HK1240111A - Compositions and methods for non-toxic delivery of antiprogestins - Google Patents

Description

Compositions and methods for non-toxic delivery of antiprogestins

The present application is a divisional application, filed on a date of 12/23 2010 and having application number 201080066943.4(PCT/US2010/062068), entitled "composition and method for non-toxic delivery of antiprogestins".

This application claims the benefit of U.S. provisional application No. 61/316,263, filed on 3/22/2010, in accordance with 35 USC 119(e), the entire contents of which are incorporated herein by reference.

Technical Field

In various embodiments, the present invention relates to compositions and methods for treating various hormone-dependent conditions that avoid hepatotoxicity. In several embodiments, the present invention relates to 19-nor steroid progesterone receptor modulators with reduced hepatotoxicity. In another embodiment, the present invention relates to a method of administering antiprogestins to a patient in need thereof, in particular avoiding the first pass metabolism of antiprogestins.

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 fertility and in the drug modulation of 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. More particularly, the present invention provides compounds having the general formula:

wherein: r¹May be in the para, ortho or meta position and are functional groups including, but not limited to: an alkyl group; an alkenyl group; a cycloalkyl group; a cycloalkenyl group; an aryl group; h; CH (CH)₃SO；CH₃SO₂(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 (e.g. -SCH)₃) Acyloxy (e.g., acetoxy, propionyloxy); si (CH)₃)₃；；；(ii) a In which X and Y are acyl radicals(ii) a Or preferably a heterocyclic ring containing at least one nitrogen atom (e.g. aziridinyl: (a)Or) Azacyclopropenyl (azirinyl) (a)Or) Azetidinyl, pyrrolidinyl, ethoxypyrrolidinyl, methoxypyrrolidinyl, pyrrole (I), (II), (III), (IV) Piperidinyl, ethoxypiperidinyl, pyridinyl: () Morpholinyl, ethoxymorpholinyl, and ethoxymorpholinyl,Azinyl, piperazinyl: () Substituted, byPiperazinyl group (、) Diazinyl and oxazoles such as pyrazole (I) (II)))。R²Functional groups including but not limited to the following: hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (akoxy) (e.g., methoxy, ethoxy, vinyloxy, ethynyloxy, cyclopropoxy, and the like), acyloxy (e.g., formyloxy, acetyloxy, propionyloxy, heptanoyloxy, glycinyloxy, and the like), alkylcarbonate, cyclopentanopropoxy (cyclopionyloxy), 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, methoxymethyl, etc.), and acyloxy, provided that R³Not acetoxy or propynyl. R⁴Functional groups including but not limited to hydrogen and alkyl. Finally, 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 (aralkylyl) 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.

In a related embodiment, the present invention provides a method wherein a compound of formula I (or a pharmaceutical composition comprising a compound of formula I) is used to treat a multiple hormone (i.e., estrogen and/or progesterone) dependent condition 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 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 one or more antiprogestin compositions (or pharmaceutical compositions comprising one or more antiprogestins) that avoid hepatotoxicity. The antiprogestin can be any antiprogestin (e.g., the antiprogestin can be a Selective Progesterone Receptor Modulator (SPRM), a compound of formula I, or any other compound that inhibits the action of progesterone) provided that the antiprogestin is administered in an amount effective to treat progesterone-dependent conditions.

In a related embodiment, a method of treating a plurality of hormone-dependent conditions in a patient in need of such treatment is provided, the method comprising administering a composition comprising one or more antiprogestins by a route that avoids first-pass metabolism. Preferably the composition is administered by a route selected from the group consisting of: cutaneous, sublingual/buccal, intravascular, intramuscular, subcutaneous, inhalation, rectal, vaginal, intrauterine and topical. Most preferably, the composition is administered topically to the vaginal mucosa for the treatment of one or more hormone-dependent conditions.

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 three doses of CDB-4124 when delivered orally in the presence of progesterone versus when delivered to the vaginal mucosa of estradiol-pretreated young rabbits, as measured by the decrease in the McPhail index. Treatment with progesterone alone (vehicle control) provided a baseline measurement of progesterone 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 particular 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" 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.

Compound (I)

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

I。

in the formula I, R¹May 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; h; CH (CH)₃SO；CH₃SO₂(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, glycinyl, etc.), alkylcarbonate, cyclopentanepropoxy, 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, methoxymethyl, etc.), and acyloxy, provided that R³Not acetoxy or propynyl. R⁴Functional groups including but not limited to hydrogen and alkyl. Finally, 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)₂NC₄H₈and-O (CH)₂)₂NC₅H₁₀Then X is not = O OR = N-OR5 where R5 is hydrogen OR alkyl.

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, 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, methoxymethyl, etc.), or acyloxy, provided that R³Is not acetoxy or propynyl; r⁴Is hydrogen or alkyl; 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); r²Is hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (such as methoxy, ethoxy, n-methoxy, n-ethoxy, n-methoxy, n-ethoxy,vinyloxy, ethynyloxy, cyclopropoxy, and the like), acyloxy (e.g., formyloxy, acetyloxy, propionyloxy, heptanoyloxy, glycinyloxy, and the like), 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, methoxymethyl, etc.), or acyloxy, provided that R³Is not acetoxy or propynyl; 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 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; h; CH3 SO; CH3SO 2; 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, or vinyloxy),Ethynyloxy, cyclopropoxy, and the like), acyloxy (e.g., formyloxy, acetyloxy, propionyloxy, heptanoyloxy, glycinyloxy, and the like), alkylcarbonate, cyclopentanepropoxy, 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, methoxymethyl, etc.), or acyloxy, provided that R³Is not acetoxy or propynyl; 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 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; h; CH3 SO; CH3SO 2; 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, ethyleneoxy, acetylene)Oxy, cyclopropoxy, etc.), acyloxy (e.g., formyloxy, acetyloxy, propionyloxy, heptanoyloxy, glycinyloxy, etc.), alkylcarbonate, cyclopentanepropoxy, 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, methoxymethyl, etc.), or acyloxy, provided that R³Is not acetoxy or propynyl; 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.

R, whether in ortho, meta or para position, is particularly preferred¹The substituent is-CHO, -COCH₃And preferably a heterocyclic ring containing at least one nitrogen atom, especially-NC₅H₁₀(piperidino).

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

Particularly preferred R³Substituents are alkoxy (in particular methoxy or ethoxy), propionyloxy, formyloxy and methoxymethyl.

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

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 and 6,900,193, 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 U.S. patent No. 6,861,415 and figures 1-11 of the U.S. patent No. can be used in conjunction with synthetic techniques known in the art to synthesize the compounds of the present invention.

The compounds of the formula I have a phenyl radical at C11 β which is ortho-or meta-positionedOr para (i.e. in position R of formula I)¹) For example, a compound having a dimethylaminophenyl group at C11 β undergoes dealkylation upon administration to produce a primary amine aniline (-phenyl-NH) at C11 β₂). 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. Furthermore, R¹Not a functional group other than a primary, secondary or tertiary amine that is itself substituted with a primary, secondary or tertiary amine. The compounds of the invention are therefore surprisingly useful for the long-term treatment of hormone-dependent conditions.

The compound of formula I is at the C17 α position (i.e. at the position R of formula I)³) Without being bound by theory, it is believed that these moieties, when present at the C17 α position, can be metabolized to alcohol upon administration, which can contribute to the formation of protein adducts and hepatotoxicity in patients to which such compounds have been administered.

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. The compounds of formula I are not expected to contribute to adverse liver reactions in patients who have received these compounds and may therefore 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 accordance with this aspect of the invention. 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 present invention relates to a method of treating progesterone-dependent conditions by orally administering any steroidal antiprogestin having a C11 β substituent other than amino, N-monoalkylamino, N-dialkylamino, or a functional group substituted with amino, N-monoalkylamino, or N-dialkylamino. For example, the C11 beta substituent of the steroid antiprogestin is other than N, N-dialkylaminoaryl, N-monoalkylaminoaryl, and aminoaryl. Steroidal antiprogestins having a C11 beta substituent other than amino, N-monoalkylamino, N-dialkylamino, or a functional group substituted with amino, N-monoalkylamino, or N-dialkylamino can be administered orally at a dosage of at least 25 mg/day, more preferably at least 50 mg/day, for at least 2,3, 4,5,6, 7, 8,9, 10 months or more. Representative steroidal antiprogestins having a C11 β substituent other than amino, N-monoalkylamino, N-dialkylamino, or a functional group substituted with amino, N-monoalkylamino, or N-dialkylamino include: CDB-4119(17 α -acetoxy-11 β - (4-acetylphenyl) -21-thioacetoxy-19-norpregna-4, 9-diene-3, 20-dione), CDB-4239(17 α -acetoxy-11 β - (4-acetylphenyl) -21-methoxy-19-norpregna-4, 9-diene-3, 20-dione), CDB-4241(17 α, 21-diacetoxy-11 β - (4-acetylphenyl) -19-norpregna-4, 9-diene-3, 20-dione), CDB-4176(17 α -acetoxy-11 β - (4-acetylphenyl) -19-norpregna-4, 9-diene-3, 20-dione), CDB-4363(17 α -acetoxy-11 β - (4 (N-piperidino) phenyl) -19-norpregna-4, 9-diene-3, 20-dione), and other compounds disclosed in U.S. Pat. nos. 6,861,415 and 6,900,193.

In another embodiment, the invention relates to the non-oral administration of compositions comprising one or more antiprogestins for the treatment of hormone (e.g., progesterone) dependent conditions. The antiprogestin according to this aspect of the invention may be any known antiprogestin, including the compounds of formula I above. 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.

In a preferred embodiment, the present invention relates to the non-oral administration of compositions comprising steroidal antiprogestins having a C11 beta substituent other than amino, N-monoalkylamino, N-dialkylamino or a functional group substituted with amino, N-monoalkylamino or N-dialkylamino, such as, but not limited to, CDB-4119, CDB-4239, CDB-4241, CDB-4176 and CDB-4363. These compounds 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 via 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 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 antiprogestins comprising a compound of formula I above may reduce liver toxicity relative to oral administration of the same compound. Preferably, the antiprogestin is 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.

Antiprogestin can be any compound that inhibits the progesterone receptor, such as a Specific Progesterone Receptor Modulator (SPRM), provided that the antiprogestin has low glucocorticoid activity. Preferably, the antiprogestin has low estrogenic/antiestrogenic activity such that serum estrogen levels in the patient are substantially retained after administration of the antiprogestin.

For the various embodiments described below, the compositions of the present invention may comprise one or more compounds of formula I described above, in which case the compositions may be administered orally or non-orally. Alternatively, the composition may comprise any antiprogestin other than those of formula I above, in which case the composition is administered by a route that avoids the first pass metabolism of antiprogestin.

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 antiprogestin to the affected area. The antiprogestins can be formulated into suitable preparations for such non-oral topical administration. For example, the antiprogestin may be formulated as, but not limited to, a long acting injection (e.g., solid or oil based subcutaneous or intramuscular long acting injection) designed to slowly release the antiprogestin over a long 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 antiprogestins are incorporated into pessaries, uterine depots, pessaries, and the like, which maintain a slow but sustained release of the antiprogestins, 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 an antiprogestin to the vagina of a patient in need of such treatment. It is understood that the antiprogestin 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 antiprogestins in the uterus. 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 an antiprogestin 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 an antiprogestin 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 antiprogestin 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, antiprogestins (e.g., compounds of formula I) can be administered chronically via 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 one or more antiprogestins are administered in an amount effective for treating 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, any of the steroid compounds disclosed in U.S. Pat. nos. 6,861,415 and 6,900,193 may be administered to a patient by a route that avoids first pass metabolism. In a preferred embodiment, the steroid compound is CDB-4124 (21-methoxy-17 α -acetoxy-11 β - (4N, N-dimethylaminophenyl) -19-norpregna-4, 9-diene-3, 20-dione) having the following structural formula:

CDB-4453 (21-methoxy-17 α -acetoxy-11 β - (4-N-methylaminophenyl) -19-norgestagen-4, 9-diene-3, 20-dione) -a mono-demethylated derivative of CDB-4124, has been shown to have anti-glucocorticoid activity even below its parent Attardi et al, 2002, mol. cell. Endocrin. 188:111-123, the contents of which are incorporated herein by reference, thus 19-nortestosterone having a monomethylamine substituted phenyl ring at the 11 β -position of carbon 11 or a 19-degestrol derived antiprogestin, such as CDB-4453, are a class of preferred compounds for use in the methods of the present invention, however, since these compounds and their di-demethylated metabolites have unexpectedly been found to cause toxic liver effects when administered orally, these compounds should be administered by a route that avoids first pass metabolism, e.g., compound 21-methoxy-11 β - (4-methyl-phenyl) -19-dione, preferred compound of U.S. Pat. No. 5,861, No. 5,861¹is-NHCH₃) As well as so.

Other compounds that may be used in the present method when administered by a route that avoids first pass metabolism include, but are not limited to, the following compounds:

mifepristone (RU-486; 11 beta- [4N, N-dimethylaminophenyl ] -17 beta-hydroxy-17- (1-propynyl) -estra-4, 9-dien-3-one), rilospirone (Lilopristone) (11 beta- (4N, N-dimethylaminophenyl) -17 beta-hydroxy-17- ((Z) -3-hydroxypropenyl) estra-4, 9-dien-3-one), Onapristone (Onapristone) (11 beta- (4N, N-dimethylaminophenyl) -17 alpha-hydroxy-17- (3-hydroxypropyl) -13 alpha-estra-4, 9-dien-3-one), Asoprisnil (benzaldehyde, 4- [ (11. beta., 17. beta. -17-methoxy-17- (methoxymethyl) -3-oxoestra-4, 9-dien-11-yl ] -1- (E) -oxime; J867), its metabolite J912 (4- [ 17. beta. -hydroxy-17. alpha. - (methoxymethyl) -3-oxoestra-4, 9-dien-11. beta. -yl ] benzaldehyde- (1E) -oxime) and the further compounds described in DE 4332283 and DE 4332284, and CDB-2914 (17. alpha. -acetoxy-11. beta. - (4-N, N-dimethylaminophenyl) -19-norpregn-4), 9-diene-3, 20-dione) and other compounds described in Stratton et al, 2000, Hu. reprod. 15: 1092-1099.

Also contemplated for use in the present invention are other compounds described in JNJ-1250132 and Allan et al, 2006, Steroids 71: 949-954; 5-aryl-1, 2-dihydrobenzopyrano [3,4-f ] as described in Zhi et al, 1998, J. Med. chem.41:291-302]Quinoline; 1, 4-dihydro-benzo [ d ] s described in U.S. Pat. Nos. 6,509,334, 6,566,358 and 6,713,478 to Zhang et al][1,3]An oxazin-2-one; 1, 3-dihydro-indol-2-ones described in U.S. Pat. No. 6,391,907 to Fentome et al; 2, 3-dihydro-1H-indole as described in U.S. Pat. No. 6,417,214 to Ulrich et al; benzimidazolones and analogs thereof described in U.S. patent No. 6,380,235 to Zhang et al; 2, 1-benzisothiazoline 2, 2-dioxide as described in U.S. Pat. No. 6,339,098 to Collins et al; cyclic carbamates and cyclic amides described in U.S. Pat. Nos. 6,306,851 and 6,441,019 to Santilli et al; cyclic urea and cyclic amide derivatives as described in U.S. Pat. No. 6,369,056 to Zhang et al and quinazolinones and benzols as described in U.S. Pat. No. 6,358,948 to Zhang et alAn oxazine derivative.

Other antiprogestins useful in the present invention include, but are not limited to: (6 α,11 β,17 β) -11 β - (4-dimethylaminophenyl) -6-methyl-4 ', 5' -dihydrospiro [ estra-4, 9-diene-17, 2 '(3' H) -furan ] -3-one (ORG-31710) and other compounds described in U.S. patent No. 4,871,724; (11 β,17 α) -11- (4-acetylphenyl) -17, 23-epoxy-19, 24-dihydrocholestane-4, 9, 20-trien-3-one (ORG-33628); (7 β,11 β,17 β) -11- (4-dimethylaminophenyl-7-methyl ] -4 ', 5' -dihydrospiro [ estra-4, 9-diene-17, 2 '(3' H) -furan ] -3-one (ORG-31806) and other compounds described in U.S. Pat. No. 4,921,845; ZK-112993 and other compounds described in Michna et al, 1992, J.Steroid biochem, Molec. biol. 41: 339-348; ORG-31376; ORG-33245; ORG-31167; ORG-31343; RU-2992; RU-1479; RU-25056; RU-49295; RU-46556; RU-26819; LG-1127; 120753; LG 1447; LG 121046; CGP-19984A; RTI-3021-022; RTI-3021-022; RTK-86020; ZK-368678; ZK-23078; RWK-23035; ZK-23067; ZI-3647; ZJ-8678; ZJ-3647-2304; ZI-3647; Zb- -136798; ZK-98229; ZK-98734 and ZK-137316.

Also contemplated for use in the present invention are 11 β -aryl-4-estrene as described in U.S. patent No. 5,728,689 such as (Z) -11 β - [ (4-dimethylamino) phenyl) ] -17 β -hydroxy-17 α - (3-hydroxy-1-propenyl) estr-4-en-3-one; 11 β -aryl-estrene derivatives as described in U.S. Pat. nos. 5,843,933 and 5,843,931; 11-benzaldoxime-estra-diene derivatives described in U.S. Pat. No. 5,693,628 such as 4- [17 β -methoxy-17 α - (methoxymethyl) -3-oxoestra-4, 9-dien-11 β -yl ] benzaldehyde-1- (E) -oxime; 11-benzaldoxime-17 β -methoxy-17 α -methoxymethyl-estradiene derivatives described in U.S. Pat. No. 5,576,310 such as 4- [17 β -methoxy-17 α - (methoxymethyl) -3-oxoestra-4, 9-dien-11 β -yl ] benzaldehyde-1- (E) - [ O- (ethylamino) carbonyl ] oxime; s-substituted 11 beta-benzaldoxime-estra-4, 9-diene-carbonic acid thioesters described in WO99/45023, such as 4- [17 beta-methoxy-17 alpha- (methoxymethyl) -3-oxoestra-4, 9-dien-11 beta-yl ] benzaldehyde-1- (E) - [ O- (ethylthio) carbonyl ] oxime; steroid esters described in DE 19652408, DE 4434488, DE 4216003, DE 4216004 and WO 98/24803, for example (Z) -6 ' - (4-cyanophenyl) -9,11 α -dihydro-17 β -hydroxy-17 α - [4- (1-oxo-3-methylbutoxy) -1-butenyl ]4 ' H-naphtho [3 ', 2 ', 1 '; 10,9,11] estr-4-en-3-one; fluorinated 17 α -alkyl chain steroids described in WO 98/34947 such as 11 β - (4-acetylphenyl) -17 β -hydroxy-17 α - (1,1,2,2, 2-pentafluoroethyl) estra-4, 9-dien-3-one; 17-spirofuran-3' -ylidenesteroids such as 11 β - (4-acetylphenyl) -19, 24-dinor-17, 23-epoxy-17 α -cholan-4, 9, 20-trien-3-one described in U.S. Pat. No. 5,292,878; (Z) -11 β,19- [4- (3-pyridyl) -o-phenylene ] -17 β -hydroxy-17 α - [ 3-hydroxy-1-propenyl ] -4-androsten-3-one and other compounds described in U.S. patent No. 5,439,913; 13-alkyl-11-beta-phenyl-stanols described in U.S. Pat. No. 5,446,036 such as 11 beta- [4- (1-methylvinyl) phenyl ] -17 alpha-hydroxy-17 beta- (3-hydroxypropyl) -13-estra-4, 9-dien-3-one; 11-aryl steroids described in U.S. Pat. No. 4,921,845 such as 4 ', 5' -dihydro-11 β - [4- (dimethylamino) phenyl ] -6 β -methylspiro [ estra-4, 9-dien-17 β,2 '(3' H) -furan ] -3-one; 11- β -aryl-estradienes described in U.S. Pat. nos. 4,829,060, 4,814,327 and 5,089,488; 11-beta-aryl-4, 9-stanoldienes (gonadiens) and 11-beta-aryl-13-alkyl-4, 9-stanol dienes as described in U.S. Pat. nos. 5,739,125, 5,407,928 and 5,273,971; 11- β -aryl-6-alkyl (or alkenyl or alkynyl) steroids described in EP 289073; 10-beta, 11-beta-bridged steroids described in U.S. patent No. 5,093,507; 11- β -aryl-14- β -steroids described in U.S. patent No. 5,244,886; 19,11- β -bridged steroids described in U.S. patent nos. 5,095,129, 5,446,178, 5,478,956 and 5,232,915; 1-arylsulfonyl, arylcarbonyl, and 1-arylphosphono-3-phenyl-1, 4,5, 6-tetrahydropyridazine as described in U.S. Pat. No. 5,684,151; 1-arylsulfonyl, arylcarbonyl, and arylthiocarbonylpyridazino derivatives described in U.S. Pat. No. 5,753,655; 1, 2-dihydro- [1,2-g ] quinoline derivatives and 1, 2-dihydro-benzopyran- [3,4-f ] quinoline derivatives described in U.S. Pat. Nos. 5,688,808, 5,693,646, 5,693,647, 5,696,127, 5,696,130 and 5,696,133; oxa-steroids 6 derived from (8S, 13S, 14R) -7-oxa-estra-4, 9-diene-3, 17-dione 1 as described in Kang et al, 2007, bioorg. Med. chem. Lett.15: 907-.

Also contemplated for use in the present invention are 19-nor steroids and 19-nor-D-homologous steroids having the general formulas disclosed in U.S. patent nos. 4,386,085, 4,447,424, 4,519,946 and 4,634,695, each of which is incorporated herein by reference in its entirety.

Also contemplated for use in the present invention are 11 β -arylestradienes having the formula I disclosed in U.S. Pat. No. 4,536,401, which is incorporated herein by reference in its entirety.

Also contemplated for use in the present invention are 13 alpha-alkyl-stanols having formula I disclosed in U.S. patent No. 4,780,461, which is incorporated herein by reference in its entirety.

Also contemplated for use in the present invention are 11 β -arylestradienes having the general formula I disclosed in U.S. Pat. No. 4,609,651, which is incorporated herein by reference in its entirety.

Also contemplated for use in the present invention are 11 β -aryl-4-estrene of formula I of U.S. Pat. No. 5,728,689, which is incorporated herein by reference in its entirety.

Also contemplated for use in the present invention are 11 β -aryl-4-estrene derivatives of formula I of U.S. patent nos. 5,843,933 and 5,843,931, each of which is incorporated herein by reference in its entirety.

Also contemplated for use in the present invention are the 11-aryl steroids disclosed in U.S. patent No. 4,921,845, which is incorporated herein by reference in its entirety.

Also contemplated for use in the present invention are 11 β -aryl-stanol-4, 9-dien-3-ones of formula I, U.S. Pat. No. 5,739,125, which is incorporated herein by reference in its entirety.

Also contemplated for use in the present invention are 11 beta-aryl-stanol-4, 9-dienes of formula I, U.S. Pat. No. 5,407,928, which is incorporated herein by reference in its entirety.

Also contemplated for use in the present invention are the oxa-steroid 6 compounds disclosed in Kang et al, bioorg. Med. chem. Lett., 17(4): 907-.

The antiprogestin compounds that can be used in accordance with the present invention can be synthesized using synthetic chemistry techniques known in the art, such as those disclosed in U.S. patent No. 6,861,415. It will be appreciated that certain functional groups may interfere with other reactants or reagents under reaction conditions and may therefore require temporary protection. The use of protecting Groups is described in 'Protective Groups in Organic Synthesis', 2 nd edition, T.W. Greene and P.G.M. Wutz, Wiley-Interscience (1991).

In one embodiment, the composition of the invention comprises a pharmaceutically acceptable salt of an antiprogestin (e.g. a compound of 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 invention may be prepared in the form of one or more dosage units suitable for oral (only in the case of compounds of formula I as described above), 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 an antiprogestin 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.

Tablets may be prepared according to any of a number of related, well-known pharmaceutical techniques. In one embodiment, a tablet or other solid dosage form may be prepared by applying a process including, but not limited to, one or a combination of the following: (1) dry blending, (2) direct compression, (3) milling, (4) dry or anhydrous granulation, (5) wet granulation, or (6) fusion.

The various steps in the wet granulation process of tablet preparation typically include: milling and sieving of the ingredients, mixing of dry powders, wet massing, granulation and final milling. Dry granulation involves compressing a powder mixture into a crude tablet or "slugs" on a heavy rotary tablet press. The pre-compressed tablets are then broken into granules by a crushing operation, typically by passing through an oscillating granulator. The various steps include mixing of the powders, compression (tableting) and milling (reduction or granulation of a pre-tablet). Typically, no wet adhesive or moisture is involved in either step.

In another embodiment, a solid dosage form may be prepared by mixing antiprogestin with one or more pharmaceutical excipients to form a substantially homogeneous preformulation mixture. The preformulation mixture may then be subdivided and optionally further processed (e.g., compressed, encapsulated, packaged, dispersed, etc.) into any desired dosage form.

Compressed tablets may be prepared by compressing a powder or granulated composition of the invention. The term "compressed tablet" generally refers to a conventional uncoated tablet suitable for oral ingestion, which is prepared by single compression or by slugging with precompression and then final compression. The tablets of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of improved handling or storage characteristics. In one embodiment, any such coating is selected such that the onset of therapeutic effect of the compositions of the invention is not substantially delayed following administration to a subject. The term "suspension tablet" as used herein refers to a compressed tablet that disintegrates rapidly upon exposure to water.

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.

Excipients optionally employed in the compositions of the present invention may be solid, semi-solid, liquid, or combinations thereof. Compositions of the invention comprising an excipient may be prepared by any of the known techniques of pharmacy, including mixing an excipient with a drug or therapeutic agent.

The compositions of the present invention optionally comprise one or more pharmaceutically acceptable diluents as excipients. Suitable diluents illustratively include (alone or in combination): lactose (including anhydrous lactose and lactose monohydrate); starches (including both directly compressible starches and hydrolyzed starches (e.g., Celutab)^TMAnd Emdex^TM) ); mannitol; sorbitol; xylitol; glucose (e.g., Cerelose)^TM2000) And glucose monohydrate; dibasic calcium phosphate dihydrate; a sucrose-based diluent; candy for candy shop; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; particulate calcium lactate trihydrate; a dextrate; inositol; hydrolyzed grainSolids-like, amylose, cellulose (including food grade sources of microcrystalline cellulose, α -cellulose, and amorphous cellulose (e.g., Rexcel @)^TM) And powdered cellulose; calcium carbonate; glycine; bentonite; polyvinylpyrrolidone, and the like. Such diluents, if present, constitute in total about 5% to about 99%, about 10% to about 85%, or about 20% to about 80% of the total weight of the composition. Preferably any one or more diluents selected exhibit suitable flow properties and, when tablets are desired, compressibility.

The use of ultra-sized microcrystalline cellulose (i.e., adding microcrystalline cellulose to the wet granulated composition after the drying step) may be used to improve hardness (for tablets) and/or disintegration time.

The compositions of the present invention optionally comprise one or more pharmaceutically acceptable disintegrants as excipients, particularly for tablets, capsules or other solid formulations. Suitable disintegrants include, alone or in combination, starches including sodium starch glycolate (e.g., Explotab from PenWest)^TM) And pregelatinized corn starch (e.g., National)^TM1551、National^TM1550 and Colocorn^TM1500) Clay (e.g., Veegum)^TMHV), cellulose such as purified cellulose, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose and sodium carboxymethyl cellulose, croscarmellose sodium (e.g., Ac-Di-Sol from FMC)^TM) Alginates, crospovidone and gums such as agar gum, guar gum, xanthan gum, locust bean gum, karaya gum, pectin and tragacanth.

The disintegrant may be added at any suitable step during the preparation of the composition, in particular during the lubrication step prior to the granulation step or prior to compression. Such disintegrants, if present, constitute in total about 0.2% to about 30%, about 0.2% to about 10%, or about 0.2% to about 5% of the total weight of the composition.

The compositions of the invention optionally comprise one or more pharmaceutically acceptable binders or adhesives as excipients, particularly for tablet formulations. Such binding agentsAnd the binder preferably imparts sufficient cohesion to the powder being tableted to allow normal processing operations such as sieving, lubrication, compression and packaging, but still allow disintegration of the tablet and absorption of the composition after ingestion. Suitable binders and adhesives include, alone or in combination: gum arabic, tragacanth; sucrose; gelatin; glucose; starches such as, but not limited to, pregelatinized starches (e.g., National)^TM1511 and National^TM1500) (ii) a Celluloses such as, but not limited to, methylcellulose and sodium carboxymethylcellulose (e.g., Tylose)^TM) (ii) a Alginic acid and alginates; magnesium aluminum silicate; PEG; guar gum; a gluconic acid; bentonite; polyvinylpyrrolidone (e.g., polyvinylpyrrolidone K-15, K-30 and K-29/32); polymethacrylates; HPMC; hydroxypropyl cellulose (e.g. Klucel)^TM) And ethyl cellulose (e.g., Ethocel)^TM). Such binders and/or adhesives, if present, constitute in total about 0.5% to about 25%, about 0.75% to about 15%, or about 1% to about 10% of the total weight of the composition.

The compositions of the present invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients. Non-limiting examples of surfactants that can be used as wetting agents in the compositions of the present invention include quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride and cetylpyridinium chlorideSodium dioctyl sulfosuccinate, polyoxyethylene alkylphenyl ethers, such as nonoxynol 9, nonoxynol 10 and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, such as polyoxyethylene (8) caprylic/capric monoglycerides and diglycerides (e.g., Labrasol by Gattefoss^TM) Polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, such as polyoxyethylene (20) cetyl stearyl ether (cetostearyl ether), polyoxyethylene fatty acid esters, such as polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters, such as polysorbate 20 and polysorbate 80 (e.g., ICI's Tween @)^TM80) Propylene glycol fatty acid esterFor example, propylene glycol laurate (e.g., Lauroglycol of Gattefoss^TM) Sodium lauryl sulfate, fatty acids and salts thereof such as oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters such as glyceryl monostearate, sorbitan esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol and mixtures thereof. Such humectants, if present, constitute in total about 0.25% to about 15%, about 0.4% to about 10%, or about 0.5% to about 5% of the total weight of the composition.

The compositions of the present invention optionally comprise one or more pharmaceutically acceptable lubricants (including anti-adherents and/or glidants) as excipients. Suitable lubricants include glyceryl behapate (e.g., Compritol), alone or in combination^TM888) (ii) a Stearic acid and its salts, including magnesium stearate (magnesium stearate), calcium stearate, and sodium stearate; hydrogenated vegetable oils (e.g. Sterotex)^TM) (ii) a Colloidal silicon dioxide; talc powder; a wax; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g., Carbowax)^TM4000 and Carbowax^TM6000) (ii) a Sodium oleate; sodium lauryl sulfate and magnesium lauryl sulfate. Such lubricants, if present, constitute in total about 0.1% to about 10%, about 0.2% to about 8%, or about 0.25% to about 5% of the total weight of the composition.

Suitable anti-adherent agents include talc, corn starch, DL-leucine, sodium lauryl sulfate and metal stearates. Talc is, for example, an anti-adherent or glidant used to reduce formulation adhesion to equipment surfaces and also to reduce static in the mixture. One or more anti-adherent agents, if present, comprise about 0.1% to about 10%, about 0.25% to about 5%, or about 0.5% to about 2% of the total weight of the composition.

Glidants can be used to promote powder flow in solid formulations. Suitable glidants include colloidal silicon dioxide, starch, talc, tribasic calcium phosphate, powdered cellulose and magnesium trisilicate. Colloidal silica is particularly preferred.

The compositions of the present invention may comprise one or more defoamers. Dimethicone is an illustrative defoamer. The defoamer, if present, comprises from about 0.001% to about 5%, from about 0.001% to about 2%, or from about 0.001% to about 1%, of the total weight of the composition.

Illustrative antioxidants useful in the present invention include, but are not limited to: butylated hydroxytoluene, butylated hydroxyanisole, potassium metabisulfite and the like. One or more antioxidants, if desired, are typically present in the compositions of the present invention in an amount of about 0.01% to about 2.5%, for example about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 1.5%, about 1.75%, about 2%, about 2.25%, or about 2.5% by weight.

In various embodiments, the compositions of the present invention may comprise a preservative. Suitable preservatives include, but are not limited to, benzalkonium chloride, methyl, ethyl, propyl or butyl parabens, benzyl alcohol, phenethyl ammonium, methyl or propyl parabens and sorbic acid or combinations thereof. Typically, the optional preservative is present in an amount of about 0.01% to about 0.5% or about 0.01% to about 2.5% by weight.

In one embodiment, the compositions of the present invention optionally comprise a buffering agent. Buffers include agents that reduce pH changes. Illustrative classes of buffers for use in various embodiments of the present invention include salts of group IA metals, including, for example, bicarbonates of group IA metals, carbonates of group IA metals, alkali or alkaline earth metal buffers, aluminum buffers, calcium buffers, sodium buffers, or magnesium buffers. Suitable buffering agents include carbonates, phosphates, bicarbonates, citrates, borates, acetates, phthalates, tartrates, succinates of any of the foregoing, for example sodium or potassium phosphate, citrate, borate, acetate, bicarbonate and carbonate.

Non-limiting examples of suitable buffers include: aluminum hydroxide, magnesium hydroxide, aluminum glycinate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate, disodium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, anhydrous alumina gel, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium aluminate silicate (magnesium aluminate), magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium silicate, magnesium succinate, magnesium tartrate, potassium acetate, potassium carbonate, potassium hydrogen borate, potassium citrate, potassium metaphosphate, potassium phthalate, potassium phosphate, potassium polyphosphate, potassium pyrophosphate, potassium succinate, potassium phosphate, potassium succinate, calcium gluconate, calcium hydrogen borate, potassium citrate, calcium metaphosphate, calcium phosphate, potassium pyrophosphate, potassium succinate, calcium gluconate, calcium phosphate, calcium glycerophosphate, calcium, Potassium tartrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, synthetic hydrotalcite, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, trisodium phosphate, and tromethamine. (based in part on the list provided in the Merck Index, Merck & Co. Rahway, N.J. (2001)). Furthermore, combinations or mixtures of any two or more of the above-mentioned buffering agents can be used in the pharmaceutical compositions described herein. One or more buffering agents, if desired, are present in the compositions of the present invention in an amount of about 0.01% to about 5% or about 0.01% to about 3% by weight.

In various embodiments, the compositions of the present invention may comprise one or more viscosity increasing substances. Illustrative agents that increase viscosity include, but are not limited to, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, carrageenan, carbopol, and/or combinations thereof. Typically, one or more tackifiers, if desired, are present in the compositions of the present invention in an amount of about 0.1% to about 10% or about 0.1% to about 5% by weight.

In various embodiments, the compositions of the present invention comprise "organoleptic agents" to improve the organoleptic properties of the compositions. The term "sensory impact agent" herein refers to any excipient that can improve the flavor or odor of the composition of the present invention, or help mask the unpleasant flavor or odor of the composition of the present invention. Such materials include sweetening agents, flavoring agents and or taste masking agents. Suitable sweetening and/or flavoring agents include any substance that sweetens or provides flavor to a pharmaceutical composition. The optional organoleptic agents are typically present in the compositions of the present invention in an amount of from about 0.1 mg/ml to about 10 mg/ml, from about 0.5 mg/ml to 5 mg/ml, or about l mg/ml.

Illustrative sweeteners or flavoring agents include, but are not limited to: acacia syrup, anethole, anise oil, aromatic elixir, benzaldehyde elixir, cyclodextrin, caraway oil, cardamom seed, cardamom spirit, cardamom tincture, cherry juice, cherry syrup, cinnamon oil, cinnamon water, citric acid syrup, clove oil, cocoa syrup, coriander oil, dextrose, eriodictyon fluid extract, eriodictyon syrup, aromatic, ethyl acetate, ethyl vanillin, anise oil, ginger fluid extract, ginger oleoresin, dextrose, glucose, sugar, maltodextrin, glycerin, licorice elixir, licorice extract, licorice pure extract, licorice fluid extract, licorice syrup, honey, isoalcohol elixir, lavender oil, lemon tincture, mannitol, methyl salicylate, nutmeg oil, bitter orange, elixir, bitter orange, orange oil, orange flower oil, sesame, Orange blossom water, orange oil, orange peel, bitter orange peel, sweet orange peel, tincture, orange peel spirit, orange peel syrup, mint, peppermint oil, peppermint spirit, peppermint water, phenylethyl alcohol, raspberry juice, raspberry syrup, rosemary oil, rose water, fortified (stronger), saccharin calcium, saccharin sodium, sarsasapor syrup, sarsasapor, sorbitol solution, spearmint oil, sucrose, sucralose, syrup, thyme oil, tulip syrup, vanilla tincture of vanilla, vanillin, wild cherry syrup, or a combination thereof.

Illustrative taste masking agents include, but are not limited to, cyclodextrins, cyclodextrin emulsions, cyclodextrin particles, cyclodextrin complexes, or combinations thereof.

Illustrative suspending agents include, but are not limited to, sorbitol syrup, methyl cellulose, glucose/syrup, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats.

Illustrative emulsifiers include, but are not limited to: lecithin, sorbitan monooleate and acacia. Non-aqueous media include, but are not limited to: edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol and ethanol.

The aforementioned excipients may have a variety of functions known in the art. For example, starch may be used as a filler and disintegrant. The above classification of excipients should not be understood as being limiting in any way.

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 500 mg/kg per day, for example from about 1. mu.g/kg to about 1mg/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 1mg/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 1mg/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 the formulations of the invention may be prepared as tablets

To obtain tablets for practicing the invention, the following ingredients may be pressed together in a tablet press:

10.0 mg of 21-methoxy-11 beta- (4-N, N-dimethylaminophenyl) -19-norpregna-4, 9-diene-3, 20-dione

140.5 mg lactose

69.5 mg corn starch

2.5mg of poly-N-vinylpyrrolidone

2.0 mg of fumed silica

0.5 mg magnesium stearate

To obtain an oily preparation for practicing the invention, for example, the following ingredients may be mixed together and filled into ampoules:

10.0 mg of 21-methoxy-11 beta- (4-N, N-dimethylaminophenyl) -19-norpregna-4, 9-diene-3, 20-dione

343.4 mg Castor oil

608.6 mg of benzyl benzoate

Example 2 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, a 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% glycerol, 1 mM DTT) and mixed with 6nM 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 6nM 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 set in a Beckmann LS-1800 liquid scintillation counterAnd (6) counting. 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 3 measurement of in vivo anti-glucocorticoid and progesterone antagonist Activity

To measure progesterone antagonist activity of test compounds in vivo, T47D-CO human breast cancer cells grown in monolayer cultures of phenolsulfonphthalein-free DMEM supplemented with 10% Fetal Bovine Serum (FBS), 10U/ml penicillin G, and 10 μ G/ml streptomycin sulfate were treated 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 phenol-free sulfonphthalein 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 4 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 with higher dose exposures for up to 6 months in european females have predicted hepatotoxicity in phase III clinical studies conducted in different populations in the united states. 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 level of liver enzymes discontinued in clinical trials was set to be greater than or equal to three times the increase in liver aminotransferase (> 3 × ULN) above 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 voluntarily 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 the 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 5 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 to the drug was much lower when given topically (comparing 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 in 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 6 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 protection from uterine gland growth, complexity and overall progesterone-induced "development". 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 1mg/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 4. 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 4.

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.

Claims (3)

1. Use of a 21-methoxy-17 α -acetoxy-11 β - (4N, N-dimethylaminophenyl) -19-norpregna-4, 9-diene-3, 20-dione in a dose of 1.3.125 mg to 12.5mg for the manufacture of a medicament for the treatment of endometriosis or uterine fibroids to be administered once daily to the vaginal mucosa of a female for a period of at least 4 months, wherein the medicament comprises a bioadhesive carrier and is in the form of a gel, cream, tablet, pill, capsule or suppository.
2. 2. The use of claim 1, wherein the medicament is to be administered for a period of at least 12 months.
3. Use of 21-methoxy-17 α -acetoxy-11 β - (4N, N-dimethylaminophenyl) -19-norpregna-4, 9-diene-3, 20-dione in a dose of 3.5-20 mg for the manufacture of a medicament for the treatment of endometriosis or uterine fibroids to be administered once daily to the vaginal mucosa of a female for a period of at least 4 months, wherein the medicament comprises a bioadhesive carrier and is in the form of a gel, cream, tablet, pill, capsule or suppository.