JP2010516686A - Methods for improving the stability of steroid derivatives - Google Patents

Abstract

  A composition having improved stability comprising a pharmaceutically acceptable salt of 11- (4-aminophenyl) -19-norpregna-4,9 (10) -diene-3,20-dione derivative. provide.

Description

  The present invention generally relates to a composition comprising a steroid, in particular a composition having potent antiprogesterone activity, minimal antiglucocorticoid activity and improved stability comprising a 19-norprogesterone I derivative. About. The present invention also relates to a method of using the composition.

  Over the past decades, many attempts have been made to prepare steroids with anti-hormonal activity. In recent years, anti-progesterone steroids have demonstrated wide applicability in individual control while anti-glucocorticoids are very effective in the treatment of other conditions characterized by, for example, Cushing syndrome and excessive endogenous production of cortisone It has been generally accepted that

  For contraceptive purposes, it is advantageous to use compounds with anti-progesterone activity that have no (or minimally) anti-glucocorticoid activity. There have been many attempts to modify the mifepristone structure to achieve separation of anti-progesterone activity from anti-glucocorticoid activity, but this goal has not yet been fully achieved. Thus, there remains a need in the art for the development of new formulations comprising steroids with anti-progesterone activity with minimal anti-glucocorticoid activity.

  US Pat. No. 6,861,415 and US Pat. No. 6,900,193, both incorporated herein by reference, disclose novel compounds with anti-progesterone activity with minimal anti-glucocorticoid activity. This compound is a steroid derivative, more specifically, these are structural variants of 19-norprogesterone I, such as 17-α-substituted-11-β-substituted-4-aryl and 21-substituted 19-nodes. Rupregnadienedione, which are sparingly soluble in water. Thus, there remains a need in the art for the development of formulations comprising steroid derivatives with improved stability and improved bioavailability.

  The present invention provides a novel formulation with potent antiprogesterone activity, minimal antiglucocorticoid activity and improved stability.

を有する化合物の医薬的に許容可能な塩を含んでなる組成物を提供する。 More specifically, the present invention relates to the following general formula I

A composition comprising a pharmaceutically acceptable salt of a compound having the formula:

Here, R ¹ preferably includes nitrogen, and is a basic functional group capable of forming a salt therein, and is not limited to, for example, —N (CH ₃ ) ₂ , —NHCH ₃ , —NC _{4. H 8, -NC 5 H 10,} -NC 4 H 8 O, -O (CH 2) 2 N (CH 3) 2, -O (CH 2) 2 NC 4 H 8 and -O (CH _{2) 2} NC ₅ H ₁₀ ; R ² is a functional group, including but not limited to, for example, hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (eg, methoxy, ethoxy, vinyloxy, ethynyloxy, cyclopropyloxy Etc.), acyloxy (eg formyloxy, acetoxy, propionyloxy, heptanoyloxy, glycinate, etc.), alkyl carbonate, cipinoyloxy, S-alkyl, -SCN, S-acyl and —OC (O) R ⁶ , wherein R ⁶ is a functional group, including but not limited to, alkyl (eg, methyl, ethyl, etc.), alkoxyalkyl (eg, —CH ₂ OCH ₃ ). R ³ is a functional group, such as, but not limited to, alkyl (eg, methyl, methoxymethyl, etc.), hydroxy, alkoxy (eg, methoxy, ethoxy, methoxy), and alkoxy (—OCH ₃ ); Ethoxy, vinyloxy, etc.), and acyloxy; R ⁴ is a functional group, including but not limited to, for example, hydrogen and alkyl; and X is a functional group, but not limited to For example, ═O and ═N—OR ⁵ , wherein R ⁵ is selected from the group consisting of hydrogen and alkyl, wherein R ¹ is —N (CH ₃ ) ₂ and R ² is methoxy. When R ³ is acetoxy, R ⁴ is methyl and X is ═O, the condition is that the salt is not an HCl or HBr salt.

  The composition has potent anti-progesterone activity, minimal anti-glucocorticoid activity and improved stability. Thus, the composition may be suitable for long-term use in the treatment of human endocrine disorders or other medical conditions in steroid sensitive tissues. Specific medical conditions for treatment include, but are not limited to, endometriosis, dysmenorrhea, uterine leiomyoma, uterine fibroma, meningiomas and metastatic breast cancer. Other uses include, but are not limited to, contraception, such as post sexual contraception and induction of cervical cramification.

  Similarly, any use of the compositions of the present invention in the manufacture of a medicament for the treatment of the human endocrine disorders described herein or other medical conditions in steroid sensitive tissues is provided and not limiting. However, there are, for example, endometriosis, dysmenorrhea, uterine leiomyoma, uterine fibroma, meningioma and metastatic breast cancer.

のステロイド誘導体を含んでなる組成物を提供する。 The following general formula I

A composition comprising a steroid derivative is provided.

According to Formula I, R ¹ is a basic functional group that preferably comprises nitrogen where it can form a salt, such as, but not limited to, —N (CH ₃ ) ₂ , —NHCH ₃ , —NC ₄ H ₈ , —NC ₅ H ₁₀ , —NC ₄ H ₈ O, —O (CH ₂ ) ₂ N (CH ₃ ) ₂ , —O (CH ₂ ) ₂ NC ₄ H ₈ and —O (CH _{2 2} NC ₅ H ₁₀ ; R ² is a functional group, including but not limited to, for example, hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (eg, methoxy, ethoxy, vinyloxy, ethynyloxy, Cyclopropyloxy etc.), acyloxy (eg formyloxy, acetoxy, propionyloxy, heptanoyloxy, glycinate, etc.), alkyl carbonate, cipinoyloxy, S-alkyl, -SCN, S-acy And a -OC (O) R ^6, wherein R ⁶ is a functional group include, but are not limited to, for example, alkyl (e.g., methyl, ethyl, etc.), alkoxyalkyl (e.g. -CH ₂ OCH ₃ ) And alkoxy (—OCH ₃ ); R ³ is a functional group, including but not limited to, for example, alkyl, hydroxy, alkoxy, and acyloxy; R ⁴ is a functional group, limiting For example, hydrogen and alkyl; and X is a functional group, including but not limited to, ═O and ═N—OR ⁵ , where R ⁵ is hydrogen and alkyl. Wherein R ¹ is —N (CH ₃ ) ₂ , R ² is methoxy, R ³ is acetoxy, R ⁴ is methyl and X is ═O, the salt is HCl or HBr salt If not That.

That is, the composition of the present invention comprises a compound of general formula I that can form a salt when the compound reacts with a suitable acid. Preferably, the compound of general formula I comprises a basic functional group added to the 4-position (ie R ¹ position) of the phenyl group located at the 11β position of the compound. However, compounds of general formula I comprising a basic functional group added at any position are within the scope of the invention as long as a salt of the compound can be formed. In addition to the basic functional groups described above, other basic functional groups suitable for R ¹ that can form salts therein include, but are not limited to, methylamine, dimethylamine, ethylamine, diethylamine, ethylmethylamine, isopropylamine, There are diisopropylamine, n-butylamine, ethanolamine, diethanolamine, methylethanolamine, isopropanolamine, diisopropanolamine, ethyleneimine, ethylenediamine, pyridine and morpholine functional groups.

The term “alkyl” refers to a branched, unbranched, monovalent hydrocarbon group having 1 to 12 carbons. If the alkyl group has 1 to 6 carbon atoms, it can be referred to as “lower alkyl”. Representative alkyl groups include, for example, methyl, ethyl, n-propyl, i-propyl, 2-propenyl (or allyl), n-butyl, t-butyl, i-butyl (or 2-methylpropyl), and the like. . As used herein, the term alkyl includes “substituted alkyl”. Substituted alkyl refers to alkyl further containing one or more functional groups, such as lower alkyl, aryl, aralkyl, acyl, halogen (ie alkylhalo, eg CF ₃ ), hydroxy (Eg, hydroxymethyl), amino, alkylamino, acylamino, acyloxy, alkoxy (eg, methoxymethyl), mercapto and the like. These groups can be added to any carbon atom of the lower alkyl moiety.

  The term “alkoxy” refers to the group —OR, where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl. Suitable alkoxy groups include, for example, methoxy, ethoxy, phenoxy, t-butoxy (eg, methoxyethoxy, methoxymethoxy, etc.) and the like.

The term “acyloxy” refers to an organic group derived from an organic acid by removal of hydrogen. This organic group may be further substituted with one or more functional groups. Examples of such functional groups include alkyl, aryl, aralkyl, acyl, halogen, amino, thiol, hydroxy, alkoxy and the like. An example of this substituted organic group is glycinate (eg, —OC (O) CH ₂ NH ₂ ). Suitable alkoxy groups, for example, acetoxy from acetic, i.e. CH ₃ COO-, formyloxy from formic acid, i.e. H (CO) O-, and 3 from cyclopentyl propionic acid, there is Shipioniruokishi.

  The term “halogen” refers to fluorine, bromine, chlorine and iodine atoms. The term “hydroxyl” refers to the —OH group. The term “acyl” refers to the group —C (O) R, where R is alkyl or substituted alkyl, aryl or substituted aryl as defined herein. The term “aryl” refers to an aromatic substituent that is a single ring or multiple rings fused together, covalently linked, or linked to a covalent group of, for example, an ethylene or methylene moiety. Aromatic ring (s) include phenyl, naphthyl, biphenyl, diphenylmethyl, 2,2-diphenyl-1-ethyl and may contain heteroatoms such as thienyl, pyridyl and quinoxalyl. is there. The aryl group may be substituted with a halogen atom or other groups such as nitro, carboxyl, alkoxy, phenoxy and the like. Furthermore, the aryl group may be added to other moieties at any position on the aryl group as long as the halogen atom is not occupied (for example, 2-pyridyl, 3-pyridyl and 4-pyridyl).

  The term “alkyl carbonate” refers to the group —OC (O) OR, where R is alkyl, substituted alkyl, aryl, substituted aryl as defined herein.

The term “S-alkyl” refers to the group —SR, where R is lower alkyl or substituted lower alkyl. The term “S-acyl” refers to a thioester derived from the reaction of an acylating agent with a thiol group. Suitable S-acyls include, for example, S-acetyl, S-propionyl and S-pivaloyl. S-acyl refers to a thioester regardless of its method of preparation. The terms “N-oxime” and “N-alkyloxime” refer to the ═N—OR ⁵ group, where R ⁵ is, for example, hydrogen (N-oxime) or alkyl (N-alkyloxime). . The oxime can consist of a syn isomer, an anti isomer, or a mixture of syn and anti isomers.

Representative compounds included in Formula I include those in which R ¹ is —N (CH ₃ ) ₂ , R ² is hydrogen, halogen or alkoxy, R ³ is acyloxy, and R ⁴ is alkyl (eg methyl And ethyl), X is ═O and ═N—OR ⁵ , and R ⁵ is hydrogen or alkyl. Further compounds include those where R ¹ is —N (CH ₃ ) ₂ , R ² is halogen, R ³ is acyloxy, and R ⁴ is alkyl, eg R ² is F, Br or Cl, R ⁴ is Methyl and the like. Also included are compounds in which R ¹ is —N (CH ₃ ) ₂ , R ² is alkyl, R ³ is acyloxy, R ⁴ is alkyl, and X is ═O. Also included are compounds in which R ¹ is —N (CH ₃ ) ₂ , R ² is alkoxy, R ³ is acyloxy, R ⁴ is alkyl, and X is ═O. Further compounds are those wherein R ² is methoxy or ethoxy and R ³ is acetoxy or methoxy. Also included are compounds in which R ¹ is —N (CH ₃ ) ₂ , R ² is hydroxy, R ³ is acyloxy, R ⁴ is alkyl, and X is ═O. Also included are compounds in which R ¹ is —N (CH ₃ ) ₂ , R ² and R ³ are both acyloxy, R ⁴ is alkyl, and X is ═O. Further compounds are those in which both R ² and R ³ are acetoxy. Also included are compounds in which R ¹ is —N (CH ₃ ) ₂ , R ² is S-acyl, R ³ is hydroxy or acyloxy, R ⁴ is alkyl, and X is ═O. Also included are compounds in which R ¹ is —N (CH ₃ ) ₂ , R ² is cyionoroxy, R ³ is acetoxy, R ⁴ is alkyl, and X is ═O. R ¹ is —N (CH ₃ ) ₂ , R ² is methoxy, R ³ is acetoxy, R ⁴ is alkyl, X is ═O and ═N—OR ⁵ , and R ⁵ is, for example, hydrogen or alkyl ( Also included are compounds such as methyl, ethyl, and the like. R ¹ is —N (CH ₃ ) ₂ , R ² and R ³ are both acetoxy, R ⁴ is alkyl, X is ═O and ═N—OR ⁵ , and R ⁵ is, for example, hydrogen or alkyl ( Also included are compounds such as methyl, ethyl, and the like.

の17α−アセトキシ−11β−［４−（Ｎ,Ｎ−ジメチルアミノ）フェニル］−21−メトキシ−19−ノルプレグナ−４,９（10）−ジエン−３,20−ジオン（CDB-4124）があるが、ただしCDB-4124の塩は、ＨＣｌ又はＨＢｒ酸塩ではない。 Exemplary compounds include, but are not limited to, the following structural formulas, for example:

17α-acetoxy-11β- [4- (N, N-dimethylamino) phenyl] -21-methoxy-19-norpregna-4,9 (10) -diene-3,20-dione (CDB-4124) However, the salt of CDB-4124 is not HCl or HBr salt.

の17α−アセトキシ−11β−［４−（Ｎ,Ｎ−ジメチルアミノ）フェニル］−19−ノルプレグナ−４,９−ジエン−３,20−ジオン（CDB-2914）がある。 Another exemplary compound has the following structural formula:

17α-acetoxy-11β- [4- (N, N-dimethylamino) phenyl] -19-norpregna-4,9-diene-3,20-dione (CDB-2914).

  Other exemplary compounds include, but are not limited to, 17α-acetoxy-21-chloro-11β- (4-N, N-dimethylaminophenyl) -19-norpregna-4,9-diene-3, 20-dione, 17α-acetoxy-21-bromo-11β- (4-N, N-dimethylaminophenyl) -19-norpregna-4,9-diene-3,20-dione, 17-, 21-diacetoxy-11β -(4-N, N-dimethylaminophenyl) 19-norpregna-4,9-diene-3,20-dione, 17α-hydroxy-21-acetylthio-11β- (4-N, N-dimethylaminophenyl)- 19-norpregna-4,9-diene-3,20-dione, 17α-acetoxy-21-acetylthio-11β- (4-N, N-dimethylaminophenyl) -19-norpregna-4,9-diene-3, 20-dione, 17α-acetoxy-21-ethoxy 11β- (4-N, N-dimethylaminophenyl) -19-norpregna-4,9-diene-3,20-dione, 17α-acetoxy-21-methyl-11β- (4-N, N-dimethylaminophenyl) ) -19-norpregna-4,9-diene-3,20-dione, 17α-acetoxy-21-methoxy-11β- (4-N, N-dimethylaminophenyl) -19-norpregna-4,9-diene- 3,20-dione, 17α-acetoxy-21-ethoxy-11β- (4-N, N-dimethylaminophenyl) -19-norpregna-4,9-diene-3,20-dione, 17α-acetoxy-21- (3′-cyclopentylpropynyloxy) 11β- (4-N, N-dimethylaminophenyl) -19-norpregna-4,9-diene-3,20-dione, 17α-acetoxy-21-hydroxy-11β- (4 -N, N-dimethylaminophenyl -19-norpregna-4,9-diene-3,20-dione, 17α, 21-diacetoxy-11β- (4-N, N-dimethylaminophenyl) -19-norpregna-4,9-diene-3,20 -Dione 3-oxime, 17α-acetoxy-21-methoxy-11β- (4-N, N-dimethylaminophenyl) -19-norpregna-4,9-diene-3,20-dione 3-oxime, 17α-acetoxy -11β- [4- (N-methylamino) phenyl] -19-norpregna-4,9-diene-3,20-dione and 17α, 21-diacetoxy-11β- [4- (N-methylamino) phenyl ] -19-norpregna-4,9-diene-3,20-dione.

R ¹ is NH (CH ₃ ) ₂ , —NC ₄ H ₈ , —NC ₅ H ₁₀ , —NC ₄ H ₈ O, —O (CH ₂ ) ₂ N (CH ₃ ) ₂ , —O (CH ₂ ) ₂ NC ₄ H ₈ , —O (CH ₂ ) ₂ NC ₃ H ₁₀ and —O (CH ₂ ) ₂ NC ₅ H ₁₀ , R ² is hydrogen, alkyloxy, alkoxy, —SAc, —SCN , —OC (O) CH ₂ N (CH ₃ ) ₂ , and —OC (O) R ⁶ , where R ⁶ is, but is not limited to, alkyl (eg, —CH ₂ CH ₃ ), alkoxy ester (Eg -CH ₂ OMe) and alkoxy (eg -OCH ₃ ), R ³ is alkyl, alkoxy, acyloxy and hydroxy, R ⁴ is alkyl (eg methyl and ethyl) and X is = O or = in N-oR ^5, wherein R ⁵ is hydrogen or alkyl, these compounds Murrell. A compound in which R ¹ is —N (CH ₃ ) ₂ , R ² is hydrogen, R ³ is methoxymethyl, R ⁴ is methyl, and X is ═O is preferable. R ¹ is —N (CH ₃ ) ₂ , R ² is hydrogen, R ³ is —OC (O) H, —OC (O) CH ₂ CH _3, or —OC (O) C ₆ H ₁₃ , R ^4. In which X is methyl and X is ═O. Also included are compounds in which R ¹ is —NC ₄ H ₈ , —NC ₅ H ₁₀ , or —NC ₄ H ₈ O, R ² is hydrogen, R ³ is acetoxy, R ⁴ is methyl, and X is ═O. It is. Also included are compounds in which R ¹ is —N (CH ₃ ) ₂ or —NC ₅ H ₁₀ , R ² is hydrogen, R ³ is methoxy, R ⁴ is methyl, and X is ═O. Also included are compounds in which R ¹ is —NC ₅ H ₁₀ , R ² and R ³ are both acetoxy, R ⁴ is methyl, and X is ═O. Also included are compounds in which R ¹ is —NC ₅ H ₁₀ or —O (CH ₂ ) ₂ N (CH ₃ ) ₂ , R ² is methoxy, R ³ is acetoxy, R ⁴ is methyl, and X is ═O. It is. R ¹ is —N (CH ₃ ) ₂ , R ² is —OC (O) CH ₂ CH ₃ , —OC (O) OCH ₃ , —OC (O) OCH ₂ CH ₃ , —OCH═CH ₂ , _{-OC (O) CH 2 N (} CH 3) ₂ or -SCN, R ³ is acetoxy, R ⁴ is includes compounds methyl, and X is = a O. Also included are compounds in which R ¹ is —N (CH ₃ ) ₂ , R ² is —OC (O) H, R ³ is —OC (O) H, R ⁴ is methyl, and X is ═O. Also included are compounds in which R ¹ is —N (CH ₃ ) ₂ , R ² is —OC (O) H, R ³ is hydroxy, R ⁴ is methyl, and X is ═O. Also included are compounds in which R ¹ is —NC ₅ H ₁₀ , R ² is hydrogen, R ³ is acetoxy, R ⁴ is methyl, and X is ═N—OR ⁵ , where R ⁵ is hydrogen. R ¹ is —N (CH ₃ ) ₂ or —NC ₅ H ₁₀ , R ² is hydrogen or methoxy, R ³ is methoxy or ethoxy, R ⁴ is methyl, and X is a N-OR ^5, wherein R ⁵ includes compounds wherein is hydrogen.

  Exemplary compounds also include, but are not limited to, 17α-acetoxy-11β- [4- (N, N-dimethylamino) phenyl] -21-methoxy-19-norpregna-4,9 (10) -diene -3,20-dione, 17α-formyloxy-11β- [4- (N, N-dimethylamino) phenyl] -19-norpregna-4,9-diene-3,20-dione, 17α-propionoxy-11β -[4- (N, N-dimethylamino) phenyl] -19-norpregna-4,9-diene-3,20-dione, 17α-heptanoyloxy-11β- [4- (N, N-dimethylamino) Phenyl] -19-norpregna-4,9-diene-3,20-dione, 17α-methoxymethyl-11β- [4- (N, N-dimethylamino) phenyl] -19-norpregna-4,9-diene- 3,20-dione, 17α-acetoxy-11β- (4-N Pyrrolidinophenyl) -19-norpregna-4,9-diene-3,20-dione, 17α-acetoxy-11β- (4-N-piperidinophenyl) -19-norpregna-4,9-diene-3, 20-dione, 17α-acetoxy-11β- (4-N-morpholinophenyl) -19-norpregna-4,9-diene-3,20-dione, 17α-methoxy-11β- [4- (N, N- Dimethylamino) phenyl] -19-norpregna-4,9-diene-3,20-dione, 17α-methoxy-11β- (4-N-piperidinophenyl) -19-norpregna-4,9-diene-3 , 20-dione, 17α, 21-diacetoxy-11β- (4-N-piperidinophenyl) -19-norpregna-4,9-diene-3,20-dione, 17α, 21-dimethoxy-11β- [4 -(N, N-dimethylamino) phenyl] -19-norpregna-4,9 -Diene-3,20-dione, 17α, 21-dimethoxy-11β- (4-N-pyrrolidinophenyl) -19-norpregna-4,9-diene-3,20-dione, 17α, 21-dimethoxy-11β -(4-N-piperidinophenyl) -19-norpregna-4,9-diene-3,20-dione, 17α-acetoxy-11β- {4- [2 '-(N, N-dimethylamino) ethoxy ] Phenyl} -21-methoxy-19-norpregna-4,9-diene-3,20-dione, 17α, 21-diformyloxy-11β- [4- (N, N-dimethylamino) phenyl] -19- Norpregna-4,9-diene-3,20-dione, 17α-acetoxy-11β- [4- (N, N-dimethylamino) phenyl] -21-propyronyloxy-19-norpregna-4,9-diene -3,20-dione, 17α-acetoxy-11β- [4- (N, N-dimethylamino) Phenyl] -21- (2′-methoxyacetyl) oxy-19-norpregna-4,9-diene-3,20-dione, 17α-acetoxy-21-hydroxy-11β- [4- (N, N-dimethylamino) ) Phenyl] -19-norpregna-4,9-diene-3,20-dione-21-methyl carbonate, 17α-acetoxy-11β- [4- (N, N-dimethylamino) phenyl] -21- (1 '-Ethenyloxy) -19-norpregna-4,9-diene-3,20-dione, 17α-acetoxy-11β- [4- (N, N-dimethylamino) phenyl] -21- (2'-N, N -Dimethylamino) acetoxy-19-norpregna-4,9-diene-3,20-dione, 17α-acetoxy-11β- [4- (N, N-dimethylamino) phenyl] -21-thiocyanato-19-norpregna- 4,9-diene-3,20-dione, 17 α-acetoxy-11β- (4-N-piperidinophenyl) -19-norpregna-4,9-diene-3,20-dione-3-oxime, 17α-methoxy-11β- [4- (N, N- Dimethylamino) phenyl] -19-norpregna-4,9-diene-3,20-dione 3-oxime, 17α-methoxy-11β- (4-N-piperidinophenyl) -19-norpregna-4,9- Diene-3,20-dione 3-oxime and 17α, 21-dimethoxy-11β- [4- (N, N-dimethylamino) phenyl] -19-norpregna-4,9-diene-3,20-dione 3 -There is an oxime.

  The stability of the compound having general formula I may be significantly increased when the compound is in the form of a salt. Compositions comprising a pharmaceutically acceptable salt of Formula I and optionally comprising a pharmaceutically acceptable carrier are provided.

  In practice, the use of the salt form is essentially the use of the free base form. Accordingly, acids suitable for salt formation are preferably those that form pharmaceutically acceptable salts when combined with the free base. The salt, in the free base state, is non-toxic to the patient at the pharmaceutical dose of the salt so that the beneficial pharmacological efficacy of these compounds is not impaired by side effects due to the anion. Salt. Compounds of general formula I may be regenerated from salts by the application or application of known methods. For example, a compound can be regenerated from its acid addition salt by treating with an alkali, such as sodium bicarbonate solution.

  Formed during final in situ isolation and purification of the compound of general formula I, or by reacting the purified compound in its free base state with a suitable organic or inorganic acid The salt can be prepared by isolating the salt. Typical salts include hydrobromides, halides, hydrochlorides, sulfides, bisulfides, phosphorus oxides, nitrates, acetates, oxalates, palates, oleates, palmitates , Stearate, laurate, borate, benzoate, lactate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptanoate, See lactiobionate, salts of lauryl sulfonate, etc. (see, eg, SM Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 66: 1-19, 1977. This content. Incorporated herein by reference). For example, a salt is prepared by isolating the salt by dissolving the free base in an aqueous solution or water-alcohol solution or other suitable solvent containing the appropriate acid and then evaporating the solution. Alternatively, if the salt is separated directly or can be obtained by concentrating the solution, it may be prepared by reacting the free base and acid in an organic solvent.

  The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic or organic acid addition salts of compounds of general formula I.

  Compositions comprising pharmaceutically acceptable salts of compounds of general formula I are provided. A salt of a compound of general formula I is expected to have improved stability compared to the same amount of the compound in the free base state under the same conditions. That is, the composition of the present invention is expected to have improved resistance to chemical modification. The stability of the pharmaceutically acceptable salt of the compound of general formula I is at least 1, 5, 10, 15, 20, 25 compared to the same amount of the free base state of the same compound and under the same conditions. , 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, or up to 1000% or more.

  A typical parameter for stability is shelf life, which is defined as the time period during which a drug product is expected to maintain specifications within the approved shelf life. The accelerated test is conducted for 6 months at 40 ° C. and 75% relative humidity. Under these conditions, a change in drug concentration of about 5% from the initial assay value is considered significant. A composition comprising a pharmaceutically acceptable salt of a compound of general formula I is observed to have an extended shelf life compared with the same composition comprising the free base state of the same compound under the same conditions. It is expected that

  As used herein, stability refers to the detection of active ingredients (ie, compounds of general formula I) in a composition, typically by HPLC, after storage intervals under specified conditions of temperature and humidity. Tell your ability to do. Any method for the detection of active ingredients capable of distinguishing chemical modifications and / or concentration changes of the active ingredients may be used, where HPLC is preferred.

  Also provided are methods for improving the stability of a compound by reacting the compound of general formula I with a suitable acid to form a pharmaceutically acceptable salt.

  The composition may have potent anti-progesterone activity and minimal anti-glucocorticoid activity combined with improved stability. Because of these properties, these compositions are suitable for oral administration.

  The composition comprises, inter alia, combating endogenous progesterone, induction of menstruation, treatment of endometriosis, treatment of dysmenorrhea, treatment of endocrine hormone dependent tumors, treatment of meningitis, treatment of uterine leiomyoma It can be advantageously used for the treatment of uterine fibroma, inhibition of endometrial proliferation, induction of labor, induction of cervical ripening, hormonal therapy, and contraception.

  A composition having anti-progesterone activity may also be characterized by antagonizing the action of progesterone. As such, the composition is particularly effective in controlling irregular hormones in the menstrual cycle, for controlling endometriosis and dysmenorrhea, and for menstrual induction. In addition, the composition can be used alone as a method of providing hormonal therapy, or in combination with estrogenic agents in postmenopausal women or in women with reduced ovarian hormone production due to other causes. .

  Furthermore, the composition can be used to control fertility throughout the reproductive cycle. For long-term contraception, the composition can be administered continuously or periodically depending on its dosage. In addition, the composition makes the uterus difficult to implant and is therefore particularly effective as a “once a month” contraceptive for post-sexual interception.

  A further important utility of this composition is its ability to slow the growth of hormone dependent tumors and / or tumors present in hormone responsive tissues. Such tumors include, but are not limited to, kidney, breast, endometrium, ovary, and prostate tumors such as cancer, characterized by having a progesterone receptor. In addition, tumors include meningeal species. Other uses of this composition include the treatment of breast and uterine fibrosis.

  The composition can be administered to any warm-blooded mammal, such as humans, domestic pets, and livestock. Domestic pets include dogs, cats and the like. Domestic animals include cattle, horses, pigs, sheep, goats and the like.

  The amount of active ingredient that can be combined with the optimal carrier material to produce a single dosage form can vary depending upon the disease being treated, the mammalian species, and the particular mode of administration. For example, a unit dose comprises an amount between 0.1 milligram and 1 gram of active ingredient, or an amount between 0.001 and 0.5 gram. However, the specific dosage level for any particular patient will vary in factors such as the activity of the specific compound used, the individual being treated, age, weight, overall health, gender and diet , Depending on the time and route of administration, elimination rate, other drugs previously administered, and the severity of the specific disease being treated.

  The composition can be administered in various ways. For example, the composition may be a solution, suspension, emulsion, tablet, such as sublingual and buccal tablets, soft gelatin capsules, such as those used in soft gelatin capsules, aqueous or oil suspensions, emulsions, pills, It may be administered via the oral route in the form of a lozenge, troche, tablet, syrup or elixir.

  The compositions can also be administered as grafts and biodegradable grafts such as SILASTIC or via intramuscular and intravenous infusion.

  The composition may comprise one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are also acceptable. These excipients are, for example, as inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, such as corn starch, or alginic acid, as binders, such as starch. Gelatin or acacia, and lubricants include, for example, magnesium stearate, stearic acid and talc. The tablets may be uncoated or they may be coated by known methods to delay disintegration and absorption in the gastrointestinal tract and provide a sustained action over a longer period. For example, as a retarder, for example, glyceryl monostearate or glyceryl distearate can be used alone or in combination with a wax.

  Formulations for oral use may be prepared as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin. Alternatively, it may be prepared as a soft gelatin capsule in which the active ingredient is mixed with a water or oil medium such as peanut oil, liquid paraffin or olive oil.

  Aqueous suspensions may contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspensions such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pororidone, gum tragacanth and acacia, and dispersing or wetting agents such as natural phospholipids (eg lectins), Condensation products of fatty acids and alkylene oxides (eg polyoxyethylene stearate), condensation products of long-chain aliphatic alcohols and ethylene oxide (eg heptadecaethyleneoxycetanol), condensation products of fatty acid and partial esters derived from hexitol and ethylene oxide (Eg, polyoxyethylene sorbitol monooleate) or condensation products of fatty acid and partial esters derived from hexitol anhydride and ethylene oxide (eg, polyethylene Monooleate) there is. Aqueous suspensions and also one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents and one or more sweetening agents such as sucrose, aspartame or Saccharin may be contained.

  Oil suspensions may be formulated by suspending the active ingredient, the suspension being carried out in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspension may contain thickening agents such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.

  Dispersed powders and granules suitable for preparation of an aqueous suspension by the addition of water can be formulated from the active ingredient in a mixture with a dispersing agent, suspending agent and / or wetting agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may be present.

  The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifiers include natural gums such as gum acacia and gum tragacanth, natural phospholipids such as soybean lectin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of ethylene oxide with these partial esters. Products such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.

  Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may contain a demulcent, a preservative, a flavoring or a coloring agent.

  The pharmaceutical compositions may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated using the suitable dispersing or wetting agents and suspending agents described above. Sterile injectable formulations are sterile injectable solutions or suspensions which can be prepared in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. As an acceptable medium and solvent, Ringer's solution which is water and isotonic sodium chloride can be used. In addition, sterile solid oils can be used as a solvent or suspending agent medium. For this purpose, sterile solid oils such as synthetic mono- or diglycerides may be used. In addition, fatty acids such as oleic acid may be used in the injectable preparations as well.

  The compounds may be administered in the form of suppositories for rectal administration of the drug. These compositions are a solid at normal temperature but liquid at rectal temperature, thus mixing the drug with a suitable non-irritating excipient that dissolves to release the drug in the rectum. Can be prepared. Such materials include cocoa butter and polyethylene glycols.

  They may also be administered by nasal, ocular, vaginal and rectal routes, for example suppositories, inhalations, powders and aerosol formulations.

  Compounds administered by the topical route may be administered as application sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, application agents, and aerosols.

  The invention is further illustrated by the following detailed but non-limiting examples.

The formulation of the present invention can be prepared as a tablet. In order to obtain a tablet for practicing the invention, the following ingredients can be pressed together in a tablet press.
10.0 mg of CDB-4124 pharmaceutically acceptable salt
140.5 mg lactose
69.5 mg corn starch
2.5 mg poly-N-vinylpyrrolidone
2.0 mg aerosil
0.5 mg magnesium stearate

In order to obtain an oily preparation for the practice of the present invention, the following ingredients can be mixed together and filled into ampoules.
100.0 mg of CDB-4124 pharmaceutically acceptable salt
343.3 mg castor oil
608.6 mg benzyl benzoate

  CDB-4124 perchlorate, methanesulfonate and phosphate formulation. CDB-4124 was dissolved in acetone and ethyl acetate in 1: 5 and the resulting solution was divided into 5 parts. To each of these solutions, either citric acid, mandelic acid, perchloric acid, methanesulfonic acid, or phosphoric acid was added in a molar amount sufficient to make the corresponding acid salt of CDB-4124. The reaction mixture was stirred for about 2 hours at 20 ° C. and then brought to below 0 ° C. for 2 hours. The resulting solid was then filtered, washed with cold ethyl acetate and dried.

  Citrate and mandelate were not formed under these conditions. All steroidal salts of perchloric acid, methanesulfonic acid and phosphoric acid were prepared in good yield (˜90%). It was readily determined that these acid steroid salts are hygroscopic and require handling in a nitrogen atmosphere glove bag. Attempts to recrystallize using various solvent systems (eg, ethanol / ethyl ether) have been unsuccessful. The starting steroid used (90% peak area purity) was not high enough in purity, and was probably responsible for making recrystallization of the acid salt difficult.

  Therefore, a higher net yield of CDB-4124 was used for the preparation of methanesulfonate by the above procedure. Methane sulfonate could be successfully recrystallized using an acetone / water solvent system.

Claims (18)

General formula:

(Where
R ¹ is a basic functional group selected from the group consisting of —N (CH ₃ ) ₂ , —NHCH ₃ , —NC ₄ H ₈ , —NC ₅ H ₁₀ and —NC ₄ H ₈ O;
R ² is hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy, acyloxy, alkyl carbonate, cypionyloxy, S-alkyl, —SCN, S-acyl and —OC (O) R ⁶ , where R ⁶ is Selected from the group consisting of alkyl, alkoxy ester and alkoxy;
R ³ is selected from the group consisting of alkyl-alkoxy, alkoxy and acyloxy;
R ⁴ is selected from the group consisting of hydrogen and alkyl;
X is selected from the group consisting of ═O and ═N—OR ⁵ , where R ⁵ is selected from the group consisting of hydrogen and alkyl)
A composition comprising a pharmaceutically acceptable salt of a compound having a pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt has improved stability compared to an equivalent amount of the free base of the compound. Provided that when R ¹ is —N (CH ₃ ) ₂ , R ² is methoxy, R ³ is acetoxy, R ⁴ is methyl and X is ═O, the salt is not an HCl or HBr salt. And a composition.   2. The compound according to claim 1, wherein the compound is 17α-acetoxy-11β- [4- (N, N-dimethylamino) phenyl] -19-norpregna-4,9 (10) -diene-3,20-dione. Composition.   2. The compound of claim 1, wherein the compound is 17 [alpha] -acetoxy-11 [beta]-[4- (N, N-dimethylamino) phenyl] -21-methoxy-19-norpregna-4,9-diene-3,20-dione. The composition as described. The compound has the structural formula:

The composition of claim 1 having The compound has the structural formula:

The composition of claim 1 having   6. A composition according to claim 5, wherein the salt is a perchlorate, methanesulfonate or phosphate of the compound.   6. A composition according to claim 5, wherein the salt is methanesulfonate.   8. A method of providing an anti-progesterone effect to a patient, comprising administering to the patient an effective amount of the composition of claim 1 or claim 6.   7. A method of inducing menstruation in a patient, comprising administering to the patient an effective amount of the composition of claim 1 or claim 6.   7. A method for the treatment of endometriosis comprising administering to a patient an effective amount of the composition of claim 1 or claim 6.   A method for the treatment of dysmenorrhea, comprising administering an effective amount of the composition of claim 1 or claim 6 to a patient.   A method for the treatment of endocrine hormone dependent tumors, comprising administering to a patient an effective amount of the composition of claim 1 or claim 6.   7. A method for the treatment of meningiomas comprising administering to a patient an effective amount of the composition of claim 1 or claim 6.   7. A method for the treatment of uterine fibroma in a patient, comprising administering to the patient an effective amount of the composition of claim 1 or claim 6.   8. A method of inhibiting endometrial proliferation in a patient, comprising administering to the patient an effective amount of the composition of claim 1 or claim 6.   8. A method of inducing labor, comprising administering to a patient an effective amount of the composition of claim 1 or claim 6.   A method of contraception, comprising administering to a patient an effective amount of the composition of claim 1 or claim 6.   A method of post sexual contraception, comprising administering to a patient an effective amount of the composition of claim 1 or claim 6.