WO2008077647A2 - Modulateurs de récepteurs de progestérone non-stéroïdiens - Google Patents

Modulateurs de récepteurs de progestérone non-stéroïdiens Download PDF

Info

Publication number
WO2008077647A2
WO2008077647A2 PCT/EP2007/011487 EP2007011487W WO2008077647A2 WO 2008077647 A2 WO2008077647 A2 WO 2008077647A2 EP 2007011487 W EP2007011487 W EP 2007011487W WO 2008077647 A2 WO2008077647 A2 WO 2008077647A2
Authority
WO
WIPO (PCT)
Prior art keywords
compounds according
alkyl
methyl
mono
cycloalkyl
Prior art date
Application number
PCT/EP2007/011487
Other languages
German (de)
English (en)
Other versions
WO2008077647A3 (fr
Inventor
Wolfgang Schwede
Thomas Andrew Kirkland
Anja Schmidt
Ulrike Fuhrmann
Carsten Moeller
Andrea Rotgeri
Original Assignee
Bayer Schering Pharma Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE102006061913A external-priority patent/DE102006061913A1/de
Priority claimed from DE102007023614A external-priority patent/DE102007023614A1/de
Application filed by Bayer Schering Pharma Aktiengesellschaft filed Critical Bayer Schering Pharma Aktiengesellschaft
Publication of WO2008077647A2 publication Critical patent/WO2008077647A2/fr
Publication of WO2008077647A3 publication Critical patent/WO2008077647A3/fr

Links

Classifications

    • 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
    • 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
    • A61P15/18—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

Definitions

  • Nonsteroidal progesterone receptor modulators are provided.
  • the present invention relates to nonsteroidal progesterone receptor modulators, a process for their preparation, the use of the progesterone receptor modulators for the production of medicaments, and pharmaceutical compositions containing these compounds.
  • progesterone decisively regulates the reproductive process in the female organism.
  • Progesterone is secreted by the ovary or placenta in large quantities during the cycle and during pregnancy.
  • progesterone causes cyclic changes of the uterine lining (endometrium) in the menstrual cycle.
  • the uterine mucosa is transferred to a state that allows the implantation of an embryo (blastocyst).
  • progesterone controls the immobilization of the myometrium and maintains the function of the decidual tissue.
  • progesterone inhibits endometrial proliferation by suppression of estrogen-mediated mitosis in the uterine tissue (K. Chwalisz, RM Brenner, U. Fuhrmann, H. Hess-Stumpp, W. Elger, Steroids 65, 2000, 741- 751).
  • Progesterone and progesterone receptors are also known in pathophysiological processes. Progesterone receptors are detected in endometriosis, but also in tumors of the uterus, the breast and the CNS. Furthermore, it is known that leiomyomas of the uterus grow progesterone dependent.
  • progesterone in the tissues of the genital organs and in other tissues are through interactions with progesterone receptors responsible for the cellular effects.
  • Progesterone receptor modulators are either pure agonists or partially or completely inhibit the action of progesterone. Accordingly, become Substances as pure agonists, partial agonists (Selective
  • Progesterone receptor modulators SPRM
  • pure antagonists SPRM
  • progesterone receptor modulators According to the ability of progesterone receptor modulators to exert their action via the progesterone receptor, these compounds have considerable potential as therapeutic agents for gynecological and oncological indications as well as for obstetrics and fertility control.
  • progesterone receptor antagonists completely inhibit the action of progesterone on the progesterone receptor. They have antiovulatory properties as well as the ability to inhibit estrogen effects in the endometrium to complete atrophy. They are therefore particularly suitable to intervene in the reproductive process of the woman, for.
  • Postovulatory in order to prevent the nidation of a fertilized egg, in pregnancy, to increase the uterine reactivity for prostaglandins or oxytocin, or to achieve opening and softening ("maturation") of the cervix, as well as high labor readiness of the myometrium In endometrial or tumor tissues, which are equipped with progesterone receptors, one expects after application of pure progesterone receptor antagonists a favorable influence on the disease process.
  • Present advantages for influencing disease states such as endometriosis or leiomyomas of the uterus could be given if by The inhibition of ovulation also eliminates part of the ovarian hormone production and thus the stimulating effect on the pathologically altered tissue that is attributable to this proportion.
  • the first described progesterone receptor antagonist, RU 486 (also called mifepristone), was followed by the synthesis and characterization of a large number of analogs with varying levels of progesterone receptor antagonist activity. While RU 486 also shows an antiglucocorticoid activity in addition to the progesterone receptor antagonistic effect, later synthesized compounds are characterized in particular by a more selective action as progesterone receptor antagonists.
  • Progesterone receptor antagonistic to antiglucocorticoid effect also, various non-steroidal structures are known whose antagonistic effect on the progesterone receptor is being investigated [see, eg, SA Leonhardt and DP Edwards, Exp. Biol. Med. 227: 969-980 (2002) and R. Winneker, A. Fensome, JE Wrobel, Z. Zhang, P. Zhang, Seminars in Reproductive Medicine, Volume 23: 46-57 (2005)].
  • previously known non-steroidal compounds have only modest antagonistic activity compared to the activity of known steroidal structures. The most potent nonsteroidal compounds are described with in vitro activities of 10% of the activity of RU 486.
  • Antiglucocorticoid activity is detrimental to a therapeutic application in which inhibition of progesterone receptors is at the forefront of therapy. Antiglucocorticoid activity causes undesirable side effects at the therapeutically required dosages. This may prevent the application of a therapeutically useful dose or lead to discontinuation of treatment.
  • the partial or complete reduction of the anti-glucocorticoid properties is therefore an important prerequisite for the treatment with progesterone receptor antagonists, in particular for those indications which require treatment lasting over weeks or months.
  • progesterone receptor partial agonists show a residual agonistic property, which can be of varying severity.
  • SPRMs progesterone receptor partial agonists
  • these substances exhibit agonistic effects on the progesterone receptor in certain organ systems (D. DeManno, W. Elger, R. Garg, R. Lee, B. Schneider, H. Hess-Stumpp, G. Schuber, K. Chwalisz, Steroids 68, 2003, 1019-1032).
  • organ specific and dissociated effect may be of therapeutic use for the described indications.
  • the object of the present invention is therefore to provide further nonsteroidal progesterone receptor modulators. These compounds are said to have a reduced anti-glucocorticoid effect and therefore be suitable for the
  • the compounds according to the invention should be suitable for the therapy and prophylaxis of hormone-dependent tumors, for example breast,
  • A is a hydrogen, optionally mono- or polysubstituted by identical or different Z-substituted C 1 -C 8 -AlkYl-, C 2 -C 8 alkenyl, C 2 -C 8 - alkynyl or optionally one or more times is equal to or differently, with M substituted C 3 -C 10 cycloalkyl or 3-12- membered heterocycloalkyl or is directly for Z, wherein Z has the following meanings:
  • M is a C 1 -C 6 -alkyl or a group -COR b , CO 2 R b , -
  • R b is a hydrogen or a d-Ce-alkyl, C 2 -C 8 -
  • Cycloalkyl C 6 -C 2 -aryl radical, a group C (O) R b having the meaning given above for R b or a hydroxy group, where, if
  • R c is a hydroxy group
  • R d is only a hydrogen
  • R e is a hydrogen, C 2 -C 8 alkenyl, C 2 -C 8 -
  • R 1 and R 2 independently of one another denote an unbranched or branched C 1 -C 5 -alkyl group or together with the carbon atom of the chain form a ring having a total of 3 to 7 members, where, when A is a hydrogen, R 1 and R 2 can not simultaneously be a methyl radical,
  • R 3 is a hydrogen or an optionally mono- or polysubstituted, identically or differently with K-substituted C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C 3 - C 10 -cycloalkyl, 3-12-membered heterocycloalkyl radical or an optionally mono- or polysubstituted by identical or different L-substituted, mono- or bicyclic C 6 -C 12 -aryl or 3-12-membered heteroaryl radical, and
  • Heterocycloalkyl radical (CH 2 ) p CN, (CH 2 ) p Hal, (CH 2 ) P NO 2 , a mono- or bicyclic (CH 2 ) p -C 6 -C 12 -aryl radical, a monocyclic or bicyclic radical, 12-membered (CH 2 ) p -heteroaryl radical, or - (CH 2 ) p PO 3 (R b ) 2 , - (CH 2 ) pNR c R d , - (CH 2 ) p NR e COR b , - (CH 2) p NR e CSR b, - (CH 2) p NR e S (O) R b, - (CH 2) p NR e S (O) 2 R b,
  • X is one oxygen or two hydrogen atoms
  • R 4 is an unsubstituted or optionally substituted with 1 to 3 of the radicals mentioned under L radicals substituted aromatic or heteroaromatic
  • C 6-ring / 5-ring systems: in which R 5 is hydrogen or C 1 -C 4 alkyl, or a partially or completely fluorinated Ci-C 4 alkyl, R 6a and R 6b are independently hydrogen, C 1 -C 4 alkyl or a partially or completely fluorinated C 1 -C 4 - A ⁇ yI or together with the ring carbon atom form a 3- to 6-membered ring,
  • the compounds of the general formula I according to the invention can be present as different stereoisomers due to the presence of asymmetric centers. Both the racemates and the separately present stereoisomers are the subject of the present invention.
  • the present invention includes the novel compounds as pharmaceutical agents, their therapeutic application and pharmaceutical dosage forms containing the new substances.
  • the compounds of the general formula (I) or their pharmaceutically acceptable salts according to the invention can be used for the preparation of a medicament, in particular for the treatment and prophylaxis of gynecological diseases such as endometriosis, uterine leiomyomas, dysfunctional bleeding and dysmenorrhea. Furthermore, the compounds according to the invention can be used for the treatment and prophylaxis of hormone-dependent tumors such as, for example, breast, prostate and endometrial carcinoma.
  • the compounds of general formula (I) according to the invention or their pharmaceutically acceptable salts are also suitable for use in female fertility control or in female hormone replacement therapy.
  • nonsteroidal compounds of the general formula I according to the invention have a strong antagonistic or partial agonistic action with high potency
  • Progesterone receptor show a strong dissociation of their effects Binding strength at the progesterone and glucocorticoid receptors. While known progesterone receptor antagonists such as mifepristone (RU 486) in addition to the desired high binding affinity for progesterone receptor also show a high affinity for glucocorticoid receptor, the compounds of the invention are characterized by a very low glucocorticoid receptor binding at the same time present high progesterone receptor affinity.
  • Ci-C 5 -, C 1 -C 6 - are understood to mean unbranched or optionally branched alkyl radicals. These are, for example, a methyl, ethyl, n-propyl, iso-propyl, n, iso, tert-butyl, n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl -, hexyl, heptyl or octyl group. In the meaning of R 1, R 2 and R 3, methyl, ethyl, n-propyl or n-butyl group and a n-pentyl group are preferred.
  • R 5 is methyl or ethyl and R 6a and R 6b are preferably hydrogen.
  • Alkenyl is understood to mean unbranched or optionally branched alkenyl radicals.
  • C 2 -C 8 -alkenyl group is understood to mean, for example, the following: vinyl, allyl, 3-buten-1-yl or 2,3-dimethyl-2-propenyl. If the aromatic in R 3 is substituted by a C 2 -C 8 -alkenyl radical, it is preferably a vinyl group.
  • Alkynyl is understood to mean unbranched or optionally branched alkynyl radicals.
  • a C 2 -C 8 -alkynyl radical should be, for example, an ethynyl, propynyl, butynyl, pentynyl, hexynyl and octynyl group, but preferably an ethynyl or propynyl group.
  • methoxymethoxy, ethoxymethoxy or 2-methoxyethoxy may stand for ⁇ -C ⁇ -alkoxyl-C 1 -C 6 -alkoxy group.
  • a radical OR b in the context of the invention is a hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n, iso, tert-butoxy or n-pentoxy radical, 2,2-dimethylpropoxy or 3-methylbutoxy group. Hydroxy, methoxy and ethoxy are preferred.
  • a halogen atom may be a fluorine, chlorine, bromine or iodine atom. Preference is given here to fluorine, chlorine or bromine.
  • 3- to 12-membered cycloalkyl and heterocycloalkyl groups are meant both monocyclic and bicyclic.
  • Monocyclic C 3 -C 0 cycloalkyl as defined in R c and R e may be mentioned, for example, cyclopropane, cyclobutane, cyclopentane and cyclohexane. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.
  • R 1 and R 2 together with the carbon atom of the chain form a ring having a total of 3-7 members, they are preferably rings of 3-7 carbon atoms in total. Particularly preferred are cyclopentyl and cyclohexyl when A is simultaneously hydrogen.
  • a mono- or bicyclic C 6 -C 12 -aryl radical in the sense of R 3 or R b , R c , R d , R e and also K and L is, for example, a phenyl or naphthyl radical, preferably a phenyl radical.
  • Examples of a 3-12-membered heteroaryl radical in the sense of R 3 , K and L 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.
  • bicyclic 3-10-membered heterocycles quinoline, quinazoline and naphthyridine may be mentioned.
  • R 4 the bicyclic ring systems mentioned under B and C are preferred according to the invention.
  • the number p for the (CH 2 ) P radical can be a number 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1 or 2.
  • radical is meant according to the invention all functional groups which are listed in connection with (CH 2 ) P under L understood.
  • the compounds of the general formula I are present as salts, this may be, for example, in the form of the hydrochloride, sulfate, nitrate, tartrate, citrate, fumarate, succinate or benzoate.
  • the compounds according to the invention are present as racemic mixtures, they can be separated into the pure optically active forms by methods of racemate resolution which are familiar to the person skilled in the art.
  • the racemic mixtures can be separated into the pure isomers by chromatography on an even optically active carrier material (CHIRALPAK AD ®).
  • CHIRALPAK AD ® even optically active carrier material
  • the optically active acid for example, mandelic acid, camphorsulfonic acid or tartaric acid can be used.
  • Preferred according to the present invention are compounds of the general formula (I) in which:
  • A is a hydrogen and R 1 and R 2 together with the C atom of the chain form a ring of 3-7 carbon atom or
  • A is a C 1 -C 6 -alkyl or C 3 -C 10 -cycloalkyl, while R 1 and R 2 are simultaneously a methyl or
  • R 3 is a d-C ⁇ -alkyl, a mono or bicyclic C 6 -C means or 2 aryl or a 3-12- membered heteroaryl
  • R 3 is a mono- or bicyclic C 6 -C 2 aryl or a 3-12-membered
  • Heteroaryl and R 4 is a 1- or 2-fold substituted mono- or bicyclic aromatic or one of the groups mentioned under R 4 B can be linked to position 6 or C with linkage at position 5.
  • R 5 is a methyl or ethyl
  • R 6 is a hydrogen, p is 0, 1 or 2 as well
  • Ci-C ⁇ -alkyl C 2 -C 8 -alkenyl I, C 2 -C 8 -alkynyl, a partially or fully fluorinated Ci-C ⁇ -alkyl, - (CH 2 ) P CN, (CH 2 ) p Hal , (CH 2 ) P NO 2 , (CH 2 ) pC e -Ci 2 -aryl, - (CH 2 ) p -Heteroaryl, - (CH 2 ) p NR c R d , - (CH 2 ) p NR e COR b , - (CH 2 ) p NR e S (O) 2 R b , - (CH 2 ) p NR e CONR c R d , - (CH 2 ) p NR e S (O) NR c R d , - ( CH 2 ) p NR e S (O) 2 NR c ,
  • progesterone receptor modulators can be carried out with the aid of simple methods, test programs known to the person skilled in the art.
  • a compound to be tested can be incubated together with a gestagen in a test system for progesterone receptor ligands and it can be tested whether the action mediated by progesterone is changed in the presence of the modulator in this test system.
  • Receptor binding affinity was determined by competitive binding of a specific binding 3 H-labeled hormone (tracer) and the compound to be tested to receptors in the cytosol from animal target organs. The aim was receptor saturation and reaction equilibrium.
  • Glucocorticoid receptor Thymus cytosol of the adrenalectomized rat, Thymi stored at -3O 0 C; Buffer: TED. Tracer: 3 H-Dexamethasone, 20 nM; Reference substance: dexamethasone.
  • the competition factors (KF values) of the compounds of general formula (I) according to the invention on the progesterone receptor are between 0.2 and 35 with respect to progesterone. At the glucocorticoid receptor, KF values are in the range of 3 to 35 based on dexamethasone.
  • the compounds according to the invention have a high affinity for the progesterone receptor but only a low affinity for the glucocorticoid receptor.
  • the transactivation assay is carried out as described in WO 02/054064.
  • the IC ⁇ o values are in the range of 0.1 to 150 nM.
  • the transactivation assay is carried out as described in Fuhrmann et al. (Fuhrmann U., Hess-Stump H., Cleve A., Neef G., Schwede W., Hoffmann J., Fritzemeier K.-H., Chwalisz K., Journal of Medicinal Chemistry, 43, 26, 2000 , 5010-5016).
  • the EC 50 values are in the range from 0.01 to 150 nM.
  • the progesterone receptor modulators can be administered orally, enterally, parenterally or transdermally.
  • satisfactory results in the treatment of the above-mentioned indications are to be expected if the daily doses range from 1 ⁇ g to 1000 mg of the compound of the invention for gynecological indications such as treatment of endometriosis, uterine leiomyomas and dysfunctional bleeding and for use in fertility control and hormone replacement therapy.
  • daily dosages ranging from 1 ⁇ g to 2000 mg of the compound of the invention are to be administered.
  • Hormone replacement therapy is 50 ⁇ g to 500 mg per day, depending on the age and Constitution of the patient, whereby the necessary daily dose can be administered by single or multiple delivery.
  • the dosage range for the compounds of the invention comprises 10 mg to 2000 mg daily.
  • the formulation of the pharmaceutical preparations based on the new compounds is carried out in a conventional manner, by processing the active ingredient with the commonly used in galenics carriers, fillers, Zerfallbeeinpoundern, binders, humectants, lubricants, absorbents, diluents, flavoring agents, colorants, etc., and in the desired
  • crystal suspensions For intraarticular injection, appropriately prepared crystal suspensions may be used.
  • aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.
  • the new compounds may be used in the form of suppositories, capsules, solutions (e.g., in the form of enemas) and ointments for both systemic and local therapy. Furthermore, may be mentioned as a preparation and agents for vaginal use.
  • these can be used in the form of aerosols and inhalants.
  • Corresponding tablets can be prepared, for example, by mixing the active compound with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or Achieve a depot effect such as carboxyl polymethylene, carboxyl methyl cellulose, cellulose acetate phthalate or polyvinyl acetate.
  • the tablets can also consist of several layers.
  • Coated tablets can accordingly be prepared by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar.
  • the dragee wrapper can also consist of several layers, wherein the auxiliaries mentioned above in the case of the tablets can be used.
  • Solutions or suspensions of the compounds of general formula I according to the invention may additionally taste-improving agents such as saccharin, cyclamate or sugar and z.
  • B. flavorings such as vanillin or orange extract. They may also contain suspending aids such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.
  • the capsules containing the compounds of the general formula I can be prepared, for example, by mixing the compound (s) of the general formula I with an inert carrier such as lactose or sorbitol and encapsulating it in gelatine capsules.
  • an inert carrier such as lactose or sorbitol
  • Suitable suppositories can be prepared, for example, by mixing with suitable carriers such as neutral fats or polyethylene glycol or derivatives thereof.
  • suitable carriers such as neutral fats or polyethylene glycol or derivatives thereof.
  • the compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts can be used for the preparation of a medicament, in particular for the treatment and prophylaxis of gynecological diseases such as endometriosis, uterine leiomyomas, dysfunctional bleeding and dysmenorrhea, because of their antagonistic or partial agonist activity.
  • gynecological diseases such as endometriosis, uterine leiomyomas, dysfunctional bleeding and dysmenorrhea
  • they can be used against hormonal irregularities, menstruation release and alone or in combination with prostaglandins and / or oxytocin to induce labor.
  • the compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts are furthermore suitable for the preparation of preparations for contraception for women (see also WO 93/23020, WO 93/21927).
  • the compounds of the invention or their pharmaceutically acceptable salts can also be used alone or in combination with a Selective Estrogen Receptor Modulators (SERM) for female hormone replacement therapy.
  • SERM Selective Estrogen Receptor Modulators
  • the compounds mentioned exert an antiproliferative effect in hormone-dependent tumors. They are therefore suitable for the therapy of hormone-dependent carcinomas, such as, for example, breast, prostate and endometrial carcinomas.
  • the compounds according to the invention or their pharmaceutically acceptable salts can be used for the treatment of hormone-dependent carcinomas both in first-line therapy and in second-line therapy, in particular after tamoxifen failure.
  • the antagonistically or partially agonistically active compounds of the general formula (I) or their pharmaceutically acceptable salts according to the invention can also be used in combination with antiestrogenic compounds (estrogen receptor antagonists or aromatase inhibitors) or selective estrogen receptor modulators (SERM) for the preparation of pharmaceutical preparations Treatment of hormone-dependent tumors can be used.
  • antiestrogenic compounds estrogen receptor antagonists or aromatase inhibitors
  • SERM selective estrogen receptor modulators
  • the compounds of the invention may also be used in combination with SERMs or an antiestrogen (estrogen receptor antagonists or aromatase inhibitors)
  • SERMs antiestrogen receptor antagonists or aromatase inhibitors
  • the following antiestrogens (estrogen receptor antagonists or aromatase inhibitors) or SERMs are suitable for combination with the nonsteroidal progesterone receptor modulators according to the invention: tamoxifen, 5- (4- ⁇ 5 - [(RS) - (4,4, 5,5,5-pentafluoropentyl) sulfinyl] pentyloxy ⁇ phenyl) -6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol (WO 00/03979), ICI 182 780 (7alpha [9- (4 , 4,5,5-pentafluoropentylsulfinyl) nonyl] estra-1, 3,5 (10) -triene
  • the present invention also relates to the use of the compounds of general formula I, optionally together with an antiestrogen or SERM, for the preparation of a medicament.
  • the present invention relates to pharmaceutical compositions containing at least one compound of the invention, optionally in the form of a pharmaceutically / pharmacologically acceptable salt.
  • compositions and pharmaceutical compositions may be for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular administration.
  • conventional carriers and / or diluents they contain at least one compound of the invention.
  • compositions of the invention are prepared in a known manner with the usual solid or liquid carriers or diluents and the pharmaceutical excipients customarily used according to the desired mode of administration with a suitable dosage.
  • the preferred formulations consist of a dosage form which is suitable for oral administration.
  • Dosage forms are, for example, tablets, coated tablets, dragees, capsules, pills, powders, solutions or suspensions, optionally as depot form.
  • compositions containing at least one of the compounds of the invention are preferably administered orally.
  • parenteral preparations such as injection solutions into consideration.
  • Further examples of preparations which may be mentioned are suppositories and vaginal administration agents.
  • the compounds of general formula I can, for. As synthesized as shown in Scheme 1. Chain extension from aldehydes of type II can e.g. via Horner-Wittig reaction. A reductone of the double bond, e.g. Hydrogenation in the presence of suitable catalysts then gives compounds of the general formula IV which, by an ⁇ -hydroxylation followed by oxidation of the alcohol formed to form the ketone, give compounds of the general formula VI.
  • ⁇ -hydroxylation to prepare compounds of general formula V various methods known in the literature, e.g. the use of 2-sulfonyloxaziridine according to one of Davis et al. Chem., 1984, 49, 3241).
  • the oxidation to compounds of general formula VI can then be carried out by known standard methods.
  • the amides of the general formula VIII are prepared, for example, via the formation of the acid chlorides and subsequent reaction with the corresponding amines.
  • the substituents A, X, Y, R 1 , R 2 , R 3 and R 4 may optionally be further modified even after the introduction.
  • Functional groups in compounds of the general formulas M-VIII may be provided with protective groups in the meantime, which are then split off again at a suitable stage.
  • 4,4-Dimethyl-2-oxopentanoic acid (0.75 g) was dissolved in 10 ml of N, N-dimethylacetamide. It added 460 ul of thionyl chloride at -10 0 C and left for one hour at -10 0 C. for. Subsequently, 1.28 g of 6-amino-4-methyl-2,3-benzoxazin-1-one were added in portions. The mixture was then stirred for 3 hours (-10 0 C to 0 ° C). Subsequently, the reaction mixture was poured onto ice-water. It was extracted with ethyl acetate.
  • Butyllithium (830 ul, 1, 6 M in hexane) added. It was left for 30 minutes at this
  • Example 2 The racemic mixture obtained in Example 2 was separated into the enantiomers 2a and 2b by preparative chiral HPLC (Chiralpak AD column 250 ⁇ 10 mm).
  • Example 3 The racemic mixture obtained in Example 3 was separated by preparative chiral HPLC (column Chiralpak AD 250 ⁇ 10 mm) into the enantiomers 3a and 3b.
  • (+) - 6- [2 (2,2-dimethylpropyl) -2-hydroxy-4- (4-trifluoromethylphenyl) but-3-ynoamino] -4-methyl-2,3-benzoxazin-1-one 4a and -) - 6- [2 (2,2-Dimethylpropyl) -2-hydroxy-4- (4-trifluoromethylphenyl) but-3-ynoamino] -4-methyl-2,3-benzoxazin-1-one 4b
  • Example 4 The racemic mixture obtained in Example 4 was separated by preparative chiral HPLC (column Chiralpak AD 250 ⁇ 10 mm) into the enantiomers 4a and 4b.
  • Example 6 The racemic mixture obtained in Example 6 was separated by preparative chiral HPLC (column Chiralpak AD 250 ⁇ 10 mm) into the enantiomers 6a and 6b.
  • 6- (4-H, 31-dioxolan-2-yl-4-methyl-2-oxovaleroylamino) -4-methyl-2,3-benzoxazin-1-one as starting material for the preparation of Examples 7 and 8:
  • the compound (35 g) described under a) was dissolved in 500 ml of dichloromethane. 70 ml of triethylamine and 250 ml of dimethyl sulfoxide were then added, with slight cooling, and the mixture was stirred for a further 3 minutes. Subsequently, 40 g of sulfur trioxide-pyridine complex were added. The mixture was stirred for 2 hours at 23 ° C. Then, the reaction mixture was poured onto saturated aqueous ammonium chloride solution. The mixture was stirred for a further 30 minutes and then extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The resulting crude product (34 g) was used without purification in the subsequent stage.
  • the crude product obtained under b) was dissolved in 300 ml of benzene. 80 ml of ethylene glycol and 2.5 g of p-toluenesulfonic acid were added and the mixture was refluxed for 5 hours on a water separator. Thereafter, the reaction mixture was poured onto saturated sodium hydrogencarbonate aqueous solution. It was extracted with ethyl acetate, then the organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The resulting crude product was chromatographed on silica gel. This gave 28 g of product.
  • Tetrahydrofuran was added at -7O 0 C 26.15 ml of a 0.5 molar solution of potassium hexamethyldisilazide in toluene. After 30 minutes at -70 0 C nachrühen and then slowly added a solution of 3.4 g of 2-phenylsulfonyl-3-phenyl-oxaziridine in 35 ml of absolute tetrahydrofuran. The mixture was then stirred at -70 0 C for one hour and then poured onto saturated aqueous ammonium chloride solution. The mixture was stirred for a further 30 minutes and then extracted with ethyl acetate.
  • Example 7 rac-6- [4,4-dimethyl-2,5-dihydroxy-2-phenylpentanoylamino] -4-methyl-2,3-benzoxazin-1-one
  • the product obtained under 7a) (317 mg) was dissolved in 10 ml of acetone. 1 ml of 2N hydrochloric acid was added and the reaction mixture was refluxed for 14 h. It was then poured onto saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The resulting crude product was dissolved in 5 ml of dimethoxyethane. It was cooled to 0 ° C. Then, 22 mg of sodium borohydride was added. Subsequently, 250 ⁇ l of methanol were added slowly.
  • Example 8 rac-6- [4,4-dimethyl-2,5-dihydroxy-2- (phenylmethyl) pentanoylamino] -4-methyl-2,3-benzoxazin-1-one
  • Example 9 The racemic mixture obtained in Example 9 was separated into the enantiomers 9a and 9b by preparative chiral HPLC (Chiralpak AD column 250 ⁇ 10 mm).
  • Example 11 The racemic mixture obtained in Example 11 was separated by preparative chiral HPLC (column Chiralpak AD 250 ⁇ 10 mm) into the enantiomers 11a and 11b.
  • Example 12 rac ⁇ - ⁇ -cyclohexyl-hydroxy- ⁇ , -methylphenylethoxypropanylamino] -methyl-2,3-benzoxazin-1-one

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne des modulateurs de récepteurs de progestérone non-stéroïdiens représentés par la formule (1), l'utilisation des modulateurs de récepteurs de progestérone pour la fabrication de médicaments et des compositions pharmaceutiques contenant ces composés. Les composés selon l'invention servent à la thérapie et à la prophylaxie de maladies gynécologiques telles que l'endométriose, les léiomyomes de l'utérus, les saignements dysfonctionnels et la dysménorrhée, à la thérapie et à la prophylaxie de tumeurs hormono-dépendantes, et à une utilisation pour le contrôle de la fertilité chez la femme et la thérapie de substitution hormonale.
PCT/EP2007/011487 2006-12-21 2007-12-20 Modulateurs de récepteurs de progestérone non-stéroïdiens WO2008077647A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE102006061913A DE102006061913A1 (de) 2006-12-21 2006-12-21 Nichtsteroidale Progesteronrezeptor-Modulatoren
DE102006061913.7 2006-12-21
DE102007023614.1 2007-05-21
DE102007023614A DE102007023614A1 (de) 2007-05-21 2007-05-21 Nichtsteroidale Progesteronrezeptor-Modulatoren

Publications (2)

Publication Number Publication Date
WO2008077647A2 true WO2008077647A2 (fr) 2008-07-03
WO2008077647A3 WO2008077647A3 (fr) 2008-10-16

Family

ID=39456752

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/011487 WO2008077647A2 (fr) 2006-12-21 2007-12-20 Modulateurs de récepteurs de progestérone non-stéroïdiens

Country Status (5)

Country Link
AR (1) AR064478A1 (fr)
PE (1) PE20081397A1 (fr)
TW (1) TW200835498A (fr)
UY (1) UY30805A1 (fr)
WO (1) WO2008077647A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103288669A (zh) * 2013-07-01 2013-09-11 南开大学 一种阿卓乳酸酰胺衍生物及应用

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253503A2 (fr) * 1986-07-18 1988-01-20 Imperial Chemical Industries Plc Anilides substitués ayant des propriétés antiandrogènes
EP0253500A2 (fr) * 1986-07-18 1988-01-20 Imperial Chemical Industries Plc Dérivés d'acylanilide
WO1993002057A1 (fr) * 1991-07-17 1993-02-04 Smithkline Beecham Corporation Inhibiteurs de proteases retrovirales
US5733882A (en) * 1994-01-17 1998-03-31 Smithkline Beecham Corporation Retroviral protease inhibitors
WO1998054159A1 (fr) * 1997-05-30 1998-12-03 Schering Aktiengesellschaft Acylanilides non steroidiques heterocycliquement substitues a effet mixte gestagene et androgene
WO2000032584A2 (fr) * 1998-11-27 2000-06-08 Schering Aktiengesellschaft Inhibiteurs d'inflammation non steroidiques
WO2002010143A1 (fr) * 2000-07-28 2002-02-07 Schering Aktiengesellschaft Anti-inflammatoires non steroidiens
WO2003059899A1 (fr) * 2002-01-14 2003-07-24 Boehringer Ingelheim Pharmaceuticals, Inc. Mimetiques de glucocorticoides, procedes de fabrication, preparations pharmaceutiques renfermant ces mimetiques et utilisations
EP1344776A1 (fr) * 2002-03-11 2003-09-17 Schering Aktiengesellschaft Dérivés de la 5- 2-hydroxy-3-[1-(3-trifluorométhylphényl)-cyclopropyl]-propionylamino -phtalide et de la 6- 2-hydroxy-3-[1-(3-trifluoromethylphenyl)-cyclopropyl]-propionylamino -4-methyl-2,3-benzoxazin-1-one avec une activité modulante du recepteur de la progesterone pour l'utilisation dans la contraception , la therapie du remplacement hormonell et le traitement des troubles gynécologiques
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
WO2005003098A1 (fr) * 2003-07-01 2005-01-13 Schering Aktiengesellschaft Derives de pentanol substitues par un heterocycle, procede de production de ces composes et leur utilisation comme agents anti-inflammatoires
WO2006108699A1 (fr) * 2005-04-14 2006-10-19 Glaxo Group Limited Indazoles en tant que ligands de recepteur glucocorticoide
WO2006136461A2 (fr) * 2005-06-24 2006-12-28 Bayer Schering Pharma Aktiengesellschaft Procede de fabrication de vaccins viraux dans des lignees de cellules souches embryonnaires aviaires derivees en suspension
WO2006136462A1 (fr) * 2005-06-24 2006-12-28 Bayer Schering Pharma Aktiengesellschaft Derives de benzofuranone utilises en tant que modulateurs non steroidiens du recepteur de la progesterone
WO2007022824A1 (fr) * 2005-06-24 2007-03-01 Bayer Schering Pharma Aktiengesellschaft Utilisation de modulateurs du recepteur de progesterone non-stedoidique

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253503A2 (fr) * 1986-07-18 1988-01-20 Imperial Chemical Industries Plc Anilides substitués ayant des propriétés antiandrogènes
EP0253500A2 (fr) * 1986-07-18 1988-01-20 Imperial Chemical Industries Plc Dérivés d'acylanilide
WO1993002057A1 (fr) * 1991-07-17 1993-02-04 Smithkline Beecham Corporation Inhibiteurs de proteases retrovirales
US5733882A (en) * 1994-01-17 1998-03-31 Smithkline Beecham Corporation Retroviral protease inhibitors
WO1998054159A1 (fr) * 1997-05-30 1998-12-03 Schering Aktiengesellschaft Acylanilides non steroidiques heterocycliquement substitues a effet mixte gestagene et androgene
DE19723722A1 (de) * 1997-05-30 1998-12-10 Schering Ag Nichtsteroidale Gestagene
WO2000032584A2 (fr) * 1998-11-27 2000-06-08 Schering Aktiengesellschaft Inhibiteurs d'inflammation non steroidiques
WO2002010143A1 (fr) * 2000-07-28 2002-02-07 Schering Aktiengesellschaft Anti-inflammatoires non steroidiens
WO2003059899A1 (fr) * 2002-01-14 2003-07-24 Boehringer Ingelheim Pharmaceuticals, Inc. Mimetiques de glucocorticoides, procedes de fabrication, preparations pharmaceutiques renfermant ces mimetiques et utilisations
EP1344776A1 (fr) * 2002-03-11 2003-09-17 Schering Aktiengesellschaft Dérivés de la 5- 2-hydroxy-3-[1-(3-trifluorométhylphényl)-cyclopropyl]-propionylamino -phtalide et de la 6- 2-hydroxy-3-[1-(3-trifluoromethylphenyl)-cyclopropyl]-propionylamino -4-methyl-2,3-benzoxazin-1-one avec une activité modulante du recepteur de la progesterone pour l'utilisation dans la contraception , la therapie du remplacement hormonell et le traitement des troubles gynécologiques
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
WO2005003098A1 (fr) * 2003-07-01 2005-01-13 Schering Aktiengesellschaft Derives de pentanol substitues par un heterocycle, procede de production de ces composes et leur utilisation comme agents anti-inflammatoires
WO2006108699A1 (fr) * 2005-04-14 2006-10-19 Glaxo Group Limited Indazoles en tant que ligands de recepteur glucocorticoide
WO2006136461A2 (fr) * 2005-06-24 2006-12-28 Bayer Schering Pharma Aktiengesellschaft Procede de fabrication de vaccins viraux dans des lignees de cellules souches embryonnaires aviaires derivees en suspension
WO2006136462A1 (fr) * 2005-06-24 2006-12-28 Bayer Schering Pharma Aktiengesellschaft Derives de benzofuranone utilises en tant que modulateurs non steroidiens du recepteur de la progesterone
WO2007022824A1 (fr) * 2005-06-24 2007-03-01 Bayer Schering Pharma Aktiengesellschaft Utilisation de modulateurs du recepteur de progesterone non-stedoidique

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
A. R. GRAHAM ET AL.: "Oxidation products of diisobutylene. III. Products from ring opening of 1,2-epoxy-2,4,4-trimethylpentane" JOURNAL OF THE CHEMICAL SOCIETY, 1954, Seiten 2190-2200, XP009103786 *
H. SCHÄCKE ET AL.: "Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, Bd. 101, Nr. 1, 6. Januar 2004 (2004-01-06), Seiten 227-232, XP002489998 *
H. TUCKER ET AL.: "Nonsteroidal Antiandrogens. Synthesis and structure-activity relationships of 3-substituted derivatives of 2-hydroxypropionanilides" J. MED. CHEM., Bd. 31, Nr. 5, 1988, Seiten 954-959, XP002489997 *
I. A. SHNYP ET AL.: "Epoxy compounds. XXXVII. Reaction of mono- and diepoxy alcohols with nitrogen-containing substances" VESTSI AKADEMII NAVUK BSSR, SERYYA KHIMICHNYKH NAVUK, Nr. 3, 1973, Seiten 107-112, XP009103781 *
R. BETAGERI ET AL.: "Trifluoromethyl group as a pharmacophore: Effect of replacing a CF(3) group on binding and agonist activity of a glucocorticoid receptor ligand" BIOORG. MED. CHEM. LETT., Bd. 15, 19. August 2005 (2005-08-19), Seiten 4761-4769, XP002489996 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103288669A (zh) * 2013-07-01 2013-09-11 南开大学 一种阿卓乳酸酰胺衍生物及应用
CN103288669B (zh) * 2013-07-01 2015-06-24 南开大学 一种阿卓乳酸酰胺衍生物及应用

Also Published As

Publication number Publication date
AR064478A1 (es) 2009-04-01
PE20081397A1 (es) 2008-12-05
WO2008077647A3 (fr) 2008-10-16
UY30805A1 (es) 2008-07-31
TW200835498A (en) 2008-09-01

Similar Documents

Publication Publication Date Title
EP0648778B1 (fr) 4 Dérivés 11-benzaldoximes de estradiene, un procédé pour leur préparation et les compositions pharmaceutiques les contenant
DE19723722A1 (de) Nichtsteroidale Gestagene
WO1998016507A2 (fr) Nouveaux derives de pyrazol heterocyclylmethyle-substitues
DE102011083725A1 (de) Estra-1,3,5(10),16-tetraen-3-carboxamid-Derivate, Verfahren zu ihrer Herstellung, pharmazeutische Präparate die diese enthalten, sowie deren Verwendung zur Herstellung von Arzneimitteln
DE4332284C2 (de) 11-Benzaldoxim-17beta-methoxy-17alpha-methoxymethyl-estradien-Derivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
WO2011098437A2 (fr) Antagonistes du récepteur de la progestérone
WO2011098436A2 (fr) Antagonistes du récepteur de la progestérone
US20060194827A1 (en) 5-Cycloalkenyl 5H-chromeno[3,4-f]quinoline derivatives as selective progesterone receptor modulator compounds
EP2456780A2 (fr) Dérivés 17-hydroxy-17-pentafluoroéthyl-estra-4,9(10)-diène-11-aryle, procédés de préparation et utilisation pour le traitement de maladies
DE102005030294A1 (de) Nichtsteroidale Progesteronrezeptor-Modulatoren
EP1060187A1 (fr) Thiolesters d'acide 11beta-benzaldoxim-estra-4,9-diene-carbonique a substitution s, leur procede de production et preparations pharmaceutiques contenant ces composes
WO2013033250A1 (fr) Entités chimiques particulières, compositions et méthodes
DE102005030292A1 (de) Nichtsteroidale Progesteronrezeptor-Modulatoren
EP1599493A1 (fr) Sulfamate estra-1,3,5(10)-triene-3-yle 2-substitue a effet antitumeur
WO2008077647A2 (fr) Modulateurs de récepteurs de progestérone non-stéroïdiens
DE102006061913A1 (de) Nichtsteroidale Progesteronrezeptor-Modulatoren
DE102007023614A1 (de) Nichtsteroidale Progesteronrezeptor-Modulatoren
DE60031557T2 (de) Steroide, ihre herstellung , pharmazeutische zusammensetzungen mit ihnen und verwendungen dieser verbindungen
AU774472B2 (en) 11beta-aryl-17,17-spirothiolane-substituted steroids
WO2008077646A1 (fr) Modulateurs de récepteurs de progestérone non-stéroïdiens
EP2070909A1 (fr) Modulateurs de récepteur de progestérone non stéroïdiens
DE102007032800A1 (de) Nichtsteroidale Progesteronrezeptor-Modulatoren
DE102007058747A1 (de) Nichtsteroidale Progesteronrezeptor-Modulatoren
DE102007049630A1 (de) Nichtsteroidale Progesteronrezeptor-Modulatoren
WO2004074309A1 (fr) Sulfamates d-homoestra-1,3,5(10)-triene-3-yle 2-substitues a effet antitumeur

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07857177

Country of ref document: EP

Kind code of ref document: A2

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07857177

Country of ref document: EP

Kind code of ref document: A2