HK1081112A

HK1081112A - 5-}2-hydroxy-3-1'-(3-trifluoromethylphenyl)-cyclopropyl!-propionylamino}-phtalide and related compounds with progesterone receptor modulating activity for use in fertility control and hormone replacement therapy

Info

Publication number: HK1081112A
Application number: HK06101277.6A
Authority: HK
Inventors: 诺贝特．施梅斯; 曼弗雷德．莱曼; 乌尔丽克．富尔曼; 彼得．穆恩; 赫丽斯塔．黑格勒-哈通; 米夏埃多．克洛茨比歇尔
Original assignee: 舍林股份公司
Priority date: 2002-03-11
Filing date: 2003-03-10
Publication date: 2006-05-12

Description

5- { 2-hydroxy-3- [' 1- (3-trifluoromethylphenyl) -cyclopropyl ] -propionylamino } -2-benzo [ C ] furanone and related compounds with progesterone receptor modulating activity for birth control and hormone replacement therapy

Technical Field

The present invention relates to a non-steroidal progestogen represented by the general formula (I) and the use of said compound for selectively modulating the modulation of progesterone receptors on different target tissues, i.e. the present invention relates to a progestogen having a segregated activity profile (segregated activity profile) on different target tissues, preferably having a uterine/breast separation. The invention also relates to the use and methods of said compounds for selectively enhancing the mediation of progesterone receptors in uterine tissue relative to the mediation of progesterone receptors in breast tissue. Due to the unique isolated activity and selective function of the progestagens of this invention, the invention is particularly directed to the use of said compounds in contraception, and in particular in the treatment of oral contraceptives, hormone replacement therapy and gynecological disorders. The progestagens of this invention are particularly suitable for use in estrogen-free oral contraceptives.

Background

Progesterone is a unique reproductive hormone which has a decisive role in the female reproductive system. The major target organs of progesterone are the uterus, ovary, breast and hypothalamic-pituitary axis. In addition to being used primarily as a pregnancy control agent for women (e.g., Oral Contraceptives (OCs)), progestins can optionally be combined with estrogens for a wide range of applications in Hormone Replacement Therapy (HRT). Progestagens are also used in the treatment of several gynecological disorders such as dysmenorrhea, endometriosis and dysfunctional uterine bleeding due to hormonal deficiencies or imbalances. Since certain actions of progestagens may be undesirable in certain applications or cross-reactive with other receptors besides the progestagen receptor, it has become a great challenge to develop novel progestagens to improve their active function. In addition, the search for therapeutic applications such as oncology also requires new active functions of progestagens.

Recently, non-steroidal progestagens with very strong affinity for the progesterone receptor but additionally androgenic action have been disclosed in WO 98/54159. These progestagens are not only suitable for female birth control (FC) and HRT (optionally in combination with estrogen), but also for the treatment of male FC, male HRT and male syndromes.

WO 00/32584 discloses specific non-steroidal glucocorticoids with a clear separation between anti-inflammatory activity and metabolic action. They have high affinity for the progestogen receptor, but their progestogenic potential is not significant.

Finally, DE 10038639.3 discloses glucocorticoids with a strong affinity for the glucocorticoid receptor, which thereby have anti-inflammatory as well as anti-allergic, immunosuppressive and antiproliferative effects, and are useful in the treatment of diseases including arthritis and allergy.

However, there is a great need, particularly in the field of female birth control and HRT, for progestogens that have a low affinity for other hormone receptors and a strong separation effect on different PR target tissues or organs, such as in the breast and reproductive tract.

In particular, as a result of many epidemiological studies concerning the incidence of breast cancer in relation to the use of Complex Oral Contraceptives (COCs) or HRTs, especially for long-term use, it seems beneficial to provide isolated progestagens with an anti-proliferative potential of breast tissue and at the same time a beneficial effect on the endometrium. (see, e.g., K.E.Malone et al, epidemic Reviews 1993, 15, 80-97 and Standford et al, epidemic Reviews 1993, 15, 98-107). Although this risk is contradictory and controversial, there is evidence that many years of progestagen administration may enhance the mitotic activity of normal breast epithelial cells in certain circumstances. Therefore, progestogens that provide beneficial effects in the breast, such as anti-proliferative effects, and that have isolated active functions of conventional progestagenic effects on the ovary and/or uterus would be suitable.

Recently, screening for tissue-specific ligands for the progestogen receptor has been tested, see WO 02/054064. One method of screening Progesterone Receptor (PR) ligands with A segregating active function is based on the fact that the progestogen is expressed in two different isoforms (PR- A and PR-B) which appear to be activated independently of each other by compounds with PR- A or PR-B selectivity.

These two PR isoforms are expressed on all progesterone target organs examined to date (e.g. breast, uterus, etc.). However, there is clear evidence that PR-A and PR-B function regulates the response to progesterone in A tissue-specific manner. Exclusion of isotype-specific mice indicates that PR- A and PR-B have different functions on the same target organ. On the basis of these studies, PR-B appears to be the most important receptor responsible for mammary gland proliferation and differentiation, while antiproliferative effects of progestogens on uterine epithelial cells and ovulation are likely mediated by PR-A (B.mulac-Jercevic, Science2000, 289, 1751-AscA 1754; OrlA Conneely, Endocrine Society Meeting, Torto, June 2000).

The invention disclosed in WO02/054064 is therefore based on the new theory that isoform-specific ligands of PR activity may lead to tissue-selective modulation of progestagenic activity in hormonal therapy and contraception. However, WO02/054064 provides tools for the determination of potential PR isoforms and/or tissue-specific PR ligands, while the present invention provides specific non-steroidal progestagens with a significant selectivity for PR isoforms while having a surprising separation effect on different PR target organs, in particular the uterus/breast separating active function.

Object of the Invention

As mentioned above, it is an object of the present invention to provide novel progestogens for use in the treatment of FC, HRT and gynecological disorders. It is another object to provide novel progestogens suitable for use in estrogen-free oral contraceptives. In particular, it would be desirable to provide novel progestagens that may have beneficial effects on certain PR target organs, such as the uterus, without enhancing side effects on other PR target organs, such as proliferation/differentiation of mammary epithelial cells. Accordingly, it is desirable to provide a novel progestogen that functions separately for different target tissues or organs, preferably a uterus/breast specific progestogen.

It is another object of the present invention to provide a method for selectively modulating progesterone-mediated effects in first selected tissue, preferably uterine tissue, relative to second selected tissue, preferably breast tissue. It would be particularly beneficial to provide a method that selectively enhances anti-proliferative effects in the uterus while preventing adverse effects such as proliferation and differentiation in breast tissue.

It is another object of the invention to provide progestagens that are selective for PR isoforms, preferably PR- A versus PR-B. It is also desirable to provide methods for selectively modulating the effects mediated by PR isoforms, preferably PR-A, and for selectively activating the transcription of PR isoforms, preferably PR-A.

All these objects are surprisingly achieved by a progestogen of the general formula (I), the use of said progestogen and the modulation of progesterone mediated effects of the present invention as further detailed below.

Disclosure of Invention

In a first aspect, the present invention provides a compound of formula (I) as follows. A preferred compound of the invention is (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone.

In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) alone (e.g. in an estrogen-free oral contraceptive) or optionally in combination with 17 α -ethinyl estradiol or another estrogen as an additional ingredient.

In a third aspect, the present invention provides the use of a compound of formula (I) in therapy.

In a fourth aspect, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (I) in therapy.

In a fifth aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutical composition comprising said compound in the manufacture of a medicament. The medicament is for selectively modulating progesterone receptor mediated effects of a preferred tissue, preferably uterine tissue, relative to a preferred tissue, preferably breast tissue, particularly for the treatment of birth control, hormone replacement therapy or gynecological disorders.

In a sixth aspect, the present invention provides the use of a compound of formula (I) as a contraceptive, preferably an estrogen-free oral contraceptive, e.g. "Progesteron-only pill" (POP).

In a seventh aspect, the present invention provides a method of selectively modulating progesterone receptor mediated effects of a tissue of choice, preferably uterine tissue, relative to a tissue of choice, preferably breast tissue, particularly for use in birth control, hormone replacement therapy or treatment of gynecological conditions. The method comprises the step of administering to the subject a compound of formula (I).

In addition, in an eighth aspect, the present invention provides the use of a compound of formula (I) for the preparation of a medicament for selectively activating transcription of progesterone receptor isoform a relative to transcription of progesterone receptor isoform B and for selectively enhancing progesterone receptor isoform a mediated effects relative to progesterone receptor isoform B mediated effects.

In a ninth aspect, the invention provides methods of selectively activating transcription of progesterone receptor isoform a relative to transcription of progesterone receptor isoform B and selectively enhancing progesterone receptor isoform a mediated effects relative to progesterone receptor isoform B mediated effects.

Drawings

FIG. 1 demonstrates the difference in the stimulation of terminal (terminal) and vesicular endbud (alveolar endbud) production by subcutaneously administered compound ((+) -1) (at a dosage ((+) -1) equivalent to 0.3mg/kg R5020) compared to the standard progestogen promegyprogesterone (R5020) in ovariectomized immature female rats.

FIG. 2 shows the stimulation of mammary epithelial cell proliferation in immature ovariectomized female rats by MIB-5 staining using compound ((+) -1) in comparison to the standard progestogen promegestrol (R5020).

FIG. 3 relates to the stimulation of terminal and vesicle termination bud formation (cut-off values) following subcutaneous application of R5020 (standard progestogen) and compound ((+) -1) to immature ovariectomized female rats.

FIG. 4 demonstrates the anti-estrogenic effect of compound ((+) -1) on rat uterine growth (wet and dry uterine weight; epithelial thickness) compared to a control group treated with estradiol.

Detailed Description

In a first aspect, the present invention provides a non-steroidal progestagen compound as shown in formula (I) or a pharmaceutically acceptable derivative or analogue thereof

Wherein R is₁And R₂Independently of one another is-H or-F,

R₃is-CH₃or-CF₃And an

Ar is

Or

With the proviso that the compound is not 5- [3- {1- (3-trifluoromethylphenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethyl-propionylamino ] -2-benzo [ C ] furanone.

For the purposes of the present invention, a "pharmaceutically acceptable derivative or analogue" of a compound of formula (I) as defined above is a compound whose structure is derived from and/or substantially similar to that of formula (I) above, as well as a compound whose biological activity (in vitro and/or in vivo) is also substantially similar, qualitatively and/or quantitatively, to that obtained with a compound of formula (I).

The compounds of formula (I) have a stereogenic center (stereogenic center) which exists in two different stereoisomeric (enantiomeric) forms. The compounds of the invention may thus be provided as racemates, i.e. mixtures of the counterparts (e.g. denoted (±). However, the compounds of the present invention may also be provided as the individual (+) or (-), i.e. the dextro-or levorotatory enantiomer, for example by enantioselective synthesis or by applying standard separation methods, for example as described in example 1a) below. It will be appreciated that by disclosing either the (+) or (-) isomers, the absolute configuration inherent to these isomers is also disclosed.

Standard separation methods are within the ability of the skilled artisan. For example, by an optically active carrier (e.g., CHIRALPAK AD)^TM) The racemate is chromatographically separated into the pure isomers. Furthermore, it can be isolated by reacting the free hydroxyl group of the (racemic) compound of the formula (I) with an optically active acid (e.g.. alpha. -hydroxyphenylacetic acid, camphorsulfonic acid or tartaric acid) to give a diastereomeric ester which can be converted into an optically pure enantiomer by fractional crystallization or by chromatography and subsequent saponification.

Preferred compounds of the invention are compounds of formula (I) as described above, which are the (+) enantiomer.

Examples of compounds of general formula (I) are as follows:

(ii) the racemates, (+) and (-) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone ((+ -) -1), (+) -1) and ((-) -1)),

the exo-chemoselective agents, (+) and (-) -6- { 2-hydroxy-3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -4-methyl-2, 3-benzoxazin-1-one ((+ -) -2), (+) -2 and ((-) -2)),

the exo-chemoselective agent, (+) and (-) -6- { 2-hydroxy-3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-methyl-propionylamino } -4-methyl-2, 3-benzoxazin-1-one ((±) -3), (+) -3 and ((-) -3)),

exo-chemoselective agents, (+) and (-) -5- { 2-hydroxy-3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone ((+ -) -4), (+) -4) and ((-) -4)),

an exo-chemostat, (+) and (-) -6- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -4-methyl-2, 3-benzoxazin-1-one ((±) -5, (+) -5) and ((-) -5)), and

the exo-chemoselective agents, (+) and (-) -6- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-methyl-propionylamino } -4-methyl-2, 3-benzoxazin-1-one ((±) -6), (+) -6 and ((-) -6)),

particularly preferred compounds of the invention are the following:

(((±)-1)、((+)-1)、((-)-1))，

(((±)-2)、((+)-2)、((-)-2))，

(((±)-3)、((+)-3)、((-)-3))，

((±) -4), (+) -4) and ((-) -4)).

The most preferred compound of the present invention is 5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone, hereinafter referred to as compound (1):

as noted above, the (+) -enantiomer of 5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone is particularly preferred and designated ((+) -1). The synthetic route and physical data for (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone ((+) -1) are as described in example 1. The results of the in vivo and in vitro experiments with this compound are described in examples 2, 3, 4 and 5.

These examples demonstrate that the preferred progestagens of the present invention ((+) -1) have desirable in vivo and in vitro functions. In terms of the in vitro function of the compound ((+) -1), it is demonstrated in example 5 below that the compound ((+) -1) is A selective PR- A agonist and shows A high PR- A to PR-B specificity (details of PR isoform specificity of the compounds of the invention are given in the eighth and ninth sections of the invention described below). As demonstrated, the compound ((+) -1) selectively activates PR-A transcription, thereby selectively enhancing PR-A mediated effects.

The compound ((+) -1) is highly isolable in terms of its in vivo active function. In particular, (+) -1) shows a high activity in the uterus for maintaining pregnancy, but a rather low activity in the mammary gland, i.e., (+) -1) does not activate proliferation and differentiation of the mammary gland (see the rat experiment of example 3), especially in the dose range in which pregnancy is maintained.

The compound ((+) -1) is one of the most potent progestogens identified to date in vivo. In ovulation inhibition experiments (see example 2), the compound ((+) -1) was at least as effective as the standard progestogen R5020 (promegestone) used in this experiment. In the maintenance pregnancy test in rats (see example 3), compound ((+) -1) was approximately 10-fold more potent than Levonorgestrel (LNG). Furthermore, in the Clauberg experiment (rabbit endometriotic degeneration; see example 4), it was noted that ((+) -1) subcutaneous and oral applications had the same progestogenic potency. This demonstrates that ((+) -1) has a strong activity when administered orally.

Furthermore, although exhibiting moderate binding to Androgen Receptor (AR), compound ((+) -1) exhibits no androgenic nor antiandrogenic effect in vivo. The lack of androgenic and antiandrogenic effects in vivo was demonstrated in testicular-resected rats (changes in prostate weight and seminal vesicles). In the pregnancy maintenance experiment in rats, no androgenic effect of the compound ((+) -1) was found even when a dose 100 times higher than that required for maintaining pregnancy was administered. In addition, although compound ((+) -1) was found to have a very strong affinity for Glucocorticoid (GR), it did not appear to exhibit any glucocorticoid or anti-glucocorticoid effect in vivo, which can be concluded from experiments aimed at measuring changes in thymus weight. Finally, since compound ((+) -1) binds with very little affinity to the Mineralocorticoid Receptor (MR) and the estrogen receptor α (era) in vitro, it is expected to have no MR or era hormonal effect resulting from interaction with these receptors.

In terms of the above-mentioned action and activity, the compound ((+) -1) is considered as an example of all other compounds of the general formula (I) in the present invention.

Due to the beneficial effects of the novel progestagens of the present invention demonstrated above, especially (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone, i.e. the compound ((+) -1), these progestagens are especially useful in contraceptives, especially estrogen-free oral contraceptives, such as Progestagen Only Pills (POP).

In a second aspect, the present invention provides a pharmaceutical composition comprising a progestogen as defined by the above general formula (I) which is not 5- [3- {1- (3-trifluoromethylphenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethyl-propionylamino ] -2-benzo [ C ] furanone. Preferred pharmaceutical compositions comprise the preferred compounds described above. A more preferred pharmaceutical composition of the invention comprises 5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone (1), most preferably (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone ((+) -1).

For example, in terms of the condition to be treated/affected or the mode of application, depending on the desired application, the pharmaceutical composition of the invention, when not applied as an estrogen-free oral contraceptive, which is one of the preferred applications of the progestogen of the present invention, contains an estrogenic component in addition to the compound of general formula (I), preferably ((+) -1). For example, in case the pharmaceutical composition is intended for use as an (oral) contraceptive (the use of which will be explained in more detail below), the estrogens that are normally used in combination (oral) contraceptives are suitable. Although any natural estrogen (especially estriol or estradiol) or synthetic estrogen, steroid or nonsteroidal may be used, preferred estrogens in this regard, especially for oral administration, are 17 α -ethinyl estradiol and its esters, ethers and other derivatives of 17 α -ethinyl estradiol.

Furthermore, estratriene-3-sulfamates derived from estradiol or ethinyl estradiol (WO96/05216 and WO 96/05217) can be used in combination with compounds of the general formula (I), preferably the compound ((+) -1). Also suitable in this respect are the 14 α, 15 α -methylene steroids derived from estrane, in particular 14 α, 15 α -methylene-17 α -estradiol and the corresponding 3-sulfamate derivatives.

For application in hormone replacement therapy, the use of which will be explained in more detail below, the estrogen, which may optionally be combined with the progestogen of general formula (I), preferably the compound ((+) -1) of the present invention, is preferably estradiol, estradiol valerate or other estradiol esters and conjugated (natural, e.g. equine) estrogens.

In the pharmaceutical compositions of the present invention, the compound as defined by general formula (I) above, in particular compound ((+) -1), and optionally other estrogenic components, preferably 17 α -ethinyl estradiol, must be in a (pharmaceutically) effective amount. The dosage administered (i.e., "(pharmaceutically) effective amount") will vary widely depending on the condition being treated, or any other desired application and mode of administration. It may include any dose effective for the desired treatment or application. Determination of a "pharmaceutically effective amount" is within the ability of those skilled in the art.

More precisely, in the pharmaceutical compositions of the invention for any envisaged application (i.e. oral contraceptives (combined oral contraceptives as well as estrogen-free oral contraceptives, such as "progestin-only pills"), HRT and the treatment of gynaecological disorders and other disease conditions), it is generally considered appropriate to administer to the individual a daily dose of the compound of general formula (I), preferably compound ((+) -1), in the range of 0.01 to 2 mg. However, particularly suitable dosages for particular applications are as follows:

when a progestogen of the present invention, preferably the compound ((+) -1), is used in combination with an estrogen as defined above in a pharmaceutical composition as a combined oral contraceptive, the individual is administered a suitable daily dose of 10 μ g to 100 mg. A suitable daily dose for administration to a subject is preferably from 10. mu.g to 1 mg.

When the progestogen of the present invention, preferably the compound ((+) -1), is used in a pharmaceutical composition for an estrogen-free oral contraceptive as a "progestogen-only pill" (POP) without any other estrogenic component, a suitable daily dosage for an individual administration is from 10 μ g to 1mg, more preferably from 30 μ g to 300 μ g or from 10 μ g to 100 μ g, although dosage ranges as low as 1 μ g to 10 μ g may also be applicable.

When a progestogen of the present invention, preferably the compound ((+) -1), is used in a pharmaceutical composition for HRT, the individual is administered a suitable daily dose of 10 μ g to 10mg, more preferably 10 μ g to 1mg (1/100 equivalent to the medroxyprogesterone acetate (MPA)) and most preferably 10 μ g to 100 μ g.

When the progestogen of the present invention, preferably the compound ((+) -1), is used in a pharmaceutical composition for other applications than contraceptives or HRT, such as the treatment of gynecological disorders such as premenstrual syndrome (which manifests as headache, depressive symptoms, water retention, etc.), dysmenorrhea, endometriosis, myoma, or dysfunctional uterine bleeding, the dosage is generally in the same ranges as described above for COC, POP and HRT, but may also differ from these values depending on the effect to be achieved.

When a progestogen of the present invention, preferably the compound ((+) -1), is used in combination with an estrogenic component, preferably 17 α -ethinyl estradiol, in a pharmaceutical composition as defined above, the individual administration of the estrogenic component is suitably at a daily dose of (or equivalent to) 0.01 to 0.05 mg. Preferably 0.015 to 0.03mg of 17 α -ethinyl estradiol.

When the progestogen, especially the compound ((+) -1), of the present invention is administered in combination with an estrogenic component, preferably 17 α -ethinyl estradiol, for use in a contraceptive, preferably a Combined Oral Contraceptive (COC) or HRT, the progestogen and the estrogen may be administered simultaneously, e.g. in the same tablet, or may even be administered separately according to a particular regimen by different routes, e.g. orally and parenterally. In contraceptive (e.g., estrogen-free oral contraceptives) and HRT applications, the daily dosage of the progestogen of the present invention as defined above, and optionally (in the case of a combined oral contraceptive) the estrogenic component as defined above, preferably compound ((+) -1), may remain constant throughout the female menstrual cycle, or may vary independently of each other throughout the female menstrual cycle, as is well known in bi-or multi-staged formulations, wherein the concentration of the progestogen and estrogen are elevated during two or more phases of the menstrual cycle. Furthermore, in sequential use it is envisaged that the estrogenic component is administered separately during the first phase of the cycle and the progestogen is added during the second phase of the cycle. Also, as with conventional oral contraceptives, the progestogen of the present invention, particularly compound ((+) -1), and optionally an additional estrogenic component as defined above, can be interrupted for x days after administration of y ═ 28-x days over a 28 day cycle, where x can be, for example, 7, 6, 5, 4 or less, and thus y can be, for example, 21, 22, 23, 24 or more. In the case of an estrogen-free oral contraceptive, such as POP, daily administration of the progestogen of this invention, particularly compound ((+) -1), should not be interrupted.

The pharmaceutical compositions of the present invention may be prepared by methods well known in the art, as will be explained in more detail below. Depending on the mode of administration desired and the particular properties of the active compound used, such as solubility, bioavailability, etc., the use of well-known adjuvants and other suitable carriers, diluents, flavoring agents, etc. may be employed. Suitable carriers and adjuvants are those recommended for pharmaceutical, cosmetic and related fields in the following documents: ullmann's Encyclopedia of Technical Chemistry, Vol.4, (1953), pp.1-39; journal of Pharmaceutical Sciences, Vol.52(1963), p.918ff; h.v. Czetsch-Lindenwald, "Hilfsstuffe fur Pharmazie und andgrenzedendeGebiete" Pharm, Ind.2, 1961, p.72ff; Dr.H.P.Fiedler, Lexikon derHilfsstuffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Cantor KG, Aulendorf in fur Monberg, 1971.

As mentioned above, suitable modes of administration of the progestagens of general formula (I), especially compound ((+) -1) or pharmaceutical compositions containing said compound free of (as in estrogen-free oral contraceptives) or including other estrogenic components such as 17 α -ethinyl estradiol are oral, e.g. by tablets, pills, dragees, capsules, granules, solutions, emulsions or suspensions and the like. The compounds suitable for the purposes of the present invention as described above can be mixed with known and common adjuvants and carriers for the preparation of pharmaceutical compositions for oral administration, such as gum arabic, talc, starch, sugars (e.g., mannose, methylcellulose, lactose, etc.), gelatin, surfactants, magnesium stearate, aqueous or non-aqueous excipients, paraffin derivatives, crosslinking agents, dispersants, emulsifiers, lubricants, preservatives, flavoring agents (e.g., essential oils, etc.), or solubilizing agents (e.g., benzyl benzoate or benzyl alcohol). In pharmaceutical compositions, the active ingredient may also be dispersed in a particulate, e.g., nanoparticle, composition.

However, other modes of application are also envisaged, such as parenteral administration, e.g. intraperitoneal, intramuscular (e.g. by injection of aqueous, oily or other solutions, e.g. by depot injection, wherein the hormone is slowly released from the depot into the blood and thereby transported to the target organ, e.g. the hypothalamus, pituitary and uterus), subcutaneous or transdermal application. For parenteral administration, the active agent may be dissolved or suspended in a physiologically acceptable diluent, for example, an oil, with or without solubilizers, surfactants, dispersants or emulsifiers. As the oil, for example, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil, and sesame oil may be used without limitation. Transdermal application may be achieved by a specific design for transdermal delivery of the active agent, optionally with a suitable patch containing a specific penetration enhancer, as is well known in the art. In addition, creams, ointments, creams or gels may also be used for transdermal delivery.

Another way of application is by implantationA depot implant with an inert carrier material. The reservoir material can be, for example, a biodegradable polymer or a synthetic polysiloxane such as silicone rubber. The implant is designed to release the active agent in a controlled manner over a longer period of time, e.g. 3 to 5 years. Yet another suitable mode of administration is via an intravaginal device (e.g. pessary) or intrauterine system (IUS) containing a reservoir for the controlled release over an extended period of time of an active agent such as a progestin and/or estrogen according to the invention. Such IUS (e.g. MIRENA)^TM) The hormone may be released continuously in determined amounts for up to 5 years (or until the system is removed) after implantation into the uterine cavity. The daily release of progestogen and/or estrogen corresponds to the daily dosage described above.

In a third aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable derivative or analogue thereof in therapy:

wherein R is₁And R₂Each independently is-H or-F,

R₃is-CH₃or-CF₃And an

Ar is

Or

With the proviso that the compound is not 5- [3- {1- (3-trifluoromethylphenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -2-benzo [ C ] furanone.

In a fourth aspect, the present invention provides the use in therapy of a pharmaceutical composition comprising a compound of formula (I) as defined above, with the proviso that the compound is not 5- [3- {1- (3-trifluoromethylphenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -2-benzo [ C ] furanone.

In the third and fourth aspects of the invention, the preferred compounds and compositions for use in therapy are the same as those described in the first and second aspects of the invention. Preferably, the compounds and compositions of the present invention, especially the compound ((+) -1) or pharmaceutical compositions comprising the compound ((+) -1), can be used for example as (co-) oral contraceptives (COCs), estrogen-free oral contraceptives such as progestogen-only "pellets" (POPs), contraceptive patches, injections, implants or intrauterine systems (IUS) for birth control, or optionally in combination with a progestogen, especially 17 α -ethinyl estradiol, for use in hormone replacement therapy or in the treatment of gynaecological disorders, such as dysmenorrhea, endometriosis, myoma, premenstrual syndrome, dysfunctional uterine bleeding and the like. Explanations of other treatable diseases or other applications, for example in the field of contraception, are discussed below in the fifth and sixth aspects of the invention.

In a fifth aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable derivative or analogue thereof in the manufacture of a medicament for selectively modulating progesterone receptor mediated effects in a preferred tissue relative to a second tissue:

wherein R is₁And R₂Each independently is-H or-F,

R₃is-CH₃or-CF₃And an

Ar is

Or

But the compound 5- [3- {1- (3-trifluoromethylphenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethyl-propionylamino ] -2-benzo [ C ] furanone is included and is excluded from the scope of the general formula (I) by the first, second, third and fourth aspects of the present invention.

As previously disclosed in various aspects of the invention, in particular the first aspect, the same compounds of general formula (I) as described above are preferred compounds for the purposes of the present invention. Thus, compound (I), particularly the compound ((+) -1), namely (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone, or pharmaceutically acceptable derivatives and analogues thereof, are likewise the most preferred compounds for the fifth aspect of the present invention.

For purposes of this aspect of the invention, "selectively modulating" a PR-mediated effect means that a compound of formula (I) as described above can achieve one or more effects on a preferred target tissue that are of a different type (e.g., inhibitory, stimulatory or non-productive effect) and/or of a different intensity (e.g., weak, strong and/or long or short duration) than the effect caused by the ligand in a second preferred target tissue.

It will be appreciated that the benefits of the present invention are of course not limited to the preferred and less preferred tissues themselves, but are equally intended to be of the preferred and less preferred organs, and therefore the fifth aspect of the invention also relates to the use of a compound of formula (1) as defined above (and including the compound 5- [3- {1- (3-trifluoromethylphenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethyl-propionylamino ] -2-benzo [ C ] furanone excluded from the scope of formula (I) by the first, second, third and fourth aspects of the invention) in the manufacture of a medicament for selectively modulating the PR-mediated effects of the preferred tissue relative to the less preferred tissue.

For the purposes of the present invention, the preferred target organ is preferably the reproductive tract, i.e., primarily the uterus, and the secondary target organ is the breast, particularly the mammary gland. Accordingly, the preferred target tissue is preferably uterine tissue and the second preferred target tissue is preferably breast tissue. Thus, the compounds of the fifth part of the invention exhibit a segregating active function relative to a first selected target tissue, preferably uterine tissue, and a second (i.e. different) selected target tissue, preferably breast tissue.

Preferably, "selectively modulating the PR-mediated effect of a preferred tissue relative to a less preferred tissue" means in the specific context of the present invention selecting a less preferred tissue relative to said preferred tissue, preferably breast tissue, to selectively enhance the PR-mediated effect in said preferred tissue, preferably uterine tissue. In other words, by the methods and uses of the present invention, PR-mediated effects in the first selected tissue (preferably uterine tissue) are selectively enhanced as opposed to (i.e., as compared to) PR-mediated effects in the second selected tissue (preferably breast tissue), i.e., a separation of PR-mediated effects is observed in the first and second selected target tissues.

The term "selectively modulating the PR-mediated effect of the first selected tissue relative to the second selected tissue" is therefore not intended to be limited to certain absolute values of PR-mediated effects in the first and second selected tissues, but includes, for example, situations in which the induced PR-mediated effect in the second selected tissue (preferably breast tissue) is low or not detectable at all, whereas the induced PR-mediated effect in the first selected tissue (preferably uterine tissue) is very pronounced or only moderate, but in any case improved relative to the induced PR-mediated effect in the second selected tissue.

Most preferably, the compounds of the invention as defined in the fifth aspect of the invention above exert a beneficial and/or protective effect on PR-mediated in the reproductive tract, such as maintenance of pregnancy, and also maintain a conventional progestogenic effect, such as inhibition of ovulation and the like, against an adverse PR-mediated effect in the breast, such as proliferation/differentiation of mammary epithelial cells.

Thus, the present invention provides progestogenic compounds with a clearly separated function of progestogenic activity, which are capable of eliciting the desired beneficial effects in one progesterone target organ, such as the uterus, while not eliciting adverse effects such as proliferation/differentiation of breast tissue (which is manifested as accelerated formation of terminal mammary buds) in another progesterone target organ, such as the breast. However, the benefits of the present invention are not limited to isolated uterine/breast tissue function, but are equally applicable to binding of other target tissues in relation to progesterone receptor modulation.

The compound of formula (I) as defined above, preferably the compound ((+) -1) used in this aspect of the invention, actually shows isolated activity (uterus against breast) is demonstrated below, for example in example 3, wherein it is demonstrated that the compound of the invention, in particular the compound ((+) -1), shows strong gestagenic activity in the uterus in vivo with respect to the maintenance of pregnancy and a significant reduction of the progestagenic activity in the breast tissue in terms of proliferation of the terminal end-buds of the breast. Also included in the examples are detailed descriptions of biological tests for determining whether a certain compound actually selectively modulates PR-mediated effects of a preferred tissue, preferably uterine tissue, relative to a less preferred tissue, preferably breast tissue.

However, in such a general sense, to determine whether a compound actually selectively modulates a PR-mediated effect of a defined target tissue relative to another target tissue, it is preferred to determine the kind of effect elicited by the compound (i.e., whether the compound inhibits, does not affect, enhances or maintains a PR-mediated effect in the target tissue) and the intensity of the effect elicited relative to the effect produced by a known standard progestagen ligand, such as the standard progestagen R5020 (promegestone). The effects of the test compounds in the first and second target tissues are then preferably compared and evaluated, taking into account the anticipated medical indication or anticipated application (e.g., birth control or HRT, etc.). Screening assays for tissue-specific progestogen receptor ligands based on in vivo assays on the one hand and in vitro assays on the other hand or in combination with in vivo/in vitro tests are described in detail in WO02/054064, the disclosure of which is incorporated herein by reference. For example, assays to determine whether a compound selectively induces PR-mediated effects of the uterus or ovary relative to the breast are bioassays for proliferation/differentiation of epithelial cells of the breast in rodents, pregnancy maintenance assays or endometrial proliferation/differentiation assays in rodents, and ovulation inhibition assays or ovulation overage assays in rodents. However, as previously mentioned, the present invention is not limited to uterus/breast selective progestagens, but is equally applicable to other tissues or organs involved in PR-mediated effects. It is clearly within the knowledge of the skilled person to select and perform suitable in vivo tests as described above in the desired target tissue which is not the preferred tissue as described above, and to determine the effect induced by a certain progestogen tested relative to a suitable standard progestogen.

Due to the significant separately active function of the progestogens of general formula (I) described above, especially of the compound ((+) -1), on PR-mediated effects in different progesterone target organs, especially in the breast and reproductive tract, the medicaments prepared from the compounds of the present invention (and optionally other estrogenic components) are suitable for the treatment of certain gynaecological disorders as well as for HRT. The use of the compounds of the invention as contraceptives is not always a medical indication but is of a sixth aspect of the invention, for which reason it will be discussed below. It is to be understood that gynaecological disorders include, but are not limited to, for example, endometriosis, myoma, dysmenorrhea, premenstrual syndrome (PMS, which is a collective term for many symptoms such as abdominal pain, headache, swelling, depression, irritability, etc., which many women experience six to eight days before menstruation), dysfunctional uterine bleeding (due to hormonal deficiencies or imbalances). The compounds of the present invention can also control menstrual cycle irregularities. HRT is used primarily to alleviate climacteric symptoms such as climacteric syndrome (e.g., hot flashes, night sweats), osteoporosis, dry mucous membranes, and psychological symptoms (e.g., depression). There is even strong evidence that HRT prevents the development of cardiovascular disease, alzheimer's disease, colon cancer, or other diseases.

Reference is made to the second aspect of the invention with respect to envisaged and preferred modes of use, envisaged and preferred dosages, envisaged and preferred further pharmaceutical ingredients and optionally further estrogenic ingredients. All statements herein regarding suitable, preferred, more preferred and most preferred embodiments apply equally to the fifth aspect of the present invention, i.e. the use of a compound of formula (I) comprising the compound 5- [3- {1- (3-trifluoromethylphenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethyl-propionylamino ] -2-benzo [ C ] furanone excluded from the scope of formula (I) by the first, second, third and fourth aspects of the present invention, for the preparation of a medicament for modulating preferred tissue PR mediated effects relative to a second tissue. Preferred embodiments of this aspect of the invention (and of other aspects of the invention) are also encompassed by the respective dependent claims for each aspect of the invention.

Whereas the fifth aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable derivative or analogue thereof for the sole medical purpose, the sixth aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable derivative or analogue thereof as a contraceptive.

Wherein R is₁And R₂Each independently is-H or-F,

R₃is-CH₃or-CF₃And an

Ar is

Or

While birth control in general and contraception in particular may be applied in certain circumstances for purely medical reasons (and thus relating this aspect to the fifth aspect of the invention described above), contraception (i.e. preventing pregnancy) is generally not considered to be intended to prevent or treat certain diseases. However, contraception using either a progestogen alone (e.g., an oral contraceptive without estrogen, such as POP) or in combination with an estrogen (e.g., COC) has beneficial (medical) effects in addition to pregnancy suppression. Contraceptives are known to treat certain conditions such as irregular bleeding in the menstrual cycle or premenstrual syndrome with the symptoms listed in the fifth section of the instant invention. Contraceptives also generally have a positive effect on the appearance of skin. In addition, women taking contraceptives are less likely to have Pelvic Inflammatory Disease (PID) and may have a reduced risk of ovarian, endometrial and colorectal cancer.

As mentioned above, the novel progestagens of this invention, especially the compound ((+) -1), are suitable for use in estrogen-free oral contraceptives, such as progestagen-only "mini-pills" (POP). These estrogen-free oral contraceptives are a suitable choice for women who are intolerant of the combined estrogen-progestin use due to some estrogenic effects, but who still want to enjoy the benefits of a hormonal contraceptive in tablet form. Furthermore, estrogen-free oral contraceptives are a good choice for women who are nursing, and because estrogen inhibits milk production during lactation, it is not advisable to take a combined estrogen-progestin contraceptive.

The novel progestogens of this invention, especially the compound ((+) -1), can be used not only in oral contraceptives that are completely free of any estrogenic component, but also in oral contraceptives that are substantially free of estrogen. "substantially free of estrogen" is understood to mean an amount of estrogen which is lower than the amount normally contained in an estrogen-progestin combination oral contraceptive.

However, in addition to the advantages of the progestagen alone (i.e., oral contraceptives without estrogen) or conjugated estrogen contraceptives described above, a contraceptive comprising the progestagen of the present invention described above, especially compound ((+) -1) above, which activates only the progestagen receptor of a particular target tissue or organ, especially the uterus, but has only a small degree of (or no) effect on any other unintended tissue or organ, especially the breast, thus making these treatments well tolerated and presenting serious side effects to a lesser extent that pose a potential health problem. Furthermore, due to their potential to tailor PR-mediated conditions and effects, the progestagens of this invention, especially compound ((+) -1), due to their target tissue specificity, can be administered at lower doses, which are much smaller than the doses of known progestagens for contraceptives (and other indications discussed in the fifth aspect of this invention). Other aspects of the use of progestagens as contraceptives are available from the following book, "Kontrazepton mit Hormonen" ("contraceptives containing hormones"), H.D.Taubert and H.kuhl, Georg Thieme Verlag Stuttgart-New York, 1995.

With regard to the preferred embodiments of the sixth aspect of the invention, reference is made, on the one hand, to the claims and, on the other hand, to the explanations and statements given in the second part of the present invention, namely pharmaceutical compositions comprising a progestogen of the general formula (I), especially the compound ((+) -1). The modes of administration, dosages, combinations of ingredients (especially with respect to optional other estrogenic ingredients), and any other preferred embodiments thereof as described are equally applicable to the sixth aspect of the invention, i.e. the use of a compound of formula (I) for contraceptive use.

A seventh aspect of the invention relates to a method of selectively modulating progesterone receptor mediated effects of a preferred tissue or organ relative to a second selected tissue or organ.

The method comprises the step of administering to a subject in need of selective modulation of progesterone receptor mediated effects an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative or analog thereof or a pharmaceutical composition comprising the compound of formula (I).

Wherein R is₁And R₂Each independently is-H or-F,

R₃is-CH₃or-CF₃And an

Ar is

Or

But includes the compound 5- [3- {1- (3-trifluoromethylphenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethyl-propionylamino ] -2-benzo [ C ] furanone which is excluded from the scope of the general formula (I) by the first, second, third, fourth and sixth aspects of the present invention.

With respect to the seventh aspect of the invention, selectively modulating progesterone-mediated effects on preferred tissues relative to less preferred tissues includes, for example-as in the other aspects of the invention described above-selectively enhancing the desired appearance and/or protective effects on preferred target tissues, preferably uterine tissue or target organs, preferably uterus relative to less preferred target tissues, preferably breast tissue or target organs, preferably mammary gland, undesirable PR-mediated effects (e.g. proliferation/differentiation). However, it is to be understood that the invention is not limited to isolated activity of the progestagens of this invention on the uterus/breast, but that the invention also encompasses isolated activity on any other preferred and sub-selected target tissues affected by the mediation of the progestagen receptor. Reference is made to the other aspects of the invention, in particular the fifth aspect, with regard to preferred embodiments and detailed explanations of "modulating the PR-mediated effect in preferred tissue relative to the sub-selected tissue".

As explained in the fifth aspect of the invention as well as the sixth aspect of the invention, the preferably mammalian, most preferably human, subject in need of selectively modulating progesterone receptor mediated effects may be, for example, a female subject in need (for medical reasons) or in desire to avoid pregnancy. Thus, as already mentioned above, the method of the seventh aspect of the invention may be used in contraceptives. In this respect, all the above-mentioned statements concerning the use of the progestogen of the present invention as a contraceptive agent apply equally to the use of the seventh aspect of the present invention, including the preferred embodiments concerning dosage, dosage regimen, mode of administration and optionally the combination of an estrogen with the progestogen of the present invention.

In addition to contraception, a medical indication that is beneficial and necessary for modulation of the effects mediated by the preferred tissue PR relative to the less preferred tissue is, for example, hormone replacement therapy or treatment of gynecological disorders. All these indications have been described in detail in, for example, the fifth aspect of the invention and are equally applicable to the seventh aspect of the invention.

The eighth and ninth aspects of the present invention relate to the use of A compound of the general formulA (I) or A pharmaceutically acceptable derivative or analogue thereof for the preparation of A medicament for selectively activating PR-A transcription relative to PR-B transcription and for selectively enhancing PR-A mediated action relative to PR-B mediated action,

wherein R is₁And R₂Are each-H or-F,

R₃is-CH₃or-CF₃，

Ar is

Or

The eighth and ninth aspects of the invention also relate to methods of selectively activating PR-A transcription relative to PR-B transcription and methods of selectively enhancing PR-A mediated effects relative to PR-B mediated effects. These methods comprise the step of separately administering to A subject in need of selective modulation of PR-A transcription and PR-A mediated effects A compound of formulA (I):

wherein R is₁And R₂Are each-H or-F,

R₃is-CH₃or-CF₃，

Ar is

Or

As demonstrated in example 5 below, the progestogen of the present invention, and in particular the compound (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone, (+) -1), has been found to selectively activate the transcription of PR-A and thereby selectively induce PR-A mediated effects, preferably without affecting the transcription of PR-B and PR-B mediated effects.

As described in the "background of the invention" section above, PR isoform B appears to be the most prominent cause of mammary proliferation and differentiation on the basis of the b.mulac-Jericevic and o.conneley studies, whereas antiproliferative effects of progestagens on uterine epithelial cells and on ovulation are likely mediated by PR isoform a (b.mulac-Jericevic, Science2000, 289, 1751-1754; Orla conneley, Endocrine Society Meeting, Toronto, June 2000). Thus, as mentioned above, it is also possible that A progestogen which shows selectivity for the progesterone receptor isoform A, i.e. A progestogen which activates PR- A transcription while preferably not affecting PR-B transcription, may selectively enhance PR-mediated effects in utero while preferably not affecting PR-mediated effects in the breast. This link between PR isoform specificity and tissue selectivity of PR ligands was demonstrated to be the subject of prior application WO 02/054064. This principle is demonstrated again by the present invention through examples 3 and 5, wherein the preferred compound of the invention, compound ((+) -1), proved to be A selective and highly potent PR- A agonist, thus showing strong separation activity function in vitro on PR isoforms A versus B and in vivo on different target tissues, including inducing desired and beneficial effects in uterine tissue without inducing adverse effects such as proliferation/differentiation of mammary gland in mammary tissue.

However, the application of the present invention is not limited to the uterus-to-breast system, but extends to other progesterone target organ systems. Substantially any condition in which a PR isoform mediated effect is implicated may be treated by use of a progestogen of this invention, or by preparation of a medicament of the eighth aspect of this invention, or by a method of the ninth aspect of this invention involving administration of the progestogen. It will be appreciated that the preferred progestogens, modes of administration, dosages and dosage regimens of the invention, combinations with other ingredients such as estrogens and the like as described in relation to the other aspects of the invention are equally applicable to the eighth and ninth aspects described herein.

It is noted that for the purposes of the present invention, the selectivity (or specificity, which term is used herein as A synonym for selectivity) of A progestin of the present invention over PR isoform B for PR isoform A is defined as the difference in transcriptional efficacy induced by this progestin in PR- A and PR-B transfected cells. Preferably, the difference is up to or more than 10%, more preferably up to or more than 15%, most preferably up to or more than 20%. "transcriptional efficacy" is defined as the response achieved by A defined concentration of the progestogen under test in PR-A or PR-B transfected cells relative to A standard progestogen (e.g., R5020).

In addition to "transcriptional efficacy", another potential parameter for assessing the selectivity of the tested progestagen for PR-A or PR-B is "competence", i.e., EC₅₀Value (or technically equivalent ED thereto)₅₀) It is determined in vitro in PR-A or PR-B transfected cells. Preferably, the difference in the ability of A particular progestogen to be tested to reach cells transfected with PR-A versus PR-B should be within A factor of 10 or A factor greater than 10. A more detailed description of the determination of transcription efficacy and capacity is given in example 5, below, and in prior application WO02/054064, which is hereby incorporated herein by reference for all purposes. As demonstrated in example 5 below, the compounds of the invention, especially compound ((+) -1), are strong agonists with PR- A selectivity.

In addition to the in vivo use of the progestagens of the present invention described above, due to their specificity for PR isoform A, this remarkable ability to selectively activate PR- A transcription may also be exploited for diagnostic or scientific research purposes for in vitro assays involving, for example, both PR isoforms. Thus, the eighth and ninth aspects of the invention also provide in vitro uses and methods that are purely at the receptor level. For example, a compound of the invention, preferably compound ((+) -1), can be used as a standard to assess potential PR isoform specificity of other PR ligands. Thus, the compounds of the invention may be incorporated into diagnostic or scientific kits for determining the ability of other compounds to selectively activate transcription of PR isoforms. The compounds of the present invention are also useful for identifying cells specific for certain PR isoforms for diagnostic or scientific applications.

For details on the in vitro assay of progestogens with PR isoform specificity used in example 5 below, see WO02/054064, incorporated herein by reference. WO02/054064 discloses, inter aliA, how to obtain cells transfected with plasmids expressing PR-A or PR-B, how to detect PR-A and PR-B transcription and how to identify those PR ligands which exhibit PR isoform specificity. Furthermore, as mentioned above, WO02/054064 also discloses screening experiments for tissue-selective PR ligands.

A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable derivative or analogue thereof

Wherein R is₁And R₂Are each-H or-F,

R₃is-CH₃or-CF₃，

Ar is

Or

With or without the limitation that the compound is not 5- [3- {1- (3-trifluoromethylphenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethyl-propionylamino ] -2-benzo [ C ] furanone, the process being similar to that disclosed in WO98/54159 for obtaining the larger class of compounds described therein. However, since the compounds of the invention are novel with respect to the compounds disclosed in WO98/54159, several different synthetic routes to the progestogen of the invention are described below. The preparation of the compounds (1), (2), (3) and (4) is described in detail in examples 1a), 1b), 1c) and 1d), respectively.

The first preferred process for obtaining the compounds of formula (I) as described above starts with compounds of formula (II)

Wherein the substituent R₁、R₂And Ar is as defined above for formula (I). Reacting a compound of formula (II) with a compound of formula CF in the presence of a catalyst₃-SiMe₃Or CF₃-Si(R^x)₃A compound shown in the specification, wherein R^xIs C₁To C₄Or with a methyl metal compound such as a grignard reagent or an alkyl lithium to produce a compound of formula (I). A basic salt such as a fluorine salt or a basic carbonate can be used as a catalyst (see J.Am.chem.Soc.111, 1989, 393).

Furthermore, the compounds of the general formula (I) of the present invention can also be synthesized from compounds of the general formula (III):

wherein R is₁And R₂Are as defined for formula (I) above, LG is a leaving group such as-Cl, -Br or a tosylate substituent. Reacting a compound of formula (III) with a compound Ar-NH-R ', wherein Ar is as defined above for formula (I) and R' is a hydrogen atom or C₁To C₅An acyl group of (1). Under certain circumstances, the substituent R' must be subsequently removed. The compound of formula (III) is also formed as an intermediate product, for example, it may be formed as an acid chloride directly from the corresponding carbonic acid.

The substituted type on the benzene ring of the compound shown in the general formula (I) of the invention contains a substituent R₁、R₂and-CF₃Can be obtained by a method for selective substitution of aromatic rings known in the art.

The present invention is further described by the following examples, which, however, do not limit the scope of the present invention.

Examples

Example 1: preparation of progestogens of the general formula (I)

a) Preparation of (+ -) -, (+) -and (-) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl]-2- Trifluoromethyl-propionylamino } -2-benzo [ C ]]Furanones ((±) -1, (+) -1 and (-) -1):1- (2-fluoro-5-trifluoromethylphenyl) -ringPropyl-nitrile:

8.15ml of N, N '-dimethylimidazolidinedione (N, N' -dimethylimidazolidinazolidinone) are added to 78ml of a 2M solution of lithium diisopropylamine (tetrahydrofuran/heptane/ethylbenzene) over the course of 10 minutes at-70 ℃ under an inert gas atmosphere. After 15 minutes, 10.6g (2-fluoro-5-trifluoromethylphenyl) -acetonitrile were added. After 10 minutes, 20.3ml of 1, 2-dichloroethane (note: also (2-fluoro-5-trifluoromethylphenyl) -acetonitrile with 1, 2-dibromoethane and Cs were added at-20 ℃ C₂CO₃Reaction) and the mixture was stirred at-20 ℃ for 2 hours and at ambient temperature for 16 hours. Then, the mixture was cooled with ice and a saturated solution of ammonium chloride and ethyl acetate were added. The ethyl acetate phase is then washed twice with a saturated solution of ammonium chloride and twice with water, dried over sodium sulfate and concentrated and distilled by a Kugelrohr apparatus.

Yield: 8.7g 1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl-nitrile, b.p.140 ℃/0.04hPa1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl-aldehyde (carbaldehyde):

8.5g of 1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl-nitrile are dissolved in 60ml of toluene. 56ml of 1M diisobutylaluminum hydride dissolved in toluene were added at-70 ℃ over 45 minutes. After 4 hours, 120ml of ethyl acetate were added dropwise at-78 ℃. The mixture was left to reach ambient temperature and washed three times with 2N sulfuric acid and once with water. The ethyl acetate phase is dried over sodium sulfate and chromatographed on silica gel (hexane/ethyl acetate: 5+ 1).

Yield: 4.5g 1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl-aldehyde

3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] 2-oxo-propionic acid:

to a solution of 5.0g of ethyl 2-diethylphosphono-2-ethoxyacetate in 40ml of tetrahydrofuran was added a solution of 10ml of a 2M lithium diisopropylamine solution in tetrahydrofuran/heptane/toluene under ice cooling over 20 minutes. The mixture was stirred at 0 ℃ for 30 minutes. 30ml of a solution of 4g of 1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl-aldehyde in tetrahydrofuran are added at 0 ℃ over 30 minutes. After standing at ambient temperature for 20 hours, 2N sulfuric acid was added to the mixture, extracted with ethyl acetate, then dried over sodium sulfate and concentrated. The crude product was then dissolved in 50ml of ethanol and saponified with 33ml of 2M sodium hydroxide solution.

Yield: 5.2g of this acid are heated under reflux with 180ml of 2N sulfuric acid for several hours while stirring well. Extraction with ethyl acetate followed by washing with water gave 4.6g of 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionic acid as a yellow oil.

5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] 2-oxo-propionylamino } -2-benzo [ C ] furanone:

to a solution of 15ml of 2.9g of 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionic acid in dimethylacetamide at-10 ℃ was added 0.84ml of thionyl chloride. The mixture was stirred at-10 ℃ for 30 minutes and at 0 ℃ for 1 hour, and then added to 1.95g of 5-amino 2-benzofuranone (or vice versa, or 5-amino 2-benzofuranone was added to the mixture). After 16 hours at ambient temperature, 2M hydrochloric acid and ethyl acetate are added and the organic phase is washed to neutrality with water, dried over sodium sulfate and concentrated. Chromatography on silica gel (hexane/ethyl acetate: 1+1) and recrystallization from diisopropyl ether gave 2.4g of 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionylamino } -2-benzo [ C ] furanone (m.p.168 ℃ C.).

(±) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone (±) -1):

2.7g of 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionylamino } -2-benzo [ C ] furanone are dissolved in 15ml of dimethylformamide; under ice-cooling, 4.25ml of trifluoromethyl-trimethylsilane and 972g of cesium carbonate were added. After stirring at ambient temperature for 18 hours, 6.5ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran was added under ice-cooling, and the mixture was stirred for 1 hour. After the addition of all water, the product was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. Chromatography on silica gel (hexane/ethyl acetate: 3+2) gave fraction 1 as 760mg of the starting material and fraction 2 as 880mg of (. + -.) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone (. + -.) -1) (m.p.158 ℃).

Isolation of the enantiomer of compound ((±) -1):

mixtures of enantiomers of compound ((+ -) -1) may be delivered using chiral Carriers (CHIRALPAKAD)^Obtained from DAICEL) chromatography, with hexane/ethanol: 97+3 as mobile phase, 2.4g of racemate were obtained:

fraction 1 was (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl-]-2-trifluoromethyl-propionylamino } -2-benzo [ C]Furanone (±) -1): 867 mg; m.p.162-163 ℃ and alpha_D+114.5 ° (c-0.5 in chloroform);

fraction 2 was (-) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl-]-2-trifluoromethyl-propionylamino } -2-benzo [ C]Furanone (±) -1): 860 mg; m.p.163-164 ℃ C,. alpha._D-113.7 ° (c ═ 0.5 in chloroform).

b) Preparation of (+ -) -, (-) -and (+) -6- { 2-hydroxy-3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropane Base of]-2-trifluoromethyl-propionylamino } -4-methyl-2, 3-benzoxazin-1-one ((±), (+) -, (-) -2):

1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl-nitrile:

preparation from (2-fluoro-3-trifluoromethylphenyl) -acetonitrile is analogous to that of 1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl-nitrile (see example 1 a)). B.p.120 ℃/0.04 hPa.

1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl-aldehyde:

the preparation from 1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl-nitrile is analogous to that of 1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl-aldehyde (see example 1 a)).

3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionic acid:

the preparation from 1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl-aldehyde is analogous to the preparation of 3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionic acid (see example 1 a)). M.p.177 ℃ (degradation).

6- {3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionylamino } -4-methyl-2, 3-benzoxazin-1-one:

the preparation from 3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionic acid is analogous to that of 6- {3- [1- (3-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionylamino } -4-methyl-2, 3-benzoxazin-1-one (see example 1 c)). M.p.117-118 ℃.

(±) -6- { 2-hydroxy-3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -4-methyl-2, 3-benzoxazin-1-one (±) -2):

analogously to the compound (+ -) -1) of example 1a), (+ -) -6- { 2-hydroxy-3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } 4-methyl-2, 3-benzoxazin-1-one (+ -) -2) is obtainable from 6- {3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionylamino } -4-methyl-2, 3-benzoxazin-1-one. M.p.200-201 ℃.

Separation of enantiomers of compound (±) -2):

the (+) and (-) enantiomers were separated as described in example 1 a). Separation yield:

fraction 1 was (-) -6- { 2-hydroxy-3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -amino]-2-trifluoromethyl-propionylamino } -4-methyl-2, 3-benzoxazin-1-one ((-) -2): m.p.171-173 deg.C, alpha_D-115.2 ° (c-0.5 in chloroform),

fraction 2 was (+) -6- { 2-hydroxy-3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -4-methyl-2, 3-benzoxazin-1-one ((+) -2): m.p.168-173 ℃.

c) Preparation of (+ -) -and (-) -6- { 2-hydroxy-3- [1- (3-trifluoromethylphenyl) -cyclopropyl-]-2- Methyl-propionylamino } -4-methyl-2, 3-benzoxazine-1-one ((±), (+) -and (-) -3):

6- {3- [1- (3-trifluoromethylphenyl) -cyclopropyl ] 2-oxo-propionylamino } -4-methyl-2, 3-benzoxazin-1-one:

1.8ml of thionyl chloride was added to 60ml of a solution of 6.0g of 3- [1- (3-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionic acid (prepared as described in WO 98/54159) in dimethylacetamide at-10 ℃. The mixture was stirred at-10 ℃ for 30 minutes and at 0 ℃ for 1 hour and then mixed with 5g of 6-amino-4-methyl-2, 3-benzoxazin-1-one. After 16 hours at ambient temperature, the mixture separated into an aqueous phase and an ethyl acetate phase. The organic phase was washed with brine, dried over sodium sulfate and concentrated. Chromatography on silica gel with hexane and ethyl acetate (10-20%) as the liquid phase gives 6.78g of 6- {3- [1- (3-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionylamino } -4-methyl-2, 3-benzoxazin-1-one (m.p.136-139 ℃ C.).

(±) -6- { 2-hydroxy-3- [1- (3-trifluoromethylphenyl) -cyclopropyl ] -2-methyl-propionylamino } -4-methyl-2, 3-benzoxazin-1-one (±) -3):

215mg of 6- {3- [1- (3-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionylamino } -4-methyl-2, 3-benzoxazin-1-one was dissolved in 7.5 dry tetrahydrofuran. Under ice-cooling conditions, 0.32ml of a 3M ether solution of methylmagnesium bromide was added. After 30 minutes, the reaction solution was poured into a saturated ammonium chloride solution at 0 ℃ and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated. Chromatography on silica gel using hexane and ethyl acetate (0-20%) as the liquid phase gave fraction 180 mg of the starting material and fraction 2 95mg of 6- { 2-hydroxy-3- [1- (3-trifluoromethylphenyl) -cyclopropyl ] -2-methyl-propionylamino } -4-methyl-2, 3-benzoxazin-1-one ((±) -3, m.p.75-76 ℃).

Separation of enantiomers of compound ((±) -3):

the (+) and (-) enantiomers were separated as described in example 1a) (+ -) -1). Separation yield:

fraction 1 was (-) -6- { 2-hydroxy-3- [1- (3-trifluoromethylphenyl) -cyclopropyl ]]-2-methyl-propionylamino } -4-methyl-2, 3-benzoxazin-1-one ((-) -3): m.p.129-130 deg.C, alpha_D-54.8 ° (c-0.5 in chloroform),

fraction 2 was (+) -6- { 2-hydroxy-3- [1- (3-trifluoromethylphenyl) -cyclopropyl-]-2-methyl-propionylamino } -4-methyl-2, 3-benzoxazin-1-one ((+) -3): m.p.132-135 deg.C, alpha_D+55.2 ° (c-0.5 in chloroform).

d) Preparation of (+ -) -, (+) -and (-) -5- { 2-hydroxy-3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropane Base of]-2-trifluoromethyl-propionylamino } -2-benzo [ C]Furanones (±), (+) -and (-) -4):

1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl-nitrile:

preparation from (2-fluoro-3-trifluoromethylphenyl) -acetonitrile was analogous to that of 1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl-nitrile (see example 1 a)). B.p.120 ℃/0.04 hPa.

1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl-aldehyde:

the preparation from 1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl-aldehyde is analogous to that of 1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl-aldehyde (see example 1 a)).

3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionic acid:

5- {3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionylamino } -2-benzo [ C ] furanone:

the preparation from 3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionic acid and 5-amino-2-benzofuranone is analogous to the preparation of 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionylamino } -2-benzo [ C ] furanone (see example 1 a)). M.p.157-158 ℃.

(±) -5- { 2-hydroxy-3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone (±) -4):

in analogy to the preparation of the compound (±) -1) in example 1a), (±) -5- { 2-hydroxy-3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone (±) -4) may be obtained from 5- {3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-oxo-propionylamino } -2-benzo [ C ] furanone. M.p.212-214 ℃.

Separation of enantiomers of compound ((±) -4):

fraction 1 was (-) -5- { 2-hydroxy-3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ]]-2-trifluoromethyl-propionylamino } -2-benzo [ C]Furanone ((-) -4): m.p.165-166 deg.C, alpha_D-115.5 ° (c-0.5 in chloroform),

fraction 2 was (+) -5- { 2-hydroxy-3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone ((+) -4): m.p.164-166 ℃.

Example 2 (in vivo progestogen activity assay-ovulation inhibition):

two menstrual cycles of female rats (body weight: 190 to 210g) were monitored before the start of treatment. Only animals with regular 4 day cycles were used for subsequent experiments. The test compound was administered to the animals for 4 days (days 1 to 4) from the start of the postestrus period, and thereafter, the cycle was controlled.

For subcutaneous application, the test compound was dissolved in benzyl benzoate/castor oil (1+9 v/v) and the daily dose was administered in a volume of 1ml/kg body weight.

For oral use, the test compound is suspended in a carrier liquid (85mg of Myrj)^RDissolved in 100ml of 0.9% w/v sodium chloride solution) and administered in a daily dose of 2ml/kg body weight.

Evaluation:

on day 4 of the test compound application, those animals in or after estrus were anesthetized with ether and one side of the ovaries was removed. The tube is prepared and the ovum is observed therein by microscopy. On day 5, all animals (whole and partially ovariectomized) were sacrificed with carbon dioxide, stored and the tubes analyzed in the same manner. Then, it was determined and expressed in percentage terms how much of the animal's ovulation inhibition occurred.

Tables 1-a and 1-b below clearly demonstrate that compound ((+) -1) effectively inhibits ovulation in adult female rats by inhibiting LH secretion. TABLE 1-a demonstrates the EC for ((+) -1)₅₀It was 45. mu.g/kg. Therefore, the compound is considered to have strong progestational activity. Comparison with the standard progestogen R5020 (promegestone) shows that compound ((+) -1) is one of the most potent progestogens currently identified in vivo. The factor is 1 to 2 (or more), and the potency is equivalent to or exceeds R5020 (refer to Table 1-b).

TABLE 1-a

(+) -1 dose [ μ g/kg]	Inhibition ratio (%)	EC₅₀[μg/kg]
(+) -1 dose [ μ g/kg]	Inhibition ratio (%)	EC₅₀[μg/kg]	01030100	0014100	45

TABLE 1-b

	R5020 (Standard)	((+)-1)	(+) -1) (factor compared to R5020)
	R5020 (Standard)	((+)-1)	(+) -1) (factor compared to R5020)	Ovulation inhibition (rat) [ EC₅₀]	0.06mg/kg	0.04mg/kg	1-2

Example 3: (in vivo measurement of Breast/uterine Selectivity)

a) Bioassay experiment for proliferation/differentiation of rat mammary epithelial cells

The purpose of this experiment was to evaluate the effect of progestogen on mammary gland development, particularly on estrogen-induced terminal bud formation in the udder of rats. Progestagens, together with other hormones (prolactins, estrogens, glucocorticoids, growth hormones, etc.), induce proliferation and differentiation of mammary epithelial cells. In particular, they involve the morphogenesis of vesicles and terminal termination buds, where milk is produced and secreted into the lumen.

To determine the effect of the progestogen to be tested in the present invention, particularly the compound ((+) -1), on mammary gland differentiation and proliferation, 21-day-old immature female rats (Wistar Han, SPF) were ovariectomized 4 to 6 days prior to initiation of treatment. Animals were given standard estrogen (estrone (E1), 70 μ g/kg) and the progestogen to be tested ((+) -1) (dose: 0.1ml/50g body weight; excipient benzyl benzoate/castor oil (1+4 v/v); subcutaneous administration) for 6 consecutive days. The control group is administered, for example, vehicle, progestagen-free estrone, estradiol with a known progestagen, for example R5020 (promeggestone). After 6 days of treatment, the animals were sacrificed with carbon dioxide.

For gross staining (whole mount staining), the mammary area in the groin of the left abdomen of the animal was shaved off and cut along with the skin. For histological/immunohistochemical analysis, mammary glands in the groin of the right abdomen of the animal were excised together with connective tissue attached thereto and fixed in 3.7% formalin PBS (phosphate buffered saline; Ca-free)²⁺/Mg²⁺) In (1).

Bulk dyeing

The specimens were fixed in ethanol-formalin solution overnight according to the Tellyesniczky method (see below). The mammary tissue and the subcutaneous tissue attached thereto were then peeled from the dermis, and the specimens were then fixed overnight. The following steps are followed: 70% ethanol: 1.5 hours; acetone: 3X 1.5 hours; acetone: overnight; isopropyl alcohol: 1.5 hours; 96% of ethanol: 2 hours; hematoxylin-iron: 3 hours; VE water: washing the sample for 2 × 0.5 hours; 70% ethanol: overnight; 80% of ethanol: 1.5 hours; 96% of ethanol: 1.5 hours; isopropyl alcohol: for 1.5 hours. The specimens were then transferred to petri dishes and placed in toluene for about 1 hour until the tissue no longer floated. The tissue was then treated with cedar wood oil (Merck, No. 1.06965). The incubation time is a minimum time and can be extended. In particular, the incubation time with 70% ethanol after fixation can be extended to at least 2.5 weeks. Preparation of solution required for bulk dyeing:

a) tellyesniczky ethanol-formalin: 37% of formaldehyde: 81.8ml, ethanol 70%: 1636ml, glacial acetic acid (added shortly before use): 81.8ml (total: 1800 ml).

b) Hematoxylin mother liquor: hematoxylin (Merck, No. 1.15938): 10g, ethanol 96%: 100 ml. This solution must be left at 37 ℃ for 48 hours before use. Can be stored for almost unlimited time when placed in dark.

c) Hematoxylin-iron solution used: hematoxylin mother liquor (after filtration): 15.2ml, ethanol 96%: 1374ml of FeCl₃×6H₂O (s.4): 91.1ml, 1mol/l HCl: 220ml (total: 1700 ml); the pH is adjusted to 1.25 with 2mol/l NaOH.

d)FeCl₃×6H₂Solution O: FeCl₃×6H₂O (Merck, No. 1.03943): 1.07g, VE water: 90.2ml, HCl: 37%: 0.92ml (total: 91.1 ml).

The number of terminal buds near the tail directional papillae was counted with 40-fold magnification. The area to be measured should be about 1.8mm². For a well-differentiated specimen, the area may be reduced, which should have at least 250 detectable buds. After the counting is finished, calculating every 1mm²The number of terminal buds.

Evaluation:

number of terminal and vesicle buds per mm²Standard deviation denotes (SD). The progestogenic effect of the progestogen being tested can be determined as a cutoff value for the termini and the terminal buds of the vesicles (see fig. 3) (i.e., the concentration at which significant progestogenic effect is first measured), or as an equivalent dose required to achieve the same differentiation as the 0.3mg/kg control compound, promegyprogesterone (R5020) (see fig. 1). For the data shown in fig. 1, differences between the respective groups to be tested were examined by ANOVA (Dunn's method). In FIG. 3, the differences between the groups were examined using the t-test compared to the estrone control group. The asterisks in fig. 1 and 3 indicate that there are significant differences.

MIB-5 immunohistochemistry (modified according to C.Gerlach et al, Lab.invest.1997, 77(6), 697-698):

for more detailed evaluation of proliferation of mammary epithelial cells, the cells were stained with proliferation labeling reagent MIB-5 as follows (refer to fig. 2): the mammary glands were fixed in 4% formaldehyde/PBS for 24 hours and embedded in paraffin. Sections of 4 μm were spread on slides, deparaffinized, microwaved for 10 minutes in citrate buffer pH6.0, and washed with PBS. 3% H for glass slide₂Blocking with O/methanol for 15 min, Blocking with Blockingkit (Vektor, No. SP-2001) was blocked for 10 min and rat serum (Sigma, No. S-7648) diluted 1: 2 in PBS for 30 min to reduce non-specific staining and washed in PBS. The slides were incubated for 1 hour with the monoclonal antibody MIB-5(Dianova, No. Dia-5055), which is specific for rat Ki-67 antigen (diluted 1: 200 with PBS/0.2% BSA). Then, the slides were washed twice with PBS/0.2% Tween 20, incubated for 1 hour in biotinylated rat anti-mouse secondary antibody (Dianova, No. 425-. Staining was performed with diaminobenzidine (Zymed substrate kit). All steps were performed at room temperature.

Evaluation:

to characterize the compounds tested, the percentage of breast epithelial cells stained with MIB-5 was determined. FIG. 2 shows the percentage of MIB-5 positive epithelial cell numbers +/-Standard Deviation (SD). Differences between groups were examined by ANOVA (Bonferroni t-test). Asterisks in FIG. 2 indicate significant differences (p < 0.05). The results of the experiments are further discussed in section c) below.

b) Experiment of rat maintenance pregnancy

In rats castration leads to termination of pregnancy. Progestagens (in combination with estrogens) are capable of maintaining pregnancy in castrated animals. However, the extent to which castrated rats maintain pregnancy is only optimal within a defined dose range. Thus, generally, either a high or low dose may result in a reduced effect. With a dose of estrone (E)₁) Concurrent treatment may enhance the pregnancy-maintaining effect of the progestogen.

Pregnant rats (Wistar Han, SPF) weighing 190 to 220g (5 to 8 animals per dose) were ovariectomized 2 hours after the first parenchymal administration on the eighth day of their pregnancy. From day eight to day fourteen rats are given daily combinations of the progestogen to be tested and a standard dose of E₁. One dayThereafter, the animals were sacrificed with carbon dioxide. For each animal, the number of fetuses surviving and dying in the animal is determined according to the heart beat of the fetus. In the case of an empty uterus, the number of implantation sites was determined by staining with a 10% ammonium sulfide solution.

Dosage forms and uses of the progestogen and estrone tested:

s.c. (subcutaneous) use: the progestogen to be tested was dissolved in benzyl benzoate/castor oil (1+4 v/v) and administered in a daily dose of 1ml/kg body weight.

P.o. (oral) use: the progestogen being tested is suspended in a carrier liquid (85mg Myrj)^RDissolved in 100ml of 0.9% w/v sodium chloride solution) and administered in a daily dose of 2ml/kg body weight.

I.p. (intraperitoneal) application: the progestogen to be tested was dissolved in propylene glycol and placed in a mini osmotic pump (model 2001, 1.0 μ l/h, 7 days) which was placed in the abdominal cavity of the rat.

The standard dosage of estrone was 0.005mg/kg body weight subcutaneously and dissolved in benzyl benzoate/castor oil (1.4 v/v).

Evaluation:

determination of pregnancy maintenance [% ] of each animal]Pregnancy maintenance rate per dose (median of single values) and EC₅₀(the dose at which pregnancy was maintained in 50% of the animals; 100% corresponds to control animals without ovariectomy). The results of the experiments are further discussed in section c) below.

c) (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl]-2-trifluoromethyl-propionylamino Radical } -2-benzo [ C]Results obtained with furanone ((+) -1) and discussion of the results

The following experimental results (table 2) were obtained from the bioassay of proliferation/differentiation of rat mammary epithelial cells (bulk staining) as described in a) above and the pregnancy maintenance experiment as described in b) above of the most preferred compound of the invention (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone ((+) -1) relative to the standard progestogen R5020 (promegestone).

Table 2 shows that in pregnancy maintenance experiments, EC is to be achieved₅₀The dose of progestogen (R5020 or ((+) -1)) to be tested per kg body weight (rat) and the dose required in the bioassay of the proliferation/differentiation of mammary epithelial cells (rat; whole body staining method) are indicated. The middle column, "equivalent dose", refers to the dose of ((+) -1) required to achieve the same effect as 0.3mg/kg R5020. The right-most column represents the factor by which the progestogen to be tested ((+) -1) differs from the activity shown by the standard progestogen R5020 in both experiments. Values derived from different pairs of three different experiments performed separately were quoted for differentiation/proliferation experiments of mammary epithelial cells. The factor of ca.1 is derived from the median of the single values (see left-most column).

Table 2:

	r5020 (Standard)	((+)-1)	(+) -1) (factor compared to R5020)
	r5020 (Standard)	((+)-1)	(+) -1) (factor compared to R5020)	Maintenance of pregnancy (rat) [ EC₅₀]	0.1mg/kg/d	0.012mg/kg/d	8
Mammary gland, whole body staining (rat) [ equivalent dose]	0.3mg/kg/d0.3mg/kg/d0.1mg/kg/d	0.6mg/kg/d0.9mg/kg/d0.03mg/kg/d	ca.1	Maintenance of pregnancy (rat) [ EC₅₀]	0.1mg/kg/d	0.012mg/kg/d	8
Mammary gland, whole body staining (rat) [ equivalent dose]	0.3mg/kg/d0.3mg/kg/d0.1mg/kg/d	0.6mg/kg/d0.9mg/kg/d0.03mg/kg/d	ca.1	Mammary gland, bulk staining (rat)) [ Critical dose]		0.1mg/kg/d

The preferred progestogenic compound of the present invention ((+) -1) causes a dose-dependent increase in the terminal and vesicle terminal buds, with a dose equivalent to 0.3mg/kg/d prometrexed of 0.6mg/kg/d (FIG. 1).

In addition, the critical dose of ((+) -1) induced ends and vesicle terminal buds was 100. mu.g/kg/d (see FIG. 3). Interestingly, MIB-5 positive cells decreased dose-dependently with increasing ((+) -1) concentration (FIG. 2). In addition, FIG. 2 demonstrates that 0.3mg/kg/d promegestone shows about 42% MIB-5 positive cells, while 1mg/kg/d ((+) -1) shows about 12% MIB-5 positive cells.

Taken together, these results show that ((+) -1) has approximately the same activity on the mammary gland as the reference compound promegestrol. Most notably, no effect on the formation of terminal and vesicle buds was found at the drug dose for full maintenance of pregnancy (see table 2) (fig. 3, table 2). Thus, (+) -1) has tissue selective activity in the uterus relative to the mammary gland. This separation of activity towards the uterus is at least 6 times greater. Furthermore, the dose of ((+) -1) is inversely related to the induction of mammary gland proliferation.

The above results clearly show that the preferred compound of the invention, (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone ((+) -1), is highly potent for pregnancy maintenance but very poorly proliferating/differentiating breast epithelial cells compared to the standard progestogen, R5020. Compared to R5020, compound ((+) -1) maintained pregnancy 8 times more potent than R5020, but had approximately the same effect on mammary glands as R5020. These experimental results strongly demonstrate that the compound of the invention ((+) -1) is a selective modulator of PR-mediated effects, enhancing the PR-mediated effects of the preferred target tissue of the invention in the uterus (pregnancy maintenance) relative to the PR-mediated effects of the invention in the sub-preferred target tissue of the breast (proliferation/differentiation of the mammary gland). In particular, as described above, when an effective pregnancy-maintaining amount of compound ((+) -1) was administered, no effect on the mammary gland was observed (see table 2 and fig. 3). Thus, as described in the "embodiments" section above, the compounds are particularly useful in contraception, HRT, and the treatment of gynecological conditions. The preferred progestogenic compounds of the present invention ((+) -1) are particularly useful in estrogen-free oral contraceptives.

The experimental results on the uterine/breast separation activity function obtained with the compound ((+) -1) as described above not only demonstrate that the compound is very useful for the indications and applications described in the "embodiments" section as a tissue specific progestogen of the present invention, but also demonstrate the viability of the concept that the PR isoform specificity of PR ligands is related to the tissue specificity of PR ligands, see WO 02/054064. Furthermore, the results show that tissue specific progestogens, in particular the uterus/breast selective progestagens of the present invention, can be recognized by A recognized progestogen as having PR isoform, i.e., PR- A versus PR-B, selectivity. The above results clearly demonstrate that, as demonstrated in example 5 below, a progestogen that is selective for PR isoform a as compared to PR isoform B selectively enhances PR-mediated effects of the uterus relative to PR-mediated effects on the breast (see table 2 above) at dosages suitable for maintaining pregnancy. It should be understood, however, that selectivity for PR- A versus PR-B (as demonstrated in example 5, where selectivity for PR- A versus PR-B has been determined for the progestins of the invention) does not result solely in uterine/breast selectivity (as the progestins of the invention are identified above), but may include any other progesterone target tissue selectivity as well as any other selective modulation of PR-mediated effects based on progesterone isoform-mediated effects.

Example 4: in vivo assay of Pre-pregnancy Activity by oral administration-denaturation of the endometrium of rabbits

Immature female rabbits (New Jersey white rabbits, 30 to 35 days old; from Schriever, Germany) were used for this experiment. To induce endometrial proliferation, all rabbits were primed with 5.0 g/kg/day 17- α estradiol (subcutaneously, 0.5ml/kg/day) on days one to four of the experiment. From the seventh to tenth days, the test compound was orally administered at a dose of 0.001, 0.01 and 0.1mg/kg/day (orally, 0.5 ml/kg/day). One group of animals served as a negative control group and only vehicle was given after estradiol challenge. The other group served as a positive control group and only progesterone was administered after estradiol priming to initiate endometrial differentiation. To investigate the progestogenic activity of the most preferred compound of the present invention ((+) -1), one treatment group administered compound ((+) -1) alone after estradiol priming.

Evaluation:

necropsy on day eleven. The parameter McPhail index (i.e. degree of differentiation) of the progestogenic activity is determined using light microscopy (fraction: 1 to 4; 1: glandless differentiation, 4: maximal differentiation).

As demonstrated in Table 3 below, the preferred compound of the invention, Compound ((+) -1), was effective in the endometrial degeneration test (Clauberg test) in rabbits. (+) -1) oral application and subcutaneous administration were determined to have the same efficacy. Therefore, when administered orally, it must be considered that the compound ((+) -1) has a strong activity.

TABLE 3

Mode of application	((+)-1)[mg/kg]	McPhail index	Critical value [ mg/kg]
Mode of application	((+)-1)[mg/kg]	McPhail index	Critical value [ mg/kg]	Subcutaneous (s.c.)	0.0010.010.1	1.02.73.8	0.001-0.01
Orally administered (p.o.)	0.0010.010.1	1.22.53.0	0.001-0.01	Subcutaneous (s.c.)	0.0010.010.1	1.02.73.8	0.001-0.01

Example five: in vitro assay for PR-A/PR-B isoform specificity

According to an eighth and ninth aspect of the invention, A progestogen of the general formulA (I), including the compound 5- [3- {1- (3-trifluoromethylphenyl) -cyclopropyl } 2-hydroxy-2-trifluoromethyl-propionylamino ] -2-benzo [ C ] furanone, which does not belong to the first, second, third, fourth or sixth aspect of the invention, is useful for selectively activating the transcription of PR- A relative to the transcription of PR-B, i.e. the progestogen of the invention preferably does not activate the transcription of PR-B, at least to A different extent than the activation of the transcription of PR- A. Thus, these progestogens may be used to selectively activate PR- A mediated effects over PR-B mediated effects, i.e. the compounds preferably do not affect PR-B mediated effects. In vitro experiments to determine whether A particular progestogen is selective for PR-A or PR-B are described below. The general formula of the invention is also demonstrated below

(I) The progestins shown are selective PR- A agonists. For A more detailed description of this experiment, see WO02/054064, incorporated herein by reference, in particular for the preparation of PR-A and PR-B transfected cells.

The method of screening for PR isoform specific progestogens of this invention was carried out by first and second SK-N-MC cells stably transfected with plasmids expressing hPR-A (first cell) or hPR-B (second cell), and a LUC reporter gene linked to a hormone-responsive MTV promoter.

Cells were grown in minimal essential medium containing Earl' S salts (S-MEM, L-glutamine free; Gibco BRL, No. 21090-.

In transcription experiments, cells were placed in 96-well dishes (2X 10)⁴Cells/dish) and incubated in the above medium, but the FCS was replaced with 3% charcoal filtered (stripeped) FCS. After 48 hours, the cells were contacted with the test compound diluted beforehand. To determine agonism, at high concentrations (10)^-6To 10^-11mol/l) of the progestogen to be tested. 10 for cells as positive control for reporter gene induction^-6To 10^-11Treatment with mol/l of R5020 (promegestone). Cells as a negative control for reporter gene induction were incubated in 1% ethanol.

After 24 hours incubation with the progestogen being tested, the medium was removed, the cells were lysed in 20. mu.l of lysis buffer (luciferase assay System E153A; Promega) and the plate was stirred for 10 minutes. 30ul of luciferase reagent (luciferase assay System E151A + 152A; Promega) was added to each dish over 30 seconds and the activity of the luciferase reporter gene product in the cell lysates was determined by a Microlite ML 3000 microtiter plate luminometer (Dynatech) in the cycling mode.

Evaluation of the effectiveness of the reaction [% ]]Evaluation of EC₅₀Values obtained are potency [ nM]. Having agonistic activity

The calculation is as follows:

the LUC activity [% ] of the measured data points was calculated as follows:

wherein, CI is 100% stimulation (R5020, 10)^-7mol/l)

CO-0% stimulation (ethanol, 1%).

Therefore, the effectiveness [% ] is calculated as follows:

potency [ nM]I.e. EC₅₀And measured by a chart.

Some of the efficacy results achieved by the different progestagens of this invention are shown in table 2 below. These results clearly demonstrate the selectivity of PR isoform a of the progestogen of this invention, especially the compound ((+) -1). Thus, these progestagens are capable of selectively activating transcription of PR-A relative to transcription of PR-B. At the same time, these progestagens are capable of selectively enhancing PR-A mediated effects over PR-B mediated effects. Thus, while the prior art has generally attempted to find more potent progestogens, the present invention provides highly selective progestogens that are suitable for selectively targeting certain desired tissues or organs, preferably isoforms of progesterone receptor, in particular isoforms of progesterone receptor a, that selectively activate PR-mediated effects in uterine tissue relative to PR-mediated effects in breast tissue.

Table 4:

	effective rate [% ] of PR-A agonism]	Effective rate [% ] of PR-B agonism]	Effective rate of delta activation (A-B)
	effective rate [% ] of PR-A agonism]	Effective rate [% ] of PR-B agonism]	Effective rate of delta activation (A-B)	(+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl]-2-trifluoromethyl-propionylamino } -2-benzo [ C]Furanone, (+) -1)	88.7	25	64
(+) -6- { 2-hydroxy-3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl]-2-trifluoromethyl-propionylamino } -4-methyl-2, 3-benzoxazin-1-one, (+) -2)	99.2	67.5	32		88.7	25	64
	99.2	67.5	32	(+) -6- { 2-hydroxy-3- [1- (3-trifluoromethylphenyl) -cyclopropyl]-2-methyl-propionylamino } -4-methyl-2, 3-benzoxazin-1-one, (+) -3)	94	71	23
(+) -5- { 2-hydroxy-3- [1- (2-fluoro-3-trifluoromethylphenyl) -cyclopropyl]-2-trifluoromethyl-propionylamino } -2-benzo [ C]Furanone, (+) -4)	100	82	18		94	71	23

Example six: rat anti-uterine activity test

Compounds with estrogenic activity induce growth of the uterus, resulting in an increase in uterine weight. They also induce specific changes in the appearance of endometrial epithelial cells by increasing epithelial thickness. PR modulators antagonize estrogenic activity by inhibiting uterine weight gain and epithelial cell proliferation. This effect is sometimes referred to as a "functional antiestrogen" effect.

To determine the anti-uterotrophic activity of the most preferred progestogen of the present invention, compound ((+) -1), ovariectomized rats were treated with 0.3 μ g/kg/d estradiol (E2) and increasing doses of ((+) -1) for 3 days (see FIG. 4). As shown in FIG. 4, each group tested contained 10 rats, except that one group (see FIG. 4, bottom panel, 150. mu.g/kg ((+) -1) indicated by "#") contained 9 rats.

Evaluation:

changes in uterine weight, luminal epithelial cell thickness, and the state of cell differentiation and keratinization in vaginal smears are all parameters of estrogenic activity. In combination with ((+) -1), both the estrogen-stimulated increase in uterine weight and the decrease in the increase in luminal epithelial cell thickness are parameters of anti-estrogen activity (see FIG. 4).

The stimulation of uterine weight and luminal epithelial cell thickness in the reference group (estradiol (E2) -treated) compared to the vehicle control group can be calculated using the formula:

in the antiestrogen test, the inhibitory effect of uterine weight or luminal epithelial cell thickness compared to that of the reference compound (estradiol) can be calculated as follows:

in the statistical analysis, 95% confidence intervals were calculated using software developed by the department of biometrics of Schering AG. Asterisks indicate significant differences (p < 0.05).

Discussion:

as shown in FIG. 4, (+) -1) has a strong functional antiestrogenic effect in terms of dose-dependent inhibition of uterine weight and epithelial cell thickness increase when administered in combination with estradiol. The 5. mu.g/kg/d dose ((+) -1) showed the next-to-maximal effect. The 15. mu.g/kg/d dose produced the greatest effect.

In summary, (+) -1) is a PR modulator with strong functional antiestrogenic activity. Maintenance of Activity in pregnancy (EC)₅₀A value of 12. mu.g/kg/d) in the same dosage range, (+) -1) having an anti-uterotrophic activity. These results demonstrate the high progestogenic potency of ((+) -1) in utero.

The cutoff of progestogen ((+) -1) for the formation of mammary terminal and vesicle termination buds was high (see FIG. 3 and Table 2), but even at very low concentrations ((+) -1), it still had an effect on the uterus (see example 6 and FIG. 4). It is demonstrated that the compounds of the invention have isolated effects in the breast and uterus.

Claims

1. A compound represented by the general formula (I) or a pharmaceutically acceptable derivative or analogue thereof,

wherein R is₁And R₂Each independently is-H or-F,

R₃is-CH₃or-CF₃And an

Ar is

Or

(+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone or a pharmaceutically acceptable derivative or analogue thereof.

3. A pharmaceutical composition comprising a compound of claim 1.

4. A pharmaceutical composition as claimed in claim 3 wherein the compound as defined in claim 1 is (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone or a pharmaceutically acceptable derivative or analogue thereof.

5. A pharmaceutical composition according to claim 3 or 4, wherein the compound as defined in claim 1 is present in an amount such that the daily dose is from 0.01 to 2 mg.

6. Pharmaceutical composition according to one of claims 3 to 5, further comprising 17 α -ethinyl estradiol or another estrogenic component.

7. A pharmaceutical composition according to claim 6 wherein 17 α -ethinyl estradiol or other estrogenic component is present in an amount such that the daily dose is from 0.01 to 0.05 mg.

8. A compound according to claim 1 for use in therapy.

(+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone or a pharmaceutically acceptable derivative or analogue thereof, for use in therapy.

10. A compound according to claim 8 or 9 for use in contraception, hormone replacement therapy or the treatment of gynaecological disorders.

11. A pharmaceutical composition according to claim 3, for use in therapy.

12. A pharmaceutical composition comprising (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone or a pharmaceutically acceptable derivative or analogue thereof, for use in therapy.

13. The pharmaceutical composition according to claim 11 or 12, for use in contraception, hormone replacement therapy or treatment of gynaecological disorders.

14. The use of a compound according to claim 1, but including the compound 5- [3- {1- (3-trifluoromethylphenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethyl-propionylamino ] -2-benzo [ C ] furanone, excluded from claim 1, in the manufacture of a medicament for selectively modulating progesterone receptor mediated effects in a preferred tissue over a less preferred tissue.

15. The use of claim 14, wherein the preferred tissue is uterine tissue and the less preferred tissue is breast tissue.

16. Use according to claim 14 or 15 for selectively enhancing progesterone-mediated effects in the uterus relative to progesterone-mediated effects in breast tissue.

17. Use according to one of claims 14 to 16, wherein the medicament is used for birth control, hormone replacement therapy or the treatment of gynaecological disorders.

18. Use according to any one of claims 14 to 17 for selectively enhancing the anti-proliferative effect of the uterus relative to the proliferative and differentiative effect of breast tissue.

19. Use according to any one of claims 14 to 18 wherein the compound as defined in claim 1 is (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone or a pharmaceutically acceptable derivative or analogue thereof.

20. The use as claimed in any one of claims 14 to 19, wherein the medicament is administered orally.

21. Use according to any one of claims 14 to 20, wherein the compound as defined in claim 1 is present in an amount such that the daily dose is from 0.01 to 2 mg.

22. The use as claimed in any one of claims 14 to 21, wherein the medicament further comprises 17 α -ethinyl estradiol or other estrogenic component.

23. Use according to claim 22, wherein 17 α -ethinyl estradiol or other estrogenic component is present in an amount such that the daily dose is from 0.01 to 0.05 mg.

24. Use according to claim 22 or 23, wherein the daily dosages of the compound as defined in claim 1 and 17 α -ethinyl estradiol or other estrogenic component vary independently from each other during the menstrual cycle of a woman.

25. Use of a compound according to claim 1 or a pharmaceutical composition according to claim 3 as a contraceptive.

26. The use as claimed in claim 25, wherein the compound as defined in claim 1 is (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone or a pharmaceutically acceptable derivative or analogue thereof.

27. The use of claim 25 or 26, wherein the contraceptive is administered orally.

28. Use according to any one of claims 25 to 27, wherein the contraceptive is an estrogen-free oral contraceptive.

29. Use according to any one of claims 25 to 28, wherein the compound as defined in claim 1 is present in an amount such that the daily dose is from 0.01 to 2 mg.

30. Use according to any one of claims 25 to 27 and 29, wherein the compound as defined in claim 1 is supplemented with 17 α -ethinyl estradiol or other estrogenic component.

31. Use according to claim 30, wherein 17 α -ethinyl estradiol or other estrogenic component is present in an amount such that the daily dose is from 0.01 to 0.05 mg.

32. Use according to one of claims 25 to 27 and 29 to 31, wherein the daily dosages of the compound as defined in claim 1 and 17 α -ethinyl estradiol or other estrogenic component vary independently of each other during the menstrual cycle of a woman.

33. Use of a compound according to claim 1, but comprising the compound 5- [3- {1- (3-trifluoromethylphenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethyl-propionylamino ] -2-benzo [ C ] furanone excluded from claim 1, in the preparation of a medicament for selectively activating transcription of progesterone receptor isoform a relative to transcription of progesterone receptor isoform B.

34. The use as claimed in claim 33, wherein the compound as defined in claim 1 is (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone or a pharmaceutically acceptable derivative or analogue thereof.

35. Use of a compound according to claim 1, but including the compound 5- [3- {1- (3-trifluoromethylphenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethyl-propionylamino ] -2-benzo [ C ] furanone excluded from claim 1, in the manufacture of a medicament for selectively enhancing the effect mediated by the progesterone receptor isoform a relative to the effect mediated by the progesterone receptor isoform B.

36. The use as claimed in claim 35, wherein the compound as defined in claim 1 is (+) -5- { 2-hydroxy-3- [1- (2-fluoro-5-trifluoromethylphenyl) -cyclopropyl ] -2-trifluoromethyl-propionylamino } -2-benzo [ C ] furanone or a pharmaceutically acceptable derivative or analogue thereof.