EP1928894A1 - Novel c18 modified retrosteroids as progesterone receptor modulator compounds - Google Patents

Novel c18 modified retrosteroids as progesterone receptor modulator compounds

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Publication number
EP1928894A1
EP1928894A1 EP06806867A EP06806867A EP1928894A1 EP 1928894 A1 EP1928894 A1 EP 1928894A1 EP 06806867 A EP06806867 A EP 06806867A EP 06806867 A EP06806867 A EP 06806867A EP 1928894 A1 EP1928894 A1 EP 1928894A1
Authority
EP
European Patent Office
Prior art keywords
ethyl
pregna
dione
group
phenyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP06806867A
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German (de)
English (en)
French (fr)
Inventor
Josef Messinger
Heinrich-Hubert Thole
Bettina Husen
Christiane Boecker
Maria Hinaje
Monika Buchholz
Christoph Mark
Vibhuti Klinger-Dabral
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Products GmbH
Original Assignee
Solvay Pharmaceuticals GmbH
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Filing date
Publication date
Application filed by Solvay Pharmaceuticals GmbH filed Critical Solvay Pharmaceuticals GmbH
Priority to EP06806867A priority Critical patent/EP1928894A1/en
Publication of EP1928894A1 publication Critical patent/EP1928894A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J15/00—Stereochemically pure steroids containing carbon, hydrogen, halogen or oxygen having a partially or totally inverted skeleton, e.g. retrosteroids, L-isomers
    • C07J15/005—Retrosteroids (9 beta 10 alfa)
    • 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
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • 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
    • 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
    • A61P5/36—Antigestagens

Definitions

  • the present invention relates to novel retrosteroidal derivatives that may be modulators (i.e., agonists, partial agonists and antagonists) of progesterone receptors, to their salts, to pharmaceutical preparations containing these compounds, to processes for the preparation of these compounds, and to uses of said compounds.
  • the invention relates to the use of a compound disclosed herein for the manufacture of a medicament giving a beneficial effect, whereby a beneficial effect is disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art.
  • the invention also relates to the use of a compound of the invention for the manufacture of a medicament for treating or preventing a disease or condition.
  • the invention relates to a new use for the treatment of a disease or condition disclosed herein or ap- parent to a person skilled in the art from the specification and general knowledge in the art.
  • specific compounds disclosed herein are used for the manufacture of a medicament useful in the treatment of disorders or conditions mediated by progesterone receptors, or of disorders or conditions that can be treated via modulation of those receptors.
  • the invention concerns the therapeutic use of said novel retrosteroidal derivatives in the treatment or prevention of benign gynecological disorders, especially endometriosis, uterine fibroids, and dysfunctional uterine bleeding, in hormonal female contraception or in hormone replacement therapy.
  • Progesterone and the Progesterone Receptor Progesterone is secreted in large amounts from the ovary or the placenta during the cycle and in pregnancy.
  • progesterone produces cyclic changes of the mucous membrane of the uterus in the menstrual cycle.
  • progesterone controls the relaxation of the myometrium and preserves the function of the decidual tissue.
  • the mucous membrane of the uterus is converted into a state that allows the nidation of an embryo (blastocyst).
  • progesterone is involved in the control of ovulation processes.
  • progesterone has anti-ovulatory properties in connection with estrogens.
  • the latter finding results from an inhibition of the hypophyseal gonadotropin secretion, which is a requirement for the maturation of a follicle and its ovulation.
  • hypophyseal mechanisms time-limited so-called positive feedback of progesterone on gonadotropin secretion
  • progesterone exerts a decisive influence on the endometrium. The endometrial proliferation is inhibited by the suppression of the estrogen-mediated mitosis in the uterus tissue.
  • progesterone receptor (PR) modulators comprise compounds which may be agonists showing high affinity and/or high specificity, partial agonists (i.e., partial activators and/or tissue-specific activators) and/or antagonists for PRs, whereby the term PR always comprises the progesterone receptor alpha (PRa) and/or the progesterone receptor beta (PR ⁇ ) isoforms.
  • PRa progesterone receptor alpha
  • PR ⁇ progesterone receptor beta
  • the (selective) PR modulators - usually called SPRMs - possess both agonistic and antagonistic activities at the PR measured in-vitro, e.g. using assays of progesterone dependent enzymes in PR expressing cell lines, and/or determined in vivo, e.g. using the classical bioassay, the McPhail test, which assesses progestagenic and antipro- gestagenic effects in rabbits [McPhail, 1934].
  • AP assay a progesterone-dependent endogenous alkaline phosphatase (AP) expression assay
  • mesoprogestins show high binding affinity to PR, but exhibit different pharmacodynamic properties compared to either pure progestins or antiprogestins.
  • Mesoprogestins possess progesterone agonistic activity which can be measured in vitro or in commonly used biological tests in vivo; however, this activity remains below that of natural progesterone in the plateau of the dose response curve. Accordingly, mesoprogestins stabilize the function of the PR at an intermediate activity level providing the rationale for the different clinical applications in gynecological therapy.
  • the capacity of mesoprogestins to antagonize progesterone function can also be tested in the McPhail test using a progesterone dose which induces a McPhail score ranging between 3 and 4.
  • a SPRM inhibits the effect of progesterone to a significant degree, but the maximum inhibition is below that which is inducible with RU 486 or other pure antiprogestins, such as onapristone.
  • PR modulators have been widely used in regulation of female reproduction systems and in treatment of female hormone dependent diseases (e.g. reviewed in Spitz [2003, Steroids].
  • benign gynecological pathologies such as endometriosis, uterine leiomyomas (uterine fibroids or myomas), adenomyosis, dysfunctional uterine bleeding (menorrhagia and metrorrhagia) and dys- menorrhoea can be treated by the administration of PR modulators.
  • SPRMs may also be useful for the treatment of endometrial hyperplasia, meningiomas, hormone-dependent cancers such as ovarian cancer, breast cancer, endometrial cancer and prostate cancer and female osteoporosis.
  • SPRMs can also be used for female hormone replacement therapy, i.e. for the treatment of hormonal disorders in postmenopausal women such as e.g. hot flushes and/or mood disorders.
  • SPRMs can be used in female contraceptives.
  • Endometriosis is a well-known gynaecological disorder that affects 10 to 15% of women in the reproductive age. It is a benign disease defined as the presence of viable endometrial gland and stroma cells outside the uterine cavity. It is most frequently found in the pelvic area. In women de- veloping endometriosis, the endometrial cells entering the peritoneal cavity by retrograde menstruation (the most likely mechanism) have the capacity to adhere to and invade the peritoneal lining, and are then able to implant and grow. The implants respond to steroid hormones of the menstrual cycle in a similar way as the endometrium in the uterus.
  • the infiltrating lesions and the blood from these lesions which are unable to leave the body cause inflammation of the surrounding tissue.
  • the most common symptoms of endometriosis are primary or acquired dysmenorrhoea, dyspareunia and (chronic) pelvic pain, especially before and in the menstruation period. Further symptoms could include dysuria, various genitourinary symptoms secondary to urethral obstruction and/or bladder invasion, painful defecation, rectal pressure, defecation urgency and bowel obstruction, bleeding abnormalities, including menorrhagia or metrorrhagia, infertility, primary or secon- dary, recurrent spontaneous abortions. The occurrence of these symptoms is not related to the extent of the lesions.
  • Endometriosis is classified according to the 4 stages set up by the American Fertility Society (AFS). Stage I corresponds to minimal disease while stage IV is severe, depending on the location and the extent of the endometriosis. Endometriosis is found in up to 50% of the women with infertility. However, currently no causal relation has been proven between mild endometriosis and infertility. Moderate to severe endometriosis can cause tubal damage and adhesions leading to infertility.
  • the aims of treatment of endometriosis are pain relief, resolution of the endometriotic tissue and restoration of fertility (if desired). The two common treatments are surgery or anti-inflammatory and/or hormonal therapy or a combination thereof.
  • Uterine leiomyomas fibroids or myomas
  • myomas benign clonal tumours
  • They are clinically apparent in up to 25% of women and are the single most common indication for hysterectomy. They cause significant morbidity, including prolonged and heavy menstrual bleeding, pelvic pressure and pain, urinary problems, and, in rare cases, reproductive dysfunction.
  • the pathophysiology of myomas is not well understood. Myomas are found submucosally (beneath the endometrium), intramurally (within the myometrium) and subserosally (projecting out of the serosal compartment of the uterus), but mostly are mixed forms of these 3 different types.
  • Dysfunctional uterine bleeding disorders are forms of pathological bleeding that are not attributable to organic changes in the uterus (such as, e.g., endometrial carcinoma, myomas, polyps, etc.), systemic coagulation disorders, or a pathological pregnancy (e.g., ectopic pregnancy, impending abortion) [American College of Obstetricians and Gynecologists, 1982].
  • the average blood loss during normal menstruation is about 30 ml, whereby the period lasts for an average of 5 days. If the blood loss exceeds 80 ml, it is classified as pathological [Zahradnik, 1992].
  • Metrorrhagias are defined as bleeding that may or may not be accompanied by pain and that cannot be linked to menstruation or cycle. If it lasts over 7 days, the blood loss often exceeds 80 ml. Menorrhagia is menstruation that may or may not be accompanied by pain, normally every 27-28 days, which, when it lasts over 7 days, is associated in most cases with an increased blood loss of over 80 ml. Menorrhagia is a syndrome of unknown origin and one of the most common problems in gynecology. 60% of women refereed with menorrhagia have a hysterectomy within five years.
  • Hypermenorrhea is defined as menstruation that may or may not be accompanied by pain, normally every 27-28 days for 4-5 days with an elevated blood loss of over 80 ml, sometimes even defined as associated with an increased blood loss of over 150 ml.
  • Forms of dysfunctional uterine bleeding (mainly metrorrhagias and me- norrhagias) are typical of adolescence and of the time of menopause, in which follicle-stimulating disorders, anovulation, and yellow-body and follicle persistence occur in clusters.
  • the incidence of dysfunctional uterine bleeding is high and represents one of the most frequent reasons for gynecological consultation for women of reproductive age.
  • the consultation rate because of dysfunctional uterine bleeding is 33% in reproductive age and 69% in perimenopause and postmenopause [Mencaglia et al. 1987].
  • This compound belongs to the class of 11 beta-benzaldoxime-substituted estratrienes that exhibit partial progesterone agonist/antagonist effects with high PR specificity in animals and humans [Schubert et al., 2005]. Asoprisnil (J867) has been described to be under development for the potential oral treatment of uterine fibroids and endometriosis.
  • the 11 ⁇ -benzaldoxime-substituted estratrienes having the general structure shown below, in which R can be a hydrogen atom or an alkyl group and R1 can be a hydrogen atom, an alkyl group or aryl group or an optionally substituted acyl function, are known as PR modulators from EP 1229906 and EP 0648778:
  • WO 99/45023 relates to S-substituted 11 ⁇ -benzaldoxim-estra-4,9-diene-carboxylic acid-thiol ester.
  • the compounds have antigestagenic properties while at the same time having an antigluocorti- coidal action that is significantly more reduced in comparison to that of RU 486.
  • WO 01/44267 describes new 11 ⁇ -phenylestradiene derivatives with fluoroalkyl groups in the aromatic side chain and production thereof.
  • the compounds or the pharmaceutical preparations that contain these compounds are antihormonally effective and are therefore suitable for the treatment of diseases that are unfavorably influenced by Cortisol or by corticoids, for the reduction of secreted Cortisol, for stimulation of lactation, for treating dysmenorrhea and myomas, for treating Cushing's disease and for cervical maturation, for improving cognitive performance, for treating endometriosis or for hormone replacement therapy (HRT).
  • Cortisol or by corticoids for the reduction of secreted Cortisol, for stimulation of lactation, for treating dysmenorrhea and myomas, for treating Cushing's disease and for cervical maturation, for improving cognitive performance, for treating endometriosis or for hormone replacement therapy (HRT).
  • HRT hormone replacement therapy
  • WO 03/093292 discloses 17 ⁇ -fluoroalkyl-11 ⁇ -benzaldoxime-steroids and production thereof, pharmaceutical preparations that contain these steroids, especially for postmenopausal substitution therapy of gynecological diseases, such as hysteromyomas or dysmenorrhoic symptoms.
  • WO 04/014935 describes further substituted 11 ⁇ -benzaldoxime-steroids, in particular 4-(3-oxo- estra-4,9-dien-11 beta-yl)-benzaldehyde oximes, which are PR modulators useful in female contraception, hormone replacement therapy and treatment of gynecological disorders.
  • WO 99/62928 discloses 17 ⁇ -amino- and 17 ⁇ - hydroxylamino-11 ⁇ -arylsteroids
  • WO 99/62929 discloses 17 ⁇ -nitro-11 ⁇ -aryl-steroids
  • WO 99/45022 discloses 20-keto-11 ⁇ -arylsteroids having agonist or antagonist hormonal properties.
  • steroidal SPRMs The effectiveness of known steroidal SPRMs is often tempered by their undesired side-effect profile, particularly during long-term administration.
  • synthetic pro- gestins such as Norgestrel
  • the progesterone antagonist, mifepristone if administered for chronic indications, such as uterine fibroids, endometriosis and certain hormone-dependent cancers, could lead to homeostatic imbalances in a patient due to its inherent cross-reactivity as a glucocorticoid receptor (GR) antagonist.
  • GR glucocorticoid receptor
  • identification of compounds which have good receptor-selectivity for the PR over other steroid hormone receptors which provide a good tissue-selectivity (e.g. selectivity for uterine tissue over breast tissue) and which are agonists, partial agonists (i.e., partial activators and/or tissue-specific activators) and/or antagonists for PRs, which preferably show a balanced agonistic / antagonistic profile, would be of significant value in the improvement of women's health.
  • Retrosteroids i.e. steroids with 9 ⁇ ,10 ⁇ conformation
  • the commercially available compound Dydrogesterone ((9 ⁇ ,10 ⁇ )-Pregna-4,6-diene-3,20-dione) of the following formula
  • Dydrogesterone is an orally active progestative hormone and is generally used to correct deficiencies of progesterone in the body.
  • the synthesis of Dydrogesterone by irradiation and photochemical reaction is for example described within European patents EP0152138B1 (US 4,601 ,855) and EP0558119B1 (US 5,304,291 ).
  • retrosteroids with progestational activity are for example 1 ,2-methylene-3-keto- ⁇ 4 ' 6 - bisdehydro-6-halo-9 ⁇ ,10 ⁇ -steroids as disclosed within US 3,937,700 and 3-keto- ⁇ 4 ' 6 -bisdehydro-6- halo-9 ⁇ ,10 ⁇ -steroids as described within BE 652,597 and US 3,304,314.
  • the patent application US 3,555,053 describes a process for the preparation of 6-halo- or 6-alkyl-9 ⁇ ,10 ⁇ - steroids. Some 6,7-dehydro-9 ⁇ ,10 ⁇ steroids are described by Westerhof & Hartog [1965]. The synthesis of further retrosteroids is disclosed within Hartog et al.
  • the goal of the present invention was to develop novel PR modulators based on the retrosteroidal core of the known progesterone agonist Dydrogesterone.
  • Another object of the present invention was to develop compounds that combine the known beneficial properties of Dydrogesterone with novel modifications of the retrosteroidal core in order to obtain PR modulators, i.e. compounds with agonistic as well as antagonistic properties towards the PR, suited for the treatment of a broad range of gynaecological diseases requiring the modulation of the PR.
  • the compounds of the invention represent PR modulators possessing agonistic and/or antagonistic activities at the PR in vivo. Accordingly, the present invention relates to compounds of general formula (I):
  • R1 is selected from the group consisting of hydrogen, -OH, -O-(Ci-C 4 )alkyl, -0-CO-(Ci-
  • R2 and R3 are both hydrogen or together form a methylen group
  • any aryl is optionally substituted by two groups attached to adjacent carbon atoms and combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8-membered ring system, optionally containing 1 , 2 or 3 heteroatoms selected from the group consisting of N, O and S, the number of N atoms being 0, 1 , 2 or 3 and the number of O and S atoms each being 0, 1 or 2;
  • R 6 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently selected from the group consisting of hydrogen, -(C- ⁇ -C 4 )alkyl, and halogenated -(Ci-C 4 )alkyl; or
  • R and R together with the nitrogen atom to which R and R are attached, form a heterocyclic A-, 5-, 6-, 7- or 8-membered ring system, which is saturated, partly unsaturated or aromatic; and which optionally contains 1 , 2 or 3 additional heteroatoms selected from the group consisting of N, O and S, the number of additional N atoms being 0, 1 , 2 or 3 and the number of O and S atoms each being 0, 1 or 2; and which ring is optionally part of a multiple condensed ring-system
  • R1 through R14 all have the same definitions as given above.
  • the present invention comprises compounds including those represented by general formulae (III)
  • R1 is selected from the group consisting of hydrogen, -OH, -O-(Ci-C 4 )alkyl, -0-CO-(C 1 - C 4 )alkyl, and -O-CO-O-(d-C 4 )alkyl;
  • R2 and R3 both are hydrogen or together form a methylen group;
  • R5 is selected from the group consisting of
  • R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently selected from the group consisting of hydrogen, -(C- ⁇ -C 4 )alkyl and halogenated -(d-C 4 )alkyl; or
  • R and R together with the nitrogen atom to which R and R are attached, form a heterocyclic A-, 5-, 6-, 7- or 8-membered ring system, which is saturated, partly unsaturated, or aromatic; and which optionally contains 1 , 2 or 3 additional heteroatoms selected from the group consisting of N, O and S, the number of additional N atoms being 0, 1 , 2 or 3 and the number of O and S atoms each being 0, 1 or 2; and which ring is optionally part of a multiple condensed ring-system.
  • Compounds of the invention include those represented by general formulae (IV)
  • R1 through R14 all have the same definitions as given above for compounds of general formula (III) and general formula (V).
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmacologically active amount of at least one compound of the invention according to any one of formulae I through Vl shown above wherein R1 through R14, and n all have the same definitions as given above, or a salt or pro-drug thereof, as an active ingredient and at least one pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance.
  • the invention relates to a compound of the invention or a salt or pro-drug thereof, for use as a medicament.
  • the invention relates to the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disorder or condition mediated by a PR, or that can be treated via modulation of that receptor.
  • the invention relates to the use of an effective amount of a compound of the invention for the treatment or prevention of a disorder or condition mediated by a PR, or that can be treated via manipulation of that receptor, in an individual, preferably in a mammal, in particular a human.
  • the disorder or condition mediated by a PR is selected from: endometriosis, uterine fibroids, uterine leiomyoma, endometrial hyperplasia, dysmenorrhea, dysfunctional uterine bleeding, menorrhagia, metrorrhagia, hypermenor- rhea, hot flushes, mood disorders, meningiomas, hormone-dependent cancer, in particular female sex steroid dependent cancer, ovarian cancer, breast cancer, endometrial cancer and prostate cancer; female osteoporosis, Cushing's syndrome, major depression, neurodegenerative diseases, Alzheimer's disease, and demyelinating diseases.
  • the present invention relates to the use of a compound of the invention for the manufacture of a medicament for female birth control, for modulation of fertility or for female hormone replacement therapy (the treatment of hormonal disorders in postmenopausal women).
  • the compounds of the present invention can be used in a wide variety of combination therapies to treat the conditions and diseases described above.
  • the compounds of the present invention can be used in combination with other hormones, in particular estrogenic compounds and estrogen receptor modulators, and other therapies, including, without limitation, chemotherapeutic agents such as cytostatic and cytotoxic agents, immunological modifiers such as interferons, interleukins, growth hormones and other cytokines, hormone therapies, surgery and radiation therapy.
  • the pharmaceutical composition of the invention further comprises at least one low- dose natural or synthetic estrogen or pro-drugpro-drugs thereof; preferably the estrogen is used as a natural estrogen, e.g. as a conjugated estrogen obtained from pregnant mare's urine (conjugated equine estrogen). Alternatively, the estrogen may be presented as the respective 3-sulfamate.
  • the estrogen is used as a natural estrogen, e.g. as a conjugated estrogen obtained from pregnant mare's urine (conjugated equine estrogen).
  • the estrogen may be presented as the respective 3-sulfamate.
  • the pharmaceutical composition of the present invention is in the form of an intrauterine device (IUD), in the form of a transdermal patch or a gel.
  • IUD intrauterine device
  • the invention also relates to a method of treating an individual, i.e. a mammal such as a human, having a condition mediated by a PR or which condition can be treated via modulation of that receptor, comprising administering to said individual an amount of a compound of this invention, or a salt or a pro-drug thereof, which amount is effective to treat the condition.
  • Administration of compounds of this invention in combination with other pharmaceuticals used in treatment of the listed conditions is contemplated.
  • the conditions to be treated include but are not limited to endometriosis, uterine fibroids, uterine leiomyoma, endometrial hyperplasia, dysmenorrhea, dysfunctional uterine bleeding, menorrhagia, metrorrhagia, hypermenorrhea, hot flushes, mood disorders, meningiomas, hormone-dependent cancers, in particular female sex steroid dependent cancer, ovarian cancer, breast cancer, endometrial cancer and prostate cancer; female osteoporosis, Cushing's syndrome, major depression, neurodegenerative diseases, Alzheimer's disease, and demyelinating diseases. Additionally, the conditions to be treated may be alleviated with female hormone replacement therapy.
  • the present invention relates to a method of modulating fertility (e. g., use of the compounds of the invention as contraceptive agents, contragestational agents or abortifacients, for in vitro fertilization, and for pregnancy maintenance) in an individual comprising administering to said individual a pharmaceutically effective amount of a compound of this invention, or a salt or a pro-drug thereof.
  • the present invention provides a method of contraception to an individual comprising administering to said individual a pharmaceutically effective amount of a compound of this invention, or a salt or a pro-drug thereof.
  • the compounds of the present invention may be used in combination or conjunction with one or more estrogenic compounds or estrogen receptor modulators, in particular for female hormone replacement therapy, as modulators of fertility and in treatment of female osteoporosis.
  • a method is disclosed of modulating a PR in an indi- vidual comprising administering to said individual a compound of this invention, or a salt or a prodrug thereof, in an amount effective to modulate a PR.
  • said modulation is activation.
  • the compounds of this invention also have utility when e.g. radio- or isotopically labelled as ligands for use in assays to determine the presence of PR in a cell background or extract. They are particularly useful due to their ability to selectively activate PRs, and can therefore be used to determine the presence of such receptors in the presence of other steroid receptors or related intracellular receptors.
  • the present invention also relates to a method of determining the presence of a progesterone receptor (PR) in a cell or cell extract comprising (a) labeling a compound of this invention, or a salt or a pro-drug thereof; (b) contacting the cell or cell extract with said labeled compound; and (c) testing the contracted cell or cell extract to determine the presence of progesterone receptor.
  • PR progesterone receptor
  • compound shall here be understood to cover any and all isomers (e. g., enantiomers, stereoisomers, diastereomers, rotomers, tautomers) or any mixture of isomers, pro-drugs, and any pharmaceutically acceptable salt of said compound, unless the formula depicting the compound explicitly shows a particular stereochemistry.
  • pro-drug represents derivatives of the compounds of the invention that are drug precursors which, following administration to a patient by any known route, release the more active metabolite drug in vivo via a chemical or physiological process.
  • Pro-drugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the par- ent drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism and targeting limitations (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F. D. King, p. 215; J. Stella, "Pro-drugs as therapeutics", Expert Opin. Ther. Patents, 14(3), 277-280, 2004; P.
  • pro-drugs are deriva- tives of the compounds of the invention in which functional groups carry additional substituents which may be cleaved under physiological conditions in vivo and thereby releasing the active principle of the compound (e. g., a pro-drug on being brought to a physiological pH or through an enzyme action is converted to the desired drug form).
  • Pro-drugs of the compounds mentioned above are also within the scope of the present invention.
  • Pro-drugs that are metabolised to compounds having formula (I) belong to the invention. In particular this relates to compounds with primary or secondary amino or hydroxy groups.
  • Such compounds can be reacted with organic acids to yield compounds having formula (I) wherein an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl- methylene derivative, an O-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.
  • an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl- methylene derivative, an O-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.
  • any of the compounds of the present invention can be synthesized as pharmaceutically acceptable salts for incorporation into various pharmaceutical compositions.
  • pharmaceutically acceptable salts refers to salt forms that are pharmacologically acceptable and substantially non- toxic to the subject being administered the compounds of the invention.
  • Pharmaceutically acceptable salts of compounds of one of the formulae I through Vl include conventional and stoichiometrical acid-addition salts or base-addition salts formed from suitable non-toxic organic or inorganic acids or inorganic bases. Acid addition salts, for example, from compounds of the invention with a basic nitrogen atom are formed preferably with organic or inorganic acids.
  • Suitable inorganic acids include, but are not limited to halogenic acids such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids include, but are not limited to carboxylic, phosphonic, or sulfonic acids, for example acetic acid, propionic acid, glycolic acid, lactic acid, hydroxybutyric acid, malic acid, malei(ni)c acid, malonic acid, nicotinic acid, salicylic acid, fumaric acid, succinic acid, oxalic acid, phenylacetic acid, stearic acid, adipic acid, tartaric acid, citric acid, glutaric acid, 2- or 3-glycerophosphoric acid and other mineral and carboxylic acids well known to those skilled in the art.
  • the salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • Compounds of the invention containing acidic substituents may also form salts with inorganic or organic bases.
  • suitable bases for salt formation include, but are not limited to, inorganic bases such as alkali or alkaline earth-metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides, and those derived from ammonium hydroxides (e.g., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide).
  • salts formed with pharmaceutical acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine, benzylamines, piperidines, pyridines, piperazines, and pyrrolidines and the like.
  • Certain compounds will be acidic in nature, e. g. those compounds which possess a carboxyl or phenolic hydroxyl group. Salts of phenols can be made by heating acidic compounds with any of the above mentioned bases according to procedures well known to those skilled in the art.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • an effective amount means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e. g., provide a positive clinical response).
  • the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
  • progesterone receptor plays a role.
  • Progesterone receptors are known to play a role in conditions including, for example, infertility, contraception, pregnancy maintenance and termination, female hormone deficiency, dysfunctional uterine bleeding, endometriosis, mood disorder, osteoporosis, and hormone-dependent cancers.
  • progesterone receptor as used herein always comprises the progesterone receptor alpha (PRa) and/or the progesterone receptor beta (PR ⁇ ) isoforms. Like other steroid hormone receptors, PR is expressed in two isoforms in certain organisms, including humans.
  • Human PRa is a truncated form of human PR ⁇ and lacks 164 amino acids at the N-terminus. Both isoforms are identical in the DNA-binding and ligand-binding domain and induce progestin-mediated gene transcription, but show a somehow different transactivation behavior (see e.g. WO 02/054064).
  • selective and “selectivity” refer to compounds that display reactivity towards a particular receptor (e.g. a progesterone receptor) without displaying substantial cross-reactivity towards another receptor (e.g. glucocorticoid receptor, androgen receptor and/or estrogen receptor).
  • a particular receptor e.g. a progesterone receptor
  • selective compounds of the present invention may display reactivity towards progesterone receptors without displaying substantial cross-reactivity towards other steroid hormone receptors.
  • a compound of the present invention has at least about 10fold selectivity to the PR, at least about 50fold selectivity to the PR, at least about 10Ofold selectivity to the PR, at least about 250fold selectivity to the PR, or at least about 500fold selectivity to the desired target.
  • Any asymmetric carbon atoms may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration, whichever is most active, unless the stereochemistry is explicitly depicted in the corresponding compound formula.
  • the compounds of the invention have a defined stereochemistry within their steroidal core structure according to the commonly used definition of the configuration of retrosteroids (i.e. steroids with 9 ⁇ ,10 ⁇ conformation):
  • stereochemistry within the retrosteroidal core structure is always shown in the corresponding compound formula and should not vary within the scope of the present invention, whereas the stereochemistry at the carbon atoms in the steroidal core carrying additional side chains and the stereochemistry of any asymmetric carbon atom within the side chains themselves is not fixed. Therefore, the terms “compounds of formula (I)” or “compounds of formula (II)” etc also comprise the stereoisomers of the depicted compounds, unless a particular stereochemistry is explicitly shown within the formula. The stereochemistry shown in the respective formula prevails over the general term "stereoisomers".
  • the compounds of the present invention may contain further asymmetric centers on the molecule, e.g. a chiral carbon atom, depending upon the nature of the various substituents.
  • asymmetric centre the compounds could thus be present in two optically active stereoisomeric forms or as a racemate.
  • asymmetry may also be present due to restricted rotation about the central bond adjoining the two aromatic rings of the specified compounds.
  • substituted means that the specified group or moiety bears one or more substituents. Where any group may carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not to be the same.
  • unsubstituted means that the specified group bears no substituents.
  • optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents.
  • halogen refers to fluorine (F, Fluoro-), bromine (Br, Bromo-), chlorine (Cl, Chloro), and iodine (J, lodo-) atoms.
  • dihalogen trihalogen
  • perhalogen refer to two, three and four substituents, respectively, each individually selected from the group consisting of fluorine, bromine, chlorine, and iodine atoms.
  • hydroxyl refers to the group -OH
  • nitrile or "cyano” refers to the group -CN.
  • carbonyl refers to the group -CHO.
  • ketal refers to a ketalized oxo group resulting from the reaction between two molecules of a monohydroxy aliphatic alcohol containing from 1 to 6 carbon atoms (e.g. Methanol, isopropa- nol, trichloroethanol, etc) and one molecule of an oxo group containing steroid, or resulting from the reaction between one molecule of a dihydroxy aliphatic alcohol containing from 2 to 6 carbon atoms (e.g. ethyleneglycol, 1 ,3-propanediol, etc.) and one molecule of an oxo group containing steroid.
  • a monohydroxy aliphatic alcohol containing from 1 to 6 carbon atoms e.g. Methanol, isopropa- nol, trichloroethanol, etc
  • a dihydroxy aliphatic alcohol containing from 2 to 6 carbon atoms e.g. ethyleneglycol, 1 ,3-propanediol, etc.
  • the carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C-C j defines the number of carbon atoms present from the integer "i" to the integer "j" inclusive.
  • Ci-C 4 -alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof.
  • alkyl stands for a hydrocarbon radical which may be linear, cyclic or branched, with single or multiple branching, whereby the alkyl group in general comprises 1 to 12 carbon atoms.
  • alkyl stands for a linear or branched (with single or multiple branching) alkyl chain of 1 to 4 carbon atoms, exemplified by the term (Ci-C 4 )alkyl.
  • the term (Ci-C 4 )alkyl is further exemplified by such groups as methyl; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; isobutyl; and tert-butyl.
  • alkyl or (Ci-C 4 )alkyl group may be partially unsaturated, forming such groups as, for example, vinyl, 1-propenyl, 2-propenyl (allyl), and butenyl.
  • alkyl further comprises cycloalkyl groups, preferably cyclo(C 3 -C 4 )alkyl which refers to cyclopropyl or cyclobutyl, and isomeric forms thereof such as methylcyclopropyl.
  • the cycloalkyl group may also be partly unsatu- rated.
  • alkyl comprises a cycloalkyl-alkyl group comprising 4 to 12 carbon atoms, preferably "-(C-rC 4 )alkyl-cyclo(C 3 -C 8 )alkyr which refers to a alkyl group of 1 to 4 carbon atoms substituted with a cyclo(C 3 -C 8 )alkyl group. Therefore, the term (d-C 4 )alkyl also comprises a cyclopropylmethyl group.
  • methylene refers to -CH 2 - and may be optionally substituted.
  • Halogenated alkyl preferably halogenated (Ci-C 6 )alkyl
  • substituents in which the alkyl moieties (preferably (Ci-C 4 )alkyl, most preferred methyl) are substituted either partially or in full with halogens, generally with chlorine and/or fluorine.
  • Preferred examples of such substituents are trifluoro- methyl, dichloromethyl, pentafluoroethyl, dichloropropyl, fluoromethyl and difluoromethyl.
  • aryl refers to an aromatic carbocyclic group comprising 6 to 14, more preferably 6 to 10, carbon atoms and having at least one aromatic ring or multiple condensed rings in which at least one ring is aromatic.
  • aryl is phenyl, naphthyl, indanyl, indenyl, or 1 ,2,3,4- tetrahydro-naphthalen-1-yl; most preferred aryl is phenyl.
  • heteroaryl refers to an aromatic carbocydic group of having a single 4 to 8 membered ring or multiple condensed rings comprising 6 to 14, more preferably 6 to 10, ring atoms and containing at least one heteroatom selected from N, O and S, within at least one ring, the number of N atoms being 0, 1 , 2 or 3 and the number of O and S atoms each being 0 or 1 ; in which group at least one heterocyclic ring is aromatic.
  • Examples of such groups include pyrrolyl, thienyl, furyl, imi- dazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyri- dazinyl, indolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoimidazolyl, 1 ,3-dihydro- benzoimidazolyl, benzofuran, benzo[b]thiophene and the like.
  • heteroaryl is quinolinyl, furyl, benzoimidazolyl, pyridinyl, thienyl, indolyl, benzo[b]thiophene, pyridinyl, imidazolyl, pyrazolyl or thiazolyl.
  • Most preferred heteroaryl refers to furyl or pyridyl.
  • the aryl may be substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 membered ring system, optionally containing 1 , 2 or 3 heteroatoms selected from N, O or S, the number of N atoms being 0, 1 , 2 or 3 and the number of O and S atoms each being 0, 1 or 2.
  • the two groups which are attached to adjacent carbon atoms are combined into a saturated cyclic 5 or 6 membered ring system, optionally containing 1 , 2 or 3 heteroatoms selected from N and O, the number of N atoms being 0, 1 , 2 or-3 and the number of O atoms each being 0, 1 or 2.
  • This cyclic ring system may optionally be further substituted by an oxo group.
  • Preferred examples of such a substituted aryl groups are benzo[1 ,3]dioxol and 1 ,3-dihydro- benzoimidazol-2-one.
  • aryl-(C-rC 4 )alkyr refers to an (Ci-C 4 )alkyl group substituted with an aryl group, wherein the aryl is phenyl, naphthyl, indanyl, indenyl, or 1 ,2,3,4-tetrahydro-naphthalen-1-yl, preferably aryl is phenyl or naphthyl, forming such groups as for example benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl or naphthylethyl.
  • the alkyl chain may be partially unsaturated, such as a vinyl group.
  • the aryl moiety may optionally be substituted as defined herein.
  • heterocyclic ring system can be optionally substituted by 1 , 2 or 3 substitu- ents, which can be attached to any carbon or nitrogen atom of the heterocyclic ring system.
  • substitu- ents which can be attached to any carbon or nitrogen atom of the heterocyclic ring system.
  • substituted heterocyclic ring systems are:
  • the optional 1 , 2 or 3 independently selected substituents for the heterocyclic ring system may be chosen among -(d-C 4 )alkyl, halogenated -(Ci-C 4 )alkyl, halogen, hydroxyl, oxo, nitrile, aryl, aryl- (Ci-C 4 )alkyl- and heteroaryl.
  • the heterocyclic ring system is optionally substituted with one or two substituents independently selected from the group of hydroxyl, oxo, (Ci-C 4 )alkyl, aryl or aryl-(Ci-C 4 )alkyl.
  • Dydrogesterone - ((9 ⁇ ,10 ⁇ )-Pregna-4,6-diene-3,20-dione - has the following formula:
  • Retroprogesterone - ((9 ⁇ ,10 ⁇ )-Pregna-4-ene-3,20-dione - has the following formula:
  • the present invention relates to compounds of general formula (I)
  • R1 is selected from the group consisting of hydrogen, -OH, -O-(Ci-C 4 )alkyl, -0-CO-(Ci-
  • R2 and R3 are both hydrogen or together form a methylen group
  • R4 is selected from the group consisting of -O-R 6 , heteroaryl and aryl. wherein any aryl is optionally substituted with one or two substituents independently selected from the group consisting of
  • any aryl is optionally substituted by two groups attached to adjacent carbon atoms and combined into a saturated or partly unsaturated cyclic 5, 6 or 7-membered ring system, optionally containing 1 or 2 heteroatoms selected from N and O, the number of N atoms being O, 1 or 2 and the number of O atoms being O, 1 or 2;
  • R 6 , R 9 , R 11 , R 12 , R 13 and R 14 are independently selected from the group consisting of hydrogen, - (Ci-C 4 )alkyl, and halogenated -(Ci-C 4 )alkyl; or
  • R and R together with the nitrogen atom to which R and R are attached, form a heterocyclic A-, 5-, 6-, 7- or 8-membered ring system, which is saturated, partly unsaturated, or aromatic; and which optionally contains 1 , 2 or 3 additional heteroatoms selected from the group consisting of N, O or S, the number of additional N atoms being 0, 1 , 2 or 3 and the number of O and S atoms each being 0, 1 or 2; and which ring is optionally part of a multiple condensed ring-system.
  • R 12 and R 13 together with the nitrogen atom to which R 12 and R 13 are attached, form a heterocyclic 5-, 6- or 7-membered ring system, which is saturated or partly unsaturated; and which optionally contains 1 or 2 additional heteroatoms selected from the group consisting of N and O, the number of additional N atoms being 0, 1 or 2 and the number of O atoms being 0 or 1.
  • the substituent R1 of the compounds of formula (I) is selected from the group consisting of hydrogen and -O-CO-O-(Ci-C 4 )alkyl.
  • the invention preferably relates to compounds of general formula (I), wherein the substituents R2 and R3 both represent hydrogen.
  • R and R together with the nitrogen atom to which R and R are attached, form a saturated heterocyclic 5-, 6- or 7-membered ring system, which optionally contains 1 additional heteroatom selected from the group consisting of N and O.
  • the compounds of the present invention have the following general formula (II)
  • the present invention relates to compounds of the general formula (III)
  • R1 is selected from the group consisting of hydrogen and -O-CO-O-(Ci-C 4 )alkyl
  • R5 is selected from the group consisting of -CHO; -CO-O-R 9 , -CO-NR 12 R 13 , -CH 2 -O-R 9 ;
  • R 9 , R 12 , R 13 and R 14 are independently selected from the group consisting of hydrogen,
  • R and R together with the nitrogen atom, to which R and R are attached, form a heterocyclic 5-, 6- or 7-membered ring system, which is saturated or partly unsaturated; and which optionally contains 1 or 2 additional heteroatoms selected from N and O, the number of additional N atoms being 0, 1 or 2 and the number of O atoms being 0 or 1.
  • the compounds of the present invention have the following general formula (IV)
  • PR modulator compounds i.e., agonists, partial agonists and antagonists
  • Representative PR modulator compounds include:
  • the method of the invention is primarily intended for treatment in a mammal, preferably in humans and other primates, of diseases, disorders or conditions mediated by progesterone receptors, or of diseases, disorders or conditions that can be treated via modulation of those receptors.
  • the invention concerns the therapeutic use of said novel retrosteroidal derivatives in the treatment or prevention of benign gynecological disorders, especially endometriosis and uterine fibroids, in hormonal female contraception or in hormone replacement therapy.
  • the compounds may be administered orally, dermally, parenterally, by injection, by pulmonal or nasal delivery, or sublingually, or by topical administration, i.e. rectally, vaginally, or within the intrauterine cavity, in dosage unit formulations.
  • administered by injection includes intravenous, intraarticular, intramuscular (e.g. by depot injection where the active compounds are released slowly into the blood from the depot and carried from there to the target organs), intraperitoneal, intradermal, subcutaneous, and intrathecal injections, as well as use of infusion techniques.
  • Dermal administration may include topical application or transdermal administration.
  • One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable auxiliaries such as excipients, adjuvants (e.g. buffers), carriers, inert solid diluents, suspensing agents, preservatives, fillers, stabilizers, anti-oxidants, food additives, bioavailability enhancers, coating materials, granulating and disintegrating agents, binding agents etc., and, if desired, other active ingredients.
  • auxiliaries such as excipients, adjuvants (e.g. buffers), carriers, inert solid diluents, suspensing agents, preservatives, fillers, stabilizers, anti-oxidants, food additives, bioavailability enhancers, coating materials, granulating and disintegrating agents, binding agents etc., and, if desired, other active ingredients.
  • the pharmaceutical composition may be formulated for example as immediate release, sustained release, pulsatile release, two or more step release, depot or other kind of release formulations.
  • auxiliaries as well as further suitable diluents, flavorings, sweetening agents, coloring agents etc. may be used, depending on the intended mode of administration as well as particular characteristics of the active compound to be used, such as solubility, bioavailability etc.
  • Suitable auxiliaries and further ingredients may be such as recommended for pharmacy, cosmetics and related fields and which preferably are listed in the European Pharmacopoeia, FDA approved or cited in the "GRAS" list (FDA List of food additives that are 'generally recognized as safe' (GRAS)).
  • One mode of application of the compounds of general formula (I) or of pharmaceutical compositions comprising one or more of said compounds is oral application, e. g., by tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixiers, solid emulsions, solid dispersions or dispersible powders.
  • the compounds suitable for the purposes of the present invention as defined above can be admixed with commonly known and used adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e. g., mannitose, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or nonaqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents (e. g., ethereal oils), solubility enhancers (e.
  • adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e. g., mannitose, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or nonaqueous solvents, paraffin derivatives, cross-linking
  • the active ingredients may also be dispersed in a microparticle, e. g. a nanoparticulate, composition.
  • the active agents can be dissolved or suspended in a physiologically acceptable diluent, such as, e. g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers.
  • a physiologically acceptable diluent such as, e. g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers.
  • oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used.
  • the active agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano-suspensions.
  • Transdermal application can be accomplished by suitable patches, as generally known in the art, specifically designed for the transdermal delivery of active agents, optionally in the presence of specific permeability enhancers. Furthermore, also emulsions, ointments, pastes, creams or gels may be used for transdermal delivery.
  • intravaginal devices e. g. vaginal rings
  • IUS intrauterine systems
  • IUD intrauterine devices
  • compositions can be prepared by mixing the drug with a suitable non- irritating exdpient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug.
  • a further drug formulation is a formulation intended for the topical, local and/or regional administration of the compound to the reproductive organs, in particular to a body region selected from the group consisting of the uterus, fallopian tubes, peritoneal space, pelvic cul-de-sac, ovaries, and urinogenital tract, in amounts effective to treat various conditions, particularly local diseases of the female reproductive system, such as pelvic, uterine, cervical and vaginal diseases, as described e.g. within EP 0977555 A1 , US 5,993,856, US 6,652,874, or US 6,416,778.
  • the formulation comprises drug particles, preferably in the form of a micro- or nano-particles, suitable for regional administration of an effective amount of drug, wherein the effective amount is a dosage which results in low serum drug levels and reduced side effects as compared to systemic administration of the drug.
  • the formulation comprises a carrier promoting quick uptake of the drug into the blood stream, a carrier manipulating release of drug, or a carrier promoting adhesion of the drug selected from the group consisting of a liquid suspension or dispersion, a hydrogel suspension or dispersion, a topical ointment, a cream, a lotion, and a foam.
  • a depot implant comprising an inert carrier material, such as biologically degradable polymers or synthetic silicones such as e. g. silicone rubber.
  • an inert carrier material such as biologically degradable polymers or synthetic silicones such as e. g. silicone rubber.
  • Such implants are designed to release the active agent in a controlled manner over an extended period of time (e. g., 3 to 5 years).
  • the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the actual dosages of the agents of this invention for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the particular composition formulated, the mode of administration, time of administration, route of administration and the particular site, host, and disease being treated, and furthermore the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.
  • the optimal course of treatment i.e., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days
  • Optimal dosages for a given set of conditions may be ascertained by those skilled in the art using conventional dosage-determination tests in view of the experimental data for a given compound.
  • an exemplary daily dose generally employed will be from about 0.001 ⁇ g/kg to about 10 mg/kg of total body weight, whereby courses of treatment may be repeated at appropriate time intervals.
  • Administration of pro-drugs may be dosed at weight levels that are chemically equivalent to the weight levels of the fully active compounds.
  • the daily dosage for parenteral administration will generally be from about 0.001 ⁇ g/kg to about 10 mg/kg of total body weight.
  • a daily rectal dosage regimen will generally be from about 0.001 ⁇ g/kg to about 20 mg/kg of total body weight.
  • a daily vaginal dosage regimen will generally be from about 0.001 ⁇ g/kg to about 10 mg/kg of total body weight.
  • the daily topical dosage regimen will generally be from about 0.01 ⁇ g to about 10 mg administered between one to four times daily.
  • the transdermal concentration will generally be that required to maintain a daily dose of from 0.001 ⁇ g/kg to 10 mg/kg of total body weight.
  • the total dosage of administration forms releasing the drug compound over a prolonged period of time depends on the time of administration, on the kind of device (intravaginal devices, intrauterine systems, intrauterine devices, implants etc.) and on the kind of release behaviour of the particular device.
  • the daily released dose of active compound will be from about 0.001 ⁇ g/kg to about 1 mg/kg of total body weight. Since the devices often only need to achieve a certain local and/or regional concentration of active compound, the daily released dosage can be lower in comparison to e.g. oral administration.
  • the compounds of the present invention may be prepared from 9 ⁇ ,10 ⁇ -steroids by use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are presented to aid the reader in synthesizing the SPRM compounds of the present invention, with specific details provided below in the experimental section to illustrate working examples. All variable groups of these methods are as described in the generic description if they are not specifically defined below.
  • PG and PG* represent conventional protective groups for the keto function of the steroidal core (e.g. forming a dialkyl or a cyclic ketal derivative), can be performed according to the procedures disclosed in US patent No. 3,555,053 and as described by van Moorselaar and Halkes [1969], and as displayed in the following general SCHEME I.
  • Dydrogesterone (9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione), which is optionally substituted in the 1 ,2 position with a methylene group is used as starting material.
  • the introduction of the 1 ,2-methylene group might be performed according to the well known procedures as described by Halkes et al [1972] and within US patent No. 3,937,700 for 17 ⁇ -Hydroxy-9 ⁇ ,10 ⁇ -pregna- 4,6-diene-3,20-dione by dehydrogenation and subsequent reaction with Dimethylsulfoxonium me- thylide.
  • step a The optionally 1 ,2 methylene substituted 9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione of general formula IX is then converted to the corresponding 9 ⁇ ,10 ⁇ -pregna-4-ene-3,20-dione (9 ⁇ ,10 ⁇ - progesterone) of general formula X under reducing conditions (step a).
  • step b the compound of general formula X is reacted with HCN to produce the corresponding 20-cyano-20-hydroxy com- pound of formula Xl, followed by irradiation in the presence of iodine and lead-tetra-acetate to yield the 18-cyano derivative of the general formula XII (step c).
  • step d the two oxo- groups of said 18- cyano derivative are protected by ketalization, preferably with a dihydroxy alcohol, in the presence of a catalyst producing the 18-cyano-3,20-diketal derivative of general formula XIII (step d), which is then transformed into the corresponding ⁇ 5-18-cyano-3,20-ketalized dione of general formula XV by isomerization, partial deketalization and chromatographic separation of the resulting mixture of the ⁇ 5-diketal and the ⁇ 4-20-monoketal derivatives (steps e and f).
  • the ⁇ 5-18- cyano-3,20-diketal of general formula XV is treated with a reducing agent such as diisobutyl- aluminium-hydride (DIBAH) to gave an aldimine intermediate, which is hydrolyzed to the desired 18-formyl-(9 ⁇ ,10 ⁇ )-pregna-5-ene-3,20-diketal compound of general formula XVI (step g).
  • DIBAH diisobutyl- aluminium-hydride
  • step h The aim of the next reaction steps is the derivatisation of the formyl group in C18 position of the retrosteroidal core using a Wittig addition reaction (step h) as displayed in the following general SCHEME II:
  • PG and PG* represent conventional protection groups for the keto function of the steroidal core (e.g. forming a dialkyl or a cyclic ketal derivative), R 2 , R 3 have the aforesaid meanings, and wherein R 7 represents hydrogen or a heteroaryl or aryl residue.
  • the heteroaryl or aryl residue is optionally substituted in the heteroaryl or aryl group with one or two substituents independently selected from the group consisting of -CH 2 -O-PG ** ; -CH 2 -O-R 9 ', -CO-O-PG ** , -CO-O-R 9 ', - CO-NR 12 K 13 ', -CN, -halogen, -0-PG ** , -O-R 9 ', -N(PG ** ) 2 , -NPG ** R 10 , -NR 12 K 13 ', -(C 1 - C 4 )alkyl, and halogenated -(d-C 4 )alkyl, whereby PG** represents a conventional protection group for the hydroxyl or amine function, and whereby R 9 ', R 12 ' and R 13 ' represent -(Ci-C 4 )alkyl or halogenated -(C- ⁇ -C 4 )alkyl
  • the aryl moiety of R 7 is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 membered ring system, optionally containing 1 , 2 or 3 heteroatoms selected from N, O and S, the number of N atoms being 0, 1 , 2 or 3 and the number of O and S atoms each being 0, 1 or 2.
  • Suitable protective groups PG** or other protective groups mentioned in this application are known in the art and can routinely be selected by a person skilled in the art; more information on addition and subsequent removal of protective groups in organic synthesis can be found in: T.W. Greene & P. G. M. Wuts "Protective groups in Organic Synthesis” John Wiley & Sons, in its latest edition.
  • the corresponding Triphenylphosphonium halogenide salt (Ph 3 P-CH 2 -R 7 )Hal is commercially available or can be synthesized by methods known to the skilled artisan, e.g. starting from the corresponding commercially available halogenide derivative by reaction with Triphenylphosphine (TPP).
  • the halogenide derivative can be prepared from the corresponding hydroxyl derivative.
  • the freshly prepared Wittig reagent is then reacted with the carbonyl function of the 18-formyl-(9 ⁇ ,10 ⁇ )-pregna-5-ene-3,20-diketal of formula XVI to produce the corresponding unsaturated addition product of general formula XVII (step h).
  • R 7 represents hydrogen
  • PG and PG* represent conventional protective groups for the keto function of the steroidal core (e.g. forming a dialkyl or a cyclic ketal derivative), PG** represents a conventional protective group for the hydroxyl function (e.g. an acyl group), and R 2 , R 3 , and R 6 have the meanings given above.
  • step j the alcohol of general formula XVIII with R6 representin hydrogen is reacted with an appropriate (C- ⁇ -C 4 )-alkyl-halogenide to produce the corresponding 18-(2-Alkoxyethyl)-(9 ⁇ ,10 ⁇ )-pregna-5-ene-3,20-diketal of general formula XVIII.
  • step m delivers the corresponding (9 ⁇ ,10 ⁇ )-pregna-4,6-diene- 3,20-dione derivatives of general formula XXII, optionally after deprotection of the free hydroxyl group (step n).
  • R 7 represents optionally substituted aryl or heteroaryl Synthesis of compounds of general formula I wherein R 4 represents optionally substituted aryl or heteroaryl:
  • PG, PG* and R 7 have the same meaning as defined above in general SCHEME II, but R 7 cannot represent hydrogen.
  • the reduction is preferably carried out by catalytic hydrogenation (step o).
  • step p deketalization reaction
  • step q dehydrogenation
  • step p shows the transformation of general compound XXIII to compounds XXIV by deketalization (step p) and XXV by dehydrogenation (step q), which compounds correspond to desired compounds XXVI and XXVII, in case that R 7 already represents the desired residue R 4 or can be transformed into R 4 by one or more additional reaction steps.
  • R 2 , R 3 , PG, PG*, R 7 and R 4 have the meanings as given above.
  • R 7 already represents the desired residue R 4 or can be easily transformed into R 4 (i.e. when R 7 represents a heteroaryl or aryl residue, optionally substituted in the heteroaryl or aryl group with one or two substituents independently selected from the group consisting of -CH 2 -O- R 9' , -CO-O-R 9' , -CO-NR 12 R 13' , -CN, -halogen, -O-R 9' , -NR 12 R 13' , -(C 1 -C 4 )alkyl, and halo- genated -(d-C 4 )alkyl, whereby R 9 , R 12 and R 13 represent -(Ci-C 4 )alkyl or halogenated -(Ci- C 4 )alkyl, or R 12 and R 13 form together with the nitrogen atom, where they are attached, a heterocyclic A-, 5-, 6-, 7- or 8-membered ring system, which
  • R 7 represents a heteroaryl or aryl residue, optionally substituted in the heteroaryl or aryl group with one or two substituents independently selected from the group consisting -CH 2 -O- PG ** ; -CO-O-PG ** , -O-PG ** , -N(PG ** )R 10 , -N(PG ** ) 2 , or -CN, and whereby one substituent may also be selected from the group consisting of -CH 2 -O-R 9' , -CO-O-R 9' , -CO-NR 12 R 13' , - halogen, -O-R 9 , -NR 12 R 13 , -(d-C 4 )alkyl, and halogenated -(Ci-C 4 )alkyl, necessary modifica- tions of R 7 and its substituents in the aryl or heteroaryl moiety, respectively, typically start with a deprotection step by removing the PG**
  • optional further modifications include the reduction the cyano group to a -CH 2 -NH 2 substituent, using a conventional reducing agent such as lithium aluminium hydride in THF, sodium borohydride in an alcoholic solvent or by catalytic reduction with e.g. Raney Nickel.
  • a conventional reducing agent such as lithium aluminium hydride in THF, sodium borohydride in an alcoholic solvent or by catalytic reduction with e.g. Raney Nickel.
  • This modification step of the substituent in the aryl or heteroaryl moiety of R 7 results in derivatives of the compounds of general formula XXIII, XXIV or XXV carrying a modified R 7 -ethyl residue, called R 71 -ethyl residue, in the C18 position of the retrosteroidal core, or directly delivers com- pounds of general formula XXVIII, XXVI or XXVI in case that the modified R 7 residue (i.e. the R 71 residue) already represents the desired residue R 4 .
  • the modified residue R 71 preferably represents an aryl or heteroaryl group, optionally substituted with one or two substituents independently selected from the group consisting of -CH 2 -OH; -COOH, -OH, -NHR 10 , -NH 2 , and - CH 2 -NH 2 , and a substituent of the group as listed above for the residue R 7 .
  • step p the deketalization of the intermediate 18-(2-R 7/71/4 -substituted-ethyl)- (9 ⁇ ,10 ⁇ )-pregna-5-ene-3,20-diketal derivatives to produce the corresponding (9 ⁇ ,10 ⁇ )-pregna-4- ene-3,20-dione (step p), optionally followed or preceded by the dehydrogenation step q, to deliver the compounds of the invention of general formula XXVI and XXVII, respectively, may be carried out where it appears to be most appropriate.
  • R 71 might be necessary to obtain the desired compounds of general formula XXVI or XXVII, wherein R 4 represents optionally substituted aryl or heteroaryl as defined above, preferably an aryl or heteroaryl group substituted with one or two substituents independ- ently selected from the group consisting of: -CHO, -CH 2 -O-CO-R 11 , -CH 2 -O-CO-NHR 12 , -CO- O-R 9 , -CO-NR 12 R 13 , -0-CO-R 11 , -O-CO-NHR 12 ,-NR 10 -CO-R 11 , -NR 10 -CO-NHR 12 ,-NR 10 - CO-O-R 14 , -CH 2 -NH-CO-NHR 12 , -CH 2 -NH-CO-R 11 , and -CH 2 -NH-CO-O-R 14 , whereby one substituent may also be selected from the group consisting
  • the derivatisation may include the oxidation of the -CH 2 -OH group into a carbonyl -CHO group, e.g. using a Jones reagent.
  • DMSO dimethyl sulphoxide
  • an electrophile for example Dicyclohexylcarbodiimide or oxalyl chloride
  • the above reaction may be carried out by electro-oxidation in the presence of the organic nitroxyl radical.
  • the oxidation reaction may be carried out in the presence of a nitroxyl radical and at least one molar equivalent of a co-oxidant selected from the group consisting of m-chloroperbenzoic acid, high-valent metal salts, sodium bromite, sodium or calcium hypochlorite, N-chlorosuccinimide or hypervalent iodine compounds such as [bis(acetoxy)iodo]benzene.
  • the co-oxidant is sodium hypochlorite.
  • the stable organic radical preferably comprises a completely ⁇ -substituted piperidin-1-oxy radical, such as 2,2,6,6- tetramethyl-1-piperidinyloxy, free radical (TEMPO, free radical).
  • the resulting carbonyl function may be further functionalized (see below).
  • R 71 represents an aryl or heteroaryl group substituted with at least one -COOH group
  • the -COOH substituent may be modified into an ester or amide derivative by nucleophilic substitution with the appropriate alcohol R 9 -0H or the appropriate amine R 12 R 13 NH by reactions well known to the skilled artisan (e.g. EDCI coupling), thereby resulting in a derivative of general compounds XXIII, XXIV or XXV with a residue R 4 representing an aryl or heteroaryl group carrying at least one substituent -CO-O-R 9 and -CO-NR 12 R 13 , respectively.
  • R 71 represents an aryl or heteroaryl group substituted with at least one -OH substituent
  • R 71 represents an aryl or heteroaryl group substituted with at least one -NHR 10 and/or -NH 2 group
  • R 71 represents an aryl or heteroaryl group substituted with at least one -CH 2 -NH 2 group
  • R 2 and R 3 have the meanings as given above; wherein the ring A represents an aryl or heteroaryl group, and wherein R 15 represents a substituent selected from the group consisting of hydrogen, -CH 2 -OR 9 ; - CO-O-R 9' , -CO-NR 12 R 13' , -halogen, -OR 9' , -NHR 10' , -NR 12 R 13' , -(d-C ⁇ alkyl, halogenated
  • NR 10' -CO-R 11' , -NR 10' -CO-NHR 12' , and -NR 10' -C0-0-R 14' , and R 15 preferably represents hydrogen; and wherein R 9' , R 10' , R 11' , R 12' , R 13' and R 14' have the meanings as given here within for R 9 , R 10 , R 11 , R 12 , R 13 and R 14 , but does not represent hydrogen, or represent a conventional protective group PG ** .
  • the compound of general formula NH 2 -O-Y is present in the form of such compound, or in a form from which the compound of the general formula NH 2 -O-Y is released under the selected conditions of the reaction.
  • the reaction is carried out with equimolar ratios of the corresponding educts.
  • acy- lating agents such as appropriately substituted acid halogenides R 11 -C0-Hal or acid anhydrides (R 11 -
  • the optional dehydrogenation step q delivering compounds of the invention of general formula XXVII may be carried out where it appears to be most appropriate in the overall reaction scheme, most preferably before addition of the NH 2 -O-Y to the carbonyl function.
  • R 1 still represents H (and below designated as compounds of general formula IV-H and Vl- H, respectively), is displayed within the following reaction SCHEME Vl for compounds of general formula IV.
  • SCHEME Vl for compounds of general formula IV.
  • the same reaction can be applied to deliver compounds of general formula Vl:
  • R 5 may have the meanings as given here within or a residue from which the desired R 5 residue can be derived by the above described reactions for derivatisation of the optional substitu- ents of the aryl or heteroaryl groups of R 7 and/or R 71 to deliver the desired residue R 4 .
  • the reaction step h refers to the Wittig addition, step o to the hydrogenation, step p to the deketalization of the 3, 20 diketo function and step q to the dehydrogenation of the 6,7 bond of the steroid core, as described above.
  • the reactions for derivatisation of R 5 may be performed when it appears to be most appropriate, i.e. before or after the deketalization (step p) and/or dehydrogenation (step q).
  • R 1 represents -OH, -O-(Ci-C 4 )alkyl, -O-CO-(C- ⁇ -C 4 )alkyl, and -O-CO-O-(C- ⁇ -C 4 )alkyl.
  • R 2 , R 3 and R 4 have the meanings as set out here within.
  • the derivatisation of the C17 position may be started from different intermediates depending on the stability and reactivity of the R 4 side chain and its predecessors R 7 and R 71 , and the substituents R 15 or R 5 in the side chain. Therefore, the starting material is preferably one of the intermediate compounds of general formula XXIV or XXVI or any intermediate there in between, or the corresponding derivatives with the still protected keto functions in C3 and C20 position of general formula XXIII and XXVIII, respectively.
  • the oxo groups in C3 and C20 position have to be deprotected by deketalization (step p).
  • one of the following intermediate compounds is preferably used as starting material for the derivatisa- tion of the C17 function, whereby any reactive groups in the R 7 , R 71 or R 4 side chains, such as hy- droxyl groups or amino functions have to be protected by adding a suitable protective group PG**.
  • R 2 and R 3 , R 7 , R 71 and R 4 have the meanings as given above, and any reactive groups in the R 7 , R 71 or R 4 side chains, such as hydroxyl groups or amino functions are protected by a suitable protective group PG**.
  • reaction SCHEME VII starts with the reduction of the 18-(R 7/71/4 -substituted)-ethyl-(9 ⁇ ,10 ⁇ )- pregna-4-ene-3,20-dione of general formula XXIV or XXVI by using a suitable reducing agent such as lithium aluminium hydride (LAH) to produce the corresponding 3,20-diol of general formula XXXI.
  • LAH lithium aluminium hydride
  • the 3-hydroxy group of this general compound is then selectively re-oxidized by means of a selective oxidizing agent such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) in an aromatic solvent or manganese dioxide.
  • DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone
  • NMMO N-methylmorpholine-N- oxide
  • the compound of general formula XXXIV may be further modified by subjection to an etherification, esterification or carboxylation reaction at the hydroxyl group at the carbon atom C17 to produce a compound of the general formula XXXV, XXXVI, or XXXVII, whereby the reactions are generally described within Belgian patent specification BE 577,615 or US patent No. 3,937,700, and displayed in the following general SCHEME VIII:
  • R 2 and R 3 , R 7 , R 71 and R 4 have the meanings as given above, and any reactive groups in the R 7 , R 71 or R 4 side chains, such as hydroxyl groups or amino functions, are protected by a suitable protective group PG**.
  • Suitable acylating agents are carboxylic acids, carboxylic acid anhydrides or carboxylic acid chlorides in the presence of a catalyst such as p-toluene sulphonic acid, trifluoroacetic acid, anhydride or pyridine-HCI or in the presence of an acid binder such as an organic base, for example, col- lidine.
  • the acylation reaction is carried out in the presence of a solvent such as a hydrocarbon, for example, benzene or toluene.
  • the reaction temperature may vary between room temperature and the boiling point of the solvent used. Since - if the starting material contains, apart from the 17-OH group, one or more further OH-groups - these will also be esterified, the further OH-groups have to be protected in advance.
  • the alkylation reaction may be carried out by the following methods: 1. A reaction with an alkylhalide in the presence of Ag 2 O.
  • Carboxylation of the C17 alpha hydroxyl group might be achieved by reaction with an alkylhalide in the presence of Ag 2 CO 3 .
  • the compounds of general formulas XXXIV, XXXV, XXXVI, or XXXVII are optionally further modified in the R 7 , R 71 and R 4 residue, respectively, to generate the desired side chain; in particular any protective groups PG** may be removed and the substituents in the aryl or heteroaryl group of R 7 or R 71 , such as a -CH 2 -OH, -CO-OH, -OH, -NHR 10 , or -CH 2 -NH 2 group are further derivatized as explained above.
  • the dehydrogenation step q to afford the 4,6 unsaturated derivative of general formula Il has to be performed where it appears to be most appropriate in the overall reaction scheme.
  • Figure 1 Antiluteolytic activity of dydrogesterone (a PR agonist), mifepristone (a PR antagonist), and compounds of the invention in guinea pigs assessed by determination of serum progesterone profiles throughout the treatment period from day 10 to day 17 after ovulation.
  • Figure 2 lmmunohistological score for uterine PR expression in guinea pigs after treatment with dydrogesterone (a PR agonist), mifepristone (a PR antagonist), and compounds of the invention (one bar represents one animal).
  • Thin-layer chromatography was performed on Merck® pre-coated glass-backed silica gel or aluminium sheets 6OA F-254 250 ⁇ m plates unless stated otherwise. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination (254 nm or 266 nm), (b) exposure to iodine vapour or iodine vapour and phosphomolybdic acid and subsequent heating, (c) spraying of the plate with Schlittler's reagent solution followed by heating, (d) spraying of the plate with anisaldehyde solution followed by heating, and/or (e) spraying of the plate with Rauxz reagent solution followed by heating.
  • Melting points (mp) were determined using a Reichert Thermovar melting point apparatus or a Met- tier DSC822 automated melting point apparatus and are uncorrected.
  • Proton (1 H) nuclear magnetic resonance (NMR) spectra were measured with a Bruker ARX (400 MHz) or Bruker ADVANCE (500 MHz) spectrometer with either Me 4 Si ( ⁇ 0.00) or residual proto- nated solvent (CHCI 3 ⁇ 7.26; CHD 2 OD ⁇ 3.30; DMSOd 5 ⁇ 2.50) as standard.
  • Carbon ( 13 C) NMR spectra were measured with a Bruker ARX (100 MHz) spectrometer with either Me 4 Si ( ⁇ 0.00) or solvent (CDCI 3 ⁇ 77.05; CD 3 OD ⁇ 49.0; DMSO-d 6 ⁇ 39.45) as standard.
  • Dydrogesterone (9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione) of formula IX-H is converted to the corresponding 9 ⁇ ,10 ⁇ -pregna-4-ene-3,20-dione (9 ⁇ ,10 ⁇ -progesterone) of formula X-H under reducing conditions (step a).
  • Dydrogesterone 160 mmol were dissolved in 550 ml of toluene.
  • step b the 9 ⁇ ,10 ⁇ -pregna-4-ene-3,20-dione (X-H) is reacted with HCN to produce the corresponding 20-cyano-20-hydroxy compound of formula Xl-H.
  • a 500 ml three-necked flask with mechanical stirrer, internal thermometer, two-neck attachment, dropping funnel and gas discharge tap is prepared with 5 downstream connected wash bottles (1 * empty, 1 * filled with CaCI 2 , 1 ⁇ empty, 1 * cone. KOH and finally alkaline H 2 O 2 solution; for absorbing and breaking down excess HCN).
  • wash bottles (1 * empty, 1 * filled with CaCI 2 , 1 ⁇ empty, 1 * cone. KOH and finally alkaline H 2 O 2 solution; for absorbing and breaking down excess HCN).
  • Three additional wash bottles (1 * empty, 1 * cone. KOH and 1 * alkaline H 2 O 2 solution), which can be shut off by a tap, are connected to the suction port of the adaptor.
  • a tube for feeding HCN gas is connected via a ground glass connector at the upper end of the jacketed coil condenser.
  • the three-necked flask is fastened in the cooling bath of a circulating condenser; the circulating pump passes cooling liquid through the jacketed coil condenser.
  • the hydrogen cyanide gas is evolved in a 1 I three-necked flask.
  • the flask is placed in a water bath, which is heatable by a magnetic stirrer. Fitted thereon are a dropping funnel (with a gas inlet for argon) and a down- wardly inclined (uncooled) distillation bridge.
  • the receiver consists of a 250 ml round-bottomed flask with adaptor, the suction port of which is connected to three further wash bottles connected in series and filled with glass wool and calcium chloride for drying the HCN gas.
  • the receiver and the wash bottles are kept at a temperature of approx 5O 0 C in a water bath in order to prevent condensation of the HCN.
  • a tube leads from the final wash bottle to the top of the above described jack- eted coil condenser in which hydrogen cyanide is subsequently condensed. All joints are clamped/wired and so secured against being unintentionally loosened.
  • the two outlets from the apparatus (downstream from the series of five wash bottles and downstream from the series of three wash bottles) are passed directly into the fume hood; a gas mask is kept to hand.
  • Reaction 1.) Initially, 35 g (111 mmol) of 9 ⁇ ,10 ⁇ -progesterone were introduced into the 500 ml three-necked flask and suspend in 425 ml of MeOH. The mixture was stirred at RT for 30 min, thereby providing an inert argon atmosphere in the entire apparatus, and then cooled down to approx -5 0 C (under a gentle stream of argon). 4.7 ml of triethylamine (33 mmol) were added to the suspension. 2.) 50 ml of water were introduced into the 1 I three-necked flask, 104 g of cone.
  • H 2 SO 4 (95%; 1.0 mol) and 0.6 g of iron(ll)sulfate were added, and the water bath was adjusted to 7O 0 C. Then the dropping funnel was charged with a solution of 82 g of sodium cyanide (1.67 mol) in 140 ml of water. 3.) The coolant circulating pump was switched on and the jacketed coil condenser cooled down for condensation of the HCN gas. The HCN evolving by slow dropwise addition of the cyanide solution to the 1 I three-necked flask condensed after some time in the jacketed coil condenser and dripped into the dropping funnel above the 500 ml flask (after approx 45 min, 58 ml liquid HCN were obtained).
  • step c the 20-cyano-20-hydroxy-9 ⁇ ,10 ⁇ -pregna-4-ene-3,20-dione of formula Xl-H is converted by irradiation in the presence of iodine and lead-tetra-acetate (LTA) to yield the 18-cyano derivative of the formula XII-H.
  • LTA lead-tetra-acetate
  • a 1 I quartz flask with magnetic stirrer, jacketed coil reflux condenser, and argon connection was prepared and equipped with a high pressure mercury vapour lamp (400 W, Philips HPA 400/30 SD-C) and an aluminium reflector (distance approx. 5 cm).
  • the flask was filled with argon, and 24 g of LTA (predried with KOH/argon) were introduced.
  • the suspension was heated to reflux under argon for 1/2 h, and subsequently cooled to approx. 35 0 C.
  • step d the two oxo groups of the 18-cyano-9 ⁇ ,10 ⁇ -pregna-4-ene-3,20-dione of formula XII-H are protected by ketalization with ethyleneglycol to produce the 18-Cyano-9 ⁇ ,10 ⁇ -pregna-4-ene- 3,20-diethylenedioxyketal of formula XIII-H.
  • steps e and f the 18-cyano-3,20-diketal derivative of formula XIII-H is transformed into the corresponding ⁇ 5-18-cyano-3,20-ketalized dione of formula XV-H by isomerization, partial deketaliza- tion and chromatographic separation of the resulting mixture of the ⁇ 5-diketal and the ⁇ 4-20- monoketal derivatives.
  • the resultant isomer mixture ( ⁇ -4/ ⁇ -5) (approx 25 g) was then dissolved in a 5 I three-necked flask in 900 ml of ACN. 380 ml of borate buffer (5 g of NaB 4 O 7 Xi OH 2 O dissolved in 500 ml water, brought up to pH 8 by addition of 18% HCI solution) were added. Then, a solution of 977 mg of cerium ammonium nitrate (Ce(NH 4 ) 2 (NO 3 ) 6 , 1.78 mmol) dissolved in 20 ml of water and 20 ml of ACN was added to the isomer mixture. The resulting mixture was stirred at RT for 15 min. Control was performed by TLC analysis.
  • step g the ⁇ 5-18-cyano-3,20-diketal of formula XV-H is treated with a reducing agent such as diisobutyl-aluminium-hydride (DIBAH) to gave an aldimine intermediate, which is hydrolyzed to the desired 18-formyl-(9 ⁇ ,10 ⁇ )-pregna-5-ene-3,20-diketal compound of formula XVI-H.
  • DIBAH diisobutyl-aluminium-hydride
  • the residue R7 represents hydrogen or a heteroaryl or aryl residue, which is optionally substituted in the heteroaryl or aryl group with one or two substituents independently selected from the group consisting of -CH 2 -O-PG ** ; -CH 2 -O-R 9 ', -CO-O-PG ** , -CO-O-R 9 ', -CO-NR 12 K 13 ', -CN, - halogen, -0-PG**, -O-R 9 ', -N(PG**) 2 , -NPG**R 10 , -NR 12 K 13 ', -(d-C ⁇ alkyl, and halogenated - (C 1 - C 4 )alkyl, whereby PG** represents a conventional protecting group for the hydroxyl or amine function, and whereby R 9 ', R 12 ' and R 13 ' represent -(C- ⁇ -C 4 )alkyl or halogenated — (Ci—
  • the aryl moiety of R 7 is optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 membered ring system, optionally containing 1 , 2 or 3 heteroatoms selected from N, O and S, the number of N atoms being 0, 1 , 2 or 3 and the number of O and S atoms each being 0, 1 or 2.
  • Preferred examples for the Wittiq reagent include:
  • This intermediate compound was prepared by a Wittig addition according to the following scheme:
  • the diketal derivative of formula XVIII-OH was converted into the 18-(2-Hydroxyethyl)-9 ⁇ ,10 ⁇ - pregna-4-ene-3,20-dione (No. 40) according to step k in general SCHEME III: 0.83 g of the 18- (hydroxyethyl)-9 ⁇ ,10 ⁇ -pregna-5-ene-3,20-diethylenedioxyketal (XVIII-OH) (1.87 mmol) were dissolved in 40 ml of acetone. Then, 3 ml of 18% H 2 SO 4 were added and the mixture was stirred at RT for approx 18 h.
  • the 18-(2-Acetoxyethyl)-9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione (XXI-Ac) is deprotected to deliver the desired 18-(2-Hydroxyethyl)-9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione - compound No. 41 of the present invention - by a reaction corresponding to step n in general SCHEME III.
  • This compound No. 7 of the invention was obtained by reactions as displayed within general reaction SCHEMES Il (step h, Wittig addition), IV, V and Vl, respectively.
  • This intermediate compound was prepared by a Wittig addition according to the following scheme:
  • 18-(2-[4-N-Ethylcarbamoyl-oximino-formylphenyl]-ethyl)-9 ⁇ , 10 ⁇ -pregna-4-ene-3,20-dione (No. 4) was obtained by reaction of the 18-(2-[4-Oximinoformylphenyl]-ethyl)-9 ⁇ ,10 ⁇ -pregna-4-ene-3,20- dione (No. 1 ) with Ethylisocyanate.
  • reaction was performed as described above in example 1.e) with the following amounts of reagents: 15 ml of dioxane/HCI (approx 170 mg HCI/ml) a column (4 x 12 cm) packed with a slurry of aluminium oxide (neutral) in DEE
  • 18-(2-[4-N-Ethylcarbamoyl-oximino-formylphenyl]-ethyl)-9 ⁇ ,10 ⁇ -pregna-4,6-diene-3,20-dione (No. 5) was obtained by reaction of the 18-(2-[4-Oximinoformylphenyl]-ethyl)-9 ⁇ ,10 ⁇ -pregna-4,6-diene- 3,20-dione (No. 2) with ethyl isocyanate.
  • This intermediate compound was prepared by a Wittig addition using the following phospho- nium salt as starting reagent:
  • a 500 ml 3-necked round bottom flask equipped with a magnetic stirrer, a thermometer and a dropping funnel was placed in an ice-salt bath and flushed with argon. Under positive argon- pressure, 1.8 g LAH (48 mmol) were placed in the flask, cooled to -1O 0 C and 100 ml THF were added under vigorous stirring.
  • the aldehyde 18-[2-(4-Formyl-phenyl)-ethyl]-3,20-dioxo-(9 ⁇ , 10 ⁇ )-pregna-4,6-diene-17-yl-carbonic acid ethyl ester (No. 12) was then transformed into the corresponding oxime derivative (compound No. 3) by a reaction as described in example 7 and purified by chromatography. Then, the purified compound No. 3 was further reacted to yield the carbamoyl oxime compound No. 6 in a reaction as described in examples 5 and 8.
  • the progesterone receptor (PR) binding assays were performed at CEREP (CeIIe I'Evescault, France).
  • the binding to the bovine progesterone receptor was measured using 3H-R5020 as ligand and uterus tissue as the source of progesterone receptor. The assay was performed as described by Hurd & Moudgil [1988].
  • the binding to the human progesterone receptor may be measured using 3H-R5020 as ligand and MCF7 cells as the source of progesterone receptor.
  • the assay is performed as described by Eckert & Katzenellenbogen [1982].
  • the assay does not discriminate between the two progesterone receptor isoforms PRa and PR ⁇ .
  • the progesterone-dependent modulation of alkaline phosphatase expression was examined using T47D human breast carcinoma cells [Keydar et al., 1979].
  • the assay was perfomed as previously described by Di Lorenzo et al. (1991 ) with the modification of using Dydrogesterone as comparative progestin to determine the antagonistic and agonistic activity.
  • the cell line was purchased from CLS Cell Lines Service (Hildastrasse 21 , D-69214 Eppelheim, Germany).
  • the cells were plated in 96-well plates at 40,000 cells/well using the following growth medium: RPMI 1640 with: 10% FBS, 1 mM Sodium Pyruvat MEM, 1OmM Hepes, 0.01 mg/ml Bovine insulin, and 25 ⁇ g/ml Gentamycin.
  • the growth medium was replaced with medium containing 2% fetal bovine serum and the test compounds were added to each well to achieve the appropriate compound concentration: For determination of agonistic activity only the test compounds were added; for measurement of antagonistic activity the test compounds and additionally Dydrogesterone as standard progesterone agonist was added to a final concentration of 1 nM.
  • the medium was removed and the cells were washed with 200 ⁇ l of Dulbecco's phosphate-buffered saline without calcium and magnesium (PBS(-)).
  • the cells were fixed with 3.7% formaldehyde in phosphate-buffered saline for 15min at 22 0 C. After washing the cells with PBS, 10O ⁇ l of a para-nitro-phenole (pNPP) solution (pNPP Liquid Substrate System; Sigma) was added to each well and incubated for 2h at room temperature protected from light. The reaction was stopped with 100 ⁇ l 1 N NaOH and the absorbance was measured with a spectrophotometer (Victor, Perkin Elmer) at 405nm.
  • pNPP para-nitro-phenole
  • results are expressed as alkaline phosphatase induction (as 100% with 1 nM Dydrogesterone) or inhibition (against alkaline phosphatase induction by 1 nM Dydrogesterone) at a certain concen- tration of test compound.
  • % stimulation (effect compound - basal) / (effect dydro 1 nM - basal) * 100
  • % inhibition (Pl) and % stimulation (PS), respectively, at a compound concentration of 100 nM was determined.
  • the corresponding values were measured for several different concentrations, and subsequently were plotted against the concentration of the test compound, and used to calculate the IC50 value (for the antagonistic potency; the IC50 value is the concentration (nM), required to reduce the maximal response by 50%) and EC50 values (for the agonistic potency; the EC50 value is the effective concentration (nM) that produced 50% of the maximum response), respectively.
  • the in vivo activity of selected PR modulator compounds of the present invention was evaluated utilizing the McPhail assay.
  • the Clauberg or McPhail assay is a classic assay utilizing rabbits to measure progestational activity and allows the assessment of the progestagenic and antipro- gestagenic effects of the compounds [McPhail, 1934].
  • the reason rabbit is used is because the results observed in rabbit have proved to be a good indicator and predictor of activity in the human.
  • immature rabbits are treated initially with estradiol, which induces growth in the uterus. This is followed by treatment with a progestin, which causes a large change in the glandular content of the uterus. It is this change in the glandular component, which is a measure of the progestational activity of a progestin.
  • the measurement of these glandular changes is carried out histologically using stained sections of the uterus. Performance
  • the test is performed in 6-week-old juvenile female rabbits (New Zealand white). From days 1 to 6, all rabbits are primed with 5.0 ⁇ g/kg/day 17 ⁇ -estradiol (s.c, 0.5 ml/kg/day) in order to induce proliferation of the endometrium. From days 7 to 11 , the test compound is applied (0.5 ml/kg/day) at doses in the range of 0,001 to 10 mg/kg/day. A group which receives only vehicle after estradiol priming serves as a negative control. A second group which receives only progesterone in order to induce endometrial differentiation after estradiol priming is used as a positive control. The antago- nistc activity is measured by the combined administration of progesterone and the test compound in the appropriate dosages.
  • the McPhail index i.e., the degree of differentiation
  • progesterone produces a maximum McPhail score of 4; treatment with a PR antagonist in the absence of progesterone leads to a McPhail score which is distinctly lower in score than 4 at the plateau of the dose response curve at the clinically relevant doses (i.e. 0.01 mg-10 mg/rabbit).
  • a SPRM leads to a McPhail score which is higher than that under any dose of RU 486 (Mifepristone), i.e. above 0.5-1.0, preferentially above 2.0-3.0.
  • the capacity of SPRMs to antagonize progesterone function can also be tested in the McPhail test using a progesterone dose which induces a McPhail score ranging between 3 and 4.
  • a SPRM inhibits the effect of progesterone to a significant degree, but the maximum inhibition is below that which is inducible with RU 486 or other pure antiprogestins, such as onapristone.
  • the preferred compounds of the invention lead to a McPhail score which is above 0.5-1.0, preferentially above 2.0-3.0.
  • the preferred compounds of the invention show a significant inhibition of the effect of the administered progesterone; however, they show a maxi- mum inhibition clearly below that which is inducible with pure antiprogestins.
  • PAs progesterone antagonists
  • PRMs progesterone receptor modula- tors
  • Inhibition of luteolysis is reflected by elevated serum progesterone levels at day 10-17 and inhibition of uterine prostaglandin F2 ⁇ , as well as by certain histological characteristics in uterus and ovary, such as increased expression of progesterone receptors and decreased glandular differentiation in the uterus, as well as persistence of large intact corpora lutea up to day 18.
  • Antiluteolytic activity is evaluated by assessment of serum progesterone profiles throughout the treatment period from day 10 to day 17 (Fig. 1 ). Progesterone levels do not decline, i.e. luteolysis is inhibited, when antiprogestins like mifepristone (RU486) are administered. With progestins (e.g. dydrogesterone) and SPRMs, progesterone levels decrease meaning that no inhibition of luteolysis is observed.
  • progestins e.g. dydrogesterone
  • SPRMs progesterone levels decrease meaning that no inhibition of luteolysis is observed.
  • PR Antiprogestational effects on the uterus are assessed by determination of the degree of PR expression.
  • PR is stained by immunohistochemistry in 5- ⁇ m cross-sections of the uteri using the DAKO Envision method according to the manufacturer's instructions and mouse-anti-human pro- gesterone receptor antibody (1 :20 dilution, DAKO Diagnostika, Hamburg, Germany).
  • a minimum histological score of 0 is assigned to sections with no PR expression, while a maximum score of 3 is assigned to strong PR expression as judged by staining intensity and number of PR-positive cells (Fig 2; 1 bar represents one animal).
  • PR-agonists reduce uterine PR expression, whereas PR-antagonists block the PR and increase PR expression.
  • the compounds of the invention support luteolysis (Fig. 1 ), but unlike pure agonists they do not decrease uterine PR expression (Fig. 2).
  • the compounds and pharmaceutical compositions of the present invention may be extremely potent modulators of the PR, while however their absolute agonistic activity remains below that of natural progesterone in the plateau of the dose response curve and their absolute antagonistc activity remains below that of known antiprogestins such as onapristone or mifepristone (RU 486).
  • the compounds and compositions of the present invention may display 50% maximal activation of the progesterone receptor at a concentration of less than 10 ⁇ M.
  • Some compounds and compositions of the present invention may display 50% maximal activation of PR at a concentration of less than 1 ⁇ M, and some may display such activity at a concentration of less than 100 nM or even 10 nM.
  • the compounds provide for 50 % maximum inhibition measured in the antagonistic mode of the AP assay at a concentration of less than 1 ⁇ M, preferably less than 100 nM and even more preferred less than 10 nM, and additionally for 50 % maximum activation measured using the agonistic AP assay as described here within at a concentration of less than 10 ⁇ M, preferably less than 1 ⁇ M and even more preferred less than 100 nM.
  • Hard gelatin capsules are prepared using the following ingredients: Ingredient Quantity (mq/capsule)
  • the above ingredients are mixed and filled into hard gelatin capsules in 120 mg quantities.
  • a tablet is prepared using the ingredients below:
  • Total 230 The components are blended and compressed to form tablets each weighing 230 mg.
  • Suppositories each containing 1 mg of active ingredient, may be made as follows: Ingredient Quantity (mq/suppositorv)
  • the active ingredient is passed through a appropriately sized mesh sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary.
  • the mixture is then poured into a suppository mold of normal 2 g capacity and allowed to cool.
  • An intravenous formulation may be prepared as follows:
  • the compound is dissolved in the glycerol and then the solution is slowly diluted with isotonic sa- line.
  • EP 0152138B1 (US 4,601 ,855) • EP 0558119B1 (US 5,304,291 )

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EP06806867A 2005-09-30 2006-09-28 Novel c18 modified retrosteroids as progesterone receptor modulator compounds Withdrawn EP1928894A1 (en)

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EP05109126 2005-09-30
EP06118034 2006-07-28
EP06806867A EP1928894A1 (en) 2005-09-30 2006-09-28 Novel c18 modified retrosteroids as progesterone receptor modulator compounds
PCT/EP2006/066842 WO2007039544A1 (en) 2005-09-30 2006-09-28 Novel c18 modified retrosteroids as progesterone receptor modulator compounds

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