AU746326B2 - Pharmaceutically acceptable salts of 5alpha-pregnan-3beta, 16alp ha-diol-20-one 3-sulfate useful as progestins and CNS disorders - Google Patents

Description

WO098/50411 PCT/US98/08454 PHARMACEUTICALLY ACCEPTABLE SALTS OF 5ALPHA-PREGNAN-3BETA, 16ALP HA-DIOL-20-ONE 3-SUL- FATE USEFUL AS PROGESTINS AND CNS DISORDERS BACKGROUND OF THE INVENTION The use of naturally occurring estrogenic compositions of substantial purity and low toxicity such as PREMARIN (conjugated equine estrogens) has become a preferred medical treatment for alleviating the symptoms of menopausal syndrome, osteoporosis/osteopenia in estrogen deficient women and in other hormone related disorders. The estrogenic components of the naturally occurring estrogenic compositions have been generally identified as sulfate esters of estrone, equilin, equilenin, 17-0-estradiol, dihydroequilenin and 17-3-dihydroequilenin (U.S.

Patent 2,834,712). The estrogenic compositions are usually buffered or stabilized with alkali metalsalts of organic or inorganic acids at a substantially neutral pH of about 6.5 to 7.5. Urea has also been used as a stabilizer 3,608,077). The o incorporation of antioxidants to stabilize synthetic conjugated estrogens and the failure of pH control with tris(hydroxymethyl)aminomethane (TRIS) to prevent hydrolysis is discussed in U.S. 4,154,820.

One of the compounds described herein, 5a(-pregnan-3p, 16a-diol-20-one I 20 3-sulfate ester sodium salt is a minor component of PREMARIN (conjugated equine estrogens).

The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the 25 material referred to was published, known or part of the common general knowledge in Australia as at the priority date of any of the claims.

Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising and "comprises", is not intended to exclude other additives, components or process steps.

DESCRIPTION OF THE INVENTION In accordance with this invention, there is provided a pharmaceutically acceptable salt of 5c-pregnan-3p, 16a-diol-20-one 3 sulfate ester which is useful as a progestational agent. The structure of 5a-pregnan-3p, 16a-diol-20-one 3-sulfate ester s.sodium salt is shown as compound in Scheme I.

-1A- Pharmaceutically acceptable salts of 5a-pregnan-3p, 16c-diol-20-one 3-sulfate ester include, but are not limited to, the alkali-.metal salts, alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, trialkylammonium salts containing 1-6 carbon atoms in each alkyl group and tetraalkylammonium salts containing 1-6 carbon atoms in each alkyl group.

C e *go* 'rr ;1 I -I i WO 98/50411 PCT/US98/08454 -2- Alkali metal salts include sodium and potassium salts, particularly preferred are sodium salts. Alkaline earth metal salts include calcium and magnesium salts. Suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl and hexyl, preferred alkyl groups being methyl and ethyl. Where more than one alkyl group is present the groups may be the same or different. Preferred trialkylammonium salts are trimethylammonium salts and triethylammonium salts.

The salts of the invention are preferably in greater than 1 percent purity.

As 5a-pregnan-3p, 16a-diol-20-one 3-sulfate ester sodium salt is a minor component of PREMARIN (conjugated equine estrogens), this invention also provides -pregnan-30, 16a-diol-20-one 3 sulfate ester sodium salt, preferably in greater than 1 percent purity.

This invention also provides a compound consisting essentially of 16a-diol-20-one 3-sulfate ester sodium salt, and a compound consisting essentially of a pharmaceutically acceptable salt of 5a-pregnan-3p, 16a-diol-20-one 3 sulfate ester.

This invention further provides a method of using 5a-pregnan-3p, 16ac-diolor a pharmaceutically acceptable salt of its 3-sulfate ester as a progestational agent.

The present invention further provides compositions comprising a pharmaceutically acceptable salt of 5a-pregnan-3p, 16a-diol-20-one 3-sulfate ester.

In particular it provides compositions comprising at least 1% of a pharmaceutically acceptable salt of 5ao-pregnan-3p, 16a-diol-20-one 3-sulfate ester. One aspect of the present invention provides compositions wherein the only progestational agent is a pharmaceutically acceptable salt of 5a-pregnan-3p, 16a-diol-20-one 3-sulfate ester Embodiments of the present invention include compositions wherein the only active compound is a pharmaceutically acceptable salt of 5a-pregnan-3p, 16a-diol-20-one 3sulfate ester. In these embodiments other excipients and carriers may be included but no further active materials are included.

I- WO 98/50411 PCT/US98/08454 -3- The present invention also provides a process for the preparation of a pharmaceutically acceptable salt of 5a-pregnan-3p, 16a-diol-20-one 3-sulfate ester which comprises: a) converting 5a-pregnan-3p, 16a-diol-20-one 3-sulfate ester to a pharmaceutically acceptable salt, b) converting a pharmaceutically acceptable salt of 5a-pregnan-3p, 16a-diol-20one 3-sulfate ester to a different pharmaceutically acceptable salt of 3p, 16a-diol-20-one 3-sulfate ester, c) converting 5a-pregnan-16a, 17 epoxy-3p-ol-20-one to a pharmaceutically acceptable salt of 5ac-pregnan-16a, 17 epoxy-3p-ol-20-one 3-sulfate ester or d) deprotecting a pharmaceutically acceptable salt of a 16-hydroxy protected pregnan-3p, 16a-diol-20-one 3-sulfate ester.

5a-pregnan-3p, 16a-diol-20-one 3-sulfate ester may be converted to a pharmaceutically acceptable salt by neutralising the acid with an appropriate base, e.g.

with an alkali metal carbonate, an alkaline earth metal carbonate or a primary, secondary, tertiary or quaternary amine carbonate. Alkali metal or alkaline earth metal salts may be prepared by using the appropriate alkali metal hydride e.g. sodium hydride, potassium hydride or lithium hydride.

A pharmaceutically acceptable salt of 5a-pregnan-3p, 16a-diol-20-one 3sulfate ester may be converted to a different pharmaceutically acceptable salt by displacement, by using an ion exchange resin or by double decomposition (metastasis).

Displacement of a weak base with a stronger one may be utilised to convert, e.g. an amine salt to an alkali metal salt or an alkaline earth metal salt using an appropriate base, e.g. a hydroxide. For example a trialkylamine salt such as a triethylamine salt may be converted to an alkali metal salt such as a sodium salt by treating it with an alkali metal hydroxide such as aqueous sodium hydroxide. The displacement may be carried out using an ion exchange resin. Alternatively one salt may be converted to another by double decomposition, e.g. an alkaline earth metal salt such as the calcium salt may be replaced with an alkali metal salt. E.g. the calcium salt of 5a-pregnan-3p, 16a-diol- 3-sulfate ester may be dissolved in water followed by the addition of e.g.

i~ -1 WO 98/50411 PCT/US98/08454 -4sodium carbonate. Insoluble calcium carbonate would then precipitate out to provide the sodium salt of 5a-pregnan-3p, 16a-diol-20-one 3-sulfate ester.

A pharmaceutically acceptable salt of 5a-pregnan-3p, 16a-diol-20-one 3sulfate ester may be prepared by directly converting 5a-pregnan-30, 16a-diol-20-one to a pharmaceutically acceptable salt of 5a-pregnan-3p, 16a-diol-20-one 3-sulfate ester. This may be performed by reacting it with the appropriate aminesulfurtrioxide complex, e.g. by reacting it with a trialkylaminesulfurtrioxide (such as triethylaminesulfurtrioxide complex) to provide the corresponding trialkylamine salt (such as the triethylamine salt). If desired the salt may then be converted to another salt of the invention as described above. Alkali metal or alkaline earth metal salts may be prepared by treating pharmaceutically acceptable salt of 5a-pregnan-3, 16a-diol-20-one with the appropriate alkali metal hydride e.g. sodium hydride, potassium hydride or lithium hydride to produce the corresponding alkoxide in situ and then adding a trialkylaminesulfurtrioxide (such as triethylaminesulfurtrioxide complex) to provide the corresponding trialkylamine salt (such as the triethylamine salt). If desired the salt may then be converted to another salt of the invention as described above.

In order to prepare the desired pharmaceutically acceptable salt of 30, 16a-diol-20-one 3-sulfate ester it may be necessary to protect the 16 hydroxy group. This may be achieved by conventional means using a suitable protecting group which will finally be removed to provide the product. Alternatively the hydroxyl group may be protected by forming the 16a, 17 epoxy derivative of the starting material and using it to prepare the desired pharmaceutically acceptable salt of 5a-pregnan-16a, 17 epoxy-3p-ol-20- 3-sulfate, which is then deprotected to give the desired compound of the invention.

The present invention also provides pharmaceutically acceptable salts of pregnan-3p, 16a-diol-20-one 3-sulfate ester prepared by a chemical process, particularly those prepared according to the processes described above. The invention also provides pharmaceutically acceptable salts of 5a-pregnan-3, 16a-diol-20-one 3sulfate ester obtainable by such processes.

The compounds of this invention can be prepared from readily available starting materials according to the processes in Scheme I, as shown for 16a-diol-20-one 3 sulfate ester sodium salt.

WO 98/50411 WO 9850411PCT/US98/08454 For example, according to Scheme 1, 5cx-pregn-16-en-3fp-ol-2O-one is treated with hydrogen peroxide/sodium hydroxide to afford l6ct, 17-epoxy-3j3-ol-20-one Epoxide is treated with one or more equivalents of triethylamnine: sulfur trioxide reagent to afford 5oc-pregnan- 1 60, 17 epoxy-30-ol-2O- 3-sulfate triethylamm-onium salt The triethylammonium salt is treated with chromous acetate in acetic acid/water then aqueous sodium hydroxide to afford Sczpregnan-3p, 16ax-diol-20-one 3 sulfate ester sodium salt Scheme I

H

2 0 2 tNaOH EtaN:SO/THF 1 Cr(OAc) 2 /HOAc 2. NaOH '1OH WO 98/50411 PCT/US98/08454 -6- The compounds of this invention are progestational agents, and are therefore useful as oral contraceptives (male and female), in hormone replacement therapy (particularly when combined with an estrogen), in the treatment of endometriosis luteal phase defects, benign breast and prostatic diseases and prostatic and endometrial cancers. The compounds of this invention are also useful in protecting against epileptic seizures, in cognition enhancement, in treating Alzheimer's disease, dementias, vasomotor symtpoms related to menopause, and other central nervous system disorders The compounds of this invention are further useful in stimulating erythropoises.

The compounds of this invention can be used alone as a sole therapeutic agent or can be used in combination with other agents, such as other estrogens, progestins, or and androgens.

The compounds of this invention can be formulated neat or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice. The pharmaceutical carrier may be solid or liquid.

A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening i.,1131 L ii ~I ll_~ WO 98/50411 PCT/US98/08454 -7agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, lethicins, and oils (e.g.

fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds of this invention can also be administered orally either in liquid or solid composition form.

The compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermiable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.

The dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated. Based on the results obtained in the standard pharmacological test procedures, projected daily dosages of active compound would be 0.02 gg/kg 750 jgg/kg. Treatment will generally be initiated with small dosages less than the :i-1 WO 98/50411 PCT/US98/08454 -8optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached; precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated. Preferably, the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

The following provides the preparation of representative compounds of this invention.

Example 1 5a-Pregnan-16a, 17-epoxy-30-ol-20-one (3) 5a-pregn-16-en-3P-ol-20-one (5.74g, 17.3 mmol) was dissolved in 500 ml of methanol, 25 ml of 30% hydrogen peroxide and 20 ml of 4 N sodium hydroxide. The solution was stirred at room temperature for 20 hours. The solution was poured into a mixture of 2.51 of water, 500 ml of methylene chloride and 25 ml of acetic acid. The methylene chloride layer was separated, washed with 500 ml of water, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dried to provide the title compound as a white solid (6g, 98%).

'H NMR (300MHz, CDCl 3 5 0.82 3H), 1.00 3H), 2.03 3H), 3.58 1H), 3.67 (bs, 1H) m/z (ES positive) 355 687 (2M+Na'), -Pregnan-16a. 1 7 -epoxy-3p-ol-20-one-3-sulfate, triethyl ammonium salt (4) -Pregnan-16a, 17-epoxy-3p-ol-20-one-(3) (6.49g, 19.6 mmol) was dissolved in 100 ml of tetrahydrofuran and sulfur trioxide. In ethylamine complex (4.4g, 24.2 mmol) was added. The mixture was stirred at room temperature for 20 hours. The product was collected on a Buchner funnel, washed with tetrahydrofuran then ether and dried to provide the title compound as a white solid 8 .2g, 82%).

'H NMR (300MHz, DMSO-d 6 8 0.76 3H), 1.16 3H), 1.19 9H), 1.96 3H), 3.11 6H), 3.91 1H), 3.93 (1H) m/z (ES negative) 411 (M-H) WO 98/50411 PCT/US98/08454 -9- -Pregnan-30, 16a-diol-20-one-3-sulfate. triethyl ammonium salt.

5a-Pregnan-16a, 1 7 -epoxy-3P-ol-20-one-3-sulfate, triethylammonium salt (7.8g, 15.2 mmol) was dissolved in 200 ml of acetic acid and 60 ml of water. Chromous acetate [freshly prepared from 26g (0.5 mol) of chromium powder] was added and the mixture was stirred for 70 hours at room temperature. The solvents were removed in vacuo and the residue was slurried in water. The mixture was neutralized with sodium bicarbonate, then made alkaline with 4N sodium hydroxide. The mixture was filtered through Celite. The aqueous solution was extracted with n-butanol. The butanol extract was filtered through Celite and concentrated. The residue was purified by HPLC (converted to the triethyl ammonium salt during chromatography).

(Primesphere, C18-HC, 10, 50x250 mm, s#171320; 10/90 to 30/70 at 4.5' to 5/45 at 7' to 60/40 at 11' to 70/30 at 18' to 90/10 at 26' (MeOH/50 mM triethylammonium acetate; pH=7) Flow=70 ml/min; UV=214 nm; 1000 PSI) to provide the title compound as a white solid g, 53%).

'H NMR (300MHz, DMSO-d 6 0.52 3H), 0.75 3H), 1.14 9H), 2.08 3H), 2.42 1H), 2.97 6H), 3.93 1H), 4.49 1H); m/z (ES negative) 413 (M-H) -Pregnan-30. 16a-diol-20-one 3 sulfate ester sodium salt -Pregnan-3p, 16a-diol-20-on-3 sulfate, triethyl ammonium salt (4g, 7.8 mmol) was dissolved in 150 ml of distilled water and the solution was passed through an ion exchange column (Dowex 50X8, Na form). The column was rinsed with 100 ml of distilled water. The eluent was concentrated and the residue was dissolved in ethanol.

The ethanol solution was concentrated in vacuo and the solid was collected with ether, filtered on a Buchner funnel and dried to provide the title compound as a white solid (3.2g, 94%).

'H NMR (300MHz, DMSO-d 6 8 0.53 3H), 0.76 3H), 2.08 3H), 2.42 1H), 3.93 1H), 4.50 3H m/z (ES negative) 413 (M-H) I

Claims (14)

1. A compound which is a pharmaceutically acceptable salt of 3P, 16ct-diol-20-one 3-sulfate ester.

2. The compound of claim 1 wherein the pharmaceutically acceptable salt of the 3- sulfate ester is an alkali metal salt, alkaline earth metal salt, ammonium salt, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, trialkylammonium salts containing 1-6 carbon atoms in each alkyl group and tetraalkylammonium salts containing 1-6 carbon atoms in each alkyl group.

3. 5Oa-Pregnan-3p, 16a-diol-20-one 3-sulfate ester sodium salt, which is at least 1 percent pure.

4. A compound which consists essentially of a pharmaceutically acceptable salt of 5a-pregnan-3p, 16a-diol-20-one 3-sulfate ester. 2

5. A compound which consists essentially of 5a(-pregnan-3p, 16a-diol-20-one 3- i 20 sulfate ester sodium salt.

6. A pharmaceutical composition which comprises a pharmaceutically acceptable salt of 5a-pregnan-3p, 16ta-diol-20-one 3-sulfate ester. tcoo

7. A pharmaceutical composition which comprises at least 1% of a pharmaceutically acceptable salt of 5a-pregnan-3p, 16a-diol-20-one 3-sulfate ester.

8. A method of providing progestational therapy to a mammal in need thereof which comprises administering a progestationally effective amount of progestationally effective amount of a pharmaceutically acceptable salt of 5a-pregnan-3p, 16a-diol-20- one 3-sulfate ester, to said mammal.

9. A method of treating or inhibiting cancers, central nervous system disorders, dementias, or Alzheimer's disease in a mammal in need thereof, which comprises administering an effective amount of progestationally effective amount of a i-- WO() 98/50411 I'CTUS9S/08451I Il pharmaceutically acceptable salt of 5a-pregnan-33, 16a-diol-20-one 3-sulfate ester, to said mammal.

A compound according to any one of claims 1 to 9 for use as a medicament.

1 1. Use of a compound as claimed in any one of claims I to 6 in the preparation of a medicament providing progestational therapy to a mammal in need thereof or a medicament for the treatment or prevention of cancers, central nervous system disorders, dementias, or Alzheimer's disease.

12. A process for the preparation of a pharmaceutically acceptable salt of pregnan-3p, 16a-diol-20-one 3-sulfate ester which comprises: a) converting 5a-pregnan-3, 16a-diol-20-one 3-sulfate ester to a pharmaceutically acceptable salt, i. b) converting a pharmaceutically acceptable salt of S33, 16ca-diol-20-one 3-sulfate ester to a different pharmaceutically 20 acceptable salt of c5a-pregnan-33, 16ca-diol-20-one 3-sulfate ester, c) converting 5a-pregnan-16a, 17-epoxy-3p-ol-20-one to a pharmaceu- tically acceptable salt of 5c-pregnan-16t, 17-epoxy-3p-ol-20-one 3- sulfate ester or Sd) deprotecting a pharmaceutically acceptable salt of a 16-hydroxy ~protected 5a-pregnan-3p, 16ct-diol-20-one 3-sulfate ester.

13. A process as claimed in Claim 12 wherein a pharmaceutically acceptable salt of 5x-pregnan-16a, 17-epoxy-3p-ol-20-one 3-sulfate ester is converted to a pharmna- ceutically acceptable salt of 5cx-pregnan-3, 16x-diol-20-one 3-sulfate ester.

14. A compound substantially as hereinbefore described with reference to the Example. -12- A process substantially as hereinbefore described with reference to the Example. DATED: 24 August, 2000 PHILLIPS ORMONDE FITZPATRICK Attorneys for: AMERICAN HOME PRODUCTS CORPORATION a.