Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/34—Gestagens
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D265/02—1,2-Oxazines; Hydrogenated 1,2-oxazines

Definitions

• Non-steroidal progesterone receptor modulators are provided.
• the present invention relates to non-steroidal progesterone receptor modulators, to a process for their preparation, to the use of the progesterone receptor modulators for producing medicaments, and to pharmaceutical compositions which comprise these compounds.
• the steroid hormone progesterone controls in a decisive manner the reproductive process in the female body.
• Progesterone is secreted in large quantities during the cycle and pregnancy respectively by the ovary and the placenta.
• Progesterone in cooperation with oestrogens brings about cyclic changes in the uterine mucosa
• progesterone controls the relaxation of the myometrium and maintains the function of the decidual tissue.
• progesterone inhibits endometrial proliferation by suppressing oestrogen-mediated mitosis in uterine tissue (K. Chwalisz, R. M. Brenner, U. Fuhrmann, H. Hess-Stumpp, W. Elger, Steroids 65, 2000, 741-751).
• Progesterone and progesterone receptors are also known to play a significant part in pathophysiological processes. Progesterone receptors have been detected in the foci of endometriosis, but also in tumours of the uterus, of the breast and of the CNS. It is further known that uterine leiomyomas grow progesterone-dependently.
• progesterone in the tissues of the genital organs and in other tissues occur through interactions with progesterone receptors which are responsible for the cellular effects.
• Progesterone receptor modulators are either pure agonists or inhibit the effect of progesterone partly or completely. Accordingly, substances are defined as pure agonists, partial agonists (SPRMs) and pure antagonists.
• progesterone receptor modulators In accordance with ability of progesterone receptor modulators to influence the effect of the progesterone receptor, these compounds have a considerable potential as therapeutic agents for gynaecological and oncological indications and for obstetrics and fertility control.
• progesterone receptor antagonists completely inhibit the effect of progesterone on the progesterone receptor. They have anti-ovulatory properties and the ability to inhibit oestrogen effects in the endometrium, as far as complete atrophy. They are therefore particularly suitable for intervening in the female reproductive process, e.g. post- ovulation, in order to prevent nidation, during pregnancy in order to increase the reactivity of the uterus to prostaglandins or oxytocin, or in order to achieve opening and softening ("ripening") of the cervix, and to induce a great readiness of myometrium to contract.
• post- ovulation in order to prevent nidation, during pregnancy in order to increase the reactivity of the uterus to prostaglandins or oxytocin, or in order to achieve opening and softening ("ripening") of the cervix, and to induce a great readiness of myometrium to contract.
• a beneficial effect on the pathological event is expected in foci of endometriosis and in tumour tissues which are equipped with progesterone receptors after administration of pure progesterone receptor antagonists.
• There might be particular advantages for influencing pathological states such as endometriosis or uterine leiomyomas if ovulation inhibition can additionally be achieved by the progesterone receptor antagonists.
• Ovulation inhibition also dispenses with some of the ovarian hormone production and thus the stimulating effect, deriving from this proportion, on the pathologically altered tissue.
• RU 486 The first progesterone receptor antagonist described, RU 486 (also mifepristone), was followed by a large number of analogues with progesterone receptor-antagonistic activity of varying strength. Whereas RU 486 shows an antiglucocorticoid effect in addition to the progesterone receptor-antagonistic effect, compounds synthesized later are notable in particular for a more selective effect as progesterone receptor antagonists.
• the antiglucocorticoid activity is disadvantageous for therapeutic use, where the inhibition of progesterone receptors is at the forefront of the therapy.
• An antiglucocorticoid activity causes unwanted side effects at the dosages necessary for therapy. This may prevent administration of a therapeutically worthwhile dose or lead to discontinuation of the treatment.
• Partial or complete reduction of the antiglucocorticoid properties is therefore an important precondition for therapy with progesterone receptor antagonists, especially for those indications requiring treatment lasting weeks or months.
• SPRMs partial progesterone receptor agonists
• SPRMs partial progesterone receptor agonists
• 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 benefit for the described indications.
• non-steroidal progesterone receptor modulators These compounds are intended to have a reduced antiglucocorticoid effect and therefore be suitable for the therapy and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea.
• the compounds according to the invention are additionally intended to be suitable for the therapy and prophylaxis of hormone- dependent tumours, for example of breast, endometrial, ovarian and prostate carcinomas.
• the compounds are intended furthermore to be suitable for use in female fertility control and for female hormone replacement therapy.
• R 1 and R 2 are independently of one another a hydrogen atom, a linear or nonlinear, branched or unbranched Ci-C 5 -alkyl group, further forming together with the C atom of the chain a ring having a total of 3-7 members, R 3 is a radical C ⁇ C-R a , where
• R a is a hydrogen or a Ci-C ⁇ -alkyI, C 2 -C 8 -alkenyl, C 2 -C 8 - alkynyl, C 3 -C 10 -cycloalkyl, heterocycloalkyl optionally substituted one or more times, identically or differently, by
• K or an aryl or heteroaryl optionally substituted one or more times, identically or differently by L, K is a cyano, halogen, hydroxy, nitro, -C(O)R",
• M is d-C 6 -alkyl or a group -COR b , CO 2 R b , -O-R b , or -NR c R d , where
• R b is a hydrogen or a Ci-C 6 -alkyl, C 2 -C 8 - alkenyl, C 2 -C 8 -alkynyl, C 3 -C 10 - cycloalkyl, C 6 -C 12 -aryl or C 1 -C 3 - perfluoroalkyl and
• R c and R d are independently of one another a hydrogen, Ci-C 6 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C 3 -C 10 -cycloalkyl,
• R c is a hydroxy group
• R d can only be a hydrogen, a Ci-C 6 -alkyl, C 2 -C 8 - alkenyl, C 2 -C 8 -alkynyl, C 3 -C 10 - cycloalkyl or C 6 -C 12 -aryl and vice versa, and
• R e is a hydrogen, C ⁇ Ce-alkyl, C 2 -C 8 - alkenyl, C 2 -C 8 -alkynyl, C 3 -C 10 -cyclo- alkyl or C 6 -C 12 -aryl, and p can be a number from 0-6,
• R 4 is a hydrogen atom, a methyl or an ethyl group or a partly or completely fluorinated C,-C 3 -alkyl group
• A is a mono- or bicyclic carbocyclic or heterocyclic aromatic ring which may optionally be substituted one or more times by Ci-C 8 -alkyl, C 2 -C 8 - alkenyl, C 2 -C 8 -alkynyl, Ci-C 6 -perfluoroalkyl, C 1 -C 6 -perfluoroalkoxy, Ci-Ce-alkoxy-CrC ⁇ -alkyl, CrCe-alkoxy-d-Ce-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 )
• R , R and R are identical or different and are independently of one another hydrogen atoms, halogen atoms, aryl radicals or an unsubstituted or partly or completely fluorinated C.,-C 5 -alkyl group, or
• A is an alkynyl group -C ⁇ CR , with the meaning stated above for R , and
• B is a carbonyl or a CH 2 group
• the compounds according to the invention of the general formula I may, owing to the presence of centres of asymmetry, exist as different stereoisomers. Both the racemates and the separate stereoisomers belong to the subject matter of the present invention.
• the present invention further includes the novel compounds as active pharmaceutical ingredients, the preparation thereof, their therapeutic use and pharmaceutical dosage forms which comprise the novel substances.
• the compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts can be used to produce a medicament, in particular for the treatment and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea.
• the compounds according to the invention may further be used for the treatment and prophylaxis of hormone-dependent tumours such as, for example, for breast, prostate and endometrial carcinoma.
• the compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts are suitable for use for female fertility control or for female hormone replacement therapy.
• the present invention additionally relates to a process for preparing the compounds of the general formula (I).
• the substituent R 3 is introduced by selective addition reaction of organometallic compounds such as lithium alkynyls or magnesium haloalkynyls onto a keto group. This leads either directly or after carrying out further modificiations to the compounds according to the invention of the general formula (I).
• the compounds according to the invention are prepared by selective addition of organometallic compounds onto keto amides which have been described for example in the published specifications US 2002/0077356, US 6,323, 199B1 , WO 200375915 and WO 9854159.
• the organometallic compounds may be for example lithium alkynyl or magnesium haloalkynyl compounds. These are generated for example by reacting the appropriate alkynes with butyllithium or Grignard compounds.
• the corresponding organometallic alkenyl compounds can also be prepared in analogy thereto.
• the reactivity of the keto groups is in this case distinctly higher by comparison with the amide carbonyl and with the benzoxazinone, so that a selective addition is achieved on suitable choice of the reaction conditions.
• alkynyl or alkenyl radicals introduced as R 3 can also be further modified later.
• Reactions suitable for these modifications are those known to the skilled person, such as oxidation, reduction, substitution, alkylation, palladium-catalysed reaction. Any protective groups present are eliminated at a suitable time.
• the non-steroidal compounds according to the invention of the general formula I have strong antagonistic or strong partial agonistic effects on the progesterone receptor. They show a strong dissociation of effects in relation to their strength of binding to the progesterone receptor and to the glucocorticoid receptor. Whereas known progesterone receptor antagonists such as mifepristone (RU 486) show, besides the desired high binding affinity for the progesterone receptor, likewise a high affinity for the glucocorticoid receptor, the compounds according to the invention are notable for a very low glucocorticoid receptor binding with simultaneously a high progesterone receptor affinity.
• C 1 -C 5 -, C 1 -C 6 - and C 1 -C 8 -alkyl group means linear or nonlinear, branched or unbranched alkyl radicals. Examples thereof are a methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl, an n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl, hexyl, heptyl or octyl group.
• R a Preferred in the meaning of R a in this connection are the methyl, ethyl, n-propyl or n-butyl group and an n-pentyl group. Preferred in the meaning of R 1 and R 2 are methyl or ethyl.
• Alkenyl means linear or nonlinear, branched or unbranched alkenyl radicals. Examples of the meaning of a C 2 -C 8 -alkenyl group in the context of the invention are the following: vinyl, allyl, 3-buten-1-yl or 2,3-dimethyl-2-propenyl. If the aromatic system A is substituted by a C 2 -C 8 -alkenyl radical, it is preferably a vinyl group.
• Alkynyl means linear or nonlinear, branched or unbranched alkynyl radicals.
• a C 2 -C 8 - alkynyl radical is intended to be for example an ethynyl, propynyl, butynyl, pentynyl, hexynyl and octynyl group, preferably an ethynyl or propynyl group.
• C 3 -Ci 0 -cycloalkyl examples which may be mentioned are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.
• Heterocycloalkyl in the meaning of R a , K and L means 3-8-membered heterocycloalkyl radicals.
• heterocycloalkyl examples include morpholinyl, tetrahydrofuranyl, pyranyl, piperazinyl, piperidinyl, pyrrolidinyl, oxiranyl, oxetanyl, aziridinyl, dioxolanyl and dioxanyl.
• the position of the heteroatom in relation to the point of linkage can be any chemically possible position.
• C 1 -C 6 -alkoxyl-C 1 -C 6 -alkoxy group Possible examples are methoxymethoxy, ethoxymethoxy or 2-methoxyethoxy.
• 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, 2,2-dimethylpropoxy or 3-methylbutoxy group. Hydroxy, methoxy and ethoxy are preferred.
• Suitable for a partly or completely fluorinated C 1 -C 5 -alkyl group are the perfluorinated alkyl groups above. Of these, preference is given in particular to the trifluoromethyl or pentafluoroethyl group and, partly fluorinated alkyl groups, for example the 5,5,5,4,4- pentafluoropentyl or 5,5,5,4,4,3,3-heptafluoropentyl group.
• a halogen atom may be a fluorine, chlorine, bromine or iodine atom. Fluorine, chlorine or bromine is preferred here.
• R 1 and R 2 form together with the C atom of the chain a 3-7 membered ring, this is for example a cyclopropyl, -butyl, -pentyl or -hexyl ring.
• the cyclopropyl and the cyclopentyl ring are preferred.
• the mono- or bicyclic carbocyclic aromatic ring A which may be substituted more than once, is a carbocyclic or heterocyclic aryl 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 radical, in particular all the possible isomers in relation to the positions of the heteroatoms.
• a monocyclic heterocyclic radical for example the thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, fur
• R 3 means in the case of an aryl radical an optionally substituted phenyl, 1- or 2-naphthyl radical, with preference for the phenyl radical.
• a heteroaryl radical are the 2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2- or 3-pyrrolyl, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radical.
• the number p for a (CH 2 ) P radical may be a number from 0 to 6, preferably 0 to 2.
• "Radical” means according to the invention all functional groups stated in connection with (CH 2 ) P .
• the compounds according to the invention are in the form of racemic mixtures, they can be fractionated by methods of racemate resolution familiar to the skilled person into the pure optically active forms.
• the racemic mixtures can be separated into the pure isomers by chromatography on a support material which is itself optically active (CHIRALPAK AD ® ).
• CHIRALPAK AD ® optically active
• optically active acid for example mandelic acid, camphorsulphonic acid or tartaric acid.
• Progesterone receptor modulators can be identified with the aid of simple methods, test programmes known to the skilled person. It is possible for this purpose for example to incubate a compound to be tested together with a progestogen in a test system for progesterone receptors and to check whether the effect mediated by progesterone is altered in the presence of the modulator in this test system.
• the receptor binding affinity was determined by competitive binding of a specifically binding 3 H-labelled hormone (tracer) and of the compound to be tested on receptors in the cytosol from animal target organs.
• the aim in this case was receptor saturation and reaction equilibrium.
• the tracer and increasing concentrations of the compound to be tested were coincubated at 0-4 0 C for 18 h with the receptor-containing cytosol fraction. After removal of unbound tracer with carbon-dextran suspension, the receptor-bound tracer content was measured for each concentration, and the IC 50 was determined from the concentration series.
• the relative receptor binding affinities (RBA values) for the compounds according to the invention of the general formula (I) on the progesterone receptor are between 3 and 100% relative to progesterone.
• the RBA values at the glucocorticoid receptor are in the range from 3 to 30% relative to dexamethasone.
• the compounds according to the invention accordingly 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 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 Chem, 43, 26, 2000, 5010-5016).
• the progesterone receptor modulators can be administered orally, enterally, parenterally or transdermal ⁇ for the use according to the invention.
• Suitable dosages of the compounds according to the invention in humans for the treatment of endometriosis, of leiomyomas of the uterus and dysfunctional bleeding and for use in fertility control and for hormone replacement therapy are from 50 ⁇ g to 500 mg per day, depending on the age and constitution of the patient, it being possible to administer the necessary daily dose by single or multiple administration.
• the dosage range for the compounds according to the invention for the treatment of breast carcinomas is 10 mg to 1000 mg per day.
• the pharmaceutical products based on the novel compounds are formulated in a manner known per se by processing the active ingredient with the carrier substances, fillers, substances influencing disintegration, binders, humectants, lubricants, absorbents, diluents, masking flavours, colorants, etc. which are used in pharmaceutical technology, and converting into the desired administration form.
• the carrier substances fillers, substances influencing disintegration, binders, humectants, lubricants, absorbents, diluents, masking flavours, colorants, etc.
• Suitable for oral administration are in particular tablets, film-coated tablets, sugar-coated tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions or solutions.
• Appropriately prepared crystal suspensions can be used for intraarticular injection.
• Aqueous and oily solutions for injection or suspensions and corresponding depot preparations can be used for intramuscular injection.
• the novel compounds can be used in the form of suppositories, capsules, solutions (e.g. in the form of enemas) and ointments, both for systemic and for local therapy.
• compositions for vaginal use may also be mentioned as preparation.
• novel compounds For pulmonary administration of the novel compounds, they can be used in the form of aerosols and inhalants.
• Patches are possible for transdermal administration, and formulations in gels, ointments, fatty ointments, creams, pastes, dusting powders, milk and tinctures are possible for topical application.
• the dosage of the compounds of the general formula I in these preparations should be 0.01% - 20% in order to achieve an adequate pharmacological effect.
• Corresponding tablets can be obtained for example by mixing active ingredient with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as maize starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or means to achieve a depot effect such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate.
• the tablets may also consist of a plurality of layers.
• coated tablets can be produced by coating cores produced in analogy to the tablets with compositions normally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar.
• the tablet covering may in this case also consist of a plurality of layers, it being possible to use the excipients mentioned above for tablets.
• Solutions or suspensions of the compounds according to the invention of the general formula I may additionally comprise taste-improving agents such as saccharin, cyclamate or sugar, and, for example, flavourings such as vanillin or orange extract. They may additionally comprise suspending excipients such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.
• Capsules comprising the compounds of the general formula I can be produced 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 gelatin capsules.
• an inert carrier such as lactose or sorbitol
• Suitable suppositories can be produced for example by mixing with carriers intended for this purpose, such as neutral fats or polyethylene glycol or derivatives.
• the compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts can be used, because of their antagonistic or partial agonistic activity, for producing a medicament, in particular for the treatment and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea. They can furthermore be employed to counteract hormonal irregularities, for inducing menstruation and alone or in combination with prostaglandins and/or oxytocin to induce labour.
• the compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts are furthermore suitable for producing products for female contraception (see also WO 93/23020, WO 93/21927).
• the compounds according to the invention or their pharmaceutically acceptable salts can additionally be employed alone or in combination with a selective estrogen receptor modulator (SERM) for female hormone replacement therapy.
• SERM selective estrogen receptor modulator
• the said compounds have an antiproliferative effect in hormone-dependent tumours. They are therefore suitable for the therapy of hormone-dependent carcinomas such as, for example, for breast, prostate and endometrial carcinomas.
• the compounds according to the invention or their pharmaceutically acceptable salts can be employed for the treatment of hormone-dependent carcinomas both in first-line therapy and in second-line therapy, especially after tamoxifen failure.
• the compounds according to the invention having antagonistic or partially agonistic activity, of the general formula (I) or their pharmaceutically acceptable salts can also be used in combination with compounds having antiestrogenic activity (estrogen receptor antagonists or aromatase inhibitors) or selective estrogen receptor modulators (SERM) for producing pharmaceutical products for the treatment of hormone-dependent tumours.
• SERM selective estrogen receptor modulators
• the compounds according to the invention can likewise be used in combination with SERMs or an antiestrogen (estrogen receptor antagonist or aromatase inhibitor) for the treatment of endometriosis or of leiomyomas of the uterus.
• the progesterone receptor modulator and the antiestrogen (estrogen receptor antagonists or aromatase inhibitors) or the SERM can be provided for simultaneous or else for sequential administration.
• the sequential administration preferably the antiestrogen (estrogen receptor antagonists or aromatase inhibitors) or SERM is administered first and subsequently the progesterone receptor modulator is administered.
• Suitable for combination with the non-steroidal progesterone receptor modulators according to the invention in this connection are for example the following antiestrogens (estrogen receptor antagonists or aromatase inhibitors) or SERMs: tamoxifen, 5-(4- ⁇ 5-[(RS)-(4, 4,5,5, 5-pentafluoropentyl)sulphinyl]pentyloxy ⁇ phenyl)-6- phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol (WO 00/03979), ICI 182 780 (7alpha-[9- (4,4,5,5-pentafluoropentylsulphinyl)nonyl]estra-1 ,3,5(10)-triene-3, 17beta-diol), 11 beta- fluoro-7alpha-[5-(methyl ⁇ 3-[(4,4,5,5,5-pentafluoropentyl)sulphanyl]propyl ⁇ a
• the present invention also relates to the use of the compounds of the general formula I 1 where appropriate together with an antiestrogen or SERM, for producing a medicament.
• the present invention further relates to pharmaceutical compositions which comprise at least one compound according to the invention, where appropriate in the form of a pharmaceutically/pharmacologically acceptable salt, without or together with pharmaceutically acceptable excipients and/or carriers.
• compositions and medicaments may be intended for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular administration.
• conventional carriers and/or diluents they comprise at least one compound according to the invention.
• the medicaments of the invention are produced with the conventional solid or liquid carriers or diluents and the excipients normally used in pharmaceutical technology appropriate for the desired mode of administration with a suitable dosage in a known manner.
• the preferred preparations consist of a dosage suitable for oral administration. Examples of such dosage forms are tablets, film-coated tablets, sugar-coated tablets, capsules, pills, powders, solutions or suspensions or else depot forms.
• compositions comprising at least one of the compounds according to the invention are preferably administered orally.
• parenteral preparations such as solutions for injection.
• Further preparations which may also be mentioned are for example suppositories and compositions for vaginal use.
• nBuLi 0.7 ml, 1.6M in hexane
• 1-hexyne 0.5 ml
• THF 4 ml
• 6-[4-(benzo[1 ,3]dioxol-4- yl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one 192 mg
• Water was then added and the mixture was allowed to reach room temp.
• Stage A Reaction of 5-(tert-butyldimethylsilyloxy)pent-1-yne (531 mg), nBuLi (0.7 ml, 1.6 M in hexane) and 6-[4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4- methyl-2,3-benzoxazin-1-one (207 mg) at -78°C as described for Example 1 gave, after column chromatography on silica gel, a colourless oil (86 mg). Stage B: The resulting oil was stirred in THF (3 ml) at room temp, under argon (3 h).
• Lithiumphenylacetylide (0.65 ml, 1M in THF) was added to 6- ⁇ 3-[1-(2-chlorophenyl)- cyclopentyl]-2-oxopropionylamino ⁇ -4-methyl-2,3-benzoxazin-1-one (110 mg) at -78 0 C and allowed to reach room temperature under argon during the night.
• Working up as described for Example 1 and column chromatography on silica gel resulted in the title compound as a foam (54 mg) after oil-pump drying.
• Stage A a suspension of the compound of Example 10 (57.8 mg), triphenylphosphine (6.8 mg), copper iodide (5 mg), 4-iodophenyl acetate (51 mg), 5 mg of palladium acetate in THF (1 ml) and triethylamine (3 ml) was reacted in an ultrasonic bath under argon for 1 h. Addition of saturated aqueous ammonium chloride solution was followed by extraction with ethyl acetate and washing with water and brine. Drying with sodium sulphate was followed by concentration and purification by column chromatography on silica gel. A white solid (46.7 mg) was obtained.
• Stage B A suspension of the compound from stage A (46.7 mg) and sodium bicarbonate (128 mg) in methanol was stirred at room temperature under argon for 6 h. A spatula tip of sodium bicarbonate was then added, and the mixture was stirred overnight. It was diluted with ethyl acetate, water was added, and separation of the phases was followed by extraction with ethyl acetate. Washing of the combined organic phases with brine, drying over sodium sulphate, concentration and column chromatography on silica gel resulted in the title compound as a viscous oil (29 mg).
• Ethynylmagnesium bromide (2.2 ml, 0.5 M in THF) was added to an ice-cold solution of 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin- 1-one (208 mg) in THF (4 ml). Under argon, the reaction solution was allowed to reach room temperature over the course of 3 h. Working up as described in Example 1 and column chromatography on silica gel resulted in the title compound as a foam (84 mg) after oil-pump drying.
• a vinylmagnesium bromide solution (0.5 ml, 1M in THF) was injected into 6-[4-(2-chloro- 4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1 -one (103 mg) in THF (3 ml) at -78 0 C, and the mixture was allowed to reach room temp, under argon overnight. Addition of aqueous ammonium chloride solution was followed by extraction with ethyl acetate and washing with sat. sodium chloride solution.
• Lithium phenylacetylide (0.65 ml, 1 M in THF) was added to 6-[4-(2-chloro-4- fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (136 mg) at
• the compounds 14 and 15 were prepared in analogy to Example 10 from 6-(4-methyl- 4-phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the alkynyl- magnesium halide:
• the compounds 15-28 were prepared in analogy to Example 1 from 6-(4-methyl-4- phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the respective lithium arylacetylide:
• the racemic mixture which was described in example 35 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 35a and 35b.

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