WO2006136462A1 - Derives de benzofuranone utilises en tant que modulateurs non steroidiens du recepteur de la progesterone - Google Patents

Derives de benzofuranone utilises en tant que modulateurs non steroidiens du recepteur de la progesterone Download PDF

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Publication number
WO2006136462A1
WO2006136462A1 PCT/EP2006/006532 EP2006006532W WO2006136462A1 WO 2006136462 A1 WO2006136462 A1 WO 2006136462A1 EP 2006006532 W EP2006006532 W EP 2006006532W WO 2006136462 A1 WO2006136462 A1 WO 2006136462A1
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Prior art keywords
compounds according
ethinyl
alkyl
group
alkenyl
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PCT/EP2006/006532
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German (de)
English (en)
Inventor
Wolfgang Schwede
Carsten Moeller
Anja Schmidt
Ulrike Fuhrmann
Norbert Schmees
Ulrich Bothe
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Bayer Schering Pharma Aktiengesellschaft
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Priority to CA002611900A priority Critical patent/CA2611900A1/fr
Priority to EA200702604A priority patent/EA200702604A1/ru
Priority to EP06762405A priority patent/EP1899315A1/fr
Priority to AU2006261049A priority patent/AU2006261049A1/en
Priority to MX2008000070A priority patent/MX2008000070A/es
Priority to JP2008517445A priority patent/JP2008543911A/ja
Priority to BRPI0612305-8A priority patent/BRPI0612305A2/pt
Publication of WO2006136462A1 publication Critical patent/WO2006136462A1/fr
Priority to IL188022A priority patent/IL188022A0/en
Priority to NO20080441A priority patent/NO20080441L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to nonsteroidal progesterone receptor modulators, a process for their production, the use of progesterone receptor modulators for the production of pharmaceutical agents as well as pharmaceutical compositions that contain these compounds.
  • progesterone regulates the reproductive process in the female organism in a decisive way.
  • progesterone is secreted in large amounts from the ovary or the placenta.
  • progesterone produces cyclic changes of the uterine mucous membrane (endometrium) in the menstrual cycle.
  • the uterine mucous membrane is converted into a state that allows the nidation of an embryo (blastocyte).
  • progesterone controls the relaxation of the myometrium and retains the function of the decidual tissue.
  • progesterone inhibits the endometrial proliferation by the suppression of the estrogen-mediated mitosis in the uterus tissue (K. Chwalisz, R. M. Brenner, U. Fuhrmann, H. Hess-Stumpp, W. Elger, Steroids 65, 2000, 741-751).
  • progesterone and the progesterone receptors are also known in pathophysiological processes. Progesterone receptors are detected in foci of endometriosis, but also in tumors of the uterus, the breast and the CNS. In addition, it is known that uterus leiomyomas grow in a progesterone-dependent manner.
  • progesterone receptor modulators are either pure agonists or partially or completely inhibit the action of progesterone. Consequently, substances are defined as pure agonists, partial agonists (SPRMS) and pure antagonists.
  • progesterone receptor modulators According to the ability of the progesterone receptor modulators to influence the action of the progesterone receptor, these compounds have a considerable potential as therapeutic agents for gynecological and oncological indications as well as for obstetrics and birth control.
  • progesterone receptor antagonists completely inhibit the action of progesterone in the progesterone receptor. They have antiovulatory properties as well as the ability to inhibit estrogen effects in the endometrium up to full atrophy. They are therefore especially suitable for intervening in the female reproductive process, e.g., in post-ovulation, to prevent nidation; in pregnancy, to increase the reactivity of the uterus to prostaglandins or oxytocin or to ensure the opening and softening ("maturation") of the cervix as well as to make the myometrium highly prepared for labor.
  • progesterone receptor antagonist RU 486 also mifepristone
  • the antiglucocorticoidal activity is disadvantageous for a therapeutic application in which the inhibition of the progesterone receptors is a primary focus of therapy.
  • An antiglucocorticoidal activity causes undesirable side effects in the case of therapeutically necessary dosages. This can prevent the application of a therapeutically useful dose or lead to termination of the treatment.
  • the partial or complete reduction of the antiglucocorticoidal properties is therefore an important requirement for the therapy with progesterone receptor antagonists, in particular for those indications that require a treatment lasting weeks or months.
  • progesterone receptor partial agonists show a residual agonistic property, which can be strongly pronounced to different degrees. This leads to the fact that these substances show potential agonistic actions of the progesterone receptor in specific 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 action can be of therapeutic use for the indications described.
  • nonsteroidal progesterone receptor modulators These compounds are to have a reduced antiglucocorticoidal action and are therefore suitable for the therapy and prophylaxis of gynecological diseases such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhea.
  • the compounds according to the invention are to be suitable for the therapy and prophylaxis of hormone-dependent tumors, for example breast, endometrial, ovarian and prostate cancers.
  • the compounds are to be suitable for use in female birth control and for female hormone replacement therapy.
  • R 1 and R 2 independently of one another, mean a hydrogen atom, a straight or nonstraight, branched or unbranched C
  • R a means a hydrogen or a Ci-C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkinyl, C 3 -Ci 0 -cycloalkyl, or heterocycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, or an aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, K is a cyano, halogen, hydroxy, nitro, -C(O)R b , CO 2 R b ,
  • L means Ci-C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkinyl, Ci-C 6 - perfluoroalkyl, C
  • R b means a hydrogen or a Ci-C ⁇ -alkyl, C 2 -Cg-alkenyl, C 2 -C 8 -alkinyl, C 3 -Cio-cycloalkyl, C 6 -Ci 2 -aryl or Ci- C 3 -perfluoroalkyl, and
  • R c and R d independently of one another, mean a hydrogen, Ci-C 6 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkinyl, C 3 -C 0 - cycloalkyl, C 6 -Ci 2 -aryl, C(O)R b or a hydroxy group, whereby if
  • R c is a hydroxy group
  • R d can be only one hydrogen, a Ci-C ⁇ -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkinyl, C 3 -C 10 - cycloalkyl or C 6 -C] 2 -aryl and vice versa, and
  • R 8 and R independently of one another, are a hydrogen or a Ci-Cs-alkyl, C 2 -C 8 -alkenyl or C 2 -Cg-alkinyl that optionally is substituted in one or more places, in the same way or differently, with X, in which X is a cyano, halogen, hydroxy, nitro, -C(O)R b , CO 2 R b ,
  • R 4a and R 4b independently of one another, mean a hydrogen atom, a C,-C 4 -alkyl,
  • A means a monocyclic or bicyclic, carbocyclic or heterocyclic aromatic ring, which optionally can be substituted in one or more places with Ci- C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkinyl, Ci-C 6 -perfluoroalkyl, Ci-C 6 - perfluoroalkoxy, C i -C 6 -alkoxy-C i -C 6 -alkyl, C i -C 6 -alkoxy-C i -C 6 -alkoxy, (CH 2 ) p -C 3 -Ci 0 -cycloalkyl, (CH 2 ) P CN, (CH 2 ) p Hal, (CH 2 ) P NO 2 , (CH 2 ) p -C 6
  • R , R and R are the same or different and, independently of one another, mean hydrogen atoms, halogen atoms, aryl radicals or an unsubstituted or partially or completely fluorinated C,-C 5 -alkyl
  • A means an alkinyl group -C ⁇ CR , with the meaning cited above for R , and
  • B means a carbonyl group or a CH 2 group
  • the compounds of general formula I according to the invention can be present as different stereoisomers because of the presence of asymmetry centers. Both the racemates and the separately present stereoisomers are part of the subject of this invention.
  • this invention comprises the new compounds as pharmaceutical active ingredients, their production, their therapeutic application and pharmaceutical dispensing forms that contain the new substances.
  • the compounds of general formula (I) according to the invention or their pharmaceutically acceptable salts can be used for the production of a pharmaceutical agent, especially for treatment and prophylaxis of gynecological diseases, such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhea.
  • the compounds according to the invention can be used for the treatment and prophylaxis of hormone-dependent tumors, such as, for example, for breast, prostate and endometrial cancers.
  • the compounds of general formula (I) according to the invention or their pharmaceutically acceptable salts are suitable for use for female birth control or for female hormone replacement therapy.
  • a process for the production of the compounds of general formula (I), moreover, is also a subject of this invention.
  • Substituent R 3 is introduced to a keto group by selective addition reaction of organometallic compounds such as lithium alkinylene or magnesium haloalkinylene. This results, either directly or after implementing additional modifications, in the compounds of general formula (I) according to the invention.
  • the production of the compounds according to the invention is carried out by selective addition of organometallic compounds to ketoamides, which were described in, e.g., laid-open specifications WO 200375915 and WO 9854159.
  • the organometallic compounds can be, for example, lithium alkinyl compounds or magnesium haloalkinyl compounds. The latter are produced by, e.g., reaction of the corresponding alkines with butyllithium or Grignard compounds. Analogously to this, the corresponding organometallic alkenyl compounds can also be produced.
  • the reactivity of the keto group in comparison to amidocarbonyl or to phthalide is in this case significantly higher, such that with suitable selection of the reaction conditions, a selective addition is achieved.
  • alkinyl or alkenyl radicals that are introduced as R can also be further modified later.
  • reactions that have become known to one skilled in the art, such as oxidation, reduction, substitution, alkylation, or palladium-catalyzed reaction, are suitable.
  • present protective groups are cleaved off at a suitable time.
  • the nonsteroidal compounds of general formula I according to the invention have a strongly antagonistic or strongly partially agonistic action on the progesterone receptor. They exhibit a strong dissociation of action with respect to their bonding strength on the progesterone receptor and on the glucocorticoid receptor. While known progesterone receptor antagonists, such as Mifepristone (RU 486), in addition to the desired high binding affinity for the progesterone receptor likewise show a high affinity for the glucocorticoid receptor, the compounds according to the invention are distinguished by a very low glutocorticoid receptor bond with simultaneously present high progesterone receptor affinity.
  • Ci-C 5 -, Ci-C 6 - or Ci-Cg-alkyl groups are defined as straight or nonstraight, branched or unbranched alkyl radicals. In this case, for example, this is a methyl, ethyl, n-propyl, iso-propyl, n-, iso-, tert-butyl, an n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl, hexyl, heptyl or octyl group.
  • R a in this case, the methyl, ethyl, n-propyl or n-butyl group as well as an n-pentyl group are preferred.
  • R 1 and R 2 methyl or ethyl is preferred.
  • a hydrogen is preferred for R4 a and R4 b .
  • Alkenyl is defined as straight or nonstraight, branched or unbranched alkenyl radicals.
  • a C 2 -Cg-alkenyl group is defined, for example, as follows: vinyl, allyl, 3-buten-l-yl- or 2,3-dimethyl-2-propenyl. If aromatic compound A is substituted with a C 2 -C 8 -alkenyl radical, this is preferably a vinyl group.
  • Alkinyl is defined as straight or nonstraight, branched or unbranched alkinyl radicals.
  • an ethinyl, propinyl, butinyl, pentinyl, hexinyl or octinyl group, but preferably an ethinyl or propinyl group is to stand for a C2-Cg-alkinyl radical.
  • C 3 -Cio-cycloalkyl for example, cyclopropane, cyclobutane, cyclopentane and cyclohexane can be mentioned. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.
  • heterocycloalkyl is defined as 3- to 8-membered heterocycloalkyl radicals.
  • heterocycloalkyl are morpholine, tetrahydrofuran, pyran, piperazine, piperidine, pyrrolidine, oxirane, oxetane, aziridine, dioxolane and dioxane.
  • the position of the heteroatom in relation to the point of linkage can be any chemically possible position.
  • methoxymethoxy, ethoxymethoxy or 2-methoxyethoxy can stand for a C
  • a radical OR b is a hydroxy, methoxy, ethoxy, n- propoxy, iso-propoxy, n-, iso-, or tert-butoxy group, or an n-pentoxy, 2,2- dimethylpropoxy or 3-methylbutoxy group. Hydroxy, methoxy and ethoxy are preferred.
  • the perfluorinated alkyl groups that appear above are considered. Of the latter, primarily the trifluoromethyl group or the pentafluoroethyl group as well as as partially fluorinated alkyl groups, for example the 5,5,4,4-pentafluoropentyl group or the 5,5,5,4,4,3,3- heptafluoropentyl group, are preferred.
  • a fluorine, chlorine, bromine or iodine atom can stand for a halogen atom. Preferred here is fluorine, chlorine or bromine.
  • R 1 and R 2 together with the C atom of the chain form a 3- to 7-membered ring, this is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
  • the cyclopropyl ring as well as the cyclopentyl ring are preferred.
  • the monocyclic or bicyclic carbocyclic aromatic ring A which can be substituted in several places, is a carbocyclic or heterocyclic aryl radical.
  • phenyl or naphthyl radical preferably a phenyl radical.
  • heterocyclic radical for example, a monocyclic heterocyclic radical, for example the thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, or tetrazolyl radical, and specifically all possible isomers relative to the positions of the heteroatoms, can be used.
  • a monocyclic heterocyclic radical for example the thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazo
  • an aryl radical is an optionally substituted phenyl, 1- or 2- naphthyl radical, whereby the phenyl radical is preferred.
  • a heteroaryl radical are the 2-, 3- or 4-pyridinyl radical, the 2- or 3-furyl radical, the 2- or 3-thienyl radical, the 2- or 3-pyrrolyl radical, the 2-, 4- or 5-imidazolyl radical, the pyrazinyl radical, the 2-, 4- or 5-pyrimidinyl radical or the 3- or 4-pyridazinyl radical.
  • the number p for the (CH 2 ) P radical can be a number from 0 to 6, preferably 0 to 2.
  • "Radicals" are defined according to the invention as all functional groups that are presented in connection with (CH 2 ) P .
  • the compounds according to the invention are present as racemic mixtures, they can be separated into the pure, optically active forms according to methods of racemate separation that are familiar to one skilled in the art.
  • the racemic mixtures can be separated into pure isomers by chromatography on an even optically
  • hydroxy group in a racemic compound of general formula I with an optically active acid and to separate the diastereomeric esters that are obtained by fractionated crystallization or by chromatography and to saponify the separated esters in each case to form the optically pure isomers.
  • an optically active acid for example, mandelic acid, camphorsulfonic acid or tartaric acid can be used.
  • progesterone receptor modulators can be performed using simple methods, test programs that are known to one skilled in the art. To this end, for example, a compound that is to be tested can be incubated together with a gestagen in a test system for progesterone receptors, and it can be examined whether the progesterone- mediated action in this test system is altered in the presence of modulators.
  • the receptor binding affinity was determined by competitive binding of a specifically binding 3 H-labeled hormone (tracer) and the compound to be tested on receptors in the cytosol from animal target organs. In this case, receptor saturation and reaction equilibrium were sought.
  • Progesterone Receptor For the receptor types, the following incubation conditions were selected: Progesterone Receptor:
  • the relative receptor binding affinities (RBA values) of the compounds of general formula (I) according to the invention on the progesterone receptor are between 3 and 100% relative to the progesterone.
  • the RBA values are in the range of 3 to 30% relative to dexamethasone.
  • the compounds according to the invention accordingly have a high affinity to the progesterone receptor but only a low affinity to the glucocorticoid receptor.
  • the transactivation assay is performed as described in WO 02/054064.
  • Agonism of Progesterone Receptor PR-B is performed as described in WO 02/054064.
  • the transactivation assay is performed 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 transdermally.
  • the daily doses encompass a range of 1 ⁇ g to 500 mg of the
  • birth control as well as for hormone replacement therapy are 50 ⁇ g to 500 mg per day, depending on age and constitution of the patient, whereby the necessary daily dose can be administered one or more times.
  • the dosage range for the compounds according to the invention comprises 10 mg to 1000 mg daily.
  • the formulation of the pharmaceutical preparations based on the new compounds is carried out in a way that is known in the art, by the active ingredient being processed with the vehicles, fillers, substances that influence decomposition, binding agents, moisturizers, lubricants, absorbents, diluents, flavoring correctives, dyes, etc., that are commonly used in galenicals and being converted into the desired form of administration.
  • the active ingredient being processed with the vehicles, fillers, substances that influence decomposition, binding agents, moisturizers, lubricants, absorbents, diluents, flavoring correctives, dyes, etc., that are commonly used in galenicals and being converted into the desired form of administration.
  • Remington's Pharmaceutical Science 15 th Ed. Mack Publishing Company, East Pennsylvania (1980).
  • tablets for oral administration, in particular tablets, film tablets, coated tablets, capsules, pills, powders, granulates, lozenges, suspensions, emulsions or solutions are suitable.
  • crystal suspensions For intraarticulate injection, correspondingly prepared crystal suspensions can be used.
  • aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.
  • the new compounds can be used in the form of suppositories, capsules, solutions (e.g., in the form of enemas) and ointments both for systemic therapy and for local therapy.
  • agents for vaginal application can also be mentioned as preparations.
  • the latter can be used in the form of aerosols and inhalants.
  • Corresponding tablets can be obtained by, for example, mixing active ingredient with known adjuvants, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, explosives such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents for achieiving a depot effect such as carboxylpolymethylene, carboxyl methyl cellulose, cellulose acetate phthalate or polyvinyl acetate.
  • the tablets can also consist of several layers.
  • coated tablets can be produced by coating cores, produced analogously to the tablets, with agents that are commonly used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar.
  • the coated tablet shell can also consist of several layers, whereby the adjuvants that are mentioned above in the tablets can be used.
  • Solutions or suspensions of the compounds of general formula I according to the invention can contain additional taste-improving agents such as saccharine, cyclamate or sugar, as well as, e.g., flavoring substances, such as vanilla or orange extract.
  • additional taste-improving agents such as saccharine, cyclamate or sugar, as well as, e.g., flavoring substances, such as vanilla or orange extract.
  • suspending adjuvants such as sodium carboxy methyl cellulose or preservatives such as p-hydroxybenzoates.
  • the capsules that contain compounds of general formula I can be produced by, for example, the compound(s) of general formula I being mixed with an inert vehicle such as lactose or sorbitol and encapsulated in gelatin capsules.
  • an inert vehicle such as lactose or sorbitol
  • Suitable suppositories can be produced by, for example, mixing with vehicles that are provided for this purpose, such as neutral fats or polyethylene glycol, or derivatives thereof.
  • the compounds of general formula (I) according to the invention or their pharmaceutically acceptable salts can be used based on their antagonistic or partial agonistic action for the production of a pharmaceutical agent, in particular for treatment and prophylaxis of gynecological diseases, such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhea. In addition, they can be used to counteract hormonal irregularities, to trigger menstruation and alone or in combination with prostaglandins and/or oxytocin to induce birth. In addition, the compounds of general formula (I) according to the invention or their pharmaceutically acceptable salts are suitable for the production of preparations for contraception for women (see also WO 93/23020, WO 93/21927).
  • the compounds according to the invention or their pharmaceutically acceptable salts can be used alone or in combination with a Selective Estrogen Receptor Modulator (SERM) for female hormone replacement therapy.
  • SERM Selective Estrogen Receptor Modulator
  • the above-mentioned compounds exert an antiproliferative action in hormone-dependent tumors. They are therefore suitable for the therapy of hormone-dependent carcinomas, such as, for example, for breast, prostate or endometrial carcinomas.
  • the compounds according to the invention or their pharmaceutically acceptable salts can be used for the treatment of hormone-dependent carcinomas, both in first-line therapy and in second-line therapy, in particular after tamoxifen failure.
  • the compounds of general formula (I) according to the invention that have an antagonistic or partial agonistic action or their pharmaceutically acceptable salts can also be used in combination with compounds that have an antiestrogenic action (estrogen receptor antagonists or aromatase inhibitors) or Selective Estrogen Receptor Modulators (SERM) for the production of pharmaceutical preparations for treating hormone- dependent tumors.
  • SERM Selective Estrogen Receptor Modulators
  • the compounds according to the invention can also be used in combination with SERMs or an antiestrogen (estrogen receptor antagonists or aromatase inhibitors).
  • 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.
  • sequential administration preferably first the antiestrogen (estrogen receptor antagonists or aromatase inhibitor) or SERM is administered, and then the progesterone receptor modulator is administered.
  • the following antiestrogens estradiose inhibitors or SERMs are considered: tamoxifen, 5-(4- ⁇ 5-[(RS)-(4,4,5,5,5-pentafluoropentyl)sulfinyl]- pentyloxy ⁇ phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol (WO 00/03979), ICI 182 780 (7alpha-[9-(4,4,5,5-pentafluoropentylsulfinyl)nonyl]estra-l,3,5(10)-triene- 3,17-beta-diol), 1 lbeta-fluoro-7alpha-[5-(methyl ⁇ 3-[(4,4,5,5,5- pentafluoropentyl)sulfinyl]- pentyloxy ⁇ phenyl)-6-phenyl-8,9-dihydro-7H-benzocycl
  • this invention also relates to the use of the compounds of general formula I, optionally together with an antiestrogen or SERM, for the production of a pharmaceutical agent.
  • compositions that contain at least one compound according to the invention, optionally in the form of a pharmaceutically/pharmacologically compatible salt, without or together with pharmaceutically compatible adjuvants and/or vehicles.
  • compositions and pharmaceutical agents can be provided for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular administration.
  • pharmaceutical compositions and pharmaceutical agents can be provided for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular administration.
  • they contain at least one compound according to the invention.
  • the pharmaceutical agents of the invention are produced in a known way with the commonly used solid or liquid vehicles or diluents and the usually used pharmaceutical-technical adjuvants corresponding to the desired type of administration with a suitable dosage.
  • the preferred preparations exist in a dispensing form that is suitable for oral administration. Such dispensing forms are, for example, tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions or else depot forms.
  • compositions that contain at least one of the compounds according to the invention are preferably administered orally.
  • Parenteral preparations such as injection solutions, are also considered.
  • suppositories and agents for vaginal application can also be mentioned as preparations.
  • Ethinyl magnesium bromide (6 ml, 0.5 M in tetrahydrofuran) was added to an ice-cold solution that consists of 5- ⁇ 3-[l-(2-fluoro-5-trifluoromethylphenyl)- cyclopropyl]-2-oxopropionylamino ⁇ phthalide (632 mg) in THF (4 ml).
  • the reaction solution under argon was allowed to come to room temperature within 3 hours. Then, the reaction mixture was poured into ice-cold, saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried on sodium sulfate.
  • the crude product that is obtained was chromatographed on silica gel. 2.2 g of product was obtained.
  • Example 2 Analogously to Example 1, 145 mg of product was obtained from 1- propinylmagnesium bromide (2 ml of 0.5 M solution in tetrahydrofuran) and 210 mg of 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3- benzoxazin- 1 -one.
  • reaction mixture was diluted with ethyl acetate. Then, it was washed
  • reaction mixture was poured into ice-cold, saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried on sodium sulfate. The crude product was chromatographed on silica gel. 130 mg of product was obtained.
  • Stage A Reaction of 4-(tert-butyldimethylsilyloxo)but-l-yne (175 mg), nBuLi (0.59 ml, 1.6 M in hexane) 5- ⁇ 3-[l-(2-Fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2- oxopropionylamino ⁇ -phthalide (200 mg) in tetrahydrofuran analogously to the process described under Example 9 yielded 165 mg of product.
  • Stage B The product obtained under stage A (160 mg) was dissolved in 5 ml of
  • the racemic mixture (80 mg) which was described in example 13 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 13a
  • Stage A Analogously to Example 11 , 300 mg of 5- ⁇ 3-[l-(2-fluoro-5- trifluoromethylphenyl)-cyclopropyl]-2-oxopropionylamino ⁇ phthalide and 282 mg of tert-butyl-( 1 , 1 -dimethylprop-2-ynyl-oxy)-dimethylsilane are reacted. 15 mg of product A is obtained.
  • Stage B 70 mg of the compound that is obtained under A was dissolved in 1 ml

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Abstract

L'invention concerne des modulateurs non stéroïdiens du récepteur de la progestérone de formule générale (I), un procédé de production de ceux-ci, leur utilisation pour la production d'agents pharmaceutiques ainsi que des compositions pharmaceutiques contenant ces composés. Les composés de l'invention sont destinés à être utilisés pour le traitement et la prophylaxie de maladies gynécologiques, de type endométriose, léiomyomes utérins, ménométrorragie et dysménorrhée, ainsi que pour le traitement et la prophylaxie de tumeurs dépendantes des hormones, en tant que moyens de contraception pour les femmes et pour le traitement hormonal de substitution.
PCT/EP2006/006532 2005-06-24 2006-06-22 Derives de benzofuranone utilises en tant que modulateurs non steroidiens du recepteur de la progesterone WO2006136462A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
CA002611900A CA2611900A1 (fr) 2005-06-24 2006-06-22 Derives de benzofuranone utilises en tant que modulateurs non steroidiens du recepteur de la progesterone
EA200702604A EA200702604A1 (ru) 2005-06-24 2006-06-22 Производные бензофуранона как нестероидные модуляторы рецептора прогестерона
EP06762405A EP1899315A1 (fr) 2005-06-24 2006-06-22 Derives de benzofuranone utilises en tant que modulateurs non steroidiens du recepteur de la progesterone
AU2006261049A AU2006261049A1 (en) 2005-06-24 2006-06-22 Benzofuranone derivatives as nonsteroidal progesterone receptor modulators
MX2008000070A MX2008000070A (es) 2005-06-24 2006-06-22 Derivados de benzofurarona como moduladores no esteroides de receptores de progesterona.
JP2008517445A JP2008543911A (ja) 2005-06-24 2006-06-22 非ステロイド性プロゲステロン受容体モジュレーターとしてのベンゾフラノン誘導体
BRPI0612305-8A BRPI0612305A2 (pt) 2005-06-24 2006-06-22 moduladores de receptor de progesterona não-esteroidal
IL188022A IL188022A0 (en) 2005-06-24 2007-12-10 Benzofuranone derivatives as nonsteroidal progesterone receptor modulators
NO20080441A NO20080441L (no) 2005-06-24 2008-01-23 Benzofuranonderivater som ikke-steroide progesteronreseptormodulatorer

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DE102005030294.7 2005-06-24
DE102005030294A DE102005030294A1 (de) 2005-06-24 2005-06-24 Nichtsteroidale Progesteronrezeptor-Modulatoren

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AU (1) AU2006261049A1 (fr)
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008077647A2 (fr) * 2006-12-21 2008-07-03 Bayer Schering Pharma Aktiengesellschaft Modulateurs de récepteurs de progestérone non-stéroïdiens
WO2009007396A1 (fr) * 2007-07-10 2009-01-15 Bayer Schering Pharma Aktiengesellschaft Modulateurs non stéroïdiens du récepteur de la progestérone
DE102007058747A1 (de) 2007-12-05 2009-06-10 Bayer Schering Pharma Aktiengesellschaft Nichtsteroidale Progesteronrezeptor-Modulatoren
WO2009134718A1 (fr) * 2008-04-28 2009-11-05 Repros Therapeutics Inc. Antagonistes de la progestérone tels que cdb-4124 dans le traitement de l'endométriose, de fibromes utérins, de la dysménorrhée, du cancer du sein, etc.
US9545411B2 (en) 2012-11-02 2017-01-17 Repros Therapeutics Inc. Methods and compositions for treating progesterone-dependent conditions
US10328022B2 (en) 2012-05-31 2019-06-25 Repros Therapeutics Inc. Formulations and methods for vaginal delivery of antiprogestins

Citations (3)

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WO2000066590A2 (fr) * 1999-05-04 2000-11-09 Ligand Pharmaceuticals, Inc. Composes modulateurs de recepteur de progesterone tetracycliques et procedes
US20020094983A1 (en) * 1999-05-04 2002-07-18 Puwen Zhang Quinazolinone and benzoxazine derivatives as progesterone receptor modulators
WO2003075915A1 (fr) * 2002-03-11 2003-09-18 Schering Ag 5-}2-hydroxy-3-`1-(3-trifluoromethylphenyl)-cyclopropyl!-propionylamino}- phtalide et composes associes ayant une activite modulatrice du recepteur de la progesterone, a utiliser en matiere de contraception et de traitement hormonal substitutif

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DE19723722A1 (de) * 1997-05-30 1998-12-10 Schering Ag Nichtsteroidale Gestagene
ATE346058T1 (de) * 2002-01-14 2006-12-15 Boehringer Ingelheim Pharma Glucocorticoid mimetika, verfahren zu ihrer herstellung, pharmazeutische formulierungen sie enthaltend und verwendungen davon
DE10346939A1 (de) * 2003-10-06 2005-05-19 Schering Ag Heterocyclisch substituierte Pentanole, ein Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066590A2 (fr) * 1999-05-04 2000-11-09 Ligand Pharmaceuticals, Inc. Composes modulateurs de recepteur de progesterone tetracycliques et procedes
US20020094983A1 (en) * 1999-05-04 2002-07-18 Puwen Zhang Quinazolinone and benzoxazine derivatives as progesterone receptor modulators
WO2003075915A1 (fr) * 2002-03-11 2003-09-18 Schering Ag 5-}2-hydroxy-3-`1-(3-trifluoromethylphenyl)-cyclopropyl!-propionylamino}- phtalide et composes associes ayant une activite modulatrice du recepteur de la progesterone, a utiliser en matiere de contraception et de traitement hormonal substitutif

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008077647A2 (fr) * 2006-12-21 2008-07-03 Bayer Schering Pharma Aktiengesellschaft Modulateurs de récepteurs de progestérone non-stéroïdiens
WO2008077647A3 (fr) * 2006-12-21 2008-10-16 Bayer Schering Pharma Ag Modulateurs de récepteurs de progestérone non-stéroïdiens
WO2009007396A1 (fr) * 2007-07-10 2009-01-15 Bayer Schering Pharma Aktiengesellschaft Modulateurs non stéroïdiens du récepteur de la progestérone
DE102007058747A1 (de) 2007-12-05 2009-06-10 Bayer Schering Pharma Aktiengesellschaft Nichtsteroidale Progesteronrezeptor-Modulatoren
WO2009071252A1 (fr) * 2007-12-05 2009-06-11 Bayer Schering Pharma Aktiengesellschaft Modulateurs non stéroïdiens du récepteur de la progestérone
WO2009134718A1 (fr) * 2008-04-28 2009-11-05 Repros Therapeutics Inc. Antagonistes de la progestérone tels que cdb-4124 dans le traitement de l'endométriose, de fibromes utérins, de la dysménorrhée, du cancer du sein, etc.
US8426394B2 (en) 2008-04-28 2013-04-23 Repros Therapeutics Inc. Progesterone antagonists such as CDB-4124 in the treatment of endometriosis, uterine fibroids, dysmenorrhea, breast cancer, etc
AU2009241355B2 (en) * 2008-04-28 2013-11-14 Allergan pharmaceuticals International Ltd. Progesterone antagonists such as CDB-4124 in the treatment of endometriosis, uterine fibroids, dysmenorrhea, breast cancer etc
US8735381B2 (en) 2008-04-28 2014-05-27 Repros Therapeutics Inc. Progesterone antagonists such as CDB-4124 in the treatment of endometriosis, uterine fibroids, dysmenorrhea, breast cancer, etc
US10328022B2 (en) 2012-05-31 2019-06-25 Repros Therapeutics Inc. Formulations and methods for vaginal delivery of antiprogestins
US9545411B2 (en) 2012-11-02 2017-01-17 Repros Therapeutics Inc. Methods and compositions for treating progesterone-dependent conditions

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MX2008000070A (es) 2008-03-19
IL188022A0 (en) 2008-03-20
EP1899315A1 (fr) 2008-03-19
CA2611900A1 (fr) 2006-12-28
AR057409A1 (es) 2007-12-05
ECSP078043A (es) 2008-01-23
UY29626A1 (es) 2007-01-31
GT200600272A (es) 2007-08-20
DE102005030294A1 (de) 2007-01-04
KR20080018275A (ko) 2008-02-27
PE20070170A1 (es) 2007-03-02
NO20080441L (no) 2008-03-07
BRPI0612305A2 (pt) 2010-11-03
ZA200800689B (en) 2009-07-29
CR9595A (es) 2008-05-05
JP2008543911A (ja) 2008-12-04
TW200738665A (en) 2007-10-16
AU2006261049A1 (en) 2006-12-28
EA200702604A1 (ru) 2008-06-30
DOP2006000150A (es) 2006-12-31
CN101248056A (zh) 2008-08-20

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