CN1330659A - Pregnane glucuronides compound - Google Patents

Abstract

This invention provides 5 alpha -pregnane-3 beta , (20S), 21-triol, 20-O- beta -glucuronide and 5 alpha -pregnane-3 beta ,20R-diol, 20-O- beta -glucuronide and pharmaceutically acceptalbe salts thereof which are useful as progestational agents.

Description

Pregnane Glucuronides

Background of the invention

The use of substantially pure and low toxicity natural estrogen compositions such as PREMARIN (conjugated pregnant equine estrogen) has been established as a method for alleviating menopausal syndrome, osteoporosis and/or bone loss in estrogen deficient women. The preferred medical treatment for hypotropic syndrome and other hormone-related disorders. The estrogenic components in natural estrogen compositions are generally identified as the sulfate esters of estrone, equilin, equilenin, 17-beta-estradiol, dihydroequalin and 17-beta- Dihydroequilenin (US Patent 2834712). Estrogenic compositions are typically buffered or stabilized with organic or inorganic acid salts of alkali metals at a substantially neutral pH of about 6.5-7.5. Urea can also be used as a stabilizer (US Patent 3608077). In U.S. Patent No. 4154820, the combination of antioxidants to stabilize synthetic conjugated estrogens and the use of tris(hydroxymethyl)aminomethane (TRIS) to regulate pH to prevent hydrolysis disorders are discussed.

Two compounds of the present invention 5α-pregnane-3β, (20S), 21 triol 20-O-β-glucuronide sodium salt and 5α-pregnane-3β, 20R-diol 20-O-β - Sodium glucuronide is a minor component of gestational estrone (conjugated gestational estrogen).

Detailed description of the invention

According to the present invention there is provided 5α-pregnane-3β, (20S), 21-triol, 20-O-β-glucuronide and 5α-pregnane-3β, 20R-diol for use as progestational agents, 20-O-β-glucuronide and pharmaceutically acceptable salts thereof. Synthetic Schemes I and II show the preparation of pregnane glucuronides 7 and 12. In addition, routes 8 and 13 also showed the conversion of glucuronide to the native sodium salt form.

Pharmaceutically acceptable salts of 5α-pregnane-3β, (20S)21-triol 20-O-β-glucuronide and 5α-pregnane-3β, 20R-diol 20-O-β-glucuronide are limited to natural forms, and include alkali metal salts, alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1 to 6 carbon atoms or dialkylammonium salts containing 1 to 6 carbon atoms in each alkyl group, and Trialkylammonium salts where each alkyl group contains 1 to 6 carbon atoms and any other positively charged atom or molecule.

Since 5α-pregnane-3β, (20S), 21-triol 20-O-β-glucuronide and 5α-pregnane-3β, 20R-diol 20-O-β-glucuronide are ketone (conjugated pregnant equine estrogen), so the present invention also provides 5α-pregnane-3β with a purity greater than 1%, (20S), 21-triol 20-O-β-glucuronide or its A pharmaceutically acceptable salt or 5α-pregnane-3β, 20R-diol 20-O-β-glucuronide or a pharmaceutically acceptable salt thereof.

The present invention further provides a compound consisting essentially of 5α-pregnane-3β, (20S), 21-triol 20-O-β-glucuronide or a pharmaceutically acceptable salt thereof or 5α-pregnane-3β, 20R-diol 20- A compound composed of O-β-glucuronide or a pharmaceutically acceptable salt thereof.

The present invention further provides the use of 5α-pregnane-3β, (20S), 21-triol glucuronide and 5α-pregnane-3β, 20R-diol glucuronide or a pharmaceutically acceptable salt of a related glucuronide as an accelerator. Pregnancy.

The starting materials used in this synthesis are either commercially available or can be prepared using standard chemical methods.

The compound of the present invention is made 5α-pregnane-3β according to the method shown in synthetic route I from the starting material that is easy to buy, (20S), 21-triol 20-O-β-glucuronide (and corresponding mono sodium salt), or synthesize 5α-pregnane-3β, 20R-diol 20-O-β-glucuronide (and the corresponding monosodium salt) according to the method shown in the synthetic route II.

In Synthetic Scheme I, pregnenolone 3-acetate 1 was used as the starting material. 1 reacts with lead tetraacetate in acetic acid to generate 2 according to the method described by Purdy et al. in "Journal of Medical Chemistry" 33(6), 1572-1581(1990). Compound ₂ was hydrogenated with PtO2 in acetic acid to generate compounds 3 and 4 in a ratio of approximately 3:1. Compound 3 was then heated with an excess equivalent of acetylbromoglucuronate methyl ester 5. The protected glucuronide was then saponified with LiOH and reprotonated with acid to give the desired 20-glucuronide counterpart 7. Titration of the free acid with a slight excess of NaOH yielded the monosodium salt 8.

In Scheme II, compound 10 was reacted with acetylbromoglucuronate methyl ester 5 and Ag ₂ CO ₃ to give the protected counterpart 11. This material was then saponified and protonated with acid to yield the deprotected glucuronic acid derivative 12. Thereafter this material was titrated with NaOH to yield sodium glucuronide 13. Synthetic route II

The compounds of the present invention are progestational agents and are therefore suitable for oral contraception (male and female), hormone replacement therapy (especially when combined with estrogen), endometriosis, luteal phase defect, benign breast and prostate disease and treatment of prostate and endometrial cancer. The compounds of the present invention are also effective against seizures, cognitive enhancement, Alzheimer's disease, dementia, vasomotor syndrome associated with menopause and other central nervous system disorders. The compounds of the present invention are further effective in promoting erythropoiesis.

The compounds of the present invention may be used alone as sole therapeutic agents, or may be used in combination with other drugs such as other estrogens, progestins or androgens.

The compounds of the present invention can be formulated for administration alone or with a pharmaceutical carrier, the ratios of which will depend on the solubility and chemical properties of the compound, the chosen route of administration and standard pharmacological practice. Pharmaceutical carriers can 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; Can be an encapsulating material. In powders, the carrier is a micronized solid, which is in admixture with the micronized 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. Powders and tablets preferably contain up to 99% active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sucrose, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low Melting point 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 may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers or odorants. Conditioner. Examples of suitable liquid carriers for oral and parenteral administration include water (partly containing the above-mentioned additives, such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols, such as dihydric alcohols) and Derivatives, lecithins and oils (such as fractionated coconut and peanut oils). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are suitable for use in sterile liquid formulations for parenteral compositions. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions which are sterile solutions or suspensions may be employed for, eg, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds of the present invention can also be administered orally in the form of liquid or solid compositions.

The compounds of the present invention may be administered rectally or intravaginally in the form of conventional suppositories. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of the invention may be formulated as aqueous or partially aqueous solutions, which may then be administered in aerosol form. The compounds of the invention may also be administered transdermally by application of a transdermal patch comprising the active compound and a carrier which is inert to the active compound and nontoxic to the skin and releases the drug through the skin for systemic absorption into the blood. The carrier can be in any number of forms, such as creams or ointments, pastes, gels and occlusive devices. Creams and ointments may be viscous liquids or semisolid emulsions of the oil-in-water or water-in-oil type. Pastes comprising absorbent powders dispersed in active ingredient-containing petroleum or hydrophilic petroleum are also suitable. The active ingredient can be released into the blood using different closure devices, such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier or a matrix containing the active ingredient. Other closure devices are disclosed in the literature.

Dosage requirements will vary with the particular composition employed, the route of administration, the severity of the present condition and the particular subject being treated. Based on the results obtained in standard pharmacological test procedures, the estimated daily dose of active compound should be in the range of 0.02 μg/kg to 750 μg/kg. Treatment is generally initiated with small dosages which are less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is achieved; the precise dosage for oral, parenteral, nasal or intrabronchial administration should be determined by the attending physician based on the experience of the individual subject being treated. Preferably the pharmaceutical composition is in unit dosage form, eg as a tablet or capsule. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active ingredient; unit dosage forms may be packaged in compositions, for example packeted powders, bottles, 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 presented in package form.

The preparation methods of representative compounds of the present invention are provided below.

       Example 1 Pregnane-3β, 20R, 21-triol 3, 21-diacetate 3

Compound ₂ (6.0 g, 14.4 mmol) was treated with PtO2 (1.75 g, 7.7 mmol) in 0.2 L AcOH and the solution was hydrogenated under 40 PSI of _H2 . After 18 hours, the catalyst was filtered and the crude reaction mixture was concentrated and chromatographed on silica gel with EtOAc/hexanes (1:4) to give two products (3 and 4). The first product to elute was the main (desired) material 3, 2.40 g of a white solid was isolated:

Mp=164-166°C; ¹ H NMR (CDCl ₃ ) 4.75-4.60 (m, 1H), 4.16 (dd, 1H, J=11.4Hz, 2.2Hz), 3.94-3.87 (m, 1H), 3.81-3.73 (m, 1H), 2.10(s, 3H), 2.10-2.05(m, 1H), 2.02(s, 3H), 1.84(d, 1H, J=5.2Hz), 1.82-0.88(m, 21H), 0.83(s, 3H), 0.76(s, 3H), 0.68(dt, 1H, J=10.6Hz); MS(+ESI) 421(M+H) ⁺ ; IR(KBr) 3520, 2920, 2880, 1740, 1710cm ^-1 .

Example 2 Pregnane-3β, 20R, 21-tri3, 20-diacetate 4

The second product 4 eluted as a minor product, 0.73 g of white solid was isolated:

Mp = 189-191°C; ¹ H NMR (DMSO) 4.91 (dq, 1H, J = 5.5Hz, 2.2Hz), 4.74-4.63 (m, 1H), 3.81-3.74 (m, 1H), 3.57-3.49 ( m, 1H), 2.09(s, 3H), 2.02(s, 3H), 1.91(dd, 1H, J=7.2Hz, 5.0Hz), 1.85-0.83(m, 22H), 0.82(s, 3H), 0.72-0.61(m, 1H), 0.65(s, 3H); MS EI420(M+); IR(KBr)3410, 2920, 1730, 1700cm ^-1 .

Example 32, 3,4-0-Triacetyl-1-0-(3β,21-diacetoxy-5α-pregnane-20S-yl)-β-D-glucuronic acid methyl ester 6

Compound 3 (6.6 g, 15.7 mmol) was dissolved in CHCl ₃ (125 mL) and mixed with Ag ₂ CO ₃ (4.3 g, 15.7 mmol) and glucuronide bromide 5 [21085-72-3] (6.2 g, 15.7 mmol) treatment. After reflux _for 1.5 h, an additional 0.5 equiv of _Ag2CO3 and 0.5 equiv of glucuronide bromide were added. After 1.5 hours, the above reagents were added in this way again and the above operation was repeated again for another 1.5 hours. The reaction was refluxed for a total of 5.5 hours. The reaction was cooled and inorganic salts were filtered off. The filtrate was concentrated and chromatographed on silica gel (3:7 EtOAc/hexanes), the product containing fractions were concentrated and rechromatographed under the same conditions to yield 4.1 g of 6 which was triturated with MeOH to give 3.05 g of 6 as a white solid : Mp=180-183°C; MS(APCI) 754(M+NH4 ⁺ ); ¹ H NMR(DMSO) 5.36(t, 1H, J=9.6Hz), 5.06(d, 1H, J=8.0Hz), 4.91( t, 1H, J=9.8Hz), 4.70(dd, 1H, J=9.5Hz, 8.1Hz), 4.63-4.50(m, 1H), 4.47(d, 1H, J=10.0Hz), 4.16(d, 1H, J=11.3Hz), 3.92-3.75(m, 2H), 3.63(s, 3H), 2.16-2.07(m, 1H), 2.04(s, 3H), 1.99(s, 3H), 1.97(s , 3H), 1.95(s, 3H), 1.93(s, 3H), 1.78-1.63(m, 3H), 1.62-1.39(m, 6H), 1.36-1.10(m, 8H), 1.06-0.85(m , 5H), 0.79(s, 3H), 0.68(s, 3H).

Example 45 α-pregnane-3β, 20S.21-triol 20-O-B-D-glucuronide 7

Compound 6 (3.76 g, 5.1 mmol) was dissolved in THF (25 ml) and treated with a solution of LiOH (1.35 g, 56.1 mmol) in _H2O (13 mL). To this solution was added MeOH (4 mL) and the reaction was heated at 75 °C for 2 hours. The solution was then cooled and concentrated. The aqueous residue was added to another 15 ml of _H2O . To the residue was added 2N HCl solution (43ml). Solid formation was initiated by scratching the glass. Filtration afforded 2.6 g of 7 as a white solid. Mp=231-235°C; ¹³ C NMR (75MHz, MeOD) (C=O disappears), 102.6, 82.1, 77.6, 76.8, 75.3, 73.1, 71.9, 63.6, 57.6, 56.1, 51.5, 49.9, 46.3, 43.6, ⁽ m, 3H), 3 59-3.22(m, 5H), 2.30(d, 1H, J=12.6Hz), 1.75-1.66(m, 6H), 1.53-1.18(m, 9H), 1.17-0.88(m , 6H), 0.83(s, 3H), 0.78(s, 3H), 0.70-0.58(m, 1H); MS(-)ESI511(MH) ^- ; IR(KBr)3410, 2910, 2830, 1730, 1700cm ^-1 .

Example 55 α-pregnane-3β, 20S, 21-triol 20-O-β-D-glucuronide sodium salt 8

Compound 7 (1.57 g, 1.7 mmol) was suspended in MeOH (20 mL) and treated with an aqueous solution of NaOH (6.4 mL, 0.5 N), stirred for 5 minutes to dissolve all starting material in solution. This solution was then mixed with 0.65 g of the product from the previous step, the mixture was stripped onto silica gel and column chromatography was performed on silica gel (MeOH _:CH2Cl2 , 4:6, then ₅ :5). Thereafter the product was triturated with a 1:1 mixture of MeOH and dioxane (total volume equal to 60 ml) to yield 1.57 g of 8 as a white solid:

Mp=240-244°C; ¹³ CNMR (75MHz, DMSO) (C=O disappears), 100.4, 79.8, 76.7, 73.9, 73.7, 72.2, 69.3, 66.3, 62.0, 55.6, 54.0, 49.8, 44.3, 41.9, 38.1 , 36.6, 35.1, 35.0, 31.8, 31.3, 28.4, 24.4, 23.9, 20.8, 12.1, 11.4; IR(KBr) 3400(H ₂ O), 2920, 2870, 1610cm ^-1 .

Example 6 Pregnane-3β, 20S, 21-triol 9

Compound 3 (1.6 g, 3.8 mmol) was dissolved in THF (8 ml). A solution of LiOH (0.27 g, 11.4 mmol) in 3 ml _H2O water was added. To make the solution one phase, 1 ml of MeOH was added to the reaction mixture. After refluxing for 30 minutes, the reaction mixture was treated with 1.1 mL of AcOH and partitioned between the organic layer consisting of 100 mL EtOAc, 20 _{mL CH2Cl2} , 10 mL MeOH and 60 mL _H2O water. The organic layer was then washed with brine and dried over MgSO ₄ . The solution was concentrated and the resulting solid was triturated with ether to give 1.1 of 9 as a white solid:

Mp = 210-212°C; ¹ H NMR (DMSO) (3OH proton disappears) 4.43 (d, 1H, J = 4.6Hz), 4.31 (t, 1H, J = 5.5Hz), 4.05 (d, 1H, J = 5.5Hz), 4.05 (d, 1H, J = 5.2Hz), 3.16-3.05(m, 1H), 2.10(d, 1H, J=12.4Hz), 1.65-0.78(m, 21H), 0.75(s, 3H), 0.68(s, 3H), 0.65- 0.54(m, 1H); MS EI336 M+; IR(KBr)3400, 2930, 2880cm ^-1 .

Example 71-O-(3β-Acetoxy-pregnane-20-yl)-2,3,4-triacetyl-β-D-glucuronide methyl ester 11

5α-pregnane-3β, 20β-diol 3-acetate 10 (3.0g, 11.0mmol), glucuronide bromide 5[21085-72-3] (5.5g, 13.8mmol) and _Ag2CO3 ( _4.5g , 16.1mmol) was stirred in toluene (40ml) (flask was protected from light with aluminum foil). After 18 hours, the reaction was diluted with _CH2Cl2 , filtered, concentrated and chromatographed on silica gel (EtOAc:Hex, 2:8, then EtOAc:Hex, 4:6) to give a solid which was triturated with MeOH to give 3.0 _g 11 as a white solid: Mp = 248-251 °C; ¹ H NMR (DMSO) 5.33 (t, 1H, J = 9.6 Hz), 4.95-4.88 (m, 2H), 4.68 (dd, 1H, J = 9.5Hz, 8.1Hz), 4.62-4.49(m, 1H), 4.44(d, 1H, J=10.0Hz), 3.71-3.65(m, 1H), 3.63(s, 3H), 2.11(d, 1H, J=12.6 Hz), 1.98(s, 3H), 1.97(s, 3H), 1.96(s, 3H), 1.95(s, 3H), 1.77-1.64(m, 2H), 1.63-1.10(m, 14H ), 0.99(d, 3H, J=5.8Hz), 0.95-0.83(m, 5H), 0.78(s, 3H), 0.66(s, 3H), 0.65-0.58(m, 1H); IR(KBr) 2930, 2900, 2830, 1750, 1730cm ^-1 ; MS(+)ESI696(M+NH ₄ ) ⁺ .

Example 85 α-pregnane-3β, 20R-diol 20-O-β-D-glucuronide 12

Compound 11 (2.5 g, 3.7 mmol) was dissolved in THF (25 ml) and MeOH (15 ml) and treated with a solution of LiOH (0.9 g, 37.5 mmol) in _H2O (10 mL). The reaction was heated at reflux for 1 hour. The reaction was allowed to cool to room temperature and concentrated. The product was taken up in water (20ml) and acidified with 2N aqueous HCl. Filtration of the resulting precipitate afforded 1.5 g of 12 as a white solid:

Mp = 255-260°; ¹ H NMR (DMSO) (3H masking) 4.98 (d, 1H, J = 3.8Hz), 4.91 (d, 1H, J = 4.6Hz), 4.42 (brs, 1H), 4.25 ( d, 1H, J=7.7Hz), 3.71-3.62(m, 1H), 3.58(d, 1H, J=9.7Hz), 3.23-3.12(m, 1H), 2.96-2.87(m, 1H), 2.15 (d, 1H, J=12.3Hz), 1.67-1.46(m, 5H), 1.45-0.80(m, 17H), 1.01(d, 3H, J=5.8Hz), 0.74(s, 3H), 0.65 (s, 3H), 0.65-0.52(m, 1H); IR(KBr)3520, 3400, 2920, 2820, 2800, 1710cm ^-1 ; MS(-)ESI495(MH) ^- .

Example 95α-pregnane-3β, 20R-diol 20-O-β-D-glucuronide 13

A suspension of compound 12 (1.5 g, 3.0 mmol) in MeOH (25 mL) was treated with aqueous NaOH (0.5 N, 6.0 ml, 3.0 mmol), stirred for 5 min and everything went into solution. The solution was concentrated to dryness and the residue was triturated with EtOH to give 1.1 g of 13 as a white solid: Mp = 223-226 °C (dec); ¹ H NMR (DMSO) 7.26 (s, 1H), 4.76 (d, 1H, J=3.6Hz), 4.67(d, 1H, J=3.6Hz), 4.43(d, 1H, J=approx4Hz), 4.12(d, 1H, J=7.6Hz), 3.78-3.71(m, 1H ), 3.45-3.35(m, 1H), 3.17-3.03(m, 3H), 3.38-3.29(m, 1H), 2.17(d, 1H, J=12.4Hz), 1.67-1.49(m, 5H), 1.45-0.80(m, 17H), 0.99(d, 3H, J=5.9Hz), 0.76(s, 3H), 0.75(s, 3H), 0.65-0.53(m, 1H); IR(KBr) 3400, 2920, 2830, 1610cm ^-1 ; MS(-)ESI495(MH) ^- .

Claims (33)

1. compound, it is 5 alpha-pregnanes-3 β, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.

2. the compound of claim 1, the pharmacologically acceptable salt of wherein said 20-glucuronide is an an alkali metal salt, alkaline earth salt, ammonium salt, the alkylammonium salt that contains 1-6 carbon atom, or contain the dialkyl ammonium salt of 1-6 carbon atom in each alkyl, or contain the trialkyl ammonium salts of 1-6 carbon atom in each alkyl.

3. compound, it is 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.

4. the compound of claim 3, the pharmacologically acceptable salt of wherein said 20-glucuronide is an an alkali metal salt, alkaline earth salt, ammonium salt, the alkylammonium salt that contains 1-6 carbon atom, or contain the dialkyl ammonium salt of 1-6 carbon atom in each alkyl, or contain the trialkyl ammonium salts of 1-6 carbon atom in each alkyl.

5.5 alpha-pregnane-3 β, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, its purity is at least one of percentage.

6.5 alpha-pregnane-3 β, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, its purity is at least one of percentage.

7. one kind mainly by 5 alpha-pregnanes-3 β, 20S, the compound that 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt are formed.

8. one kind mainly by 5 alpha-pregnanes-3 β, the compound that 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt are formed.

9. one kind mainly by 5 alpha-pregnanes-3 β, 20S, the compound that 21-triol 20-O-β-D-glucuronide sodium salt is formed.

10. one kind mainly by 5 alpha-pregnanes-3 β, the compound that 20R-glycol 20-O-β-D-glucuronide sodium salt is formed.

11. one kind contains 5 alpha-pregnanes-3 β, 20S, the pharmaceutical composition of 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.

12. one kind contains 5 alpha-pregnanes-3 β, the pharmaceutical composition of 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.

13., wherein further contain other and be selected from oestrogenic hormon, progestogen and androgenic medicine according to claim 11 or 12 described pharmaceutical compositions.

14. according to the pharmaceutical composition of claim 12, it is mainly by 5 alpha-pregnanes-3 β, 20S, and 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt and at least a pharmaceutical carrier are formed.

15. according to the pharmaceutical composition of claim 12, it is mainly by 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt and at least a pharmaceutical carrier are formed.

16. a pharmaceutical composition wherein contains 5 alpha-pregnanes-3 β greater than 1%w/w or w/v, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt and at least a pharmaceutical carrier.

17. a pharmaceutical composition wherein contains 5 alpha-pregnanes-3 β greater than 1%w/w or w/v, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt and at least a pharmaceutical carrier.

18. 5 alpha-pregnanes-3 β, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, it is used for the treatment of Mammals.

19. 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, it is used for the treatment of Mammals.

20. 5 alpha-pregnanes-3 β, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, it is as progestational agents.

21. 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, it is as progestational agents.

22. 5 alpha-pregnanes-3 β, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, it is used in the Mammals treatment of needs or suppresses cancer, central nervous system disorder, dementia or Alzheimer's.

23. 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, it is used in the Mammals treatment of needs or suppresses cancer, central nervous system disorder, dementia or Alzheimer's.

24. 5 alpha-pregnanes-3 β, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt are used as progestational agents or in treatment or suppress in cancer, central nervous system disorder, dementia or the Alzheimer's or promote application in the erythropoietic medicine in the Mammals of preparation at needs.

25. 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt are used as progestational agents in the Mammals of preparation at needs or in treatment or suppress in cancer, central nervous system disorder, dementia or the Alzheimer's or promote application in the erythropoietic medicine.

26. a method of the progestogenic treatment being provided for the Mammals that needs, it comprises 5 alpha-pregnanes-3 β that uses the progestogenic significant quantity, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.

27. a method of the progestogenic treatment being provided for the Mammals that needs, it comprises 5 alpha-pregnanes-3 β that uses the progestogenic significant quantity, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.

28. method for the treatment of or suppressing cancer, central nervous system disorder, dementia or Alzheimer's in the Mammals that needs, it comprises 5 alpha-pregnanes-3 β to this administration significant quantity, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.

29. method for the treatment of or suppressing cancer, central nervous system disorder, dementia or Alzheimer's in the Mammals that needs, it comprises 5 alpha-pregnanes-3 β to this administration significant quantity, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.

30. prepare 5 alpha-pregnanes-3 β, (20S), the method for 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, it comprises makes Vitarrine 3-acetic ester and lead tetra-acetate react the compound of the formula that obtains 2 in acetic acid:

Use PtO subsequently ₂Hydrogenation in acetic acid obtains compound 3:

Itself so with 5 heating of superstoichiometric compound:

Obtain the compound of formula 6:

With after saponification and protonated again with acid, obtain 5 alpha-pregnanes-3 β, (20S), and 21-triol 20-O-β-D-glucuronide, and this compound can optionally be converted into its pharmacologically acceptable salt.

31. prepare 5 alpha-pregnanes-3 β, the method for 20R-glycol 20-O-β-D-glucuronide, it comprises compound 10:

Compound and Ag with formula 5 ₂CO ₃Reaction:

The compound of production 11:

With after saponification and protonated again with acid, obtain 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide can optionally be converted into its pharmacologically acceptable salt according to claim and this compound.

32. 5 alpha-pregnanes-3 β, (20S), the preparation method of 21-triol 20-O-β-D-glucuronide one sodium salt, it comprises with excess NaOH solution development slightly.

33. 5 alpha-pregnanes-3 β, the preparation method of 20R-glycol 20-O-β-D-glucuronide one sodium salt, it comprises with excess NaOH solution development slightly.