HK1191339A - Novel 19-nor-steroids and their use for treating progesterone-dependent conditions - Google Patents

Description

Novel 19-nor steroids and their use for the treatment of progesterone-dependent conditions

Cross Reference to Related Applications

The present application claims the benefit of international application No. PCT/US2010/062068 filed on 12/23/2010, the contents of which are incorporated herein by reference.

Technical Field

In several embodiments, the present invention relates to 19-nor steroid progesterone receptor modulators with reduced hepatotoxicity and improved solubility, compositions comprising the modulators, and the use of these progesterone receptor modulators to treat progesterone-dependent conditions.

Background

The effect of the steroid hormone progesterone on the reproductive system is well documented. For example, progesterone is extremely important for establishing and maintaining pregnancy and plays a role in various tissues of the reproductive system. The effects of progesterone on tissues outside the reproductive system have been reported but are less well characterized.

Antiprogestins, compounds that inhibit the action of progesterone, have considerable potential for use in the pharmacological modulation of fertility as well as a variety of conditions and diseases, such as breast cancer and endometriosis (endometrisis). The first reported antiprogestin, mifepristone (RU 486), is one of many 19-nortestosterone (nortestsosterone) derivatives with strong affinity for both progesterone and glucocorticoid receptors and with antiprogestinic and antiglucocorticoid activity. A number of antiprogestins based on the 19-nortestosterone skeleton have also been synthesized.

There are several disadvantages associated with the use of known antiprogestins, making them less desirable for long-term administration. If these and other limitations associated with antiprogestin therapy could be ameliorated, significant advances would be made in the treatment of hormone-dependent disorders.

Brief description of the invention

In one embodiment, the present invention provides novel steroids having strong antiprogestinic activity, minimal antiglucocorticoid activity, and reduced hepatotoxicity. The novel steroids may also have improved handling characteristics. More particularly, the present invention provides compounds having the general formula:

wherein: r¹、R²、R³、R⁴And X is as described below.

In related embodiments, the present invention provides methods wherein the compounds of formula I (or pharmaceutical compositions comprising the compounds of formula I) are used to treat a variety of hormone (i.e., estrogen and/or progesterone) dependent conditions in a patient in need of such treatment. In a related embodiment, the compound of formula I is administered chronically to treat a chronic hormone-dependent condition. In another related embodiment, the compound of formula I is administered by any route including oral administration (i.e., to the gastrointestinal tract of a subject). In a preferred embodiment, the compounds of general formula I are administered to the vaginal mucosa for the long-term treatment of chronic hormone-dependent conditions.

In another embodiment, the present invention provides methods of administering compositions comprising one or more compounds of formula I that avoid liver toxicity.

Hormone-dependent conditions that may be treated by the compositions of the present invention include, but are not limited to: endometriosis and pain associated therewith, endometriosis (adenomyyosis), ovarian endometrioma, dysmenorrhea, endocrine hormone-dependent tumors, uterine fibroids, endometrial hyperproliferation, ovarian cancer, cervical cancer, and breast cancer. The compositions of the invention are also useful for inducing menstruation, induction of labor, and contraception.

Brief Description of Drawings

FIG. 1 illustrates a comparison of Cmax (peak serum concentration) and area under the curve (AUC) following oral and vaginal administration of CDB-4124 or CDB-4453 at a 25mg dose in beagle dogs (beagle).

Figure 2 illustrates the true Cmax observed for Proellex (CDB-4124) and its mono-demethylated metabolite CDB-4453 and the predicted Cmax for the 3 mg, 6 mg and 9 mg doses following oral administration of the 12.5mg, 25mg and 50mg doses of CDB-4124. Figure 2 also illustrates the true Cmax observed for Proellex (CDB-4124) and its mono-demethylated metabolite CDB-4453 following vaginal administration of 12.5mg, 25mg and 50mg doses of CDB-4124.

FIG. 3 illustrates a comparison of inhibition of progesterone-induced endometrial proliferation in estradiol-pretreated naive rabbits following subcutaneous injection and oral administration of CDB-4124.

Figure 4 compares the antiprogestinic effect of CDB-4124 at three doses when delivered orally to estradiol-pretreated young rabbits in the presence of progesterone compared to when delivered to the vaginal mucosa of estradiol-pretreated young rabbits, as measured by a decrease in the McPhail index. Treatment with progesterone alone (vehicle control) provided a baseline measurement of gestagenic activity.

Detailed Description

While the invention is susceptible of embodiment in various forms, the following description of several embodiments is provided so that this disclosure will be considered an exemplification of the invention, and is not intended to limit the invention to the specific embodiments illustrated. Headings are provided for convenience only and should not be construed as limiting the invention in any way. Embodiments set forth under any heading may be combined with embodiments set forth under any other heading.

It should be understood that any range, proportion, and range of proportions that may be formed from any of the numbers or data presented herein represent additional embodiments of the invention. This includes formable ranges with or without a limited upper limit and/or a limited lower limit. Thus, the skilled artisan will appreciate that many such ratios, ranges, and ranges of ratios may be explicitly derived from the data and numbers presented herein and are all representative of embodiments of the invention.

Before the present compounds, compositions, and methods are disclosed and described, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

Definition of

The term "oral" administration means that the active agent is in a formulation designed for ingestion, i.e., designed to be delivered to the gastrointestinal system for absorption.

The term "effective dose" means an amount of an effective component of a composition sufficient to treat a particular condition.

The term "selective progesterone receptor modulator" means a compound that affects the function of progesterone receptors in a tissue-specific manner. The compounds act as progesterone receptor antagonists in some tissues (e.g., in breast tissue) and as progesterone receptor agonists in other tissues (e.g., in the uterus).

The term "treatment" or "treatment" as used herein refers to any treatment of any progesterone-dependent disorder or disease and includes, but is not limited to: inhibiting, arresting the development of, or preventing a condition or disease; ameliorating the condition or disease, e.g., causing regression of the condition or disease; or relieving the condition caused by the disorder or disease, relieving the symptoms of the disorder or disease.

The terms "prevent" or "prevention" in relation to a progesterone-dependent disorder or disease mean preventing the onset of the development of the disorder or disease if the disorder or disease does not occur or preventing the further development of the disorder or disease if one is already present. For example, the compositions of the present invention may be used to prevent the recurrence of tumors. Recurrence of the tumor can occur as a result of residual microscopic populations or nests of tumor cells that subsequently expand to clinically detectable tumors.

The term "progesterone agonist" means a compound that binds to progesterone receptors and mimics the action of natural hormones.

The term "progesterone antagonist" means a compound that binds to progesterone receptors and inhibits the action of progesterone.

The term "not substantially reduced" as used herein with respect to hormone levels in females means that hormone levels remain within the normal range during administration of the compositions of the present invention. Thus, it is believed that there may be some reduction in hormone levels as long as the hormone levels remain within the normal range.

The term "not substantially increased" as used herein with respect to hormone levels in females means that hormone levels remain within the normal range during administration of the compositions of the present invention. Thus, it is believed that there may be some increase in hormone levels as long as the hormone levels remain within the normal range.

The term "alkyl" as used herein refers to a straight, branched or cyclic, saturated aliphatic hydrocarbon having from 1 to 12 carbons and preferably from 1 to 6 carbons (in which case the term "lower alkyl" is described). The term "alkyl" as used herein includes "substituted alkyl" which means that the alkyl group contains one or more functional groups: such as aryl, acyl, halogen, hydroxy (e.g., hydroxymethyl), amino, acyloxy, alkoxy (e.g., methoxymethyl), and the like. These groups may be attached to any carbon atom of the alkyl moiety. The term "alkynyl" denoting a linear or branched group containing at least one carbon-carbon triple bond is not included in the term "alkyl".

The term "alkenyl" as used herein refers to a monovalent unbranched or branched hydrocarbon chain containing one or more double bonds, including but not limited to C such as vinyl, allyl, butenyl, pentenyl, hexenyl and the like₂-C₈An alkenyl group. The term "alkenyl" includes groups containing both "cis" and "trans" directions. An alkenyl group may be unsubstituted or substituted with one or two suitable substituents. The term "alkynyl" denoting a linear or branched group containing at least one carbon-carbon triple bond is not included within the term "alkenyl".

The term "acyloxy", as used herein, refers to an organic group derived from an organic acid by the removal of hydrogen, such as acetoxy, formyloxy, and the like. The organic group may be further substituted with one or more functional groups such as alkyl, aryl, aralkyl, acyl, halogen, amino (e.g., glycine), mercapto, hydroxyl, alkoxy, and the like.

As used herein, the term "acyl" refers to the group-C (O) R, where R is alkyl or aryl (substituted or unsubstituted).

The term "alkoxy" as used herein refers to the group-OR, where R is lower alkyl, aryl OR aralkyl and includes, but is not limited to, methoxy, ethoxy, phenoxy, methoxyethoxy, t-butoxy and the like.

As used herein, the term "hydroxy" refers to the group-OH.

The term "aryl" as used herein refers to an aromatic substituent which may be a single ring or multiple rings fused together, covalently linked, or linked to a common group such as a methylene or ethylene moiety and includes phenyl, naphthyl, biphenyl, and may contain heteroatoms such as thienyl and pyridyl. The aryl group may be substituted with a halogen atom, a carboxyl group, an alkoxy group or the like.

Compound (I)

In one aspect, the present invention provides compounds having the general formula:

I

wherein R is¹May be in the para, ortho or meta position and are functional groups including, but not limited to: -CH (OH) CH₃An alkyl group; an alkenyl group; a cycloalkyl group; a cycloalkenyl group; an aryl group; alkylsulfinyl (e.g. CH)₃SO); alkylsulfonyl (e.g. CH)₃SO₂) (ii) a Acyl (e.g., formyl, acetyl, propionyl, butyryl, etc.); alkoxy (e.g. -OCH)₃、-O(CH₂)₂CH₃、-O-CH₂-CH=CH₂) (ii) a A thioalkoxy group; thioalkyl (-SCH)₃) Acyloxy (e.g., acetoxy, propionyloxy); si (CH)₃)₃；；；(ii) a In which X and Y are acyl radicals(ii) a And preferably a heterocyclic ring containing at least one nitrogen atom (e.g. aziridinyl: (a)Or) Azacyclopropenyl group (Or) Azetidinyl, pyrrolidinyl (-NC)₄H₈) Substituted pyrrolidinyl (e.g., methoxypyrrolidinyl, ethoxypyrrolidinyl), pyrrole(s) (ii)) Piperidinyl (-NC)₅H₁₀) Substituted piperidinyl radicals (e.g. -O (CH)₂)₂NC₅H₁₀) Pyridyl group (a)) Morpholinyl (NC)₄H₈O), substituted morpholinyl (e.g. ethoxymorpholinyl),Azinyl, piperazinyl: () Substituted piperazinyl (e.g. phenyl)、) Diazinyl and oxazoles such as pyrazole (I) (II)))；R²Functional groups including but not limited to the following: hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (e.g., methoxy, ethoxy, vinyloxy, ethynyloxy, cyclopropoxy, etc.), acyloxy (e.g., formyloxy, acetyloxy, propionyloxy, heptanoyloxy)Alkyl, glycine, etc.), alkyl carbonate, cyclopentane propoxy, S-alkyl, S-CN, S-acyl, and-OC (O) R⁶Wherein R is⁶Is inclusive of alkyl, alkoxyalkyl (e.g., -CH)₂OCH₃) Or alkoxy (-OCH)₃) Functional groups within; r³Functional groups including but not limited to the following: alkyl (e.g., methyl, methoxymethyl), hydroxy, alkoxy (e.g., methoxy, ethoxy, methoxyethoxy, etc.), and acyloxy; r⁴Functional groups including but not limited to hydrogen and alkyl; and X is a functional group including, but not limited to: = O, wherein R5 is hydrogen OR alkyl = N-OR5, OH, CH₂、OAlk₁And OCOAlk₂Wherein Alk₁And Alk₂Is C1-C8 alkyl or C7-C15 aralkyl, with the proviso that if R is¹In para position and is-OCH₃、-SCH₃、-NC₄H₈、-NC₅H₁₀、-NC₄H₈O、-CHO、-CH(OH)CH₃、-COCH₃、-O(CH₂)₂NC₄H₈or-O (CH)₂)₂NC₅H₁₀Then X is not = O OR = N-OR5 wherein R5 is hydrogen OR alkyl, and with the proviso that if R is²Is hydrogen, R³Is hydroxy or methyl, R⁴Is methyl and X is = O, then R¹Is not methoxy, isopropyl, phenyl or hydrogen.

In a preferred embodiment, there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: r¹In para position and is-OCH₃、-SCH₃、-NC₄H₈₍Pyrrolidino), -NC₅H₁₀(piperidino), -NC₄H₈O (morpholino), -CHO, -CH (OH) CH₃、-COCH₃、-O(CH₂)₂NC₄H₈(Methoxypyrrolidino) or-O (CH)₂)₂NC₅H₁₀(ethoxypiperidinophenyl); r²Is hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (e.g., methoxy, ethoxy, vinyloxy, ethynyloxy, cyclopropoxy, etc.), acyloxy (e.g.Formyloxy, acetoxy, propionyloxy, heptanoyloxy, glycinyloxy, and the like), alkylcarbonate groups, cyclopentanopropoxy, S-alkyl, S-CN, S-acyl, and-OC (O) R⁶Wherein R is⁶Is a functional group comprising: alkyl, alkoxyalkyl (e.g. -CH)₂OCH₃) Or alkoxy (e.g. -OCH)₃)；R³Is alkyl (e.g., methyl, methoxymethyl), hydroxy, alkoxy (e.g., methoxy, ethoxy, methoxyethoxy, etc.), or acyloxy; r⁴Is hydrogen or alkyl; and X is OH, CH₂OAlk1 or OCOAlk2, wherein Alk1 and Alk2 are C1-C8 alkyl or C7-C15 aralkyl. In a particularly preferred embodiment, R¹In para position and is-COCH₃or-CHO, R²Is alkoxy, R³Is alkyl, hydroxy, alkoxy or acyloxy, R4 is alkyl and X is OH, CH₂OAlk1 or OCOAlk2, wherein Alk1 and Alk2 are C1-C8 alkyl or C7-C15 aralkyl. Even more preferably R¹In para position and is-COCH₃，R²Is methoxy, R³Is acetoxy, R4 is methyl, and X is OH, CH₂OAlk1 or OCOAlk2, wherein Alk1 and Alk2 are C1-C8 alkyl or C7-C15 aralkyl.

In another preferred embodiment, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R is¹In meta-or ortho-position and is-OCH₃、-SCH₃、-NC₄H₈(pyrrolidino), -NC₅H₁₀(piperidino), -NC₄H₈O (morpholino), -CHO, -CH (OH) CH₃、-COCH₃、-O(CH₂)₂NC₄H₈(Methoxypyrrolidino) or-O (CH)₂)₂NC₅H₁₀(ethoxypiperidinophenyl); r²Are hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (e.g., methoxy, ethoxy, vinyloxy, ethynyloxy, cyclopropoxy, etc.), acyloxy (e.g., formyloxy, acetyloxy, propionyloxy, heptanoyloxy, glycinyl, etc.), alkylcarbonate, cyclopentanopropoxy, S-alkyl, S-CN, S-acyl, and-OC (O)R⁶Wherein R is⁶Is a functional group comprising: alkyl, alkoxyalkyl (e.g. -CH)₂OCH₃) Or alkoxy (-OCH)₃)；R³Is alkyl (e.g., methyl, methoxymethyl), hydroxy, alkoxy (e.g., methoxy, ethoxy, methoxyethoxy, etc.), or acyloxy; r⁴Is hydrogen or alkyl; and X is = O, wherein R5 is hydrogen OR alkyl = N-OR5, OH, CH₂OAlk1 or OCOAlk2 wherein Alk1 and Alk2 are C1-C8 alkyl or C7-C15 aralkyl, with the proviso that if R is²Is hydrogen, R³Is hydroxy, R⁴Is methyl, and X is = O, then R¹Is not methoxy. In a particularly preferred embodiment, R¹In meta-or ortho-position and is-COCH₃or-CHO, R²Is alkoxy, acyloxy or hydrogen, R³Alkyl, hydroxy, alkoxy OR acyloxy, R4 is alkyl and X is = O, = N-OR5, OH, CH, wherein R5 is hydrogen OR alkyl₂OAlk1 or OCOAlk2, wherein Alk1 and Alk2 are C1-C8 alkyl or C7-C15 aralkyl. Particularly preferred compounds include 21-methoxy-17 α -acetoxy-11 β - (3-acetylphenyl) -19-norpregna-4, 9-diene-3, 20-dione (wherein R is¹In the meta position and is-COCH₃，R²Is methoxy, R³Is acetoxy, R4 is methyl, and X is = O):

17 alpha-acetoxy-11 beta- (3-acetylphenyl) -19-norpregna-4, 9-diene-3, 20-dione having the formula (wherein R¹In the meta position and is-COCH₃，R²Is hydrogen, R³Is acetoxy, R4 is methyl, and X is = O):

and 21-acetoxy-17 alpha-acetoxy-11 beta- (3-acetylphenyl) -19-norpregna-4, 9-diene-3, 20-dione having the formula (wherein R¹In the meta position and is-COCH₃，R²And R³Is acetoxy, R4 is methyl, and X is = O):

。

in yet another preferred embodiment, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R is¹In the para position and is alkyl; an alkenyl group; a cycloalkyl group; a cycloalkenyl group; an aryl group; alkylsulfinyl (e.g., methylsulfinyl); alkylsulfonyl (e.g., SO2CH 3); a thioalkoxy group; si (CH)₃)₃；；；(ii) a In which X and Y are acyl radicals(ii) a Aziridinyl, azetidinyl, methoxypyrrolidinyl, ethoxymorpholinyl, azetidinyl,(ii) an oxazinyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl or diazinyl group; r²Is hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (e.g., methoxy, ethoxy, vinyloxy, ethynyloxy, cyclopropoxy, etc.), acyloxy (e.g., formyloxy, acetyloxy, propionyloxy, heptanoyloxy, glycinyl, etc.), alkylcarbonate, cyclopentanopropoxy, S-alkyl, S-CN, S-acyl, or-OC (O) R⁶Wherein R is⁶Is inclusive of alkyl, alkoxyalkyl (e.g., -CH)₂OCH₃) Or alkoxy (-OCH)₃) Functional groups within; r³Is alkyl (e.g., methyl, methoxymethyl), hydroxy, alkoxy (e.g., methoxy, ethoxy, methoxyethoxy, etc.), or acyloxy; r⁴Is hydrogen or alkyl; and X is = O, wherein R5 is hydrogen OR alkyl = N-OR5, OH, CH₂OAlk1 or OCOAlk2 wherein Alk1 and Alk2 are C1-C8 alkyl or C7-C15 aralkyl, with the proviso that if R is²Is hydrogen, R³Is hydroxy or methyl, R⁴Is methyl, and X is = O, then R¹Not isopropyl or phenyl. In a particularly preferred embodiment, R¹In the para-position and is alkylsulfinyl, R²Is alkoxy, R³Alkyl, hydroxy, alkoxy OR acyloxy, R4 is alkyl and X is = O, = N-OR5, OH, CH, wherein R5 is hydrogen OR alkyl₂OAlk1 or OCOAlk2, wherein Alk1 and Alk2 are C1-C8 alkyl or C7-C15 aralkyl. Even more preferably R¹In para position and is-SOCH₃，R²Is methoxy, R³Is acetoxy, R⁴Is methyl and X is = O.

In yet another preferred embodiment, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R is¹In the meta or ortho position and is alkyl; an alkenyl group; a cycloalkyl group; a cycloalkenyl group; an aryl group; alkylsulfinyl (e.g. CH)₃SO); alkylsulfonyl (e.g. CH)₃SO₂) (ii) a A thioalkoxy group; si (CH)₃)₃；；；(ii) a In which X and Y are acyl radicals(ii) a Aziridinyl, azetidinyl, methoxypyrrolidinyl, ethoxymorpholinyl, azetidinyl,(ii) an oxazinyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl or diazinyl group; r²Is hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (e.g., methoxy, ethoxy, vinyloxy, ethynyloxy, cyclopropoxy, etc.), acyloxy (e.g., formyloxy, acetyloxy, propionyloxy, heptanoyloxy, glycinyl, etc.), alkylcarbonate, cyclopentanopropoxy, S-alkyl, S-CN, S-acyl, or-OC (O) R⁶Wherein R is⁶Is inclusive of alkyl, alkoxyalkyl (e.g., -CH)₂OCH₃) Or alkoxy (-OCH)₃) Functional groups within; r³Is alkyl (e.g., methyl, methoxymethyl), hydroxy, alkoxy (e.g., methoxy, ethoxy, methoxyethoxy, etc.), or acyloxy; r⁴Is hydrogen or alkyl; and X is = O, wherein R5 is hydrogen OR alkyl = N-OR5, OH, CH₂OAlk1 or OCOAlk2, wherein Alk1 and Alk2 are C1-C8 alkyl or C7-C15 aralkyl. In a particularly preferred embodiment, R¹In the meta or ortho position and is alkylsulfinyl, R²Is alkoxy, R³Alkyl, hydroxy, alkoxy OR acyloxy, R4 is alkyl and X is = O, = N-OR5, OH, CH, wherein R5 is hydrogen OR alkyl₂OAlk1 or OCOAlk2, wherein Alk1 and Alk2 are C1-C8 alkyl or C7-C15 aralkyl. Even more preferably R¹In the meta position and is-SOCH₃，R²Is methoxy, R³Is acetoxy, R4 is methyl, and X is = O.

R, whether in ortho, meta or para position, is particularly preferred¹The substituent is-CHO, -COCH₃and-SOCH₃。

Particularly preferred R²Substituents are alkoxy (especially methoxy or ethoxy) and hydrogen.

Particularly preferred R³The substituent being an alkoxy radical, in particular methoxyAlkyl or ethoxy) and acyloxy (especially acetoxy, propionyloxy and formyloxy).

Particularly preferred R⁴The substituent is an alkyl group, preferably a methyl group.

A particularly preferred X substituent is = O.

The compounds of formula I can be synthesized by conventional synthetic chemistry techniques, including those used to synthesize the compounds disclosed in U.S. patent nos. 6,861,415, 6,900,193, and 6,020,328, the contents of each of which are incorporated herein by reference. In particular, the synthetic schemes described in figure 1, figure 2 and figure 3 of the U.S. patent and figures 1-11 of the U.S. patent can be used in conjunction with synthetic techniques known in the art (e.g., the synthetic technique described in 6,020,328) to synthesize the compounds of the invention.

The compounds of the formula I have a phenyl group at C11 beta which is in the ortho, meta or para position (i.e.in the position R of the formula I)¹) Substituted with a functional group that is not metabolized to produce a primary amine upon administration of the compound. For example, a compound having a dimethylaminophenyl group at the C11 β position undergoes dealkylation upon administration to produce a primary amine aniline (-phenyl-NH) at the C11 β position₂). The dealkylation occurs in two steps: first, the dimethylaminophenyl group is relatively rapidly mono-demethylated to a monomethylaminophenyl group; second, in a relatively slow reaction, the remaining alkyl groups are removed to form primary amines. Without being bound by theory, it is believed that aniline or substituted aniline (phenyl-NRH) groups may act as reactive nucleophiles that contribute to adverse liver reactions in patients who have received these compounds through the formation of protein adducts, particularly when administered chronically in relatively high doses. Thus, R¹Not a primary, secondary or tertiary amine. Furthermore, R¹A functional group other than a primary, secondary or tertiary amine that is not itself substituted by a primary, secondary or tertiary amine. The compounds of the invention are therefore surprisingly useful for the long-term treatment of hormone-dependent conditions.

Certain compounds of formula IThe compounds may also have improved solubility in a variety of solvents including water and alcohol (e.g., ethanol) based solvents. Specifically, the inventors found that R is present in the meta (or ortho) position¹= acyl (especially COCH)₃) Alkylsulfinyl or alkylsulfonyl and having R²Compounds of general formula I, in which the alkoxy group, in particular methoxy group, is surprisingly soluble in a wide variety of polar solvents (i.e. having a dielectric constant of at least 15), have strong antiprogestinic activity and minimal antiglucocorticoid activity, making them particularly suitable as therapeutic agents for the treatment of progesterone-dependent disorders.

In related embodiments, the invention relates to methods of treating progesterone-dependent conditions by administering one or more compounds of formula I (or pharmaceutical compositions comprising one or more compounds of formula I) as described above. It is not expected that the compounds of formula I will contribute to adverse liver reactions in patients who have received these compounds and therefore, in accordance with this aspect of the invention, the compounds of formula I may be administered by any route including, but not limited to, oral (i.e. administration to the gastrointestinal tract), sublingual/buccal, intravascular, intramuscular, subcutaneous, inhalation, mucosal (e.g. rectal or vaginal) and topical routes. In a preferred embodiment, a composition comprising one or more compounds of formula I is administered orally at a dose of at least 25 mg/day, more preferably at least 50 mg/day, for a period of at least 2, 3, 4,5, 6,7, 8, 9, 10 or more months to treat a hormone-dependent condition.

Method of producing a composite material

The invention also provides methods of administering antiprogestins for the treatment of hormone (e.g., progesterone) dependent conditions that avoid hepatotoxicity.

In one embodiment, the invention relates to a method of treating progesterone-dependent conditions by oral administration of a compound of formula I, preferably at a dosage of at least 25 mg/day, more preferably at least 50 mg/day. The compounds of formula I may be administered orally daily (i.e. at least once daily for a period of consecutive days) over a dosing period which may last for at least 2, 3, 4,5, 6,7, 8, 9, 10 or more months.

In another embodiment, the invention relates to the non-oral administration of compositions comprising one or more compounds of formula I for the treatment of hormone (e.g., progesterone) dependent conditions. This aspect of the invention arises in part from the following unexpected findings: certain 19-nortestosterone derived antiprogestins or 19-norprogesterone derived antiprogestins can exhibit toxic effects on the liver at therapeutic concentrations, limiting their clinical utility. In particular, it has been found that patients receiving therapeutic oral (i.e., for ingestion) doses of antiprogestin/SPRM CDB-4124 for extended daily administration exhibit hepatotoxicity. A number of mono-demethylated metabolites of CDB-4124 were detected by pharmacokinetic studies in patients following oral ingestion of CDB-4124, suggesting that CDB-4124 undergoes significant first pass metabolism in the liver, providing an opportunity for liver damage. The compounds of formula I have a C11 β substituent that is not expected to form protein adducts in the liver and further avoid toxic liver effects by circumventing first-pass metabolism through non-oral administration of the compounds.

In related embodiments, the compound is administered non-orally at a therapeutically effective dose that is relatively low compared to the therapeutically effective dose of the compound when administered orally. For example, when administered topically to the vaginal mucosa, a therapeutically effective dose may be less than 50 mg/day, less than 40 mg/day, less than 30 mg/day, less than 20 mg/day, less than 10 mg/day, less than 5 mg/day, 5 mg/day-50 mg/day, 5 mg/day-40 mg/day, 5 mg/day-30 mg/day, 5 mg/day-20 mg/day, or5 mg/day-10 mg/day. In another related embodiment, the effective amount of the compound is less than the effective amount when administered systemically, e.g., an effective amount when administered topically to the vaginal mucosa may be 1/2, 1/3, 1/4, 1/5, 1/6, 1/7, 1/8, 1/9, and even 1/10 that are administered systemically to treat endometriosis, uterine fibroids, and other diseases located in the area.

Whether delivered by oral or non-oral routes, the compounds of general formula I as described above are expected to exhibit reduced or no hepatotoxicity, making them suitable for use in the treatment of various progesterone-dependent conditions when administered via any route of administration including, but not limited to, oral, sublingual/buccal, intravascular, intramuscular, subcutaneous, inhalation, mucosal (e.g., rectal or vaginal) and topical routes.

Non-oral administration of a compound of formula I may reduce hepatotoxicity (if present) relative to oral administration of the same compound. When administered non-orally, it is preferred that the compounds be administered by a route that avoids first pass metabolism, such as, but not limited to, intravenous, intramuscular, sublingual, and mucosal (e.g., vaginal, intrauterine, or rectal) routes.

In one embodiment of the invention, a composition of the invention is administered to a breast cancer patient to treat breast cancer. In a preferred embodiment, the patient is a human female and the breast cancer expresses human estrogen receptor (hER) or human progesterone receptor (hPR) and more preferably both hER and hPR.

In a related embodiment of the invention, the compositions of the invention are administered to a breast cancer patient having one or more tumors that are resistant to treatment with an anti-estrogen to treat the breast cancer. For example, the compounds of the present invention are particularly useful for treating tamoxifen resistant breast cancer in a patient.

In a related embodiment of the invention, a composition of the invention is administered to a patient suffering from a condition selected from the group consisting of: ductal Carcinoma In Situ (DCIS), mucous (glue) carcinoma, medullary carcinoma of the breast, papillary carcinoma of the breast, Adenoid Cystic Carcinoma (ACC), Paget's disease of the breast, inflammatory breast diseases, fibroadenomas and fibrocystic breast diseases.

In another embodiment of the invention, the compositions of the invention are administered to a female undergoing estrogen treatment to prevent the development of breast cancer in the female.

In a related embodiment, the composition is administered by a (non-oral) route that avoids first-pass metabolism, the route being selected from: sublingual/buccal, intravascular, intramuscular, subcutaneous, inhalation, mucosal (e.g. rectal, intrauterine or vaginal) and topical routes. In a preferred embodiment, the composition of the invention is administered to a breast cancer patient in the form of a transdermal patch, gel or ointment which is applied directly to the breast (e.g. to the nipple or areola) to treat breast cancer.

In another embodiment of the invention, the compositions of the invention are administered to a female patient in need thereof to inhibit endometrial proliferation. In a preferred embodiment, the compositions of the present invention are vaginally administered to a patient to inhibit endometrial proliferation.

In a related embodiment of the invention, a composition of the invention is administered to a female patient in need thereof to treat endometriosis. In a preferred embodiment, the compositions of the present invention are vaginally administered to a patient to treat endometriosis.

In another embodiment of the invention, the compositions of the invention are administered to females in need thereof to treat dysmenorrhea. In a preferred embodiment, the compositions of the present invention are administered vaginally to a patient to treat dysmenorrhea.

In yet another embodiment of the invention, a composition of the invention is administered to a female in need thereof to treat uterine fibroids. In a preferred embodiment, the compositions of the present invention are vaginally administered to a patient to treat uterine fibroids.

In another embodiment of the invention, a composition of the invention is administered to a female patient in need thereof to treat endometriosis. In a preferred embodiment, the compositions of the present invention are vaginally administered to a patient to treat endometriosis.

In another embodiment of the invention, a composition of the invention is administered to a female patient in need thereof to treat an endometrioma. In a preferred embodiment, the compositions of the present invention are vaginally administered to a patient to treat endometriomas.

In another embodiment of the invention, a composition of the invention is administered to a female patient in need thereof to treat ovarian cancer. In a preferred embodiment, the compositions of the present invention are vaginally administered to a patient to treat ovarian cancer.

In another embodiment of the invention, the compositions of the invention are administered to a female patient in need thereof to treat cervical cancer. In a preferred embodiment, the compositions of the present invention are vaginally administered to a patient to treat cervical cancer.

In a particularly preferred embodiment, the compositions of the invention are administered to a patient suffering from endometriosis, dysmenorrhea, uterine fibroids, endometriosis, ovarian cancer or cervical cancer by a non-oral route of administration designed to provide local delivery of the compound to the affected area. The compounds may be formulated into suitable preparations for such non-oral topical administration. For example, the compounds can be formulated as, but are not limited to, long acting injections (e.g., solid or oil-based subcutaneous or intramuscular long acting injections) designed to slowly release the compound over an extended period of time; intravaginal preparations (e.g., ring-shaped hormone-releasing pessaries); vaginal suppositories; a vaginal pill; intrauterine preparations such as intrauterine devices (IUDs) or matrix preparations; an implantable drug delivery device; topical gels or transdermal patches. Preferably, the compounds are incorporated into pessaries, uterine depots, pessaries, and the like, which maintain a slow but sustained release of the compound, which is of local rather than systemic interest.

In a preferred embodiment, endometriosis, dysmenorrhea, uterine fibroids, endometriosis, ovarian cancer or cervical cancer is treated by administering an intravaginal preparation comprising a compound of formula I to the vagina of a patient in need of such treatment. It is understood that the compound is absorbed from the vaginal mucosa in direct contact with the intravaginal preparation. Intravaginal rings are preferred intravaginal preparations and can be designed to provide sustained release of the compound in the vagina. The insertion period may be, for example, 1-3 months, after which the preparation may be replaced with a fresh preparation to provide continued long-term treatment.

In another preferred embodiment, endometriosis, dysmenorrhea, uterine fibroids, endometriosis, ovarian cancer or cervical cancer is treated by administering a vaginal pill or pessary comprising a compound of formula I to the vagina of a patient in need of such treatment. The vaginal pills and pessaries may be produced by well known methods with additives commonly used in the production of such preparations, such as diluents, binders and suppository bases.

In another preferred embodiment, endometriosis, dysmenorrhea, uterine fibroids, endometriosis, ovarian cancer or cervical cancer is treated by administering an intrauterine preparation comprising a compound of formula I to the uterine cavity of a patient in need of such treatment. The intrauterine preparation may be a matrix preparation providing a sustained release of the compound in the uterus. The period of insertion of the intrauterine preparation may be about 6 months, after which the preparation may be removed and a new preparation inserted in order to achieve long-term treatment of the disorder. The intrauterine preparation can be produced by conventional methods using: a matrix (such as polymers including, but not limited to, silicone rubber, ethylene vinyl acetate, ethyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, carboxyvinyl polymers, or collagen), an inert intrauterine device, and optionally a suitable crosslinking agent and/or release promoter such as polysorbate 60, polysorbate 80, glycerol, isopropyl palmitate, and isopropyl myristate. The matrix preparation may be monolayer or bilayer. The form of the intrauterine preparation is not limited, but is sufficient to have a form suitable for local administration in the uterus.

In another embodiment of the invention, the compositions of the invention are administered to a female in need thereof to induce menstruation in the female.

In yet another embodiment of the invention, a composition of the invention is administered to a female in need thereof to induce labor.

In yet another embodiment of the invention, the compositions of the invention are administered to a female in need thereof as a contraceptive agent.

Compositions comprising compounds of formula I as described above may be suitable for prolonged oral administration, as these compounds are expected to exhibit reduced or no hepatotoxicity. Alternatively, the compounds of formula I may be administered chronically by a route that avoids first pass metabolism and thus reduces or eliminates metabolism through the liver. Thus, the compositions of the present invention may be administered on a long-term basis without causing toxic liver effects. Preferably, the compounds have only low glucocorticoid receptor binding activity and thus do not interfere with the glucocorticoid receptor function. Thus, the compositions of the invention may also be associated with reduced side effects (e.g. mood swings, fatigue and weight loss) which are typically present when antiprogestins with high affinity for the glucocorticoid receptor are used. Preferably, the compounds of the present invention also have low or substantially no estrogenic, antiestrogenic and antiandrogenic activity.

In one embodiment, the compositions of the invention comprising a compound of formula I are administered in an amount effective to treat a hormone-dependent condition for an administration period of at least 1,2, 3, 4,5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or more days. The composition may also be administered for an administration period of at least 1,2, 3, 4,5, 6,7, 8, 9, 10, 11, 12 months or more. The composition may also be administered for an administration period of at least 1,2, 3, 4,5, 6,7, 8, 9, 10 or more years. The composition may be administered daily or periodically (e.g., every second day, every second month, etc.) during the administration period. The composition may also be administered intermittently. For example, the composition may be administered for an administration period of 1,2, 3, 4,5 or more months, followed by discontinuation of the drug for a period of time, followed by administration for an administration period of 1,2, 3, 4,5 or more months, and so forth.

In one embodiment, the composition is administered at intervals such that the subject travels during at least one weaning period. This method is expected to avoid adverse effects associated with thickened or stagnant endometrium, which may be accompanied by prolonged treatment with progesterone antagonists, such as spot bleeding (spotting), breakthrough bleeding, endometrial hyperproliferation, or endometrial cancer. At least one, and preferably each, off-period is of sufficient length to allow the subject to menstruation. More preferably, the subject is allowed to travel during each discontinuation period. In particularly preferred embodiments, the composition is administered daily for a dosing period of four months, followed by a rest period (during which the subject is menstruating), followed by another four-month dosing period, and so on.

In one embodiment, the composition of the invention comprises a pharmaceutically acceptable salt of a compound of general formula I as described above. The obtained salt compound may be in a neutral or salt form depending on the treatment conditions. Salt forms include hydrates and other solvates and also include crystalline polymorphs. Both the free base and the salt of these end products can be used according to the invention.

Acid addition salts can be converted into the free bases in a manner known per se with basic reagents, for example bases, or by ion exchange. The free base obtained may also form salts with organic or inorganic acids.

In the preparation of acid addition salts, it is preferred to use such acids, suitably forming pharmaceutically acceptable salts. Examples of such acids are: hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, fatty acids, alicyclic carboxylic or sulfonic acids, for example formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, fumaric acid, maleic acid, hydroxymaleic acid, pyruvic acid, aspartic acid, glutamic acid, p-hydroxybenzoic acid, pamoic acid, ethanesulfonic acid, isethionic acid, phenylacetic acid, mandelic acid, allobensenesulfonic acid, toluenesulfonic acid, galactaric acid, galacturonic acid or naphthalenesulfonic acid. All crystal form polymorphs can be used according to the present invention.

Base addition salts may also be used in accordance with the present invention and may be prepared in conventional manner by contacting the free acid form with a sufficient amount of the desired base to produce the salt. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, calcium, magnesium, and the like. Examples of suitable amines are amino acids such as lysine, choline, diethanolamine, ethylenediamine, N-methylglucamine and the like.

The compositions of the present invention may be prepared in the form of one or more dosage units suitable for oral, sublingual/buccal, parenteral, transdermal, transmucosal (e.g. vaginal or rectal) or topical administration. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, and intraarticular.

In yet another embodiment, the compositions of the present invention are formulated as rectal suppositories, which may contain a suppository base including, but not limited to, cocoa butter or glycerides.

In yet another embodiment, the compositions of the present invention comprise a compound of formula I and a bioadhesive carrier, such as those described in U.S. Pat. No. 4,615,697, which is incorporated herein by reference. The bioadhesive carrier may be in the form of a gel, cream, tablet, pill, capsule, suppository or film, or in any other pharmaceutically acceptable form that can adhere to the vaginal mucosa.

The compositions of the present invention may also be formulated for inhalation, which may be in the form of solutions, suspensions or emulsions that may be administered as dry powders or in the form of aerosols with propellants, such as dichlorofluoromethane or trichlorofluoromethane.

The compositions of the invention may also be formulated for transdermal delivery, for example as a cream, ointment, lotion, paste, gel, medicated plaster, patch or film. Such compositions may comprise any suitable excipient, such as penetration enhancers and the like.

The compositions of the present invention may also be formulated for parenteral administration, including but not limited to administration by injection or continuous infusion. Formulations for injection may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles. Such compositions may also be provided in powder form for reconstitution with a suitable vehicle including, but not limited to, sterile pyrogen-free water, WFI, and the like.

The compositions of the present invention may also be formulated as long acting preparations, which may be administered by implantation or by intramuscular injection. Such compositions may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil), ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt).

The compositions of the invention may also be formulated as liposome preparations. Liposome preparations can include liposomes that penetrate the target cell or stratum corneum and fuse with the cell membrane resulting in delivery of the liposome's contents into the cell. For example, liposomes such as those described in U.S. Pat. No. 5,077,211 to Yarosh, U.S. Pat. No. 4,621,023 to Redzini, et al, or U.S. Pat. No. 4,508,703 to Redzini, et al, can be used.

The compositions of the present invention may be in the form of solid dosage units, such as tablets (e.g., suspension tablets, chewable suspension tablets, fast-dispersing tablets, chewable tablets, effervescent tablets, bilayer tablets, etc.), caplets, capsules (e.g., soft or hard gelatin capsules), powders (e.g., packaged powders, dispersible powders, or effervescent powders), lozenges, sachets, cachets, lozenges, pills, granules, microgranules, encapsulated microgranules, powder aerosol formulations, or any other solid dosage form reasonably suitable for administration.

Suitable liquid dosage forms of the compositions of the present invention include: solutions, aqueous or oily suspensions, elixirs, syrups, emulsions, liquid aerosol formulations, gels, creams, ointments and the like. Such compositions may also be formulated as a dry product for reconstitution with water or other suitable vehicle prior to use.

In one embodiment, the liquid or semi-solid composition has at least about 90%, at least about 92.5%, at least about 95%, or at least about 97.5% of the original antiprogestin compound present therein after storage in a sealed container maintained at room temperature, a refrigerated (e.g., about 5-10 ℃) temperature, or a freezing temperature for a period of about 1,2, 3, 4,5, 6,7, 8, 9, 10, 11, or 12 months.

The compositions of the present invention may contain one or more pharmaceutically acceptable excipients as desired. The term "excipient" herein means any substance, not itself a therapeutic agent, that is used as a carrier or vehicle for delivery of the therapeutic agent to a subject or that is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a unit dose of the composition. Excipients include by way of illustration and not limitation: diluents, disintegrants, binders, adhesives (e.g., bioadhesives), wetting agents, lubricants, glidants, surface modifying agents or surfactants, flavoring agents, suspending agents, emulsifiers, anhydrous vehicles, preservatives, antioxidants, adhesives, agents to adjust pH and permeability (e.g., buffers), preservatives, thickeners, sweeteners, flavoring agents, taste masking agents, colorants or dyes, permeation enhancers, and substances added to improve the appearance of the composition.

The compositions of the present invention may be administered in any manner, including but not limited to: oral, parenteral, sublingual, transdermal, rectal, transmucosal, topical, inhalation, oral administration, or a combination thereof. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, intraarticular, intracisternal, and intraventricular.

The therapeutically effective amount of the composition required for use in therapy will vary with the length of time of activity desired and the age and condition of the patient to be treated, and will ultimately be determined by the attending physician. In general, however, the dosage range for treatment of a human will typically be from about 0.001 mg/kg to about 500mg/kg per day, for example from about 1. mu.g/kg to about 1 mg/kg per day or from about 1. mu.g/kg to about 100. mu.g/kg per day. For most large mammals, the total daily dose is from about 1 to 100 mg, preferably from about 2 to 80 mg. The dosage regimen may be adjusted to provide the optimum therapeutic response. The desired dose may conveniently be administered as a single dose, or as a plurality of doses administered at suitable intervals, for example two, three, four or more sub-doses per day.

Illustratively, the compositions of the invention can be administered to a subject to provide antiprogestin in an amount of from about 1 μ g/kg to about 1 mg/kg body weight of the subject, e.g., about 1 μ g/kg, about 25 μ g/kg, about 50 μ g/kg, about 75 μ g/kg, about 100 μ g/kg, about 125 μ g/kg, about 150 μ g/kg, about 175 μ g/kg, about 200 μ g/kg, about 225 μ g/kg, about 250 μ g/kg, about 275 μ g/kg, about 300 μ g/kg, about 325 μ g/kg, about 350 μ g/kg, about 375 μ g/kg, about 400 μ g/kg, about 425 μ g/kg, about 450 μ g/kg, about 475 μ g/kg, about 500 μ g/kg, about 525 μ g/kg, about 550 μ g/kg, about, Antiprogestin in an amount of about 575 μ g/kg, about 600 μ g/kg, about 625 μ g/kg, about 650 μ g/kg, about 675 μ g/kg, about 700 μ g/kg, about 725 μ g/kg, about 750 μ g/kg, about 775 μ g/kg, about 800 μ g/kg, about 825 μ g/kg, about 850 μ g/kg, about 875 μ g/kg, about 900 μ g/kg, about 925 μ g/kg, about 950 μ g/kg, about 975 μ g/kg or about 1 mg/kg body weight.

Patients receiving treatment with the compositions of the present invention should routinely be monitored for serum estrogen and glucocorticoid levels.

The following non-limiting examples are provided to aid in understanding the teachings of the present invention.

Example 1 measurement of in vitro binding affinity of antiprogestins

Competitive binding assays were performed with cytosol preparations.

To measure binding to rabbit Progesterone Receptor (PR) and Glucocorticoid Receptor (GR), cytosol was prepared from uterus or thymus, respectively, of estradiol-pretreated young rabbits. For binding to rabbit uterine PR, cytosol containing rabbit uterine PR was prepared in TEGMD buffer (10 mM Tris, pH 7.2, 1.5 mM EDTA, 0.2 mM sodium molybdate, 10% glycerol1 mM DTT) and 6 nM 1,2-, [ 2 ]³H]Progesterone (NEN Life Science Products; 52 Ci/mmol); test compounds were added at concentrations of 2-100 nM. For binding to rabbit thymus GR, the cytosol is prepared in TEGMD buffer and complexed with 6 nM 6,7-, [ 2 ]³H]dex (NEN; 35 or 40 Ci/mmol); test compounds were added at concentrations of 2-100 nM.

To measure binding to human progesterone receptor- A (rhPR- A) or progesterone receptor-B (rhPR-B), cytosolic extracts from Sf9 insect cells infected with recombinant baculovirus expressing hPR- A or hPR-B were prepared. Sf9 cytosol (prepared in TEGMD buffer containing 100. mu.g/ml bacitracin, 2. mu.g/ml aprotinin, 94. mu.g/ml leupeptin, 200. mu.g/ml pepstatin A) and 6.8 nM 1,2,6,7,16,17-, respectively³H]Progesterone (NEN; 143 Ci/mmol); test compounds were added at a concentration of 1-100 nM.

After overnight incubation at 4C, bound and unbound [ 2 ] were separated by adding dextran-coated activated carbon and centrifuging at 2100 x g for 15 minutes at 4C³H]-a steroid. The supernatant from the GR assay was decanted and counted in a Beckman LS-1800 liquid scintillation counter. The supernatant containing PR was pipetted into a 24-well microplate and counted in a Packard TopCount liquid scintillation counter. Inputting counts per minute (cpm) into a Packard's RIASMat^TMFor EC₅₀And (4) calculating. The relative binding affinity of each test compound was calculated as follows: (EC of Standard sample₅₀) V (EC of competitor)₅₀) x 100. The standard for the PR binding assay was P4 and the standard for the GR binding assay was dex.

Example 2 measurement of in vivo anti-glucocorticoid and progesterone antagonist Activity

To measure progesterone antagonist activity of test compounds in vivo, growth was performed in serum supplemented with 10% Fetal Bovine Serum (FBS), 10U/ml penicillin G, and 10 μ G/ml sulfuric acidT47D-CO human breast cancer cells in monolayer cultures of streptomycin phenolsulfonphthalein-free DMEM with a suitable hormone sensitive reporter plasmid such as PRE₂-tk-LUC transfection, PRE₂-tk-LUC comprises two copies of a progesterone/glucocorticoid/androgen response element upstream of the thymidine kinase (tk) promoter and a firefly Luciferase (LUC) reporter gene. Transfected T47D-CO cells were incubated with a (predetermined) maximal stimulatory concentration of progesterone (e.g., P)₄) Incubate for 20 hours in the absence or presence of varying concentrations of test compound. LUC activity was determined using Promega's Luciferase Assay System (Luciferase Assay System) and IC of test compounds determined₅₀。

To measure glucocorticoid antagonist activity in vivo, HepG2 human hepatoblastoma cells grown in monolayer cultures of phenolsulfonphthalein-free MEM α supplemented with 10% FBS and penicillin/streptomycin were treated with a suitable hormone-sensitive reporter plasmid such as PRE₂-tk-LUC and GR expression plasmids were co-transfected. Transfected HepG2 cells were incubated with (pre-determined) maximal stimulatory concentrations of dexamethasone in the absence or presence of various concentrations of test compound for 20 hours. Determination of IC of test Compounds by measuring LUC Activity₅₀。

Example 3 Long-term daily administration of CDB-4124 is associated with toxic liver effects

Initial studies with Proellex (aka CDB-4124) demonstrated the efficacy of each tested dose of drug. Based on data suggesting the possibility of higher doses to inhibit endometrial thickening and breakthrough uterine bleeding, the development of Proellex focused on the two highest experimental doses of 25mg and 50 mg. Neither animal preclinical studies nor small trials in european females predicted hepatotoxicity in phase III clinical studies conducted in different populations in the united states for up to 6 months of exposure at higher doses. About 3-4% of women receiving this dose exhibited severe hepatotoxicity with Proellex delivered orally at a dose of 50 mg/day. At 12.5mg the adverse hepatotoxicity signal was not different from placebo. For the 12.5mg dose, the maximum concentration of CDB-4124 and its mono-demethylated metabolite (CDB-4453) was 25% of the 50mg dose. All hepatotoxicity was explained in those women returned for safety follow-up, including those subjects who developed liver-related Severe Adverse Effects (SAE). The effect observed when Proellex is administered orally at 50 mg/day is significantly lower in frequency and intensity than the effect observed when Proellex is delivered at 25 mg/day. This observation is explained in further detail by the fact that: longer duration of exposure was safely achieved at the 25 mg/day dose than at the 50 mg/day dose, suggesting that the duration of exposure at the lower dose does not necessarily result in the same hepatotoxicity observed at the 50 mg/day dose.

To date, over 600 patients, including women with diagnosed cases of endometriosis or uterine fibroids, have been involved in double-blind and label-open clinical trials in which patients are given an oral capsule containing a dose of 12.5mg, 25mg or 50mg of CDB-4124(Proellex) per day for more than one month. Of these patients, about 500 received Proellex and about 130 received placebo. Of the patients who received Proellex, about 190 received a 50mg dose of CDB-4124 per day, about 260 received a 25mg dose of CDB-4124 per day, and about 55 received a 12.5mg dose per day.

Liver enzymes in the participating subjects were monitored from time to time. The liver enzyme level at which the clinical trial was discontinued was set to an increase in liver aminotransferase (> 3 × ULN) greater than or equal to three times the upper limit of normal.

During the clinical trial, 13 subjects were found to exhibit an increase in liver enzymes ≧ 3 × ULN, but this was confirmed only in 9 subjects by repeated trials within 48 hours. Of 9 subjects with established increases in liver enzymes ≧ 3 × ULN, 7 were severely elevated enough to be reported to the FDA as SAE. One of the 7 subjects received a 25mg dose of CDB-4124 per day; the remaining 6 subjects received a 50mg dose of CDB-4124 daily. In 5 of 9 subjects with a determined increase in liver enzyme ≧ 3 x ULN, liver enzyme ≧ 3 x ULN persists. These 5 subjects had previously been administered with a dose of 50 mg. One of these subjects is receiving oral drug therapy for treating their liver condition. As a result of these SAEs, clinical trials involving all doses of CDB-4124 were actively suspended and subsequently placed in clinical control by the U.S. food and drug administration for safety reasons.

Pharmacokinetic studies on the participating subjects detected high C_maxAnd T1-2 hours after administration_max. A number of mono-demethylated metabolites of CDB-4124 were also tested, clearly suggesting first pass metabolism of antiprogestins. Primary cultures of human and animal hepatocytes rapidly produce mono-demethylated metabolites of CDB-4124, providing further evidence of first pass metabolism. CDB-4124 provides an opportunity for liver damage through hepatic metabolism and greatly reduces the concentration of antiprogestins before it reaches the systemic circulation. Thus, alternative routes of antiprogestin administration that avoid first-pass metabolism (such as, but not limited to, intravenous, intramuscular, and sublingual) should allow for direct absorption of antiprogestins into the systemic circulation and thus provide a means for treating progesterone-dependent conditions while avoiding hepatotoxicity. Routes of administration that avoid first pass metabolism may also require less of each dose of drug to achieve the same therapeutic benefit relative to oral administration.

Preclinical studies were performed in rodents with breast tumors induced by 7, 12-Dimethylbenzanthracene (DMBA). These studies demonstrate the efficacy of the non-oral delivery method of CDB-4124. In particular, CDB-4124 delivered by subcutaneous injection was effective in reducing the number and size of DMBA-induced breast tumors, providing proof of concept.

Example 4 vaginal delivery of CDB-4124 and CDB-4453 reduces systemic concentrations and avoids first pass metabolism compared to oral administration

Beagle dogs were administered 25mg of CDB-4124 or CDB-4453 (the mono-demethylated metabolite of CDB-4124) formulated as micronized powder or as a pessary. As shown in figure 1, CDB-4124 and CDB-4453, when administered orally as micronized powders, were rapidly metabolized after reaching peak plasma concentration (Cmax). In contrast, when the same compound is administered topically via a vaginal suppository, the drug is slowly metabolized and the peak plasma concentration (Cmax) is relatively low. In addition, systemic exposure of the drug was much lower when given topically (compare AUC for CDB-4124 and CDB-4453 when given vaginally versus orally).

The maximum circulating concentration (Cmax) of CDB-4124 obtained following vaginal administration to beagle dogs was extrapolated to humans at doses of 12.5mg, 25mg and 50mg actually administered during the phase III clinical study. As can be seen from figure 2, the expected Cmax for vaginal administration of a 12.5mg dose of CDB-4124 in humans is about 6.5% of the same dose when administered orally, and the expected Cmax for vaginal administration of a 50mg dose of CDB-4124 in humans is about 2% of the same dose when administered orally.

Example 5 bioavailability of CDB-4124 in the uterus when administered orally is surprisingly low

To determine whether low circulating levels of CDB-4124 when given topically could have any effect that predicts efficacy, an anti-Clauberg study was conducted in which estradiol-pretreated young rabbits were given progesterone and different doses of CDB-4124 simultaneously, either subcutaneously or orally. At least 3 different highly trained individuals evaluated the glandular growth, complexity and overall progesterone-induced "development" of the rabbit uterus. Inhibition of progesterone-induced endometrial proliferation (in percent) was determined at each dose. As shown in FIG. 3, maximum inhibition was observed at doses less than 1 mg/kg when CDB-4124 was administered subcutaneously. However, maximum inhibition requires a dose increase of about 8-fold (i.e., 8 mg/kg) when administered orally. Importantly, 8 mg/kg corresponds closely to the 50 mg/day dose of CDB-4124 given to the female subjects described in example 3. This demonstrates that the effective local concentration of endometrial CDB-4124 is greatly reduced when the drug is administered orally, most likely due to the first pass metabolism of the drug. Thus, in order to achieve therapeutic effects, for example for indications confined to the pelvic and reproductive tract, a relatively high dose of CDB-4124 is required when administered orally, which corresponds very well to the dose of CDB-4124 in which toxic liver effects are observed in example 3.

Another anti-Clauberg study was performed in which estradiol-pretreated young rabbits were given either vaginally or orally with progesterone alone (vehicle control) or with progesterone co-administered with three doses of CDB-4124. Inhibition of progesterone-induced endometrial proliferation was determined at each dose. Figure 3 illustrates the decrease in the McPhail index following increasing doses of CDB-4124 administered by either route. The maximum inhibition (i.e., reduction of the McPhail index to 1.5) occurred at 0.2 mg/kg CDB-4124 when administered vaginally, compared to 0.8 mg/kg when administered orally. The data from this study show that vaginal delivery of CDB-4124 exhibits four times the antiprogestin activity at the same oral dose.

Taken together, the data indicate that an 1/4 dose of antiprogestin can be administered vaginally, while achieving only a fraction of the maximum circulating concentration for oral administration, compared to the effective dose when administered orally, thereby avoiding hepatotoxicity. For example, comparable antiprogestinic activity in the uterus was observed for 50mg oral dose of CDB-4124 and 12.5mg vaginal dose; however, the Cmax observed for the 12.5mg vaginal dose was only 2% of the Cmax observed for the 50mg oral dose. The relatively high local concentration of the drug achieved by local administration allows for relatively low doses of the drug (relative to oral administration) to achieve therapeutic effects for indications localized to the pelvic and reproductive tract (e.g., endometriosis, uterine fibroids and ovarian cancer). Since high concentrations of drug in the systemic circulation (and the associated first pass metabolism of the drug) were not achieved by local administration, the avoidance of severe hepatotoxicity observed in a small percentage of subjects following oral administration of CDB-4124 at 25 and 50mg doses in previous phase III clinical studies is a surprising advantage of local administration of drugs. Similar advantages should apply to topical administration of other antiprogestins.

Example 6. R ¹ And R ² Effect of substituents on thermodynamic solubility

The thermodynamic solubility of the following compounds was tested and compared with that of CDB-4124:

21-methoxy-17 α -acetoxy-11 β - (4-acetylphenyl) -19-norpregna-4, 9-diene-3, 20-dione having the formula (wherein R is¹In para position and is-COCH₃，R²Is methoxy, R³Is acetoxy, R⁴Is methyl, and X is = O) (CDB-4239):

17 alpha-acetoxy-11 beta- (4-acetylphenyl) -19-norpregna-4, 9-diene-3, 20-dione having the formula (wherein R¹In para position and is-COCH₃，R²Is hydrogen, R³Is acetoxy, R⁴Is methyl, and X is = O) (REP-4510):

and 21-acetoxy-17 alpha-acetoxy-11 beta- (4-acetylphenyl) -19-norpregna-4, 9-diene-3, 20-dione having the formula (wherein R¹In para position and is-COCH₃，R²And R³Is acetoxy, R⁴Is methyl, and X is = O) (CDB-4241):

CDB-4239, CDB-4241 and REP-4510 were determined as crystalline solids with the following characteristics:

briefly, 300 ul of solvent (ethanol, 0.1M HCl or distilled water) was added to 14-16 mg of solid compound (5 replicates per sample of each solvent, with an average concentration of 93-107 mM). The mixture was shaken at 37 ℃ for 24 and 72 hours. The concentration of the filtrate was determined by liquid chromatography with a UV detector (LC/UV) using a three-point calibration method. No significant degradation was observed at the end of the measurement. The results are provided in tables 1 and 2:

TABLE 1

TABLE 2

The crystalline form was verified by X-ray powder diffraction (XRPD) after 24 and 72 hours recovery of the slurry. No deformation was observed for any of the compounds studied during suspension slurrying. A decreasing trend in the water solubility of CDB-4239 and 1.0M HCl solubility, measured at 24 and 72 hours, was observed. This cannot be reasonably explained by changing to a more stable form. The exact cause of this observation is still unclear.

Analysis of these data indicates R in the meta (or ortho) position¹= acyl (especially COCH)₃) Alkylsulfinyl or alkylsulfonyl and having R²Compounds of the general formula I, in particular methoxy, which are surprisingly soluble and can be used as inhibitors of the enzymeMaintaining antiprogestinic activity and low antiglucocorticoid activity.

Claims (22)

1. A compound having the general formula:

wherein: r¹Selected from: CH (OH) CH₃(ii) a An alkylsulfinyl group; an alkylsulfonyl group; alkylthio; an acyl group; an alkoxy group; and an acyloxy group; r²Selected from: hydrogen, alkoxy and acyloxy; r³Selected from: alkyl, hydroxy, alkoxy, and acyloxy; r⁴Is hydrogen or alkyl; and X is selected from: = O, wherein R5 is hydrogen OR alkyl = N-OR5, OH, CH₂、OAlk₁And OCOAlk₂Wherein Alk₁And Alk₂Is C1-C8 alkyl or C7-C15 aralkyl, with the proviso that if R is¹In para position and is-OCH₃、-SCH₃、-CHO、-CH(OH)CH₃、-COCH₃、-O(CH₂)₂NC₄H₈or-O (CH)₂)₂NC₅H₁₀Then X is not = O OR = N-OR5 wherein R5 is hydrogen OR alkyl, and with the proviso that if R is²Is hydrogen, R³Is hydroxy, R⁴Is methyl, X is = O, and R¹In the meta position, then R¹Is not methoxy.

2. The compound of claim 1, or a salt thereof, wherein R₁In para-position and being acyl or CH (OH) CH₃；R²Is an alkoxy group; r⁴Is alkyl or hydrogen.

3. The compound of claim 2, wherein R¹is-COCH₃，R²Is methoxy, R³Is acetoxy; r⁴Is methyl and X is selected from OH, CH₂、OAlk₁And OCOAlk₂Wherein Alk₁And Alk₂Is C1-C8 alkyl or C7-C15 aralkyl.

4. The compound of claim 1, or a salt thereof, wherein R¹In meta-or ortho-position and is acyl or CH (OH) CH₃(ii) a And R is²Selected from alkoxy, acyloxy and hydrogen.

5. A compound of claim 4, or a salt thereof, wherein R¹In the meta position and is-COCH₃；R²Is an alkoxy group; r⁴Is an alkyl group; and X is = O.

6. A compound of claim 5, or a salt thereof, wherein R²Is methoxy and R⁴Is methyl.

7. A compound of claim 6, or a salt thereof, wherein R³Is acetoxy.

8. A compound of claim 4, or a salt thereof, wherein R¹In the meta position and is-COCH₃；R²Is hydrogen; r³Is acetoxy; r⁴Is methyl; and X is = O.

9. A compound of claim 4, or a salt thereof, wherein R¹In the meta position and is-COCH₃；R²And R³Is acetoxy; r⁴Is methyl; and X is = O.

10. The compound of claim 1, or a salt thereof, wherein R¹At the ortho, meta or para position and is alkylsulfinyl; r²Is an alkoxy group; r⁴Is an alkyl group.

11. The compound of claim 10, or a salt thereof, wherein R¹is-SOCH₃；R²Is methoxy; r³Is acetoxy; r⁴Is methyl; and X is = O.

12. The compound of claim 1, or a salt thereof, wherein R¹In the para position.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-12, or a salt thereof, and a pharmaceutically acceptable excipient.

14. A method of producing an antiprogestinic effect in a patient, comprising administering to said patient a therapeutically effective amount of a compound or salt according to any one of claims 1-12.

15. A method of treating a progesterone-dependent condition selected from the group consisting of endometriosis and pain associated therewith, endometriosis, ovarian endometrioma, dysmenorrhea, uterine fibroids, endometrial hyperproliferation, ovarian cancer, and cervical cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or salt thereof according to any one of claims 1 to 12.

16. A method of treating a progesterone-dependent condition selected from the group consisting of endometriosis and pain associated therewith, endometriosis, ovarian endometrioma, dysmenorrhea, uterine fibroids, endometrial hyperproliferation, ovarian cancer, and cervical cancer, comprising administering to a patient in need thereof a composition of claim 13.

17. The method of claim 16, wherein the composition is administered via a route selected from the group consisting of vaginal route, intrauterine route, and topical route and wherein the effective amount is less than the effective amount when administered systemically.

18. The method of claim 17, wherein the composition is in a form suitable for vaginal administration.

19. The method of claim 18, wherein the composition is in the form of a pessary, gel, or cream.

20. The method of claim 19, wherein the composition is administered topically to the vaginal mucosa of the patient.

21. The method of any one of claims 14-20, wherein the compound is administered at a dose of 0.5mg/kg to 500 mg/kg.

22. The method of claim 21 wherein said compound is administered at a dose of about 12.5-50 mg daily.