WO2006136461A2 - Non-steroidal progesterone receptor modulators - Google Patents

Non-steroidal progesterone receptor modulators Download PDF

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Publication number
WO2006136461A2
WO2006136461A2 PCT/EP2006/006531 EP2006006531W WO2006136461A2 WO 2006136461 A2 WO2006136461 A2 WO 2006136461A2 EP 2006006531 W EP2006006531 W EP 2006006531W WO 2006136461 A2 WO2006136461 A2 WO 2006136461A2
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Prior art keywords
methyl
compounds according
ethynyl
alkyl
hydroxy
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PCT/EP2006/006531
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French (fr)
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WO2006136461A3 (en
Inventor
Alexander Hillisch
Ulrich Bothe
Guenter Kaufmann
Lothar Sobek
Ulrike Fuhrmann
Peter Droescher
Norbert Schmees
Wolfgang Schwede
Carsten Moeller
Anja Schmidt
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Bayer Schering Pharma Aktiengesellschaft
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Priority to AU2006261048A priority Critical patent/AU2006261048A1/en
Priority to BRPI0611903-4A priority patent/BRPI0611903A2/en
Priority to EA200702524A priority patent/EA200702524A1/en
Priority to JP2008517444A priority patent/JP2008543910A/en
Priority to CA002611897A priority patent/CA2611897A1/en
Priority to MX2008000072A priority patent/MX2008000072A/en
Priority to EP06762404A priority patent/EP1902049A2/en
Publication of WO2006136461A2 publication Critical patent/WO2006136461A2/en
Publication of WO2006136461A3 publication Critical patent/WO2006136461A3/en
Priority to IL188021A priority patent/IL188021A0/en
Priority to NO20080440A priority patent/NO20080440L/en

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    • 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.
  • 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 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.
  • 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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Abstract

The present invention relates to non-steroidal progesterone receptor modulators of the general formula (I), a process for their preparation, the use of the progesterone receptor modulators for producing medicaments, and pharmaceutical compositions comprising these compounds. The compounds according to the invention are suitable for the therapy and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional (bleeding )and dysmenorrhoea, and for the therapy and prophylaxis of hormone-dependent tumours and for use for female fertility control and for hormone replacement therapy.

Description

Non-steroidal progesterone receptor modulators
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
(endometrium) during the menstrual cycle. Elevated progesterone levels after ovulation influence the uterine mucosa to convert it into a state permitting nidation of an embryo (blastocyst). During pregnancy, progesterone controls the relaxation of the myometrium and maintains the function of the decidual tissue.
It is further known that 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.
The effects of 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.
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.
Pure 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.
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.
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.
Besides steroidal compounds such as onapristone or lilopristone, which are notable by comparison with RU 486 for a better dissociation of the progesterone receptor- antagonistic effect and the antiglucocorticoid effect, also known from the literature are various non-steroidal structures whose antagonistic effect on the progesterone receptor is being investigated [see, for example, S. A. Leonhardt and D. P. Edwards, Exp. Biol.
Med. 227: 969-980 (2002) and R. Winneker, A. Fensome, J. E. Wrobel, Z. Zhang, P.
Zhang, Seminars in Reproductive Medicine, Volume 23: 46-57 (2005)]. However, compounds disclosed to date have only moderate antagonistic activity compared with the known steroidal structures. The most effective non-steroidal compounds are reported to have in vitro activities which are 10% of the activity of RU 486.
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.
In contrast to the pure antagonists, partial progesterone receptor agonists (SPRMs) show a residual agonistic property which may vary in strength. This leads to these substances showing potentially 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 an organ- specific and dissociated effect may be of therapeutic benefit for the described indications.
It is therefore an object of the present invention to provide further 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.
The object is achieved according to the present invention by the provision of nonsteroidal compounds of the general formula I
Figure imgf000004_0001
in which
R1 and R2 are independently of one another a hydrogen atom, a linear or nonlinear, branched or unbranched Ci-C5-alkyl group, further forming together with the C atom of the chain a ring having a total of 3-7 members, R3 is a radical C≡C-Ra, where
Ra is a hydrogen or a Ci-Cβ-alkyI, C2-C8-alkenyl, C2-C8- alkynyl, C3-C10-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",
CO2Rb, -O-Rb, -S-Rb, SO2NRcRd, -C(O)-NRcRd, -OC(O)-NRcRd, -C=NORb -NRcRd or C3-C10-cyclo- alkyl, heterocycloalkyl optionally substituted one or more times, identically or differently, by M, or aryl or heteroaryl optionally substituted one or more times by L, L is Ci-Cβ-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C6- perfluoroalkyl, Ci-Ce-perfluoroalkoxy, CrCe-alkoxy- d-Ce-alkoxy, (CH2)p-C3-C10-cycloalkyl, (CH2)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)pNReCONRcRd, -(CH2)pNReCOORb, -(CH2)pNReC(NH)NRcRd, -(CH2)pNReCSNRcRd, -(CH2)pNReS(O)NRcRd,
-(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, -(CH2)pCO2Rb, -(CH2)pCONRcRd,
-(CH2)pCSNRcRd, -(CH2)pORb, -(CH2)pSRb, -(CH2)pCRb(OH)-Re, -(CH2)p-C=NORb, -O-(CH2)n-O-, -0-(CHz)n-CH2-, -0-CH=CH- or -(CH2)n+2-, where n is 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring carbon atoms,
M is d-C6-alkyl or a group -CORb, CO2Rb, -O-Rb, or -NRcRd, where
Rb is a hydrogen or a Ci-C6-alkyl, C2-C8- alkenyl, C2-C8-alkynyl, C3-C10- cycloalkyl, C6-C12-aryl or C1-C3- perfluoroalkyl and
Rcand Rd are independently of one another a hydrogen, Ci-C6-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C3-C10-cycloalkyl,
C6-C12-aryl, C(O)Rb or a hydroxy group, where if
Rc is a hydroxy group, then Rd can only be a hydrogen, a Ci-C6-alkyl, C2-C8- alkenyl, C2-C8-alkynyl, C3-C10- cycloalkyl or C6-C12-aryl and vice versa, and
Re is a hydrogen, C^Ce-alkyl, C2-C8- alkenyl, C2-C8-alkynyl, C3-C10-cyclo- alkyl or C6-C12-aryl, and p can be a number from 0-6,
or
R3 is a radical C=C-R9Rh, where R9 and Rh are independently of one another a hydrogen or a
CrCβ-alkyl, C2-C8-alkenyl or C2-C8-alkynyl optionally substituted one or more times, identically or differently, by X, in which X is a cyano, halogen, hydroxy, nitro, -C(O)Rb, CO2Rb, -O-Rb, -C(O)-NRcRd,
-NRcRd with the meanings already mentioned before for Rb, Rc and Rd, and
R4 is a hydrogen atom, a methyl or an ethyl group or a partly or completely fluorinated C,-C3-alkyl group, A is a mono- or bicyclic carbocyclic or heterocyclic aromatic ring which may optionally be substituted one or more times by Ci-C8-alkyl, C2-C8- alkenyl, C2-C8-alkynyl, Ci-C6-perfluoroalkyl, C1-C6-perfluoroalkoxy, Ci-Ce-alkoxy-CrCβ-alkyl, CrCe-alkoxy-d-Ce-alkoxy, (CH2)P-C3-C10- cycloalkyl, (CH2)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)pNReCONRcRd, -(CH2)pNReCOORb, -(CH2)pNReC(NH)NRcRd, -(CH2)pNReCSNRcRd, -(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)pCONRcRd, -(CH2)pCSNRcRd, -(CH2)pORb, -(CH2)pSRb, -(CH2)pCRb(OH)-Rd, -(CH2)p-C=NORb, -0-(CHz)n-O-, -0-(CH2Jn-CH2-, -O-CH=CH- or -(CH2)n+2-, where n is 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring carbon atoms, or
is a radical -CO2R0, C(O)NR0R0, COR°
or
A is an alkenyl group -CR =CR R , where
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.,-C5-alkyl group, or
5 5
A is an alkynyl group -C≡CR , with the meaning stated above for R , and
B is a carbonyl or a CH2 group,
and their pharmaceutically acceptable salts. 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 R3 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).
Figure imgf000008_0001
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. Alternatively, the alkynyl or alkenyl radicals introduced as R3 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.
The substituents, defined as groups, of the compounds according to the invention of the general formula I may in each case have the following meanings:
C1-C5-, C1-C6- and C1-C8-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.
Preferred in the meaning of Ra in this connection are the methyl, ethyl, n-propyl or n-butyl group and an n-pentyl group. Preferred in the meaning of R1 and R2 are methyl or ethyl.
Alkenyl means linear or nonlinear, branched or unbranched alkenyl radicals. Examples of the meaning of a C2-C8-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 C2-C8-alkenyl radical, it is preferably a vinyl group.
Alkynyl means linear or nonlinear, branched or unbranched alkynyl radicals. A C2-C8- alkynyl radical is intended to be for example an ethynyl, propynyl, butynyl, pentynyl, hexynyl and octynyl group, preferably an ethynyl or propynyl group.
Examples which may be mentioned of C3-Ci0-cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.
Heterocycloalkyl in the meaning of Ra, K and L means 3-8-membered heterocycloalkyl radicals. Examples of heterocycloalkyl are morpholinyl, tetrahydrofuranyl, pyranyl, piperazinyl, piperidinyl, pyrrolidinyl, oxiranyl, oxetanyl, aziridinyl, dioxolanyl and dioxanyl. In this connection, the position of the heteroatom in relation to the point of linkage can be any chemically possible position.
Possible examples of C1-C6-alkoxyl-C1-C6-alkoxy group are methoxymethoxy, ethoxymethoxy or 2-methoxyethoxy.
A radical ORb 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 C1-C5-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.
If R1 and R2 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.
In the former case it is for example a phenyl or naphthyl radical, preferably a phenyl radical.
It is possible to use as 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.
R3 means in the case of an aryl radical an optionally substituted phenyl, 1- or 2-naphthyl radical, with preference for the phenyl radical. Examples of 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 (CH2)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 (CH2)P.
In the case where the compounds of the general formula I (B = -CH2-) are in the form of salts, this is possible for example in the form of the hydrochloride, sulphate, nitrate, tartrate, citrate, fumarate, succinate or benzoate.
If 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. For example, the racemic mixtures can be separated into the pure isomers by chromatography on a support material which is itself optically active (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 hydrolyse the separated esters in each case to the optically pure isomers. It is possible to use as optically active acid for example mandelic acid, camphorsulphonic acid or tartaric acid.
The compounds specified below, and the use thereof, are preferred according to the invention:
Figure imgf000012_0001
Figure imgf000013_0002
Figure imgf000013_0001
Figure imgf000014_0002
Figure imgf000014_0001
Figure imgf000015_0001
14
Figure imgf000016_0001
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Figure imgf000040_0002
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Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000063_0001
Figure imgf000063_0002
Biological characterization of the compounds according to the invention
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 substances according to the invention of the general formula I were tested in the following models:
Progesterone receptor-binding assay
Measurement of the receptor binding affinity:
The receptor binding affinity was determined by competitive binding of a specifically binding 3H-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 (competitor) were coincubated at 0-40C 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 IC50 was determined from the concentration series. The relative molar binding affinity (RBA) was calculated as ratio of the IC50 values for reference substance and compound to be tested (x 100%) (RBA of the reference substance = 100%).
The following incubation conditions were chosen for the receptor types:
Progesterone receptor:
Uterus cytosol of the estradiol-primed rabbit, homogenized in TED buffer (20 mMTris/HCI, pH 7.4; 1 mM ethylenediaminetetraacetate, 2 mM dithiothreitol) with 250 mM sucrose; stored at -3O0C. Tracer: 3H-ORG 2058, 5 nM; reference substance: progesterone.
Glucocorticoid receptor:
Thymus cytosol from the adrenalectomized rat, thymi stored at -300C; buffer: TED. Tracer: 3H-dexamethasone, 20 nM; reference substance: dexamethasone. 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.
Antagonism at the PR-B progesterone receptor
The transactivation assay is carried out as described in WO 02/054064.
Agonism on the PR-B progesterone receptor
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).
Figure imgf000065_0001
Dosage
The progesterone receptor modulators can be administered orally, enterally, parenterally or transdermal^ for the use according to the invention.
Satisfactory results are generally to be expected in the treatment of the indications mentioned hereinbefore when the daily doses cover a range from 1 μg to 500 mg of the compound according to the invention.
Suitable dosages of the compounds according to the invention in humans for the treatment of endometriosis, of leiomyomas of the uterus and dysfunctional bleeding and for use in fertility control and for hormone replacement therapy are from 50 μg 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. Reference should be made in this connection to Remington's Pharmaceutical Sciences, 15th ed. Mack Publishing Company, Easton, Pennsylvania (1980).
Suitable for oral administration are in particular tablets, film-coated tablets, sugar-coated tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions or solutions.
Preparations for injection and infusion are possible for parenteral administration.
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.
For rectal administration, 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.
Furthermore, compositions for vaginal use may also be mentioned as preparation.
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.
Correspondingly, 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.
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.
In addition, 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. 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. In the treatment of hormone-dependent tumours 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. In 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}amino)pentyl]- estra-1 ,3,5(10)-triene-3,17beta-diol (WO98/07740), 11 beta-fluoro-7alpha-{5- [methyl(7, 7,8,8,9,9, 10, 10, 10-nonafluorodecyl)amino]pentyl}estra-1 ,3,5(10)-triene-3, 17- beta-diol (WO 99/33855), 11 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, and further compounds having antiestrogenic activity, and aromatase inhibitors such as, for example, fadrozole, formestane, letrozole, anastrozole or atamestane.
Finally, the present invention also relates to the use of the compounds of the general formula I1 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.
These pharmaceutical compositions and medicaments may be intended for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular administration. Besides 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.
The pharmaceutical compositions comprising at least one of the compounds according to the invention are preferably administered orally.
Also suitable are parenteral preparations such as solutions for injection. Further preparations which may also be mentioned are for example suppositories and compositions for vaginal use.
The following examples serve to illustrate the subject-matter of the invention in more detail without wishing to restrict it thereto.
Preparation of the starting compounds 6-[4-(2-chloro-5-fluorophenyl)-4-methyl-2- oxovaleroylamino]-4-methyl-2,3-benzoxazin-1 -one, 6-[4-(2-chloro-4-fluorophenyl)-4- methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one and 6-{3-[1-(2-chloro- phenyl)cyclopentyl]-2-oxopropionylamino}-4-methyl-2,3-benzoxazin-1 -one has been described in the patent US 2002/0077356, the compound 6-[4-(2,3-dihydro-7- benzofuranyl)-4-methyl-2-oxopentanoylamino]-4-methyl-2,3-benzoxazinone in US patent 6,323, 199B1 (example 87 therein), the compound 6-(4-methyl-4-phenyl-2- oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one in the patent WO 199854159 and the compound 6-[3-[1 -(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionyl- amino]-4-methyl-2,3-benzoxazin-1-one in the patent WO 200375915.
General methods
1-(Benzo[1,3]dioxol-4-yl)-1-methylethanol
57.2 ml of methyl magnesium chloride solution (3M in THF) were added to 25.5 g of
4-acetylbenzo[1 ,3]dioxole in 375 ml of THF at RT under argon. The mixture was stirred at RT for 16 h and added to ice/2N hydrochloric acid. It was then extracted with ethyl acetate, and the organic phase was washed with water and brine and dried (Na2SO4).
27.89 g of 1-[benzo(1 ,3)dioxol-4-yl]-1-methylethanol were obtained as a brown oil.
1H-NMR (CDCI3, ppm) = 1.6 (s, 6H), 5.95 (s, 2H), 6.76 (dd, 1 H), 6.82 (t, 1 H), 6.91 (dd,
1 H)
4-(Benzo[1, 3]dioxol-4-yl)-4-methyl-2-oxopentanoic acid
47 ml of tin(IV) chloride were added to 9.5 g of 1-(benzo[1 ,3]dioxol-4-yl)-1- methylethanol and 14.2 g of ethyl 2-trimethylsilyloxyacrylate in 200 ml of dichloromethane at -700C. After 15 minutes, the solution was added to potassium carbonate solution. After extraction with diethyl ether, the organic phase was washed with water, dried and evaporated.
14.4 g of the ethyl 4-(benzo[1 ,3]dioxol-4-yl)-4-methyl-2-oxopentanoate obtained in this way were stirred with 150 ml of 1 M sodium hydroxide and 300 ml of methanol at RT for
10 hours. The methanol was then removed in vacuo, and the remaining solution was extracted with diethyl ether. The aqueous phase was acidified with 1 M hydrochloric acid and extracted with diethyl ether. Drying and evaporation resulted in 11.1 g of 4-(benzo[1 ,3]dioxol-4-yl)-4-methyl-2-oxopentanoic acid as yellowish oil. MS (ei) m/e: M+ = 251
6-[4-(Benzo[1,3]dioxol-4-yl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1- one
10 g of 4-(benzo[1 ,3]dioxol-4-yl)-4-methyl-2-oxopentanoic acid were dissolved in 125 ml of dimethylacetamide and, at -00C under argon, 3.5 ml of thionyl chloride were added. After stirring at -3 to +3°C for 20 minutes, 7.6 g of 6-amino-4-methyl-2,3-benzoxazin-1- one (WO 00/32584) were added. The mixture was stirred at room temperature for 96 hours and, after addition of water, extracted with ethyl acetate, the organic phase was washed with water and dried (Na2SO4), and evaporation of the solvent and chromatography of the crude product on silica gel with hexane/ethyl acetate (100:0 -> 60:40) resulted in 6.56 g of 6-[4-(benzo[1 ,3]dioxol-4-yl)-4-methyl-2-oxovaleroylamino]-4- methyl-2,3-benzoxazin-1-one as a beige solid, m.p. = 165-166°C, MS (ei) m/e: M+ = 409
Synthesis examples
(-)-6-{2-[2-(2,3-(Methylenedioxy)phenyl)-2-methylpropyl]-2-hydroxyoct-3-ynoyl}-4- methyl-2,3-benzoxazin-1-one 1 and (+)-6-{2-[2-(2,3-(methylenedioxy)phenyl)-2- methylpropyl]-2-hydroxyoct-3-ynoyl}-4-methyl-2,3-benzoxazin-1-one 2
Figure imgf000072_0001
nBuLi (0.7 ml, 1.6M in hexane) was added to a solution of 1-hexyne (0.5 ml) in THF (4 ml) at -780C. The mixture was stirred at -78°C for 20 min, 6-[4-(benzo[1 ,3]dioxol-4- yl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (192 mg) was added, and the mixture was stirred at -780C for 4 h. Water was then added and the mixture was allowed to reach room temp. Extraction with ethyl acetate, washing with saturated sodium chloride solution, drying over sodium sulphate and purification by column chromatography on silica gel resulted in 82 mg of a white foam which was then converted by preparative chiral HPLC (Chiralpak AD 250 x 10 mm, eluent: acetonitrile/water 55/45 v/v, flow rate 4.7 ml/min, temperature 400C, retention times: 12.2 min (+)-enantiomer, 15.7 min (-)-enantiomer) into the compounds (-)-6-{2-[2-(2,3- (methylenedioxy)phenyl)-2-methylpropyl]-2-hydroxyoct-3-ynoyl}-4-methyl-2,3- benzoxazin-1-one (Example 1) and (+)-6-{2-[2-(2,3-(methylenedioxy)phenyl)-2- methylpropyl]-2-hydroxyoct-3-ynoyl}-4-methyl-2,3-benzoxazin-1 -one (Example 2).
1 H-NMR (ppm, CDCI3, 400 MHz): 0.91 (t, J = 7.2 Hz, 3H, CH3), 1.32 - 1.49 (m, 4H), 1.55 (s, 3H), 1.58 (s, 3H), 2.17 (t, J = 7.2 Hz, 2H), 2.56 (s, 3H, CH3), 2.59 (d, J = 14.4 Hz, 1H), 2.74 (d, J = 14.8 Hz, 1H), 2.80 (s, 1H, OH), 5.94 - 5.96 (m, 2H)1 6.46 - 6.49 (m, 1 H), 6.64 (t, J = 7.8 Hz, 1 H), 7.47 - 7.49 (m, 1H), 8.25 - 8.28 (m, 1 H), 8.76 (s, 1 H, NH). C28H30N2O6 (490.6):
rac-6-{2-[2-(2-Chloro-5-fluorophenyl)-2-methylpropyl]-2,7-dihydroxyhept-3-ynoyl}- 4-methyl-2,3-benzoxazin-1-one 3
Figure imgf000073_0001
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). Addition of water, extraction with ethyl acetate and washing with saturated brine were followed by drying with sodium sulphate. Purification by column chromatography on silica gel led to the title compound as a white foam (43 mg). 1 H-NMR (ppm, CDCI3, 400 MHz): 1.58 (s, 3H, Me), 1.59 (s, 3H, Me), 1.71 - 1.74 (m, 2H, CH2), 2.2 - 2.3 (m, 2H), 2.56 (s, 3H, CH3), 2.75 (d, J = 15.2 Hz, 1 H, CH), 2.92 (d, J = 14.8 Hz, 1 H, CH), 3.26 (s, 1 H, OH), 3.74 - 3.78 (m, 2H), 6.67 - 6.78 (m, 1 H), 7.09 - 7.19 (m, 2H), 7.66 - 7.69 (m, 2H), 8.20 - 8.21 (m, 1 H), 8.27 - 8.29 (m, 1 H), 8.99 (s, 1 H, NH). C26H26CIFN2O5 (501.0): LC-MS: m/z = 501 [M + H+]. rac-6-{2-[2-(2-Chloro-5-fluorophenyl)-2-methylpropyl]-2-hydroxyoct-3-ynoyl}-4- methyl-2,3-benzoxazin-1-one 4
Figure imgf000074_0001
Reaction of 1-hexyne (0.6 ml), 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 -780C as described for Example 1 gave, after column chromatography on silica gel and preparative thin-layer chromatography a viscous oil (12 mg).
1 H-NMR (ppm, CDCI3, 400 MHz): 0.90 (t, J = 7.2 Hz, 3H, Me), 1.32 - 1.47 (m, 4H), 1.57 (S, 3H, Me), 1.62 (s, 3H, Me), 2.13 (t, J = 7.2 Hz, CH2C=C), 2.56 (s, 3H, Me), 2.81 - 2.95 (m, 3H), 6.68 - 6.71 (m, 1 H), 7.11 - 7.17 (m, 2H), 7.56 - 7.58 (m, 1 H), 8.21 (d, J = 2.0 Hz, 1 H), 8.29 (d, J = 12.6 Hz, 1 H), 8.73 (br. s., 1H, NH). C27H28CIFN2O4 (499.0): LC- MS: m/z = 499 [M + H+].
rac-6-{2-[(2-Chlorophenyl)cyclopentyl]methyl-2-hydroxy-4-phenylbut-3-ynoyl- amino}-4-methyl-2,3-benzoxazin-1-one 5
Figure imgf000074_0002
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 -780C 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. 1 H-NMR (ppm, CDCI3, 400 MHz): 1.59 - 1.85 (m, 5H), 2.18 - 2.35 (m, 3H), 2.54 (s, 3H, Me), 2.7 - 3.09 (3H), 6.94 - 7.58 (m, 10H), 8.18 (d, J = 1.1 Hz), 8.25 (d, J = 8.6 Hz, 1 H), 8.81 (br. s., 1 H, NH). C31H27CIN2O4 (526.0): HPLCMS: m/z = 526 [M], purity 97%. 6-{2-[2-(2,3-Dihydro-7-benzofuranyl)-2-methylpropyl]-2-hydroxy-3- octynoylamino}-4-methyl-2,3-benzoxazin-1-one 6
Figure imgf000075_0001
Reaction of 1-hexyne (0.4 ml), nBuLi (0.7 ml, 1.6 M in hexane) and 6-[4-(2,3-dihydro-7- benzofuranyl)-4-methyl-2-oxopentanoylamino]-4-methyl-2,3-benzoxazin-1-one (99.5 mg) at -78°C in THF (3 ml) as described for Example 1 gave, after column chromatography on silica gel and drying in vacuo, a solidified colourless oil (42 mg). 1 H NMR (ppm, CDCI3, 400 MHz): 0.89 (t, J =7.2 Hz, 3H, Me), 1.35 - 1.56 (m, 10H), 2.14 - 2.18 (m, 2H), 2.56 (s, 3H, Me), 2.66 (d, J =14.8 Hz, 1 H)1 2.73 (d, J = 14.8 Hz, 1H), 3.0 -3.2 (m, 2H), 3.27 (s, 1 H), 4.57 (t, J = 9.3 Hz, 2H), 6.75 (t, J = 7.5 Hz, 1 H), 6.95 (d, J = 6.3 Hz, 1 H), 7.05 (d, J = 7.8 Hz, 1 H), 7.50 - 7.52 (m, 1 H), 8.23 - 8.29 (m, 2H), 8.78 (br. s., NH). C29H32CIN2O5 (488): LC-MS: m/z = 489 [M + H+].
rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-2-[(4-hydroxyphenyl)ethynyl]-4- methylpentanoylamino}-4-methyl-2,3-benzoxazin-1 -one 7
Figure imgf000075_0002
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). 1 H-NMR (ppm, CDCI3, 400 MHz): 1.63 (s, 3H, Me), 1.69 (s, 3H, Me), 2.56 (s, 3H, Me), 2.94 - 3.01 (m, 3H), 5.48 (br. s, 1 H1 OH), 6.74 - 6.77 (m, 2H), 6.84 - 6.93 (m, 2H), 7.21
- 7.25 (m, 2H), 7.43 (dd, J = 9.0, 6.1 Hz, 1 H), 7.57 - 7.59 (dd, J = 8.6, 2.3 Hz, 1H), 8.22
- 8.23 (m, 1H), 8.31 (d, J = 8.6 Hz, 1 H), 8.80 (br. s, 1 H, NH). C29H24CIFN2O5 (534.98): LC-MS: m/z = 535 [M + H+].
rac-6-{2-[2-(2-Chloro-4-fluorophenyl)-2-methylpropyl]-2-hydroxydec-3-ynoyl- amino}-4-methyl-2,3-benzoxazin-1-one 8
Figure imgf000076_0001
Reaction of 1-octyne (0.4 ml), nBuLi (0.6 ml, 1.6 M in hexane) and 6-[4-(2-chloro-4- fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (110 mg) in THF (3 ml) at -78°C as described for Example 1 gave, after column chromatography on silica gel, a white solid (25 mg). 1 H-NMR (ppm, CDCI3, 400 MHz): 0.87 (t, J = 7.0 Hz, 3H), 1.26 - 1.46 (m, 8H), 1.58 (s, 3H, Me), 1.63 (s, 3H, Me), 2.12 (t, J = 7.0 Hz, CH2C≡C), 2.56 (s, 3H, Me)2.79 - 2.91 (m, 3H), 6.92 - 6.95 (m, 2H), 7.40 (dd, J = 8.9, 6.3 Hz, 1 H), 7.53 (dd, J = 8.6, 1.9 Hz, 1 H), 8.21 (d, J = 1.9 Hz, 1 H), 8.30 (d, J = 8.6 Hz, 1 H), 8.71 (br. s., 1 H, NH); C29H32CIFN2O4 (527.0): LC-MS: m/z = 527 [M + H+]. rac-6-{2-[2-(2-Chloro-4-fluorophenyl)-2-methylpropyl]-2-hydroxy-5-phenylpent-3- ynoylamino}-4-methyl-2,3-benzoxazin-1-one 9
Figure imgf000077_0001
Reaction of 3-phenyl-1-propyne (0.17 ml), nBuLi (0.51 ml, 1.6 M in hexane) and 6-[4-(2- chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (140 mg) in THF (3 ml) at -78°C as described for Example 1 gave, after column chromatography on silica gel and drying in vacuo, a white foam (116 mg). 1 H-NMR (ppm, CDCI3, 400 MHz): 1.59 (s, 3H1 Me), 1.61 (s, 3H, Me), 2.55 (s, 3H, Me), 2.79 - 2.95 (m, 3H), 3.4 - 3.6 (m, 2H, CH2C≡C), 6.8 - 6.93 (m, 2H), 7.23 - 7.42 (m, 7H), 8.15 (d, J = 2.3 Hz, 1H), 8.27 (d, J = 8.6 Hz, 1 H), 8.64 (br. s., 1 H, NH). C30H26CIFN2O4 (533.0): LC-MS: m/z = 533 [M + H+].
rac-6-{4-(2-Chloro-4-fluorophenyl)-2-ethynyl-2-hydroxy-4-methylpentanoylamino}- 4-methyl-2,3-benzoxazin-1-one 10
Figure imgf000077_0002
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. 1 H-NMR (ppm, CDCI3, 400 MHz): 0.8 - 0.9 (m, 1 H), 1-58 (s, 3H, Me), 1.65 (s, 3H, Me), 2.56 - 2.96 (6H), 6.86 - 6.94 (m, 2H), 7.41 (dd, J = 9.0, 6.2 Hz, 1 H), 7.56 (dd, J = 8.6, 1.9 Hz, 1 H), 8.19 (d, J = 1.9 Hz, 1 H), 8.31 (d, J = 8.6 Hz, 1 H), 8.63 (br. s., 1 H1 NH). C23H20CIFN2O4 (542.9): LC-MS: m/z = 543 [M + H+]. rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-4-methyl-2-vinyl-pentanoylamino}-4- methyl-2,3-benzoxazin-1-one Λ±
Figure imgf000078_0001
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 -780C, 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. Drying with sodium sulphate was followed by concentration in a rotary evaporator and purification by column chromatography on silica gel to result in the title compound as solidified oil (18 mg). 1 H-NMR (ppm, CDCI3, 400 MHz, selected signals): 1.53 (s, 3H, Me), 1.57 (s, 3H, Me), 2.35 (s, 1 H), 2.56 (s, 3H, Me), 2.74 (d, J = 15.3 Hz, 1H), 2.89 (d, J = 15.3 Hz, 1 H), 5.15 (d, J = 10.5 Hz, 1 H), 5.27 (d, J = 17.6 Hz, 1 H), 6.10 (dd, J = 17.2, 10.6 Hz, 1 H), 6.81 - 6.86 (m, 1 H),
rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-2-[(4-methoxyphenyl)ethynyl]-4- methylpentanoylamino}-4-methyl-2,3-benzoxazin-1 -one Λ2
Figure imgf000078_0002
Reaction of 4-methoxyphenylacetylene (0.4 ml), nBuLi (0.6 ml, 1.6 M in hexane) and 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin- 1-one (110 mg) at -78°C as described for Example 1 gave, after column chromatography on silica gel, the title compound as a white solid (44 mg). 1 H-NMR (ppm, CDCI3, 400 MHz): 1.63 (s, 3H, Me), 1.69 (s, 3H, Me), 2.91 - 3.01 (m, 3H), 3.81 (s, 3H, Me), 6.81 - 6.94 (m, 3H), 7.25 - 7.29 (m, 3H), 7.43 (dd, J = 8.4, 6.3 Hz, 1 H), 7.58 (dd, J = 8.6, 2.3 Hz1 1 H), 8.24 (d, J = 1.9 Hz, 1 H), 8.31 (d, J = 8.6 Hz, 1H), 8.79 (br. s., 1 H, NH). C30H26CIFN2O5 (549.0): LC-MS: m/z = 549 [M + H+].
rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-4-methyl-2-(phenylethynyl)- pentanovlamino)-4-methyl-2,3-benzoxazin-1-one 13
Figure imgf000079_0001
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
-78°C and the mixture was stirred at -780C under argon for 2.5 h. Working up as described for Example 1 and column chromatography on silica gel resulted in the title compound as a white foam (102 mg) after oil-pump drying.
1 H-NMR (ppm, CDCI3, 400 MHz): 1.64 (s, 3H, Me), 1.70 (s, 3H, Me), 2.57 (s, 3H, Me), 2.92 - 3.03 (m, 3H), 6.82 - 6.86 (m, 1 H), 6.91 - 6.93 (m, 1 H), 7.30 - 7.36 (m, 5H), 7.44
(dd, J = 9.0, 6.2 Hz, 1 H), 7.59 (dd, J = 8.6, 2.0 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1 H), 8.31
(d, J = 8.2 Hz, 1H), 8.79 (br. s., NH); C29H24CIFN2O4 (519.0): HPLC-MS: m/z = 518 [M].
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:
rac-6-[2-Ethynyl-2-hydroxy^-methyWφhenylpentanoylamino]-4-methyl-2,3- benzoxazin-1-one 14
Figure imgf000079_0002
1 H-NMR (ppm, CDCI3, 400 MHz): 1.42 (3H), 1.59 (3H), 2.57 (3H), 2.64 (4H), 7.15 (1H), 7.31 (2H), 7.46 (2H), 7.58 (1 H), 8.25 (1 H), 8.30 (1 H), 8.81 (1 H). rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-propynylpentanoylamino]-4-methyl-2,3- benzoxazin-1-one 15
Figure imgf000080_0001
1 H-NMR (ppm, CDCI3, 400 MHz): 1.42 (3H)1 1.59 (3H), 2.50-2.65 (6H)1 7.11 (1 H), 7.30 (2H), 7.43 (2H), 7.58 (1 H), 8.29 (2H), 8.85 (1 H).
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:
rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-(phenylethynyl)pentanoylamino]-4-methyl- 2,3-benzoxazin-1-one 16
Figure imgf000080_0002
1 H-NMR (ppm, CDCI3, 300 MHz): 1.47 (3H), 1.65 (3H), 2.57 (3H), 2.62-2.78 (3H), 7.15 (1H), 7.27-7.37 (5H), 7.40 (2H), 7.50 (2H), 7.59 (1 H), 8.29 (2H), 8.90 (1 H).
(+)-6-[2-Hydroxy-4-methyl-2-[(4-methylphenyl)ethynyl]-4-phenylpentanoylamino]- 4-methyl-2,3-benzoxazin-1-one 17a and
(-)-6-[2-Hydroxy-4-methyl-2-[(4-methylphenyl)ethynyl]-4-phenylpentanoylamino]- 4-methyl-2,3-benzoxazin-1-one 17b
Figure imgf000081_0001
1 H-NMR (ppm, CDCI3, 300 MHz): 1.48 (3H), 1.64 (3H), 2.36 (3H), 2.57 (3H), 2.60-2.80 (3H), 7.08-7.20 (3H), 7.30 (4H), 7.49 (2H), 7.60 (1 H), 8.29 (2H), 8.90 (1 H). 16a: [α]D 20: +28.4° (CHCI3, 1.03 g/100 ml; λ=589 nm) 16b: [α]D 20: -28.6° (CHCI3, 1.01 g/100 ml; λ=589 nm)
rac-6-[2-Hydroxy-2-[(4-methoxyphenyl)ethynyl]-4-methyl-4-phenylpentanoyl- amino]-4-methyl-2,3-benzoxazin-1 -one 18
Figure imgf000081_0002
1 H-NMR (ppm, CDCI3, 300 MHz): 1.47 (3H), 1.63 (3H), 2.56 (3H), 2.60-2.78 (3H), 3.80 (3H), 6.81 (2H), 7.13 (1 H), 7.25-7.38 (4H), 7.48 (2H), 7.60 (1 H), 8.28 (2H), 8.89 (1 H).
(+)-6-[2-Hydroxy-2-[(4-methoxyphenyl)ethynyl]-4-methyl-4- phenvlpentanovlamino1-4-methyl-2,3-benzoxazin-1-one 18a and (-)-6-[2-Hydroxy-2-[(4-methoxyphenyl)ethynyl]-4-methyl-4- phenvlpentanovlamino1-4-methyl-2.3-benzoxazin-1-one 18b
The racemic mixture which was described in example IjJ was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 18a and 18b. 18a : [α]D 20: + 29.3° (CHCI3, 1.12 g/100 ml; λ=589 nM) 18b : [α]D 20: - 30.0° (CHCI3, 1.14 g/100 ml; λ=589 nM) rac-6-[2-Hydroxy-2-[(4-(N,N-dimethylamino)phenyl)ethynyl]-4-methyl-4-phenyl- pentanoylamino]-4-methyl-2,3-benzoxazin-1-one l9
Figure imgf000082_0001
1 H-NMR (ppm, CDCI3, 400 MHz): 1.48 (3H), 1.62 (3H), 2.57 (3H), 2.60-2.75 (3H), 2.98 (6H), 6.58 (2H), 7.12 (1 H), 7.23-7.38 (4H), 7.48 (2H); 7.57 (1 H), 8.28 (2H), 8.90 (1 H).
rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-trifluoromethylphenyl)ethynyl]- pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 20
Figure imgf000082_0002
1 H-NMR (ppm, CDCI3, 400 MHz): 1.48 (3H), 1.63 (3H), 2.57 (3H), 2.64-2.80 (3H), 7.17 (1 H), 7.33 (2H), 7.48 (4H), 7.56 (2H), 7.61 (1H), 8.30 (2H), 8.92 (1 H).
(+)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-trifluormethylphenyl)ethynyl]- pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 20a and (-)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-trifluormethylphenyl)ethynyl]- pentanovlaminol-4-methyl-2,3-benzoxazin-1-one 20b
The racemic mixture which was described in example 20 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 20a and 20b. 20a : [α]D 20: + 19.9° (CHCI3, 1.05 g/100 ml; λ=589 nM) 20b : [α]D 20: - 20.4° (CHCI3, 1.01 g/100 ml; λ=589 nM) rac-6-[2-[(4-Cyanophenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]- 4-methyl-2,3-benzoxazin-1-one 21
Figure imgf000083_0001
1 H-NMR (ppm, CDCI3, 400 MHz): 1.50 (3H), 1.62 (3H), 2.57 (3H), 2.63-2.82 (3H), 7.18 (1 H)1 7.35 (2H), 7.48 (4H), 7.55-7.68 (2H), 7.62 (1H), 8.30 (2H), 8.94 (1 H).
(+)-6-[2-[(4-Cyanophenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]- 4-methyl-2,3-benzoxazin-1 -one 21a and
(-)-6-[2-[(4-Cyanophenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4- methyl-2,3-benzoxazin-1-one 21b
The racemic mixture which was described in example 21 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 21a and 21b. 21a : [α]D 20: + 26.6° (CHCI3, 1.12 g/100 ml; λ=589 nM) 21b : [α]D 20: - 26.8° (CHCI3, 1.02 g/100 ml; λ=589 nM)
rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-phenylphenyl)ethynyl]pentanoylamino]- 4-methyl-2,3-benzoxazin-1-one 22
Figure imgf000083_0002
1 H-NMR (ppm, CDCI3, 400 MHz): 1.50 (3H), 1.68 (3H), 2.58 (3H), 2.64-2.81 (3H), 7.18 (1H), 7.30-7.40 (3H), 7.41-7.61 (11 H), 8.30 (2H), 8.92 (1 H).
(+)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-phenylphenyl)ethynyl]pentanoylamino]- 4-methyl-2,3-benzoxazin-1 -one 22a and
(-)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-phenylphenyl)ethynyl]pentanoylamino]- 4-methyl-2,3-benzoxazin-1 -one 22b
The racemic mixture which was described in example 22 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 22a and 22b. 22a : [α]D 20: + 38.4° (CHCI3, 1.06 g/100 ml; λ=589 nM) 22b : [α]D 20: - 30.6° (CHCI3, 1.12 g/100 ml; λ=589 nM)
rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(3-trifluoromethylphenyl)ethynyl]- pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 23
Figure imgf000084_0001
1 H-NMR (ppm, CDCI3, 300 MHz): 1.52 (3H)1 1.68 (3H)1 2.60 (3H), 2.65-2.88 (3H), 7.21 (1 H), 7.49 (2H)1 7.42-7.70 (7H), 8.34 (2H), 8.96 (1 H).
rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(2-trifluoromethylphenyl)ethynyl]- pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 24
Figure imgf000084_0002
1 H-NMR (ppm, CDCI3, 600 MHz): 1.52 (3H), 1.65 (3H), 2.62 (3H), 2.69 (1H), 2.78 (1 H), 2.91 (1 H), 7.11 (1 H)1 7.32 (3H), 7.51 (3H), 7.57 (2H), 7.70 (1 H), 8.20 (1H), 8.45 (1 H), 8.75 (1 H).
(+)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(2-trifluormethylphenyl)ethynyl]- pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 24a and (-)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(2-trifluormethylphenyl)ethynyl]- pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 24b
The racemic mixture which was described in example 24 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 24a and 24b. 24a : [α]D 20: + 21.3° (CHCI3, 1.00 g/100 ml; λ=589 nM) 24b : [α]D 20: - 19.4° (CHCI3, 1.00 g/100 ml; λ=589 nM)
rac-6-[2-Hydroxy-4-methyl-2-[(4-nitrophenyl)ethynyl]-4-phenylpentanoylamino]-4- methyl-2,3-benzoxazin-1-one 25
Figure imgf000085_0001
1 H-NMR (ppm, CDCI3, 600 MHz): 1.47 (3H), 1.62 (3H), 2.55 (3H), 2.79 (1H), 2.81 (2H), 7.18 (1H), 7.34 (2H), 7.50 (4H), 7.63 (1 H), 8.17 (2H), 8.80 (2H), 8.94 (1 H).
rac-6-[2-[[4-(1,1-Dimethylethyl)phenyl]ethynyl]-2-hydroxy-4-methyl- 4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 26
Figure imgf000085_0002
1 H-NMR (ppm, CDCI3, 300 MHz): 1.32 (9H), 1.51 (3H), 1.68 (3H), 2.62 (3H), 2.65-2.82 (3H), 7.18 (1H), 7.30-7.40 (6H), 7.52 (2H), 7.63 (1 H), 8.32 (2H), 8.93 (1 H).
rac-6-[2-Hydroxy-4-methyl-2-[(3-methylphenyl)ethynyl]-4-phenylpentanoylamino]- 4-methyl-2,3-benzoxazin-1-one 27
Figure imgf000086_0001
1 H-NMR (ppm, CDCI3, 400 MHz): 1.47 (3H), 1.63 (3H), 2.30 (3H), 2.58 (3H), 2.62-2.80 (3H), 7.12-7.26 (5H), 7.32 (2H), 7.50 (2H), 7.60 (1 H), 8.30 (2H), 8.90 (1 H).
rac-6-[2-Hydroxy-4-methyl-2-[(2-methylphenyl)ethynyl]-4-phenylpentanoylamino]- 4-methyl-2,3-benzoxazin-1-one 28
Figure imgf000086_0002
1 H-NMR (ppm, CDCI3, 300 MHz): 1.47 (3H), 1.65 (3H), 2.38 (3H), 2.58 (3H), 2.62-2.80 (3H), 7.08-7.42 (7H), 7.49 (2H), 7.60 (1H), 8.22-8.36 (2H), 8.90 (1 H).
rac-6-[2-(3,3-Dimethylbutynyl)-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4- methyl-2,3-benzoxazin-1-one 29
Figure imgf000087_0001
1 H-NMR (ppm, CDCI3, 300 MHz): 1.20 (9H), 1.43 (3H), 1.60 (3H), 2.46 (1 H), 2.50-2.63 (5H), 7.11 (1 H), 7.28 (2H), 7.43 (2H), 7.54 (1 H), 8.22 (1H), 8.29 (1H), 8.32 (1H).
The following compound was prepared in analogy to Example 7 from the compound described in Example 13 and 4'-iodoacetophenone:
rac-6-[2-[(4-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]- 4-methyl-2,3-benzoxazin-1-one 30
Figure imgf000087_0002
1 H-NMR (ppm, CDCI3, 300 MHz): 1.48 (3H), 1.63 (3H), 2.56 (3H), 2.60 (3H), 2.63-2.82 (3H), 7.18 (1 H)1 7.33 (2H), 7.40-7.56 (4H), 7.62 (1 H), 7.90 (2H), 8.30 (2H), 8.93 (1 H).
(+)-6-[2-[(4-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4- methyl-2,3-benzoxazin-1-one 30a and
(-)-6-[2-[(4-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4- methyl-2,3-benzoxazin-1-one 30b
The racemic mixture which was described in example 30 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 30a and 30b. 30a : [α]D 20: + 31.3° (CHCI3, 1.09 g/100 ml; λ=589 nM) 30b : [α]D 20: - 28.4° (CHCI3, 1.09 g/100 ml; λ=589 nM) The compounds 30 and 31 were prepared in analogy to Example 1 from 6-[3-[1-(2- fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionylamino]-4-methyl-2,3- benzoxazin-1-one
rac-6-[2-[(2-Fluoro-5-trifluoromethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4- trifluoromethylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1-one 31
Figure imgf000088_0001
1H-NMR (ppm, CDCI3, 400 MHz): 0.90 (1H), 1.00-1.15 (3H), 2.51 (1H), 2.55 (3H), 2.68 (1H), 3.18 (1 H), 7.01 (1 H), 7.30 (1 H), 7.41 (2H), 7.56 (2H), 7.63 (1 H)1 7.68 (1 H), 8.19 (1 H), 8.31 (1 H), 8.98 (1H).
(+)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4- trifluormethvlphenvl)but-3-inovlamino1-4-methyl-2,3-benzoxazin-1-one 31a and (-)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4- trif luormethvlphenvl)but-3-inovlamino1-4-methyl-2,3-benzoxazin-1 -one 31 b
The racemic mixture which was described in example 3_1 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 31a and 31b. 31a : [α]D 20: + 2.3° (CHCI3, 1.00 g/100 ml; λ=589 nM) 31b : [α]D 20: - 1.9° (CHCI3, 1.00 g/100 ml; λ=589 nM) rac-6-[2-[(2-Fluoro-5-trifluoromethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4- methylphenyl)but-3-ynoylamino]-4-methyl-2,3-benzoxazin-1 -one 32
Figure imgf000089_0001
1 H-NMR (ppm, CDCI3, 400 MHz): 0.88 (1H), 0.98-1.13 (3H), 2.34 (3H), 2.44 (1 H), 2.55 (3H), 2.70 (1 H), 3.02 (1H), 7.01 (1 H), 7.10 (2H), 7.22 (2H), 7.30 (1 H), 7.64 (2H), 8.19 (1H), 8.31 (1 H), 8.98 (1 H).
(+)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4- methvlphenvl)but-3-inovlamino1-4-methyl-2.3-benzoxazin-1 -one 32a and (-)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4- methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1 -one 32b
The racemic mixture which was described in example 32 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 32a and 32b. 32a : [α]D 20: + 8.6° (CHCI3, 1.00 g/100 ml; λ=589 nM) 32b : [α]D 20: - 8.7° (CHCI3, 1.00 g/100 ml; λ=589 nM)
The following compound was prepared in analogy to example 7 from compound which was described in example 14 and 3'-lodacetophenon: rac-6-[2-[(3-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]- 4-methyl-2,3-benzoxazin-1 -one 33
Figure imgf000089_0002
1 H-NMR (ppm, CDCI3, 300 MHz): 1.49 (3H), 1.63 (3H), 2.57 (6H), 2.62-2.81 (3H), 7.16 81 H), 7.28-7.70 (7H), 7.90-8.00 (2H), 8.30 (2H), 8.94 (1 H). Compounds 34 and 35 were prepared in analogy to example 1 from 6-(4-Methyl-4- phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the according Lithium arylacetylide.
rac-6-[2-[(2,5-Dimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4- phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 34
Figure imgf000090_0001
1 H-NMR (ppm, CDCI3, 400 MHz): 1.49 (3H), 1.62 (3H), 2.27 (3H), 2.33 (3H), 2.57 (3H), 2.65-2.78 (3H), 7.03 (2H), 7.13 (2H), 7.30 (2H), 7.50 (2H), 7.61 (1H), 8.22 (1H), 8.30 (1H), 8.89 (1 H).
rac-6-[2-[(2,4,5-Trimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4- phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 35
Figure imgf000090_0002
1 H-NMR (ppm, CDCI3, 400 MHz): 1.47 (3H), 1.64 (3H), 2.18 (3H), 2.21 (3H), 2.30 (3H), 2.56 (3H), 2.65-2.77 (3H), 6.93 (1 H), 7.12 (2H), 7.30 (2H), 7.48 (2H), 7.59 (1 H), 8.22 (1 H), 8.29 (1 H), 8.90 (1 H).
(+)-6-[2-[(2,4,5-Trimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4- phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 35a and (-)-6-[2-[(2,4,5-Trimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4- phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 35b 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. 35a : [α]D 20: + 30.6° (CHCI3, 0.97 g/100 ml; λ=589 nM) 35b : [α]D 20: - 28.0° (CHCI3, 0.96 g/100 ml; λ=589 nM)
The following compound was prepared in analogy to example 9 from 3-Phenyl-1- propine, nBuLi and 6-(4-Methyl-4-phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin- 1-one: rac-6-{2-(2-phenyl)-2-methylpropyl]-2-hydroxy-5-phenylpent-3-inoylamino}-4- methyl-2,3-benzoxazin-1-one 36
Figure imgf000091_0001
1 H-NMR (ppm, CDCI3, 400 MHz): 1.42 (3H), 1.53 (3H), 2.55-2.70 (6H), 3.58 (2H), 7.11 (1 H), 7.20-7.35 (7H), 7.41 (2H), 7.48 (1 H), 8.20 (1 H), 8.28 (1 H), 8.80 (1 H).
Compounds 37 and 38 were prepared in analogy to example 1 from 6-(4-Methyl-4-(2- chlor-6-fluorphenyl)-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the according Lithium arylacetylide. rac-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-methylphenyl- ethinyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 37
Figure imgf000091_0002
1 H-NMR (ppm, CDCI3, 300 MHz): 1.73 (3H), 1.82 (3H), 2.33 (3H), 2.57 (3H), 2.88-3.02 (3H), 6.75-6.96 (2H)1 7.01 (1 H), 7.09 (2H), 7.27 (2H), 7.60 (1 H), 8.22-8.35 (2H), 8.96 (1 H). (+)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-methylphenyl- ethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 37a and (-)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-methylphenyl- ethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 37b
The racemic mixture which was described in example 37 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 37a and 37b. 37a : [α]D 20: + 21.5° (CHCI3, 1.00 g/100 ml; λ=589 nM) 37b : [α]D 20: - 21.0° (CHCI3, 1.04 g/100 ml; λ=589 nM)
rac-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-(trifluormethyl)phenyl- ethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 38
Figure imgf000092_0001
1 H-NMR (ppm, CDCI3, 400 MHz): 1.60 (3H), 1.93 (3H), 2.36 (1 H), 2.56-2.72 (5H), 7.04 (1 H), 7.14 (2H), 7.45 (2H), 7.53 (2H), 7.80 (1 H), 8.35-8.45 (2H), 8.90 (1H).
(+)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-(trifluormethyl)phenyl- ethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 38a_and (-)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-(trifluormethyl)phenyl- ethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 38b
The racemic mixture which was described in example 38 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 38a and 38b. 38a : [α]D 20: + 143.2° (CHCI3, 1.05 g/100 ml; λ=589 nM) 38b : [α]D 20: - 137.8° (CHCI3, 1.12 g/100 ml; λ=589 nM)
Compounds 39 and 40 were prepared in analogy to example 1 from 6-(4-Methyl-4-(2- chlorphenyl)-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the according Lithium arylacetylide. rac-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-methylphenyl)but-3- inoylamino]-4-methyl-2,3-benzoxazin-1 -one 39
Figure imgf000093_0001
1 H-NMR (ppm, CDCI3, 400 MHz): 0.84 (1 H), 1.00 (1 H), 1.08-1.22 (2H), 2.36 (3H), 2.53 (3H), 2.90 (1 H), 7.03-7.18 (4H), 7.23-7.38 (3H), 7.50 (1 H), 7.60 (1 H), 8.22 (1 H), 8.29 (1H), 8.91 (1H).
(+)-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-methylphenyl)but-3- inovlamino1-4-methyl-2,3-benzoxazin-1-one 39a and
(-)-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-methylphenyl)but-3- inoylamino]-4-methyl-2,3-benzoxazin-1 -one 39b
The racemic mixture which was described in example 39 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 39a and 39b. 39a : [α]D 20: + 30.8° (CHCI3, 1.00 g/100 ml; λ=589 nM) 39b : [α]D 20: - 28.3° (CHCI3, 1.00 g/100 ml; λ=589 nM)
rac-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-trifluor- methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1 -one 40
Figure imgf000093_0002
1 H-NMR (ppm, CDCI3, 300 MHz): 0.91 (1H), 1.02 (1 H), 1.08-1.25 (2H), 2.53 (3H)1 3.00 (1H), 7.02-7.18 (2H), 7.28 (1H), 7.42-7.54 (3H), 7.55-7.67 (3H), 8.22 (1H), 8.32 (1H), 8.91 (1 H).
(+)-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-trifluor- methvlphenvl)but-3-inovlamino1-4-methyl-2,3-benzoxazin-1 -one 40a and (-)-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-trifluor- methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1-one 40b
The racemic mixture which was described in example 40 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 40a and 40b. 40a : [α]D 2o: + 20.9° (CHCI3, 1.06 g/100 ml; λ=589 nM) 40b : [α]D 20: - 20.6° (CHCI3, 1.05 g/100 ml; λ=589 nM)
rac-6-[2-[[3-(1-Hydroxy-1-methylethyl)phenyl]ethynyl]-2-hydroxy-4-methyl- 4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 41.
Figure imgf000094_0001
59 μl of 3 molar solution of Methylmagnesium chloride was diluted with 1 ml of pure Tetrahydrofurane. The solution was cooled to -700C and a solution of 30 mg of the compound which was described in example 33 in 0,5 ml of pure Tetrahydrofurane was added. After stirring for 2,5 hours at -700C the mixture was given to a saturated solution of ammonium chloride. After extracting the mixture with Ethyl acetate the combined organic phases were washed with saturated sodium chloride and dried over sodium sulphate. After column chromatography 16 mg of the product was obtained. 1H-NMR (ppm, CDCI3, 400 MHz): 1.46 (3H), 1.53 (6H), 1.62 (3H), 1.80 (1H), 2.55 (3H)1 2.65-2.90 (3H)1 7.12 (1 H), 7.30 (3H)1 7.40-7.52 (3H), 7.53 (1 H), 7.60 (1H), 8.27 (2H)1 8.95 (1 H).
The following compound was prepared in analogy to example 7 from the compound which was described in example 14 and 4-lodobenzylalcohol: rac-6-[2-[[4-(Hydroxymethyl)phenyl]ethynyl]-2-hydroxy-4-methyl- 4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 42
Figure imgf000095_0001
1 H-NMR (ppm, CDCI3, 300 MHz): 1.47 (3H), 1.60 (3H), 1.80 (1 H), 2.57 (3H), 2.62-2.83 (3H), 4.68 (2H), 7.13 (1H), 7.25-7.43 (6H), 7.48 (2H), 7.59 (1 H), 8.25-8.32 (2H), 8.91 (1 H).
The following compound was prepared in analogy to example 7 from the compound which was described in example 14 and 4-lodobenzylalcohol: rac-6-[2-[[3-(Hydroxymethyl)phenyl]ethinyl]-2-hydroxy-4-methyl- 4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one 43
Figure imgf000095_0002
1 H-NMR (ppm, CDCI3, 400 MHz): 1.48 (3H), 1.62 (3H), 1.79 (1 H), 2.57 (3H), 2.62-2.80 (3H), 4.68 (2H), 7.15 (1 H), 7.25-7.39 (5H), 7.40 (1 H), 7.49 (2H), 7.60 (1H), 8.29 (2H), 8.91 (1 H).
The following compound was prepared in analogy to example 41 from the compound which was described in example 30 and a solution of Methyl magnesium chloride: rac-6-[2-[[4-(1-Hydroxy-1-methylethyl)phenyl]ethynyl]-2-hydroxy-4-methyl- 4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 44
Figure imgf000096_0001
1 H-NMR (ppm, CDCI3, 400 MHz): 1.47 (3H), 1.55 (6H), 1.62 (3H), 1.70 (1H), 2.55 (3H), 2.60-2.80 (3H), 7.14 (1H), 7.28-7.40 (4H), 7.41 (2H), 7.48 (2H), 7.60 (1H), 8.25-8.32 (2H), 8.90 (1 H).

Claims

Claims
1. Compounds of the general formula I
Figure imgf000097_0001
R1 and R2 are independently of one another a hydrogen atom, a linear or nonlinear, branched or unbranched d-C5-alkyl group, further forming together with the C atom of the chain a ring having a total of 3-7 members,
R3 is a radical C≡C-Ra, where
Ra is a hydrogen or a d-C8-alkyl, C2-C8-alkenyl, C2-C8- alkynyl, C3-C10-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)Rb, CO2R", -O-Rb, -S-Rb, SO2NRcRd, -C(O)-NRcRd, -OC(O)-NRcRd, -C=NORb -NRcRd or C3-C10-cyclo- alkyl, heterocycloalkyl optionally substituted one or more times, identically or differently, by M, or aryl or heteroaryl optionally substituted one or more times by L,
L is d-Cβ-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C6- perfluoroalkyl, C1-C6-perfluoroalkoxy, d-C6-alkoxy- d-Ce-alkoxy, (CH2)p-C3-C10-cycloalkyl, (CH2)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, -(CH^pNR^ONR^, -(CH2)pNReCOORb, -(CH2)pNReC(NH)NRcRd, -(CH2)pNReCSNRcRd, -(CH2)pNReS(O)NRcRd, -(CH2)pNReS(O)2NRcRd, -(CH2)pCORb, -(CH2)pCSRb, -(CH2)pS(O)Rb, -(CH2)pS(O)(NH)Rb, -(CH2)pS(O)2Rb,
-(CH2)PS(O)2NR^1 -(CH2)PSO2OR6, -(CH2)pCO2Rb, -(CH2)pCONRcRd, -(CH2)pCSNRcRd, -(CH2)pORb, -(CH2)pSRb, - (CH2)pCRb(0H)-Re, -(CH2)p-C=NORb, -0-(CHz)n-O-, -0-(CH2Jn-CH2-, -O-CH=CH- or
-(CH2)n+2-, where n is 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring carbon atoms, M is d-Ce-alkyl or a group -C0Rb, CO2Rb, -O-Rb, or -NRcRd, where
Rb is a hydrogen or a C1-C6-alkyl, C2-C8- alkenyl, C2-C8-alkynyl, C3-C10- cycloalkyl, C6-C12-aryl or C1-C3- perfluoroalkyl and
Rc and Rd are independently of one another a hydrogen, d-C6-alkyl, C2-C8-alkenyl,
C2-C8-alkynyl, C3-C10-cycloalkyl,
C6-C12-aryl, C(O)Rb or a hydroxy group, where if
Rc is a hydroxy group, then Rd can only be a hydrogen, a d-Ce-alkyl, C2-C8- alkenyl, C2-C8-alkynyl, C3-C10- cycloalkyl or C6-C12-aryl and vice versa, and
Re is a hydrogen, d-C6-alkyl, C2-C8- alkenyl, C2-C8-alkynyl, C3-C10-cyclo- alkyl or C6-C12-aryl, and p can be a number from 0-6,
or R3 is a radical C=C-R9Rh, where
R9 and Rh are independently of one another a hydrogen or a d-Cβ-alkyl, C2-C8-alkenyl or C2-C8-alkynyl optionally substituted one or more times, identically or differently, by X1 in which
X is a cyano, halogen, hydroxy, nitro,
-C(O)Rb, CO2Rb, -O-Rb, -C(O)-NRcRd, -NRcRd with the meanings already mentioned before for Rb, Rc and Rd, and
R4 is a hydrogen atom, a methyl or an ethyl group or a partly or completely fluorinated C^C8-alkyl group,
A is a mono- or bicyclic carbocyclic or heterocyclic aromatic ring which may optionally be substituted one or more times by CrCβ-alkyl, C2-C8- alkenyl, C2-C8-alkynyl, Ci-C6-perfluoroalkyl, Ci-Cβ-perfluoroalkoxy,
Ci-Ce-alkoxy-CrCe-alkyl, CrCβ-alkoxy-Ci-Ce-alkoxy, (CH2)p-C3-C10- cycloalkyl, (CHzJp-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)pNReCONRcRd,
-(CH2)pNReCOORb, -(CH2)pNReC(NH)NRcRd, -(CH2)PNR8CSNR0R11, -(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)pCONRcRd, -(CH2)pCSNRcRd, -(CH2)pORb, -(CH2)pSRb, -(CH2)pCRb(OH)-Rd,
-(CH2)p-C=NORb, -O-(CH2)n-O-, -O-(CH2)n-CH2-, -O-CH=CH- or -(CH2Jn+2-, where n is 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring carbon atoms, or
A is a radical -CO2Rb, C(O)NRcRd, CORb,
or
A is an alkenyl group -CR5=CR6R7, where R5, R6 and R7 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^C8-alkyl group, or
A is an alkynyl group -C≡CR5, with the meaning stated above for R , and
B is a carbonyl or a CH2 group
and their pharmaceutically acceptable salts.
2. Compounds according to Claim 1 , in which R1 and R2 are preferably a hydrogen atom, a methyl or ethyl group.
3. Compounds according to Claim 1 , in which R1 and R2 preferably form together with the C atom of the chain a ring having a total of 3-7 members.
4. Compounds according to Claim 1 to 3, in which R3 is preferably alkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, cycloalkylalkynyl, heterocycloalkylalkynyl.
5. Compounds according to any of the preceding claims, in which R3 is preferably a vinyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, hydroxypropynyl, hydroxybutynyl, 3-hydroxy-3-methylbutynyl, hydroxypentynyl, carboxypropynyl, t-butylcarboxypropynyl, phenylethynyl, (hydroxyphenyl)ethynyl, (methoxyphenyl)ethynyl, (dimethylaminophenyl)ethynyl, (methylphenyl)ethynyl, (cyanophenyl)ethynyl, (trifluoromethyl)ethynyl, (diphenyl)ethynyl,
(nitrophenyl)ethynyl, (tert-butylphenyl)ethynyl, (acetylphenyl)ethynyl, (acetoxyphenyl)ethynyl, (carboxyphenyl)ethynyl or a benzylethynyl group.
6. Compounds according to any of the preceding claims, in which A is preferably an aromatic ring.
7. Compounds according to any of the preceding claims, in which A is preferably a phenyl or naphthyl radical.
8. Compounds according to Claim 7, in which A is preferably an unsubstituted or optionally mono- or polysubstituted phenyl radical.
9. Compounds according to Claim 8, where the phenyl radical is preferably substituted by one or two halogen atoms or one trifluoromethyl group.
10. Compounds according to Claim 9, in which the halogen atoms are preferably chlorine and/or fluorine.
11. Compounds according to Claims 1-8, in which A is preferably a phenyl ring substituted by -O-(CH2)n-O- or -O-(CH2)n-CH2-, where the respectively directly adjacent ring carbon atoms are linked.
12. Compounds according to any of the preceding claims, in which R4 is a hydrogen atom, a methyl or a trifluoromethyl radical.
13. Compounds according to Claim 1 to 5, namely
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000104_0002
Figure imgf000104_0003
Figure imgf000105_0001
Figure imgf000106_0002
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000108_0002
Figure imgf000108_0003
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0002
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000113_0003
Figure imgf000113_0002
Figure imgf000114_0001
Figure imgf000115_0002
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000117_0002
Figure imgf000117_0003
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0002
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000122_0002
Figure imgf000122_0003
Figure imgf000123_0001
Figure imgf000124_0002
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000126_0002
Figure imgf000126_0003
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0002
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0002
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000135_0002
Figure imgf000135_0003
Figure imgf000136_0001
Figure imgf000137_0002
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000139_0002
Figure imgf000139_0003
Figure imgf000140_0001
Figure imgf000141_0002
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000143_0002
Figure imgf000143_0003
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0002
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000148_0002
Figure imgf000148_0003
Figure imgf000149_0001
Figure imgf000150_0002
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000151_0002
Figure imgf000152_0001
14. Pharmaceutical composition comprising at least one compound of the general formula I according to any of Claims 1 to 13 and, where appropriate, at least one further active ingredient together with pharmaceutically suitable excipients and/or carriers.
15. Pharmaceutical composition according to Claim 14, where the further active ingredient is a SERM (selective estrogen receptor modulator), an aromatase inhibitor, an antiestrogen or a prostaglandin.
16. Pharmaceutical composition according to Claim 14, where the active ingredient may be tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-pentafluoropentyl)sulphinyl]pentyloxy}phenyl)- 6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol, 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}amino)pentyl]estra-1 , 3,5(10)-triene-3,17beta-diol, 11 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, 11 beta-fluoro-17alpha-methyl-7alpha-{5-[methyl(8,8, 9,9,9- pentafluorononyl)amino]pentyl}estra-1 ,3,5(10)-triene-3, 17beta-diol, clomifen, raloxifen, fadrozole, formestane, letrozole, anastrozole or atamestane.
17. Use of compounds according to any of Claims 1 to 13 for producing a medicament.
18. Use of compounds according to Claim 17 for producing a medicament for the therapy and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea.
19. Use of compounds according to Claim 17 for producing a medicament for the therapy and prophylaxis of hormone-dependent tumours.
20. Use of compounds according to Claim 17 for producing a medicament for the therapy and prophylaxis of breast carcinomas.
21. Use of compounds according to Claim 17 for producing a medicament for the therapy and prophylaxis of endometrial carcinoma.
22. Use of compounds according to Claim 17 for producing a medicament for the therapy and prophylaxis of ovarian carcinomas.
23. Use of compounds according to Claim 17 for producing a medicament for the therapy and prophylaxis of prostate carcinomas.
24. Use of compounds according to Claim 17 for producing a medicament for female hormone replacement therapy.
25. Use of compounds according to Claim 17 for female fertility control.
26. Process for the selective addition of lithium alkynyl and magnesium haloalkynyl compounds onto a keto amide.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008077647A2 (en) * 2006-12-21 2008-07-03 Bayer Schering Pharma Aktiengesellschaft Alpha- amino alcohols as non-steroidal progesterone receptor modulators
WO2009007396A1 (en) * 2007-07-10 2009-01-15 Bayer Schering Pharma Aktiengesellschaft Nonsteroidal progesterone receptor modulators
DE102007058747A1 (en) 2007-12-05 2009-06-10 Bayer Schering Pharma Aktiengesellschaft Nonsteroidal progesterone receptor modulators
JP2011519916A (en) * 2008-07-02 2011-07-14 ファーマコステック カンパニー リミテッド Method for producing amide derivative

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1344776A1 (en) * 2002-03-11 2003-09-17 Schering Aktiengesellschaft 5- 2-hydroxy-3-[1-(3-trifluoromethylphenyl)-cyclopropyl]-propionylamino -phtalide and 6- 2-hydroxy-3-[1-(3-trifluoromethylphenyl)-cyclopropyl]-propionylamino -4-methyl-2,3-benzoxazin-1-one derivatives with progesterone receptor modulating activity for use in fertility control, hormone replacement therapy and the treatment of gynecological disorders
WO2005003098A1 (en) * 2003-07-01 2005-01-13 Schering Aktiengesellschaft Heterocyclically substituted pentanol derivatives, method for the production thereof, and use thereof as anti-inflammatory agents

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19856475A1 (en) * 1998-11-27 2000-05-31 Schering Ag Nonsteroidal anti-inflammatories

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1344776A1 (en) * 2002-03-11 2003-09-17 Schering Aktiengesellschaft 5- 2-hydroxy-3-[1-(3-trifluoromethylphenyl)-cyclopropyl]-propionylamino -phtalide and 6- 2-hydroxy-3-[1-(3-trifluoromethylphenyl)-cyclopropyl]-propionylamino -4-methyl-2,3-benzoxazin-1-one derivatives with progesterone receptor modulating activity for use in fertility control, hormone replacement therapy and the treatment of gynecological disorders
WO2005003098A1 (en) * 2003-07-01 2005-01-13 Schering Aktiengesellschaft Heterocyclically substituted pentanol derivatives, method for the production thereof, and use thereof as anti-inflammatory agents

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE BEILSTEIN Beilstein Institut zur Förderung der Wissenschaften, Frankfurt/Main, DE; XP002406053 Database accession no. 1735553, 1964392, 2329868, 3529064 (RID). & J. PHARM.SCI., vol. 82, no. 6, 1993, pages 605-609, *
DATABASE BEILSTEIN Beilstein Institut zur Förderung der Wissenschaften, Frankfurt/Main, DE; XP002406062 Database accession no. 2214047 (RID) & J. CHEM. SOC. CHEM. COMMUN., vol. 4, 1990, pages 294-296, *
DATABASE BEILSTEIN Beilstein Institut zur Förderung der Wissenschaften, Frankfurt/Main, DE; XP002406063 Database accession no. 4338477 (RID) & J. HETEROCYCL. CHEM., vol. 32, no. 4, 1995, pages 1133-1140, *
DATABASE BEILSTEIN Beilstein Institut zur Förderung der Wissenschaften, Frankfurt/Main, DE; XP002406064 Database accession no. 9573837 (RID) & BIOORG. MED. CHEM., vol. 11, no. 18, 2003, pages 4133-4142, *
DATABASE BEILSTEIN Beilstein Institut zur Förderung der Wissenschaften, Frankfurt/Main, DE; XP002406065 Database accession no. 4064999 (RID) & J. AM. CHEM. SOC., vol. 116, no. 24, 1994, pages 10955-10965, *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008077647A2 (en) * 2006-12-21 2008-07-03 Bayer Schering Pharma Aktiengesellschaft Alpha- amino alcohols as non-steroidal progesterone receptor modulators
WO2008077647A3 (en) * 2006-12-21 2008-10-16 Bayer Schering Pharma Ag Alpha- amino alcohols as non-steroidal progesterone receptor modulators
WO2009007396A1 (en) * 2007-07-10 2009-01-15 Bayer Schering Pharma Aktiengesellschaft Nonsteroidal progesterone receptor modulators
DE102007058747A1 (en) 2007-12-05 2009-06-10 Bayer Schering Pharma Aktiengesellschaft Nonsteroidal progesterone receptor modulators
WO2009071252A1 (en) * 2007-12-05 2009-06-11 Bayer Schering Pharma Aktiengesellschaft Nonsteroidal progesterone receptor modulators
JP2011519916A (en) * 2008-07-02 2011-07-14 ファーマコステック カンパニー リミテッド Method for producing amide derivative

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UY29624A1 (en) 2007-01-31
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AR054519A1 (en) 2007-06-27
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