifluormethylphenyl)amid19c) rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-acetoxy-phenylethynyl)] - propionic acid} (4-cyano-3-trifluoromethyl-phenyl) -amide

Figure imgf000091_0003
Figure imgf000091_0003

Zu einer Lösung Triethylamin (3.9 ml_) in THF (7 ml_) wurde Palladium (II) acetat (3.7 mg), Triphenylphosphin (8.7 mg) und Kupfer (I) iodid (6.9 mg) addiert. Man ließ 2 Minuten nachrühren. Danach wurde 4-Acetoxyiodobenzol (64mg) addiert. Man ließ 5 Minuten nachrühren. Danach wurde die unter 19b) beschriebenen Verbindung (80 mg) addiert und man ließ man 2 Stunden im Ultraschadbad reagieren. Anschließend wurde das Reaktionsgemisch auf eiskalte gesättigte Ammoniumchloridlösung gegossen. Es wurde mit Ethylacetat extrahiert. Die vereingten organischen Phasen wurden mit gesättigter Natruimchloridlösung gewaschen, über Natruimsulfat getrocknet und konzentriert. Das Rohprodukt wurde an Kieselgel chromatographiert und dann mit HPLC chromatographiert. Man enhielt 23mg Produkt.To a solution of triethylamine (3.9 ml) in THF (7 ml) was added palladium (II) acetate (3.7 mg), triphenylphosphine (8.7 mg) and copper (I) iodide (6.9 mg). The mixture was stirred for 2 minutes. Thereafter, 4-acetoxyiodobenzene (64 mg) was added. The mixture was stirred for 5 minutes. Thereafter, the compound described under 19b) (80 mg) added and allowed to react for 2 hours in Ultraschalladbad. Subsequently, the reaction mixture was poured onto ice-cold saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was chromatographed on silica gel and then chromatographed by HPLC. One contained 23mg of product.

1H-NMR (ppm, CDCI3, 400 MHz): 0.88-0.94 (1 H), 1.02-1.13 (3H), 2.34 (3H), 2.44 (1 H), 2.77 (1 H), 3.10 (1 H), 7.03-7.10 (3H), 7.34-7.40 (3H), 7.63 (1 H), 7.84 (2H), 7.96 (1 H), 8.90 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.88-0.94 (1H), 1.02-1.13 (3H), 2.34 (3H), 2.44 (1H), 2.77 (1H), 3.10 (1H ), 7.03-7.10 (3H), 7.34-7.40 (3H), 7.63 (1H), 7.84 (2H), 7.96 (1H), 8.90 (1 H).

19d) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4-hydroxy- phenylethinyl)]-propionsäure} (4-cyano-3-trifluormethylphenyl)amid19d) rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-hydroxyphenylethynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide

Figure imgf000092_0001
Figure imgf000092_0001

Einer Lösung der unter 19c) beschriebenen Verbindung (18 mg) und Natriumhydrogencarbonat (41 mg) in MeOH (1 mL) wurde 2 Stunden nachgerührt. Das Reaktionsgemisch wurde mit Ethylacetat verdünnt. Die vereingten organischen Phasen wurden mit gesättigter Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet und konzentriert. Das Rohprodukt wurde an präperativer DC chromatographiert. Man erhielt 11 mg Produkt.To a solution of the compound described under 19c) (18 mg) and sodium bicarbonate (41 mg) in MeOH (1 mL) was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was chromatographed on preparative TLC. 11 mg of product were obtained.

1H-NMR (ppm, CDCI3, 400 MHz): 0.83-0.88 (1 H), 0.96-1.09 (3H), 2.38 (1 H), 2.71 (1 H), 2.98 (1 H), 5.17 (1 H), 6.75 (2H), 7.01 (1 H), 7.21 (2H), 7.32 (1 H), 7.58 (1 H), 7.79 (2H), 7.91 (1 H), 8.87 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.83-0.88 (1H), 0.96-1.09 (3H), 2.38 (1H), 2.71 (1H), 2.98 (1H), 5.17 (1 H), 6.75 (2H), 7.01 (1H), 7.21 (2H), 7.32 (1H), 7.58 (1H), 7.79 (2H), 7.91 (1H), 8.87 (1H).

Beispiel 20: rac-{2-Hydroxy-3-[1-(2-chlorphenyl)-cyclopropyl]-2-phenylethinyl)]-propionsäure}Example 20: Rac- {2-Hydroxy-3- [1- (2-chlorophenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid}

(4-cyano-3-trifluormethylphenyl)amid 20a) {3-[1-(2-chlorphenyl)-cyclopropyl]-2-oxopropionsäure}(4-cyano-3-trifluormethyl- phenyl)amid

Figure imgf000093_0001
(4-cyano-3-trifluoromethylphenyl) amide 20a) {3- [1- (2-chlorophenyl) -cyclopropyl] -2-oxopropionic acid} (4-cyano-3-trifluoromethylphenyl) amide
Figure imgf000093_0001

Die unter Beispiel 20a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Chlorphenyl)-cyclopropyl]-2-oxopropionsäure und 4-Amino-2-trifluormethylbenzonitril hergestellt.The compound described under Example 20a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-chlorophenyl) -cyclopropyl] -2-oxopropionic acid and 4-amino-2-trifluoromethylbenzonitrile.

1H-NMR (ppm, CDCI3, 300 MHz): 1.02 (4H), 3.36 (2H), 7.15-7.19 (2H), 7.32 (1 H), 7.47 (1 H), 7.82 (1 H), 7.92 (1 H), 8.04 (1 H), 8.94 (1 H). 1 H-NMR (ppm, CDCl 3 , 300 MHz): 1.02 (4H), 3.36 (2H), 7.15-7.19 (2H), 7.32 (1H), 7.47 (1H), 7.82 (1H), 7.92 (1H), 8.04 (1H), 8.94 (1H).

20b) rac-{2-Hydroxy-3-[1-(2-chlorphenyl)-cyclopropyl]-2-phenylethinyl]-propionsäure} (4- cyano-3-trifluormethylphenyl)amid20b) rac- {2-Hydroxy-3- [1- (2-chlorophenyl) -cyclopropyl] -2-phenylethynyl] -propionic acid} (4-cyano-3-trifluoromethyl-phenyl) -amide

Figure imgf000093_0002
Figure imgf000093_0002

Die unter Beispiel 20b) beschriebene Verbindung wurde aus 20a) analog zu Beispiel 1 b) hergestellt. 1H-NMR (ppm, CDCI3, 400 MHz): 0.80-0.88 (1 H), 0.96-1.03 (1 H), 1.09-1.28 (2H), 2.94 (2H), 7.04-7.14 (2H), 7.27-7.48 (8H), 7.79 (2H), 7.93 (1 H), 8.80 (1 H).The compound described under Example 20b) was prepared from 20a) analogously to Example 1 b). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.80-0.88 (1H), 0.96-1.03 (1H), 1.09-1.28 (2H), 2.94 (2H), 7.04-7.14 (2H), 7.27- 7.48 (8H), 7.79 (2H), 7.93 (1H), 8.80 (1H).

Beispiel 20c und 2Od:Example 20c and 2Od:

(+)-{2-Hydroxy-3-[1-(2-chlorphenyl)-cyclopropyl]-2-phenylethinyl)]-propionsäure} (4-cyano-3-trifluormethylphenyl)amid 20a und(+) - {2-Hydroxy-3- [1- (2-chlorophenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide 20a and

(-)-{2-Hydroxy-3-[1-(2-chlorphenyl)-cyclopropyl]-2-phenylethinyl)]-propionsäure}(-) - {2-Hydroxy-3- [1- (2-chlorophenyl) cyclopropyl] -2-phenylethynyl)] - propionic acid}

(4-cyano-3-trifluormethylphenyl)amid 20b(4-cyano-3-trifluoromethylphenyl) amide 20b

Das unter Beispiel 20b erhaltene racemische Gemisch wurde durch präparative chiraleThe racemic mixture obtained in Example 20b was purified by preparative chiral

HPLC (Säule Chiralpak AD 250x10 mm) in die Enantiomeren 20c und 2Od getrennt. 20c: [α]D 2o = +17.9° (CHCI3, 10.4 mg/1 ml_; λ=589 nM)HPLC (column Chiralpak AD 250x10 mm) separated into the enantiomers 20c and 2Od. 20c: [α] D 2 o = + 17.9 ° (CHCl 3 , 10.4 mg / 1 ml, λ = 589 nM)

2Od: [α]D 2o = -17.5° (CHCI3, 10.3 mg/1 ml_; λ=589 nM)2Od: [α] D 2 o = -17.5 ° (CHCl 3 , 10.3 mg / 1 ml, λ = 589 nM)

Beispiel 21 : rac-{2-Hydroxy-3-[1-(2-chlorphenyl)-cyclopropyl]-2-phenylethinyl)]-propionsäure} (4-cyano-3-chlorphenyl)amid 21 a) {3-[1 -(2-chlorphenyl)-cyclopropyl]-2-oxopropionsäure}(4-cyano-3-chlorphenyl)amid

Figure imgf000094_0001
Example 21: Rac- {2-Hydroxy-3- [1- (2-chlorophenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} (4-cyano-3-chlorophenyl) amide 21 a) {3- [1- (2-chlorophenyl) -cyclopropyl] -2-oxopropionic acid} (4-cyano-3-chlorophenyl) amide
Figure imgf000094_0001

Die unter Beispiel 21 a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-chlorphenyl)-cyclopropyl]-2-oxopropionsäure und 4-Amino-2-chlorbenzonitril hergestellt.The compound described in Example 21 a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-chlorophenyl) -cyclopropyl] -2-oxopropionic acid and 4-amino-2-chlorobenzonitrile.

1H-NMR (ppm, CDCI3, 300 MHz): 1.01 (4H), 3.35 (2H), 7.15-7.18 (2H), 7.32 (1 H), 7.45- 7.53 (2H), 7.64 (1 H), 7.91 (1 H), 8.81 (1 H). 1 H NMR (ppm, CDCl 3 , 300 MHz): 1.01 (4H), 3.35 (2H), 7.15-7.18 (2H), 7.32 (1H), 7.45-7.53 (2H), 7.64 (1H), 7.91 (1H), 8.81 (1H).

21 b) rac-{2-Hydroxy-3-[1 -(2-Chlorphenyl)-cyclopropyl]-2-phenylethinyl)]-propionsäure}- (4-cyano-3-chlorphenyl)amid21 b) rac- {2-hydroxy-3- [1- (2-chlorophenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} - (4-cyano-3-chlorophenyl) amide

Figure imgf000094_0002
Figure imgf000094_0002

Die unter Beispiel 21 b) beschriebene Verbindung wurde aus 21a) analog zu Beispiel 1 b) hergestellt. 1H-NMR (ppm, CDCI3, 400 MHz): 0.83 (1 H), 1.00 (1 H), 1.08-1.20 (2H), 2.89 (1 H), 7.07- 7.15 (2H), 7.29-7.49 (8H), 7.59 (1 H), 7.81 (1 H), 8.86 (1 H).The compound described in Example 21 b) was prepared from 21a) analogously to Example 1 b). 1 H NMR (ppm, CDCl 3 , 400 MHz): 0.83 (1H), 1.00 (1H), 1.08-1.20 (2H), 2.89 (1H), 7.07-7.15 (2H), 7.29-7.49 (8H ), 7.59 (1 H), 7.81 (1 H), 8.86 (1 H).

Beispiel 21c und 21d:Example 21c and 21d:

(+)-{2-Hydroxy-3-[1-(2-chlorphenyl)-cyclopropyl]-2-phenylethinyl)]-propionsäure}- (4-cyano-3-chlorphenyl)amid 21 c und(+) - {2-Hydroxy-3- [1- (2-chlorophenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} - (4-cyano-3-chlorophenyl) amide 21c and

(-)-{2-Hydroxy-3-[1-(2-chlorphenyl)-cyclopropyl]-2-phenylethinyl)]-propionsäure}-(-) - {2-Hydroxy-3- [1- (2-chlorophenyl) cyclopropyl] -2-phenylethynyl)] - propionic acid} -

(4-cyano-3-chlorphenyl)amid 21 d(4-cyano-3-chlorophenyl) amide 21 d

Das unter Beispiel 21 b erhaltene racemische Gemisch wurde durch präparative chiraleThe racemic mixture obtained in Example 21 b was purified by preparative chiral

HPLC (Säule Chiralpak AD 250x10 mm) in die Enantiomeren 21 c und 21d getrennt. 21 c: [α]D 20 = +26.9° (CHCI3, 10.3 mg/1 ml_; λ=589 nM)HPLC (column Chiralpak AD 250x10 mm) separated into the enantiomers 21 c and 21d. 21 c: [α] D 20 = + 26.9 ° (CHCl 3 , 10.3 mg / 1 ml, λ = 589 nM)

21 d: [α]D 2o = -26.5° (CHCI3, 10.4 mg/1 ml_; λ=589 nM) Beispiel 22: rac-{2-Hydroxy-3-[1-(2-chlorphenyl)-cyclopropyl]-2-phenylethinyl)]-propionsäure}-21 d: [α] D 2 o = -26.5 ° (CHCl 3 , 10.4 mg / 1 ml, λ = 589 nM) Example 22: Rac- {2-Hydroxy-3- [1- (2-chlorophenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} -

(4-nitro-3-trifluormethylphenyl)amid(4-nitro-3-trifluoromethylphenyl) amide

22a) {3-[1 -(2-Chlorphenyl)-cyclopropyl]-2-oxopropionsäure}(4-nitro-3-trifluormethyl- phenyl)amid22a) {3- [1- (2-chlorophenyl) -cyclopropyl] -2-oxopropionic acid} (4-nitro-3-trifluoromethylphenyl) amide

Figure imgf000095_0001
Figure imgf000095_0001

Die unter Beispiel 22a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Chlorphenyl)-cyclopropyl]-2-oxopropionsäure und 4-Nitro-3-trifluormethylanilin hergestellt.The compound described in Example 22a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-chlorophenyl) -cyclopropyl] -2-oxopropionic acid and 4-nitro-3-trifluoromethylaniline.

1H-NMR (ppm, CDCI3, 300 MHz): 1.07 (4H), 3.41 (2H), 7.20-7.24 (2H), 7.37 (1 H), 7.52 (1 H), 8.03 (2H), 8.09 (1 H), 9.01 (1 H). 1 H-NMR (ppm, CDCl 3 , 300 MHz): 1.07 (4H), 3.41 (2H), 7.20-7.24 (2H), 7.37 (1H), 7.52 (1H), 8.03 (2H), 8.09 ( 1H), 9.01 (1H).

22b) rac-{2-Hydroxy-3-[1 -(2-chlorphenyl)-cyclopropyl]-2-phenylethinyl)]-propionsäure}- (4-nitro-3-trifluormethylphenyl)amid22b) rac- {2-hydroxy-3- [1- (2-chlorophenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} - (4-nitro-3-trifluoromethylphenyl) amide

Figure imgf000095_0002
Figure imgf000095_0002

Die unter Beispiel 22b) beschriebene Verbindung wurde aus 22a) analog zu Beispiel 1 b) hergestellt. 1H-NMR (ppm, CDCI3, 400 MHz): 0.85 (1 H), 1.01 (1 H), 1.12-1.20 (2H), 2.93 (2H), 7.06- 7.14 (2H), 7.28-7.48 (7H), 7.87-7.97 (3H), 8.84 (1 H).The compound described under Example 22b) was prepared from 22a) analogously to Example 1 b). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.85 (1H), 1.01 (1H), 1.12-1.20 (2H), 2.93 (2H), 7.06- 7.14 (2H), 7.28-7.48 (7H) , 7.87-7.97 (3H), 8.84 (1H).

Beispiel 23: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-dimethyl- aminopropinj-propionsäure} (4-cyano-3-trifluormethylphenyl)amid

Figure imgf000096_0001
Example 23: Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-dimethyl-aminopropine-propionic acid} (4-cyano-3-trifluoromethyl-phenyl) -amide
Figure imgf000096_0001

Die unter Beispiel 23 beschriebene Verbindung wurde aus {3-[1-(2-Fluor-5- trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure} (4-cyano-3- trifluormethylphenyl)amid und 3-(N,N-dimethylamino)propin in Analogie zu Beispiel 1 b) hergestellt.The compound described in Example 23 was prepared from {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid} (4-cyano-3-trifluoromethylphenyl) amide and 3- (N, N-dimethylamino ) propyne in analogy to Example 1 b).

1H-NMR (ppm, CDCI3, 400 MHz): 0.80-0.87 (1 H), 0.93-1.07 (3H), 2.26-2.31 (7H), 2.74 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.80-0.87 (1H), 0.93-1.07 (3H), 2.26-2.31 (7H), 2.74

(1 H), 3.19 (2H), 7.06 (1 H), 7.37 (1 H), 7.56 (1 H), 7.82 (2H), 7.94 (1 H), 9.03 (1 H).(1h), 3.19 (2h), 7.06 (1h), 7.37 (1h), 7.56 (1h), 7.82 (2h), 7.94 (1h), 9.03 (1h).

Beispiel 24: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(1-methyl-1 H- imidazol-5-ylethinyl)]-propionsäure} (4-cyano-3-trifluormethylphenyl)amidExample 24: Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (1-methyl-1H-imidazol-5-ylethynyl)] - propionic acid} (4 cyano-3-trifluoromethylphenyl) amide

Figure imgf000096_0002
Figure imgf000096_0002

Die unter Beispiel 24 beschriebene Verbindung wurde aus {3-[1-(2-Fluor-5- trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure} (4-cyano-3- trifluormethylphenyl)amid und 1-Methyl-1-imidazol-5-ylethin analog zu Beispiel 1 b) hergestellt.The compound described in Example 24 was prepared from {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid} (4-cyano-3-trifluoromethylphenyl) amide and 1-methyl-1-imidazole 5-ylethine analogously to Example 1 b).

1H-NMR (ppm, CDCI3, 400 MHz): 0.77-0.84 (1 H), 0.91-1.05 (3H), 2.28 (1 H), 2.81 (1 H), 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.77-0.84 (1H), 0.91-1.05 (3H), 2.28 (1H), 2.81 (1H),

3.57 (3H), 7.01 (1 H), 7.09 (1 H), 7.28 (1 H), 7.38 (1 H), 7.52 (1 H), 7.73-7.81 (2H), 7.923.57 (3H), 7.01 (1H), 7.09 (1H), 7.28 (1H), 7.38 (1H), 7.52 (1H), 7.73-7.81 (2H), 7.92

(1 H), 9.24 (1 H).(1H), 9.24 (1H).

Beispiel 24a und 24b: (+)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(1-methyl-1 H- imidazol-5-ylethinyl)]-propionsäure}(4-cyano-3-trifluormethylphenyl)amid 24a und (-){2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(1-methyl-1 H- imidazol-5-ylethinyl)]-propionsäure}(4-cyano-3-trifluormethylphenyl)amid 24b Das unter Beispiel 24 erhaltene racemische Gemisch wurde durch präparative chirale HPLC (Säule Chiralpak AD 250x10 mm) in die Enantiomeren 24a und 24b getrennt. 24a: [α]D2o = +41.7° (CHCI3, 10.3 mg/1 ml_; λ=589 nM) 24b: [αf20 = -42.9° (CHCI3, 10.5 mg/1 ml_; λ=589 nM)Examples 24a and 24b: (+) - {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (1-methyl-1H-imidazol-5-ylethynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide 24a and (-) {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (1-methyl-1 H- imidazol-5-ylethynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide 24b The racemic mixture obtained in Example 24 was separated into the enantiomers 24a and 24b by preparative chiral HPLC (Chiralpak AD column 250 × 10 mm). 24a: [α] D 2o = + 41.7 ° (CHCl 3 , 10.3 mg / 1 ml, λ = 589 nM) 24b: [αf 20 = -42.9 ° (CHCl 3 , 10.5 mg / 1 ml, λ = 589 nM).

Beispiel 25: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(2-pyridyl- ethinyl)]-propionsäure}(4-cyano-3-trifluormethylphenyl)amidExample 25: Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (2-pyridylethynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide

Figure imgf000097_0001
Figure imgf000097_0001

Die unter Beispiel 25 beschriebene Verbindung wurde aus {3-[1-(2-Fluor-5- trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure} (4-cyano-3- trifluormethylphenyl)amid und 2-pyridinylethin analog zu Beispiel 1 b) hergestellt. 1H-NMR (ppm, CDCI3, 400 MHz): 0.78-0.83 (1 H), 0.92-1.03 (3H), 2.45 (1 H), 2.75 (1 H), 5.39 (1 H), 6.95 (1 H), 7.24 (1 H), 7.27-7.34 (2H), 7.54 (1 H), 7.67 (1 H), 7.74 (1 H), 7.82 (1 H), 7.94 (1 H), 8.42 (1 H), 9.34 (1 H).The compound described in Example 25 was prepared from {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid} (4-cyano-3-trifluoromethylphenyl) amide and 2-pyridinylethine analogously to Example 1b ) produced. 1 H NMR (ppm, CDCl 3 , 400 MHz): 0.78-0.83 (1H), 0.92-1.03 (3H), 2.45 (1H), 2.75 (1H), 5.39 (1H), 6.95 (1H ), 7.24 (1H), 7.27-7.34 (2H), 7.54 (1H), 7.67 (1H), 7.74 (1H), 7.82 (1H), 7.94 (1H), 8.42 (1H) , 9.34 (1 H).

Beispiel 26: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4-carboxy- ethinyl)]-propionsäure}(4-cyano-3-trifluormethylphenyl)amidExample 26: Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-carboxyethynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide

26a) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4-methoxy- carbonylethinyl)]-propionsäure}(4-cyano-3-trifluormethylphenyl)amid26a) rac- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-methoxycarbonylethynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide

Figure imgf000097_0002
Die unter Beispiel 26a) beschriebene Verbindung wurde aus 19b) und 4- lodbenzoesäuremethylester analog zu Beispiel 19c) hergestellt.
Figure imgf000097_0002
The compound described under Example 26a) was prepared from 19b) and methyl 4-iodobenzoate analogously to Example 19c).

1H-NMR (ppm, CDCI3, 400 MHz): 0.85-0.92 (1 H), 0.96-1.06 (3H), 2.44 (1 H), 2.62 (1 H), 3.18 (1 H), 3.92 (3H), 7.01 (1 H), 7.21-7.38 (3H), 7.58 (1 H), 7.75-7.83 (2H), 7.92 (1 H), 7.94 (2H), 8.84 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.85-0.92 (1H), 0.96-1.06 (3H), 2.44 (1H), 2.62 (1H), 3.18 (1H), 3.92 (3H ), 7.01 (1H), 7.21-7.38 (3H), 7.58 (1H), 7.75-7.83 (2H), 7.92 (1H), 7.94 (2H), 8.84 (1H).

26b) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4-carboxy- ethinyl)]-propionsäure}(4-cyano-3-trifluormethylphenyl)amid26b) rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-carboxyethynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide

Figure imgf000098_0001
Figure imgf000098_0001

Eine Lösung der unter 26a) beschriebenen Verbindung (40 mg) und NatriumhydroxidA solution of the compound described under 26a) (40 mg) and sodium hydroxide

(2M aq, 90 μl_) in THF (2 ml_) und EtOH (1 ml_) wurde 16 Stunden bei 23°C nachgerührt. Das Reaktionsgemisch wurde mit HCl (2N aq, 350 μl_) versetzt und mit Dichlormethan extrahiert. Die vereingten organischen Phasen wurden mit gesättigter Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet und konzentriert. Das Rohprodukt wurde an präperativer DC chromatographiert. Man enhalt 15mg Produkt. 1H-NMR (ppm, DMSOd6, 400 MHz): 0.60-0.66 (1 H), 0.94-1.00 (2H), 1.10-1.16 (1 H), 2.05 (1 H), 2.94 (1 H), 7.22 (1 H), 7.33 (1 H), 7.37 (2H), 7.53-7.67 (2H), 7.88 (2H), 8.04 (2H), 8.20 (1 H), 10.67 (1 H).(2M aq, 90 μl_) in THF (2 ml) and EtOH (1 ml) was stirred for 16 hours at 23 ° C. The reaction mixture was treated with HCl (2N aq, 350 μl) and extracted with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was chromatographed on preparative TLC. It contains 15mg of product. 1 H-NMR (ppm, DMSOd 6 , 400 MHz): 0.60-0.66 (1H), 0.94-1.00 (2H), 1.10-1.16 (1H), 2.05 (1H), 2.94 (1H), 7.22 (1H), 7.33 (1H), 7.37 (2H), 7.53-7.67 (2H), 7.88 (2H), 8.04 (2H), 8.20 (1 H), 10.67 (1 H).

Beispiel 26c und 26d:Example 26c and 26d:

(+)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4-carboxy- ethinyl)]-propionsäure}(4-cyano-3-trifluormethylphenyl)amid 26c und (-)-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(4-carboxy- ethinyl)]-propionsäure}(4-cyano-3-trifluormethylphenyl)amid 26d(+) - {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-carboxyethynyl)] - propionic acid} (4-cyano-3-trifluoromethyl-phenyl) -amide 26c and (-) - {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (4-carboxyethynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl ) amid 26d

Das unter Beispiel 26b erhaltene racemische Gemisch wurde durch präparative chirale HPLC (Säule Chiralpak AD 250x10 mm) in die Enantiomeren 26c und 26d getrennt. 26c: [α]D2o = +3.8° (CHCI3, 5.2 mg/1 mL; λ=589 nM) 26d: [α]D 2o = -2.4° (CHCI3, 5.2 mg/1 mL; λ=589 nM) Beispiel 27: rac-2-{Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenyl)]- propionsäure}(3,4-dichlorphenyl)amidThe racemic mixture obtained in Example 26b was separated by preparative chiral HPLC (column Chiralpak AD 250 × 10 mm) into the enantiomers 26c and 26d. 26c: [α] D 2o = + 3.8 ° (CHCl 3 , 5.2 mg / 1 mL, λ = 589 nM) 26d: [α] D 2 o = -2.4 ° (CHCl 3 , 5.2 mg / 1 mL, λ = 589 nM) Example 27: rac-2- {hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) cyclopropyl] -2-phenyl)] - propionic acid} (3,4-dichlorophenyl) amide

27a) {3-[1 -(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure}(3,4-dichlor- phenyl)amid27a) {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid} (3,4-dichlorophenyl) amide

Figure imgf000099_0001
Figure imgf000099_0001

Die unter Beispiel 27a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- oxopropionsäure und 3,4-Dichloranilin hergestellt.The compound described under example 27a) was prepared analogously to the process described under example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and 3,4-dichloroaniline.

1H-NMR (ppm, CDCI3, 300 MHz): 1.00 (4H), 3.30 (2H), 7.09 (1 H), 7.40 (2H), 7.48 (1 H), 7.71 (1 H), 7.84 (1 H), 8.62 (1 H). 1 H-NMR (ppm, CDCl 3 , 300 MHz): 1.00 (4H), 3.30 (2H), 7.09 (1H), 7.40 (2H), 7.48 (1H), 7.71 (1H), 7.84 (1 H), 8.62 (1 H).

27b) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenylethinyl)]- propionsäure}(3,4-dichlorphenyl)amid27b) rac- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} (3,4-dichlorophenyl) amide

Figure imgf000099_0002
Figure imgf000099_0002

Die unter Beispiel 27b) beschriebene Verbindung wurde aus 27a) analog zu Beispiel 1 b) hergestellt. 1H-NMR (ppm, CDCI3, 400 MHz): 0.90-0.94 (1 H), 1.02-1.13 (3H), 2.49 (1 H), 2.65 (1 H), 3.06 (1 H), 7.05 (1 H), 7.32-7.43 (8H), 7.67 (1 H), 7.77 (1 H), 8.52 (1 H).The compound described under Example 27b) was prepared from 27a) analogously to Example 1 b). 1 H NMR (ppm, CDCl 3 , 400 MHz): 0.90-0.94 (1H), 1.02-1.13 (3H), 2.49 (1H), 2.65 (1H), 3.06 (1H), 7.05 (1H ), 7.32-7.43 (8H), 7.67 (1H), 7.77 (1H), 8.52 (1H).

Beispiel 27c und 27d:Example 27c and 27d:

(+)-2-{Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenyl)]- propionsäure}(3,4-dichlorphenyl)amid 27c und(+) - 2- {hydroxy-3- [1- (2-fluoro-5-trifluoromethyl-phenyl) -cyclopropyl] -2-phenyl) -propionic acid} (3,4-dichlorophenyl) -amide 27c and

(-)-2-{Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenyl- ethinyl)]-propionsäure}(3,4-dichlorphenyl)amid 27d(-) - 2- {Hydroxy-3- [1- (2-Fluoro-5-trifluoromethyl-phenyl) -cyclopropyl] -2-phenyl-ethynyl) -propionic acid} (3,4-dichlorophenyl) -amide 27d

Das unter Beispiel 27b erhaltene racemische Gemisch wurde durch präparative chiraleThe racemic mixture obtained in Example 27b was purified by preparative chiral

HPLC (Säule Chiralpak AD 250x10 mm) in die Enantiomeren 27c und 27d getrennt. 27c: [α]D 2o = +15.4° (CHCI3, 9.1 mg/1 ml_; λ=589 nM) 27d: [α]D2o = -15.9° (CHCI3, 10.1 mg/1 ml_; λ=589 nM)HPLC (column Chiralpak AD 250x10 mm) separated into the enantiomers 27c and 27d. 27c: [α] D 2 o = + 15.4 ° (CHCl 3 , 9.1 mg / 1 ml, λ = 589 nM) 27d: [α] D 2o = -15.9 ° (CHCl 3 , 10.1 mg / 1 ml, λ = 589 nM)

Beispiel 28: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3-(1- piperidenyl)propinyl)]-propionsäure} (4-cyano-3-trifluormethylphenyl)amidExample 28: rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3- (1-piperidenyl) propynyl)] - propionic acid} (4-cyano-3 trifluoromethylphenyl) amide

28a) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3-bromo- propinyl)]-propionsäure}(4-cyano-3-trifluormethylphenyl)amid28a) rac- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3-bromopropynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide

Figure imgf000100_0001
Zu einer Lösung von 320 μl Diisopropylamin in Tetrahydrofuran (5 ml) wurde bei -300C n-Butyllithium (170 μl, 1 ,6 M in Hexan) addiert. Man ließ 30 Minuten bei dieser Temperatur nachrühren und nach -78°C abgekühlt. Dann tropfte man eine Lösung 3- Brompropin (170 μL) in 4 mL Tetrahydrofuran hinzu. Man ließ 1 Stunde bei dieser Temperatur nachrühren und tropfte dann eine Lösung {3-[1-(2-Fluor-5- trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure} (4-cyano-3- trifluormethylphenyl)amid (530 mg) in 4 ml Tetrahydrofuran hinzu. Anschließend ließ man ca. 3 h bei dieser Temperatur nachrühren. Danach wurde das Reaktionsgemisch auf eiskalte gesättigte Ammoniumchloridlösung gegossen. Es wurde mit Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden mit gesättigter Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet und konzentriert. Das Rohprodukt wurde an Kieselgel chromatographiert. Man erhielt 184 mg Produkt. 1H-NMR (ppm, CDCI3, 400 MHz): 0.83-0.88 (1 H), 0.93-1.06 (3H), 2.28 (1 H), 2.64 (1 H), 2.99 (1 H), 3.80 (2H), 7.07 (1 H), 7.39 (1 H), 7.59 (1 H), 7.78 (2H), 7.90 (1 H), 8.75 (1 H).
Figure imgf000100_0001
To a solution of 320 ul of diisopropylamine in tetrahydrofuran (5 ml) was added at -30 0 C n-butyl lithium (170 uL, 1 6 M in hexane). The mixture was stirred for 30 minutes at this temperature and cooled to -78 ° C. Then a solution of 3-bromopropyne (170 μL) in 4 mL tetrahydrofuran was added dropwise. The mixture was stirred at this temperature for 1 hour and then a solution of {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid} (4-cyano-3-trifluoromethylphenyl) amide (530 mg) was added dropwise. in 4 ml of tetrahydrofuran. Then allowed to stir for about 3 h at this temperature. Thereafter, the reaction mixture was poured onto ice-cold saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was chromatographed on silica gel. This gave 184 mg of product. 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.83-0.88 (1H), 0.93-1.06 (3H), 2.28 (1H), 2.64 (1H), 2.99 (1H), 3.80 (2H) , 7.07 (1 H), 7.39 (1 H), 7.59 (1 H), 7.78 (2H), 7.90 (1 H), 8.75 (1 H).

28b) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3-(1- piperidenyl)propinyl)]-propionsäure} (4-cyano-3-trifluormethylphenyl)amid28b) rac- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3- (1-piperidenyl) propynyl)] - propionic acid} (4-cyano-3-) trifluoromethylphenyl) amide

Figure imgf000100_0002
Zu einer Suspension der unter 28a) beschriebenen Verbindung (50 mg) und Kaliumcarbonat (24 mg) in Dimethylformamid (2 ml_) wurde Piperidin (17 μl_) addiert. Man ließ 2 Stunden nachgerühren. Das Reaktionsgemisch wurde mit Ethylacetat verdünnt. Die vereingten organischen Phasen wurden mit Wasser und gesättigter Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet und konzentriert. Das Rohprodukt wurde an präperativer DC chromatographiert. Man erhielt 37mg Produkt. 1H-NMR (ppm, CDCI3, 400 MHz): 0.76-0.81 (1 H), 0.89-1.02 (3H), 1.41 (2H), 1.57 (4H), 2.24 (1 H), 2.42 (4H), 2.68 (1 H), 3.15 (2H), 7.02 (1 H), 7.34 (1 H), 7.52 (1 H), 7.77 (2H), 7.87 (1 H), 8.95 (1 H).
Figure imgf000100_0002
To a suspension of the compound described under 28a) (50 mg) and potassium carbonate (24 mg) in dimethylformamide (2 ml) was added piperidine (17 μl). The mixture was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was chromatographed on preparative TLC. 37mg product was obtained. 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.76-0.81 (1H), 0.89-1.02 (3H), 1.41 (2H), 1.57 (4H), 2.24 (1H), 2.42 (4H), 2.68 (1H), 3.15 (2H), 7.02 (1H), 7.34 (1H), 7.52 (1H), 7.77 (2H), 7.87 (1H), 8.95 (1H).

Beispiel 29: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3-(4-methyl-1- piperazinyl)propin)]-propionsäure}(4-cyano-3-trifluormethylphenyl)amidExample 29: Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3- (4-methyl-1-piperazinyl) propyne)] - propionic acid} (4 cyano-3-trifluoromethylphenyl) amide

Figure imgf000101_0001
Figure imgf000101_0001

Die unter Beispiel 29 beschriebene Verbindung wurde aus rac-{2-Hydroxy-3-[1-(2-Fluor- 5-trifluormethylphenyl)-cyclopropyl]-2-(3-bromopropinyl)]-propionsäure} (4-cyano-3- trifluormethylphenyl)amid (siehe Beispiel 28a) und 1-Methylpiperazin in analog zu Beispiel 28b) hergestellt.The compound described in Example 29 was prepared from rac - {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3-bromopropinyl)] - propionic acid} (4-cyano-3 - trifluoromethylphenyl) amide (see Example 28a) and 1-methylpiperazine prepared in analogy to Example 28b).

1H-NMR (ppm, CDCI3, 400 MHz): 0.75-0.83 (1 H), 0.90-1.03 (3H), 1.86 (4H), 2.24 (1 H), 2.28 (3H), 2.55 (4H), 2.72 (1 H), 3.26 (2H), 7.01 (1 H), 7.32 (1 H), 7.51 (1 H), 7.78 (2H), 7.88 (1 H), 8.95 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.75-0.83 (1H), 0.90-1.03 (3H), 1.86 (4H), 2.24 (1H), 2.28 (3H), 2.55 (4H), 2.72 (1H), 3.26 (2H), 7.01 (1H), 7.32 (1H), 7.51 (1H), 7.78 (2H), 7.88 (1H), 8.95 (1H).

Beispiel 30: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3-(4-carboxy- piperidin-1-yl)propinyl)]-propionsäure}(4-cyano-3-trifluormethylphenyl)amidExample 30: Rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3- (4-carboxy-piperidin-1-yl) -propynyl)] -propionic acid} (4-cyano-3-trifluoromethylphenyl) amide

30a) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3-(4-carboxy- methylpiperidin-1-yl)propinyl)]-propionsäure}(4-cyano-3-trifluormethylphenyl)amid

Figure imgf000102_0001
30a) rac- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3- (4-carboxymethylpiperidin-1-yl) propynyl)] - propionic acid} ( 4-cyano-3-trifluoromethylphenyl) amide
Figure imgf000102_0001

Die unter Beispiel 30a beschriebene Verbindung wurde aus rac-{2-Hydroxy-3-[1-(2- Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3-bromopropinyl)]-propionsäure} (4-cyano- 3-trifluormethylphenyl)amid und Piperidine-4-carboxylsäuremethylester in Analogie zu Beispiel 28b) hergestellt.The compound described in Example 30a was prepared from rac - {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3-bromopropinyl)] - propionic acid} (4-cyano-3 -trifluoromethylphenyl) amide and piperidine-4-carboxylate in analogy to Example 28b).

1H-NMR (ppm, CDCI3, 400 MHz): 0.77-0.82 (1 H), 0.91-1.02 (3H), 1.72-1.80 (2H), 1.91 (2H), 2.15 (2H), 2.23 (1 H), 2.30-2.25 (1 H), 2.70 (1 H), 2.82 (2H), 3.19 (2H), 3.67 (3H), 7.02 (1 H), 7.33 (1 H), 7.52 (1 H), 7.77 (2H), 7.88 (1 H), 8.93 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.77-0.82 (1H), 0.91-1.02 (3H), 1.72-1.80 (2H), 1.91 (2H), 2.15 (2H), 2.23 (1H ), 2.30-2.25 (1H), 2.70 (1H), 2.82 (2H), 3.19 (2H), 3.67 (3H), 7.02 (1H), 7.33 (1H), 7.52 (1H), 7.77 (2H), 7.88 (1H), 8.93 (1H).

30b) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3-(4-carboxy- piperidin-1-yl)propinyl)]-propionsäure}(4-cyano-3-trifluormethylphenyl)amid30b) rac- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3- (4-carboxy-piperidin-1-yl) -propynyl)] - propionic acid} ( 4-cyano-3-trifluoromethylphenyl) amide

Figure imgf000102_0002
Figure imgf000102_0002

Die unter Beispiel 30b) beschriebene Verbindung wurde aus 30a) analog zu Beispiel 26b) hergestellt.The compound described under Example 30b) was prepared from 30a) analogously to Example 26b).

1H-NMR (ppm, CDCI3, 400 MHz): 0.76 (1 H), 0.86 (1 H), 0.94 (1 H), 1.03 (1 H), 1.72 (2H), 1.98 (2H), 2.15-2.26 (4H), 2.58 (1 H), 3.15-3.29 (4H), 6.92 (1 H), 7.25-7.28 (1 H), 7.50 (1 H), 7.73 (1 H), 7.95 (2H), 9.71 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.76 (1H), 0.86 (1H), 0.94 (1H), 1.03 (1H), 1.72 (2H), 1.98 (2H), 2.15- 2.26 (4H), 2.58 (1H), 3.15-3.29 (4H), 6.92 (1H), 7.25-7.28 (1H), 7.50 (1H), 7.73 (1H), 7.95 (2H), 9.71 (1H).

Beispiel 31 : rac-2-{Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenyl- ethinyl)]-propionsäure}(5-indanyl)amidExample 31: rac-2- {hydroxy-3- [1- (2-fluoro-5-trifluoromethyl-phenyl) -cyclopropyl] -2-phenyl-ethynyl) -propionic acid} (5-indanyl) -amide

31 a) {3-[1 -(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure} (5-indanyl)- amid31 a) {3- [1- (2-Fluoro-5-trifluoromethyl-phenyl) -cyclopropyl] -2-oxo-propionic acid} (5-indanyl) -amide

Figure imgf000102_0003
Die unter Beispiel 31 a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- oxopropionsäure und 5-Aminoindan hergestellt.
Figure imgf000102_0003
The compound described in Example 31 a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and 5-aminoindan.

1H-NMR (ppm, CDCI3, 300 MHz): 0.99 (4H), 2.07 (2H), 2.88 (4H), 3.32 (2H), 7.09 (1 H), 7.18 (1 H), 7.25-7.28 (1 H), 7.45-7.51 (2H), 7.73 (1 H), 8.57 (1 H). 1 H-NMR (ppm, CDCl 3 , 300 MHz): 0.99 (4H), 2.07 (2H), 2.88 (4H), 3.32 (2H), 7.09 (1H), 7.18 (1H), 7.25-7.28 ( 1H), 7.45-7.51 (2H), 7.73 (1H), 8.57 (1H).

31 b) rac-2-{Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenylethinyl)]- propionsäure} (5-indanyl)amid31 b) rac-2- {hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} (5-indanyl) amide

Figure imgf000103_0001
Die unter Beispiel 31 b) beschriebene Verbindung wurde aus 31a) analog zu Beispiel 1 b) hergestellt.
Figure imgf000103_0001
The compound described in Example 31 b) was prepared from 31a) analogously to Example 1 b).

1H-NMR (ppm, CDCI3, 400 MHz): 0.84-1.08 (4H), 2.08 (2H), 2.45 (1 H), 2.54 (1 H), 2.89 (4H), 3.19 (1 H), 6.99 (1 H), 7.17 (2H), 7.28-7.34 (6H), 7.43 (1 H), 7.64 (1 H), 8.32 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.84-1.08 (4H), 2.08 (2H), 2.45 (1H), 2.54 (1H), 2.89 (4H), 3.19 (1H), 6.99 (1H), 7.17 (2H), 7.28-7.34 (6H), 7.43 (1H), 7.64 (1H), 8.32 (1H).

Beispiel 32: rac-2-{Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenyl- ethinyl)]-propionsäure}(3,4-dimethylphenyl)amidExample 32: rac-2- {hydroxy-3- [1- (2-fluoro-5-trifluoromethyl-phenyl) -cyclopropyl] -2-phenyl-ethynyl) -propionic acid} (3,4-dimethyl-phenyl) -amide

32a) {3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure}(3,4- dimethylphenyl)amid32a) {3- [1- (2-fluoro-5-trifluoromethyl-phenyl) -cyclopropyl] -2-oxo-propionic acid} (3,4-dimethyl-phenyl) -amide

Figure imgf000103_0002
Figure imgf000103_0002

Die unter Beispiel 32a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- oxopropionsäure und 3,4-Dimethylanilin hergestellt. 1H-NMR (ppm, CDCI3, 300 MHz): 0.99 (4H), 2.23 (3H), 2.25 (3H), 3.32 (2H), 7.06-7.11 (2H), 7.31 (1 H), 7.36 (1 H), 7.48 (1 H), 7.73 (1 H), 8.53 (1 H).The compound described under Example 32a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and 3,4-dimethylaniline. 1 H NMR (ppm, CDCl 3 , 300 MHz): 0.99 (4H), 2.23 (3H), 2.25 (3H), 3.32 (2H), 7.06-7.11 (2H), 7.31 (1H), 7.36 (1H ), 7.48 (1H), 7.73 (1H), 8.53 (1H).

32b) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenylethinyl)]- propionsäure}(3,4-dimethylphenyl)amid

Figure imgf000104_0001
32b) rac- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} (3,4-dimethylphenyl) amide
Figure imgf000104_0001

Die unter Beispiel 32b) beschriebene Verbindung wurde aus 32a) analog zu Beispiel 1 b) hergestellt.The compound described under Example 32b) was prepared from 32a) analogously to Example 1 b).

1H-NMR (ppm, CDCI3, 400 MHz): 0.86 (1 H), 0.94 (1 H), 0.98-1.05 (2H), 2.23 (3H), 2.25 (3H), 2.45 (1 H), 2.53 (1 H), 3.18 (1 H), 6.99 (1 H), 7.08 (1 H), 7.23-7.33 (8H), 7.64 (1 H), 8.28 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.86 (1H), 0.94 (1H), 0.98-1.05 (2H), 2.23 (3H), 2.25 (3H), 2.45 (1H), 2.53 (1H), 3.18 (1H), 6.99 (1H), 7.08 (1H), 7.23-7.33 (8H), 7.64 (1H), 8.28 (1H).

Beispiel 33: rac-2-{Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenyl- ethinyl)]-propionsäure}(6-quinonlinyl)amidExample 33: rac-2- {hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenyl-ethynyl) -propionic acid} (6-quinonyl-linyl) -amide

33a) {3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-oxopropionsäure}(6- quinolinyl)amid33a) {3- [1- (2-Fluoro-5-trifluoromethyl-phenyl) -cyclopropyl] -2-oxo-propionic acid} (6-quinolinyl) -amide

Figure imgf000104_0002
Figure imgf000104_0002

Die unter Beispiel 33a) beschriebene Verbindung wurde analog zum unter Beispiel 1a) beschriebenen Verfahren aus 3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2- oxopropionsäure und 6-Aminochinolin hergestellt.The compound described in Example 33a) was prepared analogously to the process described under Example 1a) from 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-oxopropionic acid and 6-aminoquinoline.

1H-NMR (ppm, CDCI3, 300 MHz): 1.02 (4H), 3.37 (2H), 7.10 (1 H), 7.41 (1 H), 7.49 (1 H), 7.66 (1 H), 7.75 (1 H), 8.1 1 (2H), 8.37 (1 H), 8.85-8.87 (2H). 1 H-NMR (ppm, CDCl 3 , 300 MHz): 1.02 (4H), 3.37 (2H), 7.10 (1H), 7.41 (1H), 7.49 (1H), 7.66 (1H), 7.75 ( 1H), 8.1 1 (2H), 8.37 (1H), 8.85-8.87 (2H).

33b) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-phenylethinyl)]- propionsäure} (6-quinolinyl)amid33b) rac- {2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2-phenylethynyl)] - propionic acid} (6-quinolinyl) amide

Figure imgf000104_0003
Die unter Beispiel 33b) beschriebene Verbindung wurde aus 33a) analog zu Beispiel 1 b) hergestellt.
Figure imgf000104_0003
The compound described under Example 33b) was prepared from 33a) analogously to Example 1 b).

1H-NMR (ppm, CDCI3, 400 MHz): 0.86-1.09 (4H), 2.52 (1 H), 2.66 (1 H), 3.74 (1 H), 6.97 (1 H), 7.28-7.41 (7H), 7.56 (1 H), 7.66 (1 H), 8.05 (1 H), 8.12 (1 H), 8.29 (1 H), 8.74 (1 H), 8.83 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.86-1.09 (4H), 2.52 (1H), 2.66 (1H), 3.74 (1H), 6.97 (1H), 7.28-7.41 (7H ), 7.56 (1 H), 7.66 (1 H), 8.05 (1 H), 8.12 (1 H), 8.29 (1 H), 8.74 (1 H), 8.83 (1 H).

Beispiel 34: rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3-amino- propinyl)]-propionsäure} (4-cyano-3-trifluormethylphenyl)amidExample 34: rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3-amino-propynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide

34a) rac-{2-Hydroxy-3-[1-(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3- azidopropinyl)]-propionsäure} (4-cyano-3-trifluormethylphenyl)amid34a) rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3-azidopropynyl)] - propionic acid} (4-cyano-3-trifluoromethylphenyl) amide

Figure imgf000105_0001
Zu einer Lösung der unter 28a) beschriebenen Verbindung (130 mg) in Dimethylformamid (2 ml_) wurde Natriumazid (28 mg) addiert. Man ließ 4 Stunden nachgerühren. Das Reaktionsgemisch wurde mit Ethylacetat verdünnt. Die vereingten organischen Phasen wurden mit Wasser und gesättigter Natruimchloridlösung gewaschen, über Natruimsulfat getrocknet und konzentriert. Das Rohprodukt wurde mit Kieselgel chromatographiert. Man erhielt 86mg Produkt.
Figure imgf000105_0001
To a solution of the compound described under 28a) (130 mg) in dimethylformamide (2 ml) was added sodium azide (28 mg). The mixture was stirred for 4 hours. The reaction mixture was diluted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was chromatographed with silica gel. 86mg product was obtained.

1H-NMR (ppm, CDCI3, 400 MHz): 0.82-1.03 (4H), 2.32 (1 H), 2.68 (1 H), 3.12 (1 H), 3.85 (2H), 7.06 (1 H), 7.38 (1 H), 7.56 (1 H), 7.77 (2H), 7.88 (1 H), 8.76 (1 H). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.82-1.03 (4H), 2.32 (1H), 2.68 (1H), 3.12 (1H), 3.85 (2H), 7.06 (1H), 7.38 (1H), 7.56 (1H), 7.77 (2H), 7.88 (1H), 8.76 (1H).

34b) rac-{2-Hydroxy-3-[1 -(2-Fluor-5-trifluormethylphenyl)-cyclopropyl]-2-(3-amino- propinyl)]-propionsäure} (4-cyano-3-trifluormethylphenyl)amid34b) rac- {2-Hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl] -2- (3-amino-propynyl)] - propionic acid} (4-cyano-3-trifluoromethyl-phenyl) -amide

Figure imgf000105_0002
Figure imgf000105_0002

Zu einer Lösung der unter 34a) beschriebenen Verbindung (73 mg) in Tetra h yd rofu ranTo a solution of the compound described under 34a) (73 mg) in Tetra h yd rofu ran

(2 mL) und Wasser (20 μL) wurde Triphenylphosphin (42 mg) addiert. Man ließ 7.5 Stunden nachgerührt. Das Reaktionsgemisch wurde mit Ethylacetat verdünnt. Die vereingten organischen Phasen wurden mit gesättigter(2 mL) and water (20 μL) were added to triphenylphosphine (42 mg). The mixture was stirred for 7.5 hours. The reaction mixture was diluted with ethyl acetate. The The combined organic phases were saturated

Natriumhydrogenkarbonatlösung und gesättigter Natruimchloridlösung gewaschen, über Natruimsulfat getrocknet und konzentriert. Das Rohprodukt wurde mit Kieselgel chromatographiert. Man erhielt 12mg Produkt. 1H-NMR (ppm, CDCI3, 400 MHz): 0.83 (1 H), 0.92-1.00 (3H), 2.28 (1 H), 2.60 (1 H), 3.36 (2H), 7.04 (1 H), 7.35 (1 H), 7.53 (1 H), 7.78 (2H), 7.91 (1 H), 8.97 (1 H). Washed sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was chromatographed with silica gel. This gave 12 mg of product. 1 H NMR (ppm, CDCl 3 , 400 MHz): 0.83 (1H), 0.92-1.00 (3H), 2.28 (1H), 2.60 (1H), 3.36 (2H), 7.04 (1H), 7.35 (1H), 7.53 (1H), 7.78 (2H), 7.91 (1H), 8.97 (1H).

Claims

Patentansprüche claims 1. Verbindungen der allgemeinen Formel I gelöst1. compounds of general formula I solved
Figure imgf000107_0001
worin
Figure imgf000107_0001
wherein R1 und R2 unabhängig voneinander ein Wasserstoffatom, eine verzweigte oder unverzweigte CrC5- Alkylgruppe, ferner gemeinsam mit dem C-Atom der Kette einen Ring mit insgesamt 3-7 Gliedern bilden, R3 ein Rest C≡C-Ra, wobeiR 1 and R 2 are each independently a hydrogen atom, a branched or unbranched C r C 5 - alkyl group, further together with the C atom of the chain form a ring having a total of 3-7 members, R 3 is a radical C≡CR a , wherein Ra ein Wasserstoff oder ein gegebenenfalls ein- oder mehrfach, gleich oder verschieden mit K substituiertes C1- C8-AIkVl, C2-C8-Alkenyl, C2-C8-Al kiny I, C3-Ci0-Cycloalkyl, 3-8-gliedriges Heterocycloalkyl oder ein gegebenenfalls ein- oder mehrfach, gleich oder verschieden mit L substituiertes C6-Ci2-Aryl oder 3-8-gliedriges Heteroaryl oder Silicium bedeutet, K ein Cyano, Halogen, Hydroxy, Nitro, Azido,R a is hydrogen or an optionally mono- or polysubstituted, identically or differently, with K-substituted C 1 - C 8 -alkyl, C 2 -C 8 alkenyl, C 2 -C 8 -alkyl kiny I, C 3 -C 0 - cycloalkyl, 3-8 membered heterocycloalkyl or optionally substituted one or more times, identically or differently, with L C 6 -C 2 signifies aryl or 3-8-membered heteroaryl or silicon, K is a cyano, halogen, hydroxy, nitro, azido, -C(O)Rb, CO2Rb, -O-Rb, -OSiRbRcRd -S-Rb, SO2NRcRd, -C(O)-NRcRd, -OC(O)-NRcRd,-C (O) R b , CO 2 R b , -OR b , -OSiR b R c R d -SR b , SO 2 NR c R d , -C (O) -NR c R d , -OC (O ) -NR c R d , -C=NORb, -NRcRd oder ein gegebenenfalls ein- oder mehrfach, gleich oder verschieden mit M substituiertes C3-Ci0-Cycloalkyl, 3-8-gliedriges Heterocycloalkyl oder gegebenenfalls ein- oder mehrfach, gleich oder verschieden mit L substituiertes C6-C12-Aryl oder 3-8-gliedriges Heteroaryl ist,-C = NOR b, -NR c R d, or an optionally mono- or polysubstituted, identically or differently, with M substituted C 3 -C 0 cycloalkyl, 3-8 membered heterocycloalkyl or optionally substituted one or more times, identically or differently, with L is substituted C 6 -C 12 -aryl or 3-8-membered heteroaryl, L d-C8-Alkyl, C2-C8-Alkenyl, C2-C8-Alkinyl, C1-C6- Perfluoralkyl, CrC6-Perfluoralkoxy, C1-C6-AIkOXy- d-C6-alkoxy, (CH2)p-C3-C10-Cycloalkyl, (CH2)P-L dC 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 6 perfluoroalkyl, CrC 6 perfluoroalkoxy, C 1 -C 6 alkoxy dC 6 alkoxy, (CH 2 ) p -C 3 -C 10 -cycloalkyl, (CH 2 ) P - Heterocycloalkyl, (CH2)PCN, (CH2)pHal, (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)PNR6CONR0R0, -(CH2)pNReCOORb, -(CH2)pNReC(NH)NRcRd,Heterocycloalkyl, (CH 2) p CN, (CH 2) p Hal, (CH 2) p NO 2, (CH 2) P -C 6 -C 12 aryl, (CH 2) P -heteroaryl, - (CH 2 ) p PO 3 (R b ) 2 , - (CH 2 ) P NR c R d , - (CH 2 ) P NR e COR b , - (CH 2 ) p NR e CSR b , - (CH 2 ) p NR e S (O) R b , - ( CH 2 ) p NR e S (O) 2 R b , - (CH 2 ) P NR 6 CONR 0 R 0 , - (CH 2 ) p NR e COOR b , - (CH 2 ) p NR e C (NH) NR c R d , 5 -(CH2)PNR6CSNR0R0, -(CH2)pNReS(O)NRcRd,5 - (CH 2 ) P NR 6 CSNR 0 R 0 , - (CH 2 ) p NR e S (O) NR c R d , -(CH2)pNReS(O)2NRcRd, -(CH2)pCORb, -(CH2)pCSRb, -(CH2)pS(O)Rb, -(CH2)pS(O)(NH)Rb, -(CH2)pS(O)2Rb, -(CH2)pS(O)2NRcRd, -(CH2)pSO2ORb,- (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 , 10 -(CH2)pCO2Rb, -(CH2)pCONRcRd,10 - (CH 2 ) p CO 2 R b , - (CH 2 ) p CONR c R d , -(CH2)pCSNRcRd, -(CH2)pORb, -(CH2)pOCORb,- (CH 2 ) p CSNR c R d , - (CH 2 ) p OR b , - (CH 2 ) p OCOR b , -(CH2)pSRb, -(CH2)pCRb(OH)-Re, -(CH2)P-- (CH 2 ) p SR b , - (CH 2 ) p CR b (OH) -R e , - (CH 2 ) P - C=NORb,C = NOR b , -O-(CH2)n-O-, -O-(CH2)n-CH2-, -0-CH=CH--O- (CH 2 ) n -O-, -O- (CH 2 ) n -CH 2 -, -O-CH = CH- 15 oder -(CH2)n+2-, wobei n=1 oder 2 ist und die endständigen Sauerstoffatome und/ oder Kohlenstoffatome mit direkt benachbarten Ringkohlenstoffatomen verknüpft sind, M d-Ce-Alkyl oder eine Gruppe -CORb, CO2Rb,15 or - (CH 2 ) n + 2 -, where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms are linked to directly adjacent ring carbon atoms, M d-Ce-alkyl or a group -COR b , CO 2 R b , 20 -O-Rb, oder -NRcRd bedeutet, wobei20 -OR b , or -NR c R d , where Rb ein Wasserstoff oder eine Ci-C6-Alkyl,R b is a hydrogen or a C 1 -C 6 -alkyl, C2-C8-Alkenyl, C2-C8-Alkinyl, C3-Ci0- Cycloalkyl, C6-Ci2-Aryl oder d-C3- 25 Perfluoralkyl undC 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 0 - cycloalkyl, C 6 -C 2 aryl or C 3-25 perfluoroalkyl and Rc und Rd unabhängig voneinander ein Wasserstoff, d-Ce-Alkyl, C2-C8-Alkenyl, C2- C8-Alkinyl, C3-Ci0-Cycloalkyl, C6-Ci2- Aryl, C(0)Rb oder eine Hydroxygruppe 30 bedeuten, wobei wennR c and R d independently represent a hydrogen, d-Ce-alkyl, C 2 -C 8 alkenyl, C 2 - C 8 alkynyl, C 3 -C 0 cycloalkyl, C 6 -C 2 - aryl, C ( 0) R b or a hydroxy group 30, where if Rc eine Hydroxygruppe ist, Rd nur einR c is a hydroxy group, R d is only one Wasserstoff, ein d-C6-Alkyl, C2-C8-Hydrogen, a C 1 -C 6 -alkyl, C 2 -C 8 - Alkenyl, C2-C8-Alkinyl, C3-Ci0-Alkenyl, C 2 -C 8 alkynyl, C 3 -Ci 0 - Cycloalkyl oder C6-d2-Aryl sein kannCycloalkyl or C 6 -d 2 -aryl can be 35 und umgekehrt sowie Re ein Wasserstoff, Ci-Ce-Alkyl, C2-C8- Alkenyl, C2-C8-Alkinyl, C3-Ci0-CyCIo- alkyl oder C6-Ci2-Aryl bedeutet und ein ganzzahliger Wert von von 0- 6 sein kann,35 and vice versa as well R e is hydrogen, Ci-Ce-alkyl, C 2 -C 8 - alkenyl, C 2 -C 8 alkynyl, C 3 -C 0 -CyCIo- alkyl or C 6 -C 2 aryl means and an integer value of from 0 to 6, oder R3 ein Rest C=C R9Rh, wobeior R 3 is a radical C = CR 9 R h , where R9 und Rh unabhängig voneinander ein Wasserstoff oder ein gegebenenfalls ein- oder mehrfach, gleich oder verschieden mit X substituiertes d-C8-Alkyl, C2-C8- Alkenyl oder C2-C8-Alkinyl ist, worin X ein Cyano, Halogen, Hydroxy, Nitro, -C(O)Rb, CO2Rb, -O-Rb, -C(O)-NRcRd, -NRcRdmit den bereits weiter oben genannten Bedeutungen für Rb, Rc und Rd ist undAlkenyl or C 2 -C 8 alkynyl, wherein X is a cyano, - R 9 and R h independently of one another a hydrogen or an optionally mono- or polysubstituted, identically or differently, with X substituted dC 8 alkyl, C 2 -C 8 Halogen, hydroxy, nitro, -C (O) R b , CO 2 R b , -OR b , -C (O) -NR c R d , -NR c R d having the meanings given above for R b , R c and R d is and R4 ein gegebenenfalls mit 1 -3 Resten gleich oder verschieden substituierter 3-8-gliedriger aromatischer oder heteroaromatischer Mono- oder Bicyclus sein kann oder eine der folgenden Gruppen:R 4 may be a 3-8-membered aromatic or heteroaromatic mono- or bicyclic radical which may be identical or differently substituted by 1 -3 radicals, or one of the following groups: A: 6-Ring/6-Ring-Systeme:A: 6-ring / 6-ring systems:
Figure imgf000109_0001
Figure imgf000109_0001
 Verknüpfung an Position 5,6,7 oder 8 B: 6-Ring/5-Ring-Systeme:Link at positions 5, 6, 7 or 8 B: 6-ring / 5-ring systems:
Figure imgf000110_0001
Figure imgf000110_0001
 Verknüpfung an Position 4,5,6 oder 7Link at position 4,5,6 or 7 R£ Wasserstoff oder C1-C4 Alkyl, oder C1-C4 Perfluoralkyl sein kannR £ is hydrogen or C 1 -C 4 alkyl, or C 1 -C 4 perfluoroalkyl may be R und R unabhängig voneinander ein Wasserstoffatom, eine C1-C4-AIkYl, eine C2-C4-Alkenyl oder gemeinsam mit dem Ringkohlenstoffatom einen 3- 6-gliedrigen Ring bilden,R and R independently of one another form a hydrogen atom, a C 1 -C 4 -alkyl, a C 2 -C 4 -alkenyl or together with the ring carbon atom form a 3-membered 6-membered ring, ein mono- oder bicyclischer carbocyclischer oder heterocyclischer aromatischer Ring, der gegebenenfalls ein oder mehrfach, gleich oder verschieden substituiert sein kann mit Ci -C8-Al kyl, C2-C8-Alkenyl, C2- C8-Al kinyl, CrC6-Perfluoralkyl, CrC6-Perfluoralkoxy, C1-C6-AIkOXy-C1- Ce-alkyl, C1 -C6-AIkOXy-C1 -C6-alkoxy, (CH2)p-C3-C10-Cycloalkyl, (CH2)P- Heterocycloalkyl, (CH2)PCN, (CH2)pHal, (CH2)PNO2, (CH2)P-C6-C12-Aryl, (CH2)P-Heteroaryl,a mono- or bicyclic carbocyclic or heterocyclic aromatic ring which may optionally be mono- or polysubstituted by identical or different substituents selected from Ci -C 8 -alkyl, C 2 -C 8 alkenyl, C 2 - C 8 -alkyl kinyl, C r C 6 perfluoroalkyl, C r C 6 perfluoroalkoxy, C 1 -C 6 alkoxy-C 1 - Ce-alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, (CH 2 ) p - C 3 -C 10 cycloalkyl, (CH 2) P - heterocycloalkyl, (CH 2) p CN, (CH 2) p Hal, (CH 2) p NO 2, (CH 2) P -C 6 -C 12 - Aryl, (CH 2 ) P heteroaryl, -(CH2)pPO3(Rb)2, -(CH2)pNRcRd, -(CH2)pNReCORb, -(CH2)pNReCSRb, -(CH2)pNReS(O)Rb, -(CH2)pNReS(O)2Rb, -(CH2)PNR6CONR0R0, -(CH2)pNReCOORb, -(CH2)pNReC(NH)NRcRd, -(CH2)PNR6CSNR0R0, -(CH2)pNReS(O)NRcRd, -(CH2)pNReS(O)2NRcRd, -(CH2)pCORb, -(CH2)pCSRb, -(CH2)p S(O)Rb, -(CH2)pS(O)(NH)Rb, -(CH2)pS(O)2Rb, -(CH2)pS(O)2NRcRd, -(CH2)pSO2ORb, -(CH2)pCO2Rb, -(CH2)PCONR0R0, -(CH2)pCSNRcRd, -(CH2)pORb, -(CH2)pSRb, -(CH2)pCRb(OH)-Rd, -(CH2)p-C=NORb, -0-(CHz)n-O-, -O-(CH2)n-CH2-, -0-CH=CH- oder -(CH2)n+2-, wobei n=1 oder 2 ist und die endständigen Sauerstoffatome und/oder Kohlenstoffatome mit direkt benachbarten Ring- kohlenstoffatomen verknüpft sind oder- (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 6 CONR 0 R 0 , - (CH 2 ) p NR e COOR b , - (CH 2 ) p NR e C (NH) NR c R d , - (CH 2 ) p NR 6 CSNR 0 R 0 , - (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 ) pCSR b , - (CH 2 ) p S (O) R b , - (CH 2 ) p S (O) (NH) R b , - (CH 2 ) p S (O) 2 R b , - (CH 2 ) p S (O) 2 NR c R d , - (CH 2 ) p SO 2 OR b , - (CH 2 ) p CO 2 R b , - (CH 2 ) p CONR 0 R 0 , - (CH 2 ) p CSNR c R d , - (CH 2 ) p OR b , - (CH 2 ) p SR b , - (CH 2 ) p CR b (OH) -R d , - (CH 2 ) p -C = NOR b , -O- (CHz) n -O-, -O- (CH 2 ) n -CH 2 -, -O-CH = CH- or - (CH 2 ) n + 2, where n = 1 or 2 and the terminal oxygen atoms and / or carbon atoms are linked to directly adjacent ring carbon atoms, or A ein Rest -CO2Rb, C(O)NRcRd, CORb,A is a radical -CO 2 R b , C (O) NR c R d , COR b , oderor A eine Alkenylgruppe -CR =CR R , wobeiA is an alkenyl group -CR = CR R, where R5, R6 und R7 gleich oder verschieden sind und unabhängig voneinander Wasserstoffatome,R 5 , R 6 and R 7 are the same or different and are independently hydrogen atoms, Halogenatome, Arylreste oder eine unsubstituierte oder teilweise oder vollständig fluorierte C1-C5- Alkylgruppe bedeuten oderHalogen atoms, aryl radicals or an unsubstituted or partially or completely fluorinated C 1 -C 5 - alkyl group or A eine Alkinylgruppe -C≡CR , mit der für R oben angeführten Bedeutung undA is an alkynyl group -C≡CR, with the meaning given above for R and B eine Carbonyl- oder eine CH2-GruppeB is a carbonyl or a CH 2 group bedeuten sowie ihre pharmazeutisch annehmbaren Salze.and their pharmaceutically acceptable salts. 2. Verbindungen nach Anspruch 1 , worin R1 und R2 jeweils unabhängig voneinander ein Wasserstoff atom, ein Methyl- oder Ethylrest sind oder gemeinsam mit dem C-Atom der Kette einen Ring mit insgesamt 3-7 Gliedern bilden.2. Compounds according to claim 1, wherein R 1 and R 2 are each independently a hydrogen atom, a methyl or ethyl radical or together with the carbon atom of the chain form a ring having a total of 3-7 members. 3. Verbindungen nach Anspruch 2, worin R1 und R2 bevorzugt gleichzeitig ein Wasserstoff atom, ein Methyl- oder Cyclopropylrest, besonders bevorzugt ein Methyloder Cyclopropylrest sind.3. Compounds according to claim 2, wherein R 1 and R 2 are preferably simultaneously a hydrogen atom, a methyl or cyclopropyl radical, particularly preferably a methyl or cyclopropyl radical. 4. Verbindungen nach Anspruch 1 , worin R3ein Alkinylrest der Formel Rest C≡C-Ra mit Ra ein gegebenenfalls mit K substituiertes CrC4 Alkyl, C3-Ci0-Cycloalkyl,4. Compounds according to claim 1, wherein R 3 is an alkynyl radical of the formula radical C≡CR a with R a is optionally substituted with C -C 4 alkyl, C 3 -C 0 cycloalkyl, 3-8-gliedriges Heterocycloalkyl oder gegebenenfalls mit L substituiertes C6-Ci2-Aryl oder 3-8-gliedriges Heteroaryl,3-8 membered heterocycloalkyl or optionally substituted L C 6 -C 2 aryl or 3-8-membered heteroaryl, K Cyano, Halogen, Hydroxy, -O-Rb, SO2NRcRd, -C(O)-NRcRd, -NRcRd oder ein gegebenenfalls ein- oder mehrfach, gleich oder verschieden mit M substituiertes 3-8-gliedriges Heterocycloalkyl oder ein gegebenenfalls mehrfach, gleich oder verschieden mit L substituiertes Aryl oder Heteroaryl,K cyano, halogen, hydroxy, -OR b , SO 2 NR c R d , -C (O) -NR c R d , -NR c R d or an optionally mono- or polysubstituted by identical or different substituents 3 8-membered heterocycloalkyl or an aryl or heteroaryl which is optionally multiply, identically or differently substituted by L, L d-C4-Alkyl, CrC4-Perfluoralkyl, (CH2)p-C3-Cio-Cycloalkyl, (CH2)P- Heterocycloalkyl, (CH2)PCN, (CH2)pHal, (CH2)PNO2, (CH2)P-C6-C12-Aryl,L dC 4 alkyl, C r C 4 perfluoroalkyl, (CH 2 ) pC 3 -Cio cycloalkyl, (CH 2 ) p - heterocycloalkyl, (CH 2 ) p CN, (CH 2 ) p Hal, (CH 2 ) P NO 2 , (CH 2 ) P -C 6 -C 12 aryl, (CH2)P-Heteroaryl, -(CH2)pNRcRd, -(CH2)pNReS(O)2Rb, -(CH2)pS(O)2NRcRd, -(CH2)pCONRcRd, -(CH2)pORb, -(CH2)pOCORb, -(CH2)pCRb(OH)-Re, -(CH2)pCO2Rb,(CH 2 ) P -heteroaryl, - (CH 2 ) p NR c R d , - (CH 2 ) p NR e S (O) 2 R b , - (CH 2 ) p S (O) 2 NR c R d , - (CH 2 ) p CONR c R d , - (CH 2 ) p OR b , - (CH 2 ) p OCOR b , - (CH 2 ) p CR b (OH) -R e , - (CH 2 ) p CO 2 R b , M Ci-C4-Alkyl oder eine Gruppe -CO2Rb, -O-Rb oder -NRcRd bedeutet, wobeiM is C 1 -C 4 -alkyl or a group -CO 2 R b , -OR b or -NR c R d , where Rb ein Wasserstoff oder eine Ci-C6-Alkyl, C3-Ci0-Cycloalkyl,R b is hydrogen or a Ci-C 6 alkyl, C 3 -C 0 cycloalkyl, C6-Ci2-Aryl oder d-C3-Perfluoralkyl undC 6 -C 2 aryl or C 3 perfluoroalkyl and Rc und Rd unabhängig voneinander ein Wasserstoff, Ci-Ce-Alkyl, C3- Cio-Cycloalkyl, C6-Ci2-Aryl, C(O)Rb oder eineR c and R d are independently a hydrogen, Ci-Ce-alkyl, C 3 - Cio-cycloalkyl, C 6 -C 2 -aryl, C (O) R b or a Hydroxygruppe bedeuten, wobei wenn Rc eine Hydroxygruppe ist,Hydroxy group, where when R c is a hydroxy group, Rd ein Wasserstoff, ein Ci-Ce-Alkyl, C2-C8-Alkenyl, C2-C8- Alkinyl, C3-Ci 0-Cycloalkyl oder C6-Ci2-Aryl sein kann und umgekehrt sowieR d is a hydrogen, a Ci-Ce alkyl, C 2 -C 8 alkenyl, C 2 -C 8 - alkynyl, C 3 -C 0 -C 6 cycloalkyl or C 2 can be aryl, and vice versa, and Re ein Wasserstoff, Ci-Ce-Alkyl, oder C6-Ci2-Aryl bedeutet undR e is hydrogen, Ci-Ce alkyl, or C 6 -C 2 denotes aryl, and p eine Zahl 0, 1 , 2 oder 3 ist.p is a number 0, 1, 2 or 3. 5. Verbindungen nach Anspruch 4, worin Ra ein gegebenenfalls mit K substituierter d- C4-Alkylrest, ein gegebenenfalls mit L substituierter Phenyl- oder Hetarylrest ist.5. Compounds according to claim 4, wherein R a is an optionally substituted d- with K C 4 alkyl optionally substituted with phenyl or hetaryl radical L. 6. Verbindungen nach Anspruch 5, worin L ein Methyl-, Trifluormethyl-, Methoxy-, Acetoxy, Hydroxy-, Carboxyl- oder Carboxyalkylrest ist.6. Compounds according to claim 5, wherein L is a methyl, trifluoromethyl, methoxy, acetoxy, hydroxy, carboxyl or carboxyalkyl. in in 7. Verbindungen nach Anspruch 1 , worin R4 bevorzugt ein Phenylring, besonders bevorzugt ein mit 1 -3 Resten gleich oder verschieden substituierter Phenylring ist.7. Compounds according to claim 1, in which R 4 is preferably a phenyl ring, particularly preferably a phenyl radical which is identical or differently substituted by 1 to 3 radicals. 8. Verbindungen nach Anspruch 7, worin der Phenylring bevorzugt mit Nitro, Trifluormethyl, Pentafluorethyl, Cyano, Chlor, Fluor, Methyl substituiert ist.8. Compounds according to claim 7, wherein the phenyl ring is preferably substituted by nitro, trifluoromethyl, pentafluoroethyl, cyano, chlorine, fluorine, methyl. 9. Verbindungen nach Anspruch 1 , worin R4 bevorzugt eine der folgenden Gruppen ist9. Compounds according to claim 1, wherein R 4 is preferably one of the following groups A: 6-Ring/6-Ring-Systeme:A: 6-ring / 6-ring systems:
Figure imgf000113_0001
Figure imgf000113_0001
 oderor B: 6-Ring/5-Ring-Systeme:B: 6-ring / 5-ring systems:
Figure imgf000113_0002
Figure imgf000113_0002
 worin R sowie R und R die im Anspruch 1 genannten Bedeutungen haben.wherein R and R and R have the meanings mentioned in claim 1. 10. Verbindungen nach Anspruch 1 , worin A bevorzugt mit folgenden Resten substituiert sein kann: d-C8-Alkyl, d-C6-Perfluoralkyl, d-C6-Perfluoralkoxy, C1-C6-AIkOXy-C1-C6- alkyl, Ci-C6-Alkoxy-Ci-C6-alkoxy, (CH2)p-C3-Cio-Cycloalkyl, (CH2)P-Heterocycloalkyl,10. Compounds according to claim 1, wherein A may be preferably substituted by the following radicals: dC 8 alkyl, dC 6 perfluoroalkyl, dC 6 perfluoroalkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 - alkyl, Ci- C 6 alkoxy-Ci-C 6 alkoxy, (CH 2 ) pC 3 -Cio-cycloalkyl, (CH 2 ) p -Heterocycloalkyl, (CH2)PCN, (CH2)pHal, (CH2)PNO2, (CH2)P-C6-C12-Aryl, (CH2)P-Heteroaryl, -(CH2)pNRcRd,(CH 2 ) P CN, (CH 2 ) p Hal, (CH 2 ) P NO 2 , (CH 2 ) P -C 6 -C 12 aryl, (CH 2 ) P heteroaryl, - (CH 2 ) p NR c R d , -(CH2)pNReCORb, -(CH2)pNReS(O)2Rb, -(CH2)PNR6CONR0R0, -(CH2)pNReS(O)2NRcRd, -(CH2)pCORb, -(CH2)pCSRb, -(CH2)pS(O)(NH)Rb, -(CH2)pS(O)2Rb, -(CH2)pS(O)2NRcRd, -(CH2)pCO2Rb, -(CH2)pCONRcRd, -(CH2)pORb, -(CH2)pSRb, -(CH2)pCRb(OH)-Rd, -(CH2)p-C=NORb, -O-(CH2)n-O-, -O-(CH2)n-CH2-, -0-CH=CH- oder -(CH2)n+2-, wobei n=1 oder 2 ist und die endständigen 5 Sauerstoffatome und/oder Kohlenstoffatome mit direkt benachbarten Ringkohlenstoffatomen verknüpft sind.- (CH 2 ) p NR e COR b , - (CH 2 ) p NR e S (O) 2 R b , - (CH 2 ) P NR 6 CONR 0 R 0 , - (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) (NH) R b , - (CH 2 ) p S (O) 2 R b , - (CH 2 ) p S (O) 2 NR c R d , - (CH 2 ) p CO 2 R b , - (CH 2 ) p CONR c R d , - (CH 2 ) p OR b , - (CH 2 ) p SR b , - (CH 2 ) p CR b (OH) -R d , - (CH 2 ) p -C = NOR b , - O- (CH 2 ) n -O-, -O- (CH 2 ) n -CH 2 -, -O-CH = CH- or - (CH 2 ) n + 2 -, where n = 1 or 2 and the terminal 5 oxygen atoms and / or carbon atoms are linked to directly adjacent ring carbon atoms. 1 1 . Verbindungen nach Anspruch 10, worin A besonders bevorzugt mit CrC4-Alkyl, CrC2-1 1. Compounds according to claim 10, in which A particularly preferably contains C 1 -C 4 -alkyl, C -C 2 - Perfluoralkyl, CrC2-Perfluoralkoxy, (CH2)PCN, (CH2)pHal, -(CH2)pNRcRd, -Perfluoroalkyl, C r C 2 perfluoroalkoxy, (CH 2 ) p CN, (CH 2 ) p Hal, - (CH 2 ) p NR c R d , - 10 (CH2)pS(O)(NH)Rb, -(CH2)pS(O)2Rb, -(CH2)pS(O)2NRcRd, -(CH2)pORb oder -(CH2)pSRb substituiert ist und p sowie Rb, Rc und Rd die im Anspruch 1 genannten Bedeutung haben.10 (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 OR b or - (CH 2 ) p SR b is substituted and p and R b , R c and R d have the meaning given in claim 1. 12. Verbindungen nach Anspruch 1 , worin A bevorzugt ein unsubstituierter Phenylring ist.12. Compounds according to claim 1, wherein A is preferably an unsubstituted phenyl ring. 1515 13. Verbindungen nach Anspruch 1 1 , worin A bevorzugt ein ein- oder zweifach, gleich oder verschieden mit Fluor, Chlor, Brom, Methyl, Trifluormethyl oder Methoxy substituierter Phenylring ist.13. Compounds according to claim 1 1, wherein A is preferably a one or two times, identically or differently with fluorine, chlorine, bromine, methyl, trifluoromethyl or methoxy substituted phenyl ring. 20 14. Verbindungen nach Anspruch 1 , worin B eine Carbonylgruppe ist.Compounds according to claim 1, wherein B is a carbonyl group. 15. Verbindungen nach Anspruch 1 , worin B eine Gruppe -CH2- ist.15. Compounds according to claim 1, wherein B is a group -CH 2 -. 16. Verbindungen nach Anspruch 1 , worin p bevorzugt 0 oder 1 ist.16. Compounds according to claim 1, wherein p is preferably 0 or 1. 2525 17. Verbindungen nach einem der Ansprüche 1 bis 16, nämlich17. Compounds according to one of claims 1 to 16, namely Die nachstehend genannten Verbindungen sowie deren Verwendung sind erfindungsgemäß bevorzugt:The compounds mentioned below and their use are preferred according to the invention:
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 18. Pharmazeutische Zusammensetzung enthaltend mindestens eine Verbindung der allgemeinen Formel I nach einem der Ansprüche 1 bis 17 und gegebenenfalls mindestens einen weiteren Wirkstoff zusammen mit pharmazeutisch verträglichen Hilfs- und/ oder Trägerstoffen.18. A pharmaceutical composition containing at least one compound of general formula I according to any one of claims 1 to 17 and optionally at least one further active ingredient together with pharmaceutically acceptable excipients and / or carriers. 19. Pharmazeutische Zusammensetzung gemäß Anspruch 18, wobei der weitere Wirkstoff ein SERM (Selektiver-Estrogen-Rezeptor-Modulator), ein Estrogen, Estrogenderivat oder eine estrogen wirksame Substanz, ein Aromatasehemmer, Antiestrogen oder ein Prostaglandin ist.19. A pharmaceutical composition according to claim 18, wherein the further active ingredient is a SERM (Selective Estrogen Receptor Modulator), an estrogen, estrogen derivative or an estrogen-active substance, an aromatase inhibitor, antiestrogen or a prostaglandin. 20. Pharmazeutische Zusammensetzung gemäß Anspruch 19, wobei als Estrogenderivate folgende in Betracht kommen: 17ß-Estradiol-3-alkyl-sulfonate, 17ß-Ethinylestradiol-3- alkyl-sulfonate, 17ß-Estradiol-3- oder 17-ester, 17ß-Ethinylestradiol-3-ether.20. A pharmaceutical composition according to claim 19, wherein suitable as estrogen derivatives are: 17β-estradiol-3-alkyl sulfonates, 17β-ethinyl estradiol-3-alkyl sulfonates, 17β-estradiol-3 or 17-ester, 17β-ethinylestradiol -3-ether. 21 . Pharmazeutische Zusammensetzung gemäß Anspruch 19, wobei die weiteren Wirkstoffe Tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-Pentafluorpentyl)sulfinyl]pentyloxy}- phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol, ICI 182 780 (7alpha-[9- (4,4,5,5-Pentafluorpentylsulfinyl)nonyl]estra-1 ,3,5(10)-trien-3,17-beta-diol), 1 1 beta- Fluor-7alpha-[5-(methyl{3-[(4,4,5,5,5-pentafluorpentyl)sulfanyl]propyl}amino)- pentyl]estra-1 ,3,5(10)-trien-3,17beta-diol, 1 1 beta-Fluor-7alpha-{5-[methyl(7,7,8,8,- 9,9,10,10,10-nonafluordecyl)amino]pentyl}estra-1 ,3,5(10)-trien-3,17beta-diol, 1 1 beta- Fluor-17alpha-methyl-7alpha-{5-[methyl(8, 8,9,9, 9-pentafluornonyl)amino]pentyl}estra- 1 , 3,5(10)-trien-3,17beta-diol, Clomifen, Raloxifen, Fadrozol, Formestan, Letrozol, Anastrozol, Atamestan, 17ß-Estradiol, 17ß-Ethinylestradiol, Estriol, 17ß-Estradiol-3- isopropyl-sulfonat, 17ß-Ethinylestradiol-propyl-sulfonat (Turisteron), Estradiol-3- 5 benzoat, Estradiol-17-valerat, 17ß-Ethinylestradiol-3-methylether (Mestranol) oder konjugierte equine Estrogene (CEE) sein können.21. A pharmaceutical composition according to claim 19, wherein the further active ingredients tamoxifen, 5- (4- {5 - [(RS) - (4,4,5,5,5-pentafluoropentyl) sulfinyl] pentyloxy} - phenyl) -6-phenyl- 8,9-dihydro-7H-benzocyclohepten-2-ol, ICI 182 780 (7alpha [9- (4,4,5,5-pentafluoropentylsulfinyl) nonyl] estra-1,3,5 (10) -triene-3 , 17-beta-diol), 1 1 beta-fluoro-7alpha- [5- (methyl {3 - [(4,4,5,5,5-pentafluoropentyl) sulfanyl] propyl} amino) pentyl] estra-1 , 3,5 (10) -triene-3,17beta-diol, 1 l beta-fluoro-7alpha- {5- [methyl (7,7,8,8,9,9,10,10,10-nonafluorodecyl ) amino] pentyl} estra-1, 3,5 (10) -triene-3,17beta-diol, 1 liter of Fluoro-17alpha-methyl-7alpha- {5- [methyl (8, 8,9,9, 9-pentafluorononyl) amino] pentyl} estra-1,3,5 (10) -triene-3,17beta-diol, clomifene , Raloxifene, fadrozole, formestane, letrozole, anastrozole, atamestane, 17β-estradiol, 17β-ethinylestradiol, estriol, 17β-estradiol-3-isopropyl-sulfonate, 17β-ethinylestradiol-propyl-sulfonate (Turisteron), estradiol-3-benzoate , Estradiol-17-valerate, 17β-ethinylestradiol-3-methyl ether (mestranol) or conjugated equine estrogens (CEE). 22. Verbindungen nach einem der Ansprüche 1 bis 17 zur Herstellung eines Arzneimittels.22. Compounds according to any one of claims 1 to 17 for the manufacture of a medicament. 10 23. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 17 zur Herstellung eines Arzneimittels zur Therapie und/ oder Prophylaxe von gynäkologischen Erkrankungen wie Endometriose, Leiomyomen des Uterus, dysfunktionelle Blutungen und Dysmenorrhoe.10 23. Use of compounds according to any one of claims 1 to 17 for the manufacture of a medicament for the therapy and / or prophylaxis of gynecological diseases such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhea. 15 24. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 17 zur Herstellung eines Arzneimittels zur Therapie und/ oder Prophylaxe von hormonabhängigen Tumoren.15 24. Use of compounds according to any one of claims 1 to 17 for the manufacture of a medicament for the therapy and / or prophylaxis of hormone-dependent tumors. 25. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 17 zur Herstellung 20 eines Arzneimittels zur Therapie und/ oder Prophylaxe von Mammakarzinomen.25. Use of compounds according to one of claims 1 to 17 for the preparation of a medicament for the therapy and / or prophylaxis of breast cancer. 26. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 17 zur Herstellung eines Arzneimittels zur Therapie und/ oder Prophylaxe des Endometriumskarzinoms.26. Use of compounds according to any one of claims 1 to 17 for the manufacture of a medicament for the therapy and / or prophylaxis of endometrial carcinoma. 25 27. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 17 zur Herstellung eines Arzneimittels zur Therapie und/ oder Prophylaxe von Ovarkarzinomen.25 27. Use of compounds according to any one of claims 1 to 17 for the manufacture of a medicament for the therapy and / or prophylaxis of ovarian carcinomas. 28. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 17 zur Herstellung eines Arzneimittels zur Therapie und/ oder Prophylaxe von Prostatakarzinomen.28. Use of compounds according to any one of claims 1 to 17 for the manufacture of a medicament for the therapy and / or prophylaxis of prostate carcinomas. 3030 29. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 17 zur Herstellung eines Arzneimittels für die weibliche Hormonersatztherapie.29. Use of compounds according to any one of claims 1 to 17 for the manufacture of a medicament for female hormone replacement therapy. 30. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 17 für die weibliche 35 Fertilitätskontrolle. 30. Use of compounds according to any one of claims 1 to 17 for the female 35 fertility control.
PCT/EP2008/058921 2007-07-10 2008-07-09 Nonsteroidal progesterone receptor modulators Ceased WO2009007396A1 (en)

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