TW499435B - Pregnane glucuronides - Google Patents

Abstract

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

Description

499435 A7 _B7_ BACKGROUND OF THE INVENTION Naturally estrogen-producing compositions that are pure in nature and of low toxicity, such as the use in combination with estrogen (PREMARIN) (combined with horse estrogen), have become a method for alleviating the symptoms of menopausal syndrome and estrogen deficiency Better medication for osteoporosis / osteopenia and other hormone-related disorders. The estrogen component of the natural estrogen composition has been widely identified as the sulfate ester of estrone, maleestrone, dehydroestrone, 17- / 3-estradiol, and dihydrodehydroestrone. Estrone and 17-/?-Dihydrodehydroestrone (U.S. Patent 2,834,712). The estrogen composition is usually buffered or stabilized by alkali metal salts of organic or inorganic acids to a pH of about 6.5 to 7,5 in nature. Urea can also be used as a stabilizer (US 3,608,077). The incorporation of antioxidants to stabilize and artificially bind estrogen and the use of tris (hydroxymethyl) aminomethane (TR IS) to control pH to prevent the failure of hydrolysis are discussed in US 4,154,820. The two compounds described here, 5 α-pregnane _ 3 /?, (2 0 S), 2 1 triol 20_0_ling-glucose sodium salt and 5α _pregnant hospital 3 /?, 201?- Diol 20-0- / 3 _ Sodium glucuronide is a minority component of estrogen binding (horse estrogen binding). DETAILED DESCRIPTION OF THE INVENTION According to the present invention, 5oc-pregnane-3 / ?, (20S), 21triol, 20-0- / 3 —gluconic acid and 5ot-pregnant house-3, 20R-diol, 20-0-cold-glucuronic acid and its pharmaceutically acceptable salts are useful as fertility inhibitors. The preparations of pregnane " glucuronic acids 7 and 12 are shown in schemes I and E, respectively. In addition, it also shows that the conversion of glucuronic acid into days-3- This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) Please read the note on the back page printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 499435 A7 B7 printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the invention (>) Naturally produced sodium salt forms 8 and 13. 5ot-pregnane_3 / 3, (20S), 21 triol 20.-0-/?-Glucuronic acid and 5α-pregnane-3 / ?, 20R-diol 20-0- / 3-glucuron Acid pharmaceutically acceptable salts are not limited to natural forms, but also include alkali metal salts, alkaline earth metal salts, ammonium salts, alkyl ammonium salts containing 1 to 6 sulfonic atoms in each alkyl group, or Dialkylammonium salts containing 1 to 6 sulfonic atoms, trialkylammonium salts containing 1 to 6 sulfonic atoms in each alkyl group, and any other atom or molecule having a positive charge. Because 5α-pregnane-3 / 3, (20S), 21 triol 20-0- / S-glucuronic acid and 5α-pregnane-3 / 3, 20R-diol 20-0- / S glucaldehyde Acid is a minority component that binds estrogen (combined with horse estrogen), so the present invention also provides 5oc-pregnane-3々, (20S), 21triol 20-0- > 3-glucose wake up greater than 1% purity. Acid and 5α-Pregnant House-3 / 3, 20R-diol 20-0-cold-glucuronic acid and their pharmaceutically acceptable salts. The present invention also provides 5α-pregnane-3 / 8, (20S), 21triol 20-0-ling-glucuronic acid or a pharmaceutically acceptable salt thereof, or 5ot-pregnane-3 /? 20R-diol 20-0-/?-Glucuronic acid or a pharmaceutically acceptable salt thereof. The present invention further provides the use of 5oc-pregnane-, (20S), 21 triol 20-0-/?-Glucuronic acid and 5oc-pregnane-3 / 9, 20-diol 20-0-cold-glucose Method of uronic acid or pharmaceutically acceptable related glucuronide as a progestational agent. The starting materials used in this synthesis are either commercially available or prepared using standardized methodologies. -4 I (Please read the precautions on the back before you install ----- -HI this page); Line · This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 499435 A7 B7 V. Invention Explanation (i) Preparation of the alcohol 20-0-cold-glucose from the chemically starting material of the present invention -0-cold-glucose in liquid according to the scheme I. Root (1990) to 20% of the acetic acid glucose glucose solution titration chart I According to Purdy described in bromoglucuronic acid at 3: 1 acetic acid co-formed with uronic acid can be obtained, such as glucuraldehyde Among the methods, alginic acid, et al., In the method P t 0: compound uronic acid L iOH soap conjugate 7 monosodium salt according to the method of flow chart I is easily available from 5oc -pregnancy- 3/8, (20S), 21 triacid (and corresponding monobasic sodium salt) or roots as shown 5α-pregnane-3 / 3, 20 diol 20 synthesis (and corresponding monobasic sodium salt) ). Using pregnenolone 3-acetate 1 as a starting material in the Journal of Medical Chemistry 3 3 (6), 1 5 7 2-1 5 8 1, reacting 1 with lead tetraacetate in acetic acid can be performed on 2 Hydrogenation is obtained with about 3 and 4. Compound 3 is then heated with over-equivalent methyl ester 5. It is then protected and deprotected with acid to obtain the desired 20-. Free acid can dissolve in a slight excess of NaOH 8 〇 Please read the notes on the back page printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, printed by the employee consumer cooperatives. A7 B7 AHP-98160 V. Description of the Invention (4) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

(Please read the notes on the back first, then this page.) Packing.- • Thread · This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 499435 A7 B7

X

AiCO ^ CHa V. Description of the invention (In the scheme I [, the compound 10 is reacted with acetobromoglucuronic acid methyl ester 5 and Ag2CO3 to obtain a protected co-product 11. Then this material is saponified, and then The M acid is protonated to obtain a deprotected glucuronic acid derivative 12. This material is then titrated with KNaOH to obtain sodium glucuronic acid sodium 13.

Flowchart I

LiOH ΤΗΡ / ΜθΟΗ / Η2〇 (Please read the precautions on the back before this page)

The compound of the present invention is printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs as a progestational agent, so it is useful as an oral contraceptive (male or female), for hormone replacement therapy (especially when combined with estrogen), and for Treatment of endometriosis, luteal phase defect, benign breast and prostate disease M and endometrial cancer. The compound of the present invention is also used for protection against the onset of paralysis, enhancement of recognition, and treatment of AZ-7. This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 499435 Α7 Β7 Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperatives 5. Description of the invention (6) Hemmer's disease, dementia, vasomotor symptoms during menopause, and other central nervous system disorders. The compounds of the invention are additionally useful for stimulating erythrocyte formation. The compounds of the invention can be used alone as the sole therapeutic agent or can be used in combination with other agents, such as other estrogen, progesterone, and androgens. The compound of the present invention may be administered purely or in combination with a pharmaceutical carrier B. These ratios are determined by the solubility and chemical properties of the compound, the selected route of administration and the quasi-physical operation. Medical carriers can be solid or liquid. The solid pith may include one or more substances that can act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, pressure aids, binders, or tablet disintegrating agents; it can also be Making capsule material. In powders * The carrier is a finely divided solid, which is mixed with the finely divided active ingredients. In lozenges, the active ingredient is mixed with a carrier having the desired compression properties in an appropriate ratio and compacted to the shape and size. Powders and lozenges preferably contain up to 99 × active ingredients. Suitable solid carriers include, for example, calcium sulfate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium methyl cellulose, polyvinyl pyrrolidine, low Melt 蟠 Κ and chick exchange resin. Liquid carriers are used in the preparation of solutions, suspensions, emulsions, syrups, brewers M and pressurized compositions. The active ingredient can be dissolved or suspended in a technically acceptable liquid such as water, an organic solvent, or a mixture of the two or a pharmaceutically acceptable oil or wax. The liquid carrier may contain other appropriate peony additives, such as dissolving agents, milk cocoons, buffering agents, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity adjustments. 8- (please first Read the note on the back 2 items before re-installing-11 ^ this page) · --- · The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 499435 A7 B7 V. Description of the invention (7) Agent, stabilizer or osmolyte. Examples of suitable liquid carriers for oral, parenteral and parenteral administration include water (partially containing entrapment additives such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), yeast (including monobasic yeast And multiple enzymes, such as secondary enzymes) and their derivatives, lecithin, M and oils (such as fractionated coconut oil and peanut oil). For parenteral administration, the carrier may also be oily, such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are provided in sterile liquid form for parenteral administration. The liquid carrier used for the pressurized composition may be a halogenated hydrocarbon or other technically acceptable advancement. Liquid pharmaceutical compositions in 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 the present invention can also be administered orally in the form of liquid or solid compositions. The compounds of this invention can be administered rectally or vaginally in the form of a conventional suppository. For inhalation or insufflation by intranasal or intratracheal administration, the compounds of the present invention are formulated into aqueous or partially aqueous solutions, and then used in the form of their M aerosol cocoons. The compounds of the present invention can also be obtained via a transdermal patch containing an active compound, which is inert to the active compound, non- Use while giving 蕖. This carrier can come in many forms, such as creams and ointments, pastes, gels, M and closed designs. Creamer I and ointment_ can be viscous liquid or semi-solid emulsions in oil-in-water or water-in-oil form. A paste consisting of an absorbent powder dispersed in petroleum ether or a hydrophilic petroleum ether containing an active ingredient is also applicable. Various closed designs can be used. M will work -9- This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back first for this page)

Τ, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 499435 A7 _B7_ V. Description of the invention (/) Sexual ingredients are released into the bloodstream, such as those coated with active ingredients with or without a carrier, or a reservoir containing an active ingredient matrix Semi-permeable membrane. Other closed designs are known in the references. The required dosage will vary with the particular composition used, the route of administration, the severity of the symptoms presented, and the particular subject of the desired treatment. Based on the results obtained by the standard pharmacological test method, the planned dosage of the active compound is from 0.02 μg / kg to 750 μg / kg. Treatment generally begins as a small dose that is less than the optimal dose of active compound. Thereafter, the dose is increased until the optimal effect is obtained in that environment; the precise dose for oral, parenteral, nasal, or intratracheal administration is determined by the pharmacist based on the experience of the individual subject to be treated. Preferably, the pharmaceutical composition is in a unit dosage form, such as a lozenge or capsule. In this form, the composition is subdivided into unit doses containing appropriate amounts of the active ingredient; the unit dose form may be a packaged composition such as a powder, a vial, an ampoule, a pre-filled syringe, or a sachet containing liquid. The unit dosage form may be, for example, a capsule or lozenge itself, or it may be in the form of a suitable number of any of these compositions. The preparation of representative compounds of the invention is provided below. Example 1 Pregnane-3/3 .20R-Tri-3.21-Diethylpyrene B. 3 Compound 2 (6.0 g, 14.4 mmol) dissolved in 0.2 liters of AcOH with Pt02 (1.75 g, 7.7 mmol) Mol), and this solution was subjected to hydrogenation at P 2 at 40 PSI. After 18 hours, the catalyst was filtered off, and the crude reaction mixture was concentrated and chromatographed on silica gel using EtOAc / hexane (1: 4) to obtain the second product (3 and 4). The first product obtained by the dissolution is the main (required) substance 3, which can be isolated as 2.40 -10- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back first (Reprinted on the next page). Printed by the Employees 'Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 499435 A7 B7 Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. -4.60 (m, 1 Η), 4.16 (dd, 1 Η, J = 11.4 Hz, 2.2 Hz), 3.94-3.87 (m, 1 H), 3.81-3.73 (m, 1 H), 2.10 (s, 3H ), 2.10-2.05 (m, lH), 2.02 (s, 3H), 1.84 (d, lH, J = 5.2Hz), 1.82-0.88 (m, 21 H), 0.83 (s, 3 H), 0.76 ( s, 3 H), 0.68 (dt, 1 H, J = 10.6 Hz); MS (+ ESI) 421 (M + H) +; IR (KBr) 3520, 2920, 2880, 1740, 1710 cm g-Example 2 '»Pregnane-3θ · 20Ι ?, 21-triol 3, 20-diacetate 4 The second product 4 obtained by the dialysis is a minor product and can be isolated to 0.73 g of white solid: melting point = 189-191t: ; WNMRPMSOH.W (dq, 1 Η, J = 5.5 Hz, 2.2 Hz), 4.74-4.63 (m, 1 H), 3.81-3.74 (m, 1 H), 3.57-3.49 (m, 1 H), 2.09 (s, 3 Η), 2 · 02 (s, 3 Η), 1.91 (dd, 1 H, J 7.2 Hz, 5.0 Hz), 1.85-0.83 (m, 22 H), (X82 (s, 3 H), 0.72-0.61 (m, 1 H), 0.65 (s, 3 H); MS El 420 (M +); IR (KBr) 3410, 2920, 1730, 1700 cm, tube 3 2 · 3 · 4-0- three 71 醮- 1-0- (3fen-21, di-Z-Hydroxy-5-α-pregnane-20S-X-)-θ-D-glucose IS aldehyde aldehyde methyl ester 6 Compound 3 (6.6 g, 15.7 mmol Ear) was dissolved in CHC13 (125 ml) and treated with MAg2CO3 and bromoglucuronide 5 [21085-72-3] (6.2 g, 15.7 mmol). After 1.5 hours at reflux, additional 0.5 equivalents of Ag2CO3 and 0.5 equivalents of bromoglucuronide were added. After another 1.5 hours, repeat adding these reagents again, and after another 15 hours, repeat again. The reaction was refluxed for a total of 5.5 hours. The reaction was cooled and the inorganic salts were filtered off. The filtrate was concentrated and chromatographed on a silica gel (3: 7, EtOAn / hexane), and the fraction containing the product was -11- This paper is in accordance with China National Standard (CNS) A4 (210 X 297) Mm) (Please read the Zhuyin on the back? Matters

(This page) Order--_ line ·, > 499435 A7 B7 V. Description of the invention (1 ()) Concentrated, and then chromatographed again under the same conditions to obtain 4 · 1 g of 6 • Grind it with MeOH to obtain 3.05 g white solid 6: melting point = 180-183 ° C; MS (APCI) 754 (M + NH4 +); Ή NMR (DMSO) 5.36 (t, 1 H, J = 9.6 Hz), 5.06 (d, 1 H, J = 8.0 Hz), 4.91 (t, 1 H, J = 9.8 Hz), 4.70 (dd, 1 H, J = 9.5 Hz, 8.1 Hz), 4.63-4.50 (m, 1 H), 4.47 (d, 1 H , J = 10.0 Hz), 4.16 (d, 1 H, J = 11.3 Hz), 3.92 -3.75 (m, 2 H), 3.63 (s, 3 H), 2.16-2.07 (m, 1 H), 2.04 ( s, 3 H), 1.99 (s, 3 H), 1.97 (s, 3 H), 1.95 (s, 3 H), 1.93 (s, 3 H), 1.78-1.63 (m, 3 H), 1.62- 1.39 (m, 6 H), 1.36 -1.10 (m, 8H), 1.06-0.85 (m, 5 H), 0.79 (s, 3 H), 0.68 (s, 3 H). Example 4

So (-Heptane.20S.21-Tris-0-0-glucuronic acid J Compound 6 (3.76 g, 5.1 mmol) was dissolved in T F (25 ml), and M contained in H 2 O. (13 ml) of a solution of LiOH (1.35 g · 56 · 1 mmol). MeOH (4 ml) was added to the solution and the reaction was heated to 75 C for 2 hours. The solution was then cooled and concentrated. Then 2N HC1 solution (43 ml) was added to the residue. Solid formation was induced by scraping glass K. Filtration yielded 2.6 g of a white solid 7: 雠 = 23 235 ° C; l3C NMR (75 MHz, MeOD) ( 00 disappears), K) 2.6, 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, 40.3, 39.0, 38.3, 36.9, 36.7, 33.5, 32.2, 30.0, 25.9, 25.4, 22,3, 12 · 8, 11.9; Η NMR (300 MHz, MeOD) 4.54 (d, 1 Η, J = 7.7 Hz), 3.82-3.71 (m, 3 Η), 3.59-3.22 (m, 5 Η), 2.30 (d, I Η, J = 12.6 Hz), 1.75-1.66 (m, 6 H), 1.53-1.18 (m, 9 H), 1.17-0.88 (m, 6 U), 0.83 (s, 3 11), 0.78 (s, 3 H), 0.70-0.58 (m, 1 H); MS (-) ESI 511 (MH); IR (KBr) 3410, 2910, 2830, 1730 , 1700 cm 4 Example 5 5 c < -Pregnane-3.205.21-triamidine- (1-zhao-0-glucosamine sodium sugar) Only compound 7 (1.57 g, 1.7 mmol) was suspended in Me0H (20 mmol -12- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the note on the back? Matters II-II on this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ^ 9435 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, 1. Description of the Invention (11 liters), and treated with MNaOH aqueous solution (6.4ml · 0.5N), and stirred for 5 minutes to dissolve all the starting materials in the solution The solution was then mixed with 0.6 5 g of the product obtained the previous time, and the composition was stripped on a silica gel and subjected to column layer on silica gel (MeOH: CH2CI2, 4: 6 then 5: 5). Analysis. The product was then triturated once with a 1: 1 mixture of MeOH and dioxane (total volume was 60 liters) to obtain 1.57 g of a white solid 8: melting point = 240-244t !; GC NMR (75 MHz, DMS0) ( C = 0 disappears), 100.4, 79 · 8, 76 · 7, 73 · 9, 72 · 2, 69 · 3, 66 · 3, 62 · 0, 55 · 6, 54 · 0, 49 · 8, 44 · 3 · 41 · 9, 38 · 1, 36 · 6, 35 · 5, 35 · 0, 31 · 8, 31 · 3, 28 · 4, 24 · 4, 23 · 9, 20 · 8, 12 · 1, 11 · 4; IR (KBr) 3400 (Η2 0), 2920, 2870, 1610 Miao 'Fen 锎 β Lift cake β .20S, 2 1_Three 醵 9 Dissolve compound 3 (1.6 g, 3.8 millimolar) in THF (8 mL). A solution of LiOH (0.27 g, 11.4 mmol) in 3 ml of H2O was added. To make the solution a single phase, 1 ml of MeOH was added to the reaction residue. After refluxing for 30 minutes, the reaction mixture M1 · 1 ml hexa <: 011 was treated, and the reaction mixture containing 100 ml [1; (^ € :, 20 ml (: 112 (: 12 C organic layer and 60 ml) The mixture was partitioned between 200 and then the organic layer was washed with brine and dried over Mg S0 4. The solution was concentrated and the resulting solid was triturated with ether to obtain 1.1 g of a white solid 9: melting point = 210-212t: 1 H NMR (DMS0) (30H protonation disappears) 4.43 (d, 1H, J = 4.6 Hz), 4.31 (t, 1H, J = 5.5Hz), 4.05 (d, 1H, J = 5.2Hz), 3.16 -3 · 05 (π, 1H), 2.10 (d, 1H, J = 12.4Hz), 1.65- -1 3 ~ (Please read the precautions on the back first

(This page) Order: Line · This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 499435 Printed by A7 B7__ 12 of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention () 0,78 ( m, 21H), 〇, 75 (s, 3H), 〇68 (s, 3H), 0.65-0.54 (m, 1H); MS El 336M +; IRUBrO 3400, 2930, 2880 cm. Example 7 1-0 -(3 Ling Di B. 醢 基-pregnant 粽-2 ft-a)-; three Z brewing a certain-厶 -D- Portuguese box W beer 1 1 5α-Pregnane-3 , 20 / 3-diol 3-ethyl acetate 10 (3.0 g, 11.0 mmol), bromoglucuron 5 [21085-72-3] (5.5 g, 13.8 mmol) and Ag2C03 (4.5 G, 16.1 mmol) in toluene (40 ml) (conical flasks are protected from light with aluminum foil). After 18 hours, the reaction MCH2C12 was diluted, filtered, concentrated, and chromatographed on silica gel (EtOAc: hexane, 2: 8 then EtOAc: hexane, 4: 6) to obtain a solid. It was triturated with HeOH to obtain 3.0 g of white solid 11: «= 248-251 ° C; lH NMR (DMSO) 5.33 (t, 1 H, J = 9.6 Hz), 4.95-4.88 (m, 2 H) , 4.68 (dd, 1 H, J = 9.5 Hz, 8.1 Hz), 4.62-4.49 (m, 1 H), 4.44 (d, 1 H, J = 10.0 Hz), 3.71-3.65 (m, 1 H), 3.63 (s, 3 H), 2.11 (d, 1 H, J = 12.6 Hz), 1.98 (s, 3 H), 1.97 (s, 3 H), 1.96 (s, 3 H), 1.95 (s, 3 H), 1.77-1.64 (m, 2 H), 1.63-1; 10 (m, 14 H), 0.99 (d, 3 H, J = 5.8 Hz), 0.95-0.83 (m, 5 H), 0.78 ( s, 3 H), 0.66 (s, 3 H), 0.65-0.58 (m, 1 H); IR (KBr) 2930, 2900, 2830, 1750, 1730 cm. 1; MS (+) ESI 696 (M + NHX window example 8 5 forks, one green cake, 3θ.20R—second brewed 20-n-/?-D-glucuronic acid 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 H20 (10 ml). The reaction was heated at reflux -14- (Please read the precautions on the back --- This page) Ordering and threading '' This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 499435 A7 B7_ V. Description of the invention (13) 1 hour. The solution was then cooled to room temperature and concentrated. M water (20 mL) absorbed the product and acidified with aqueous 2N HC1. The precipitate formed was filtered to obtain 1.5 g of a white solid 12: melting point = 255-260t !; 1 Η NMR (DMSO) (3Η mask) 4.98 (d, 1 H, J = 3.8 Hz), 4.91 (d, 1 H, J = 4 · 6 Ηζ), 4.42 (br s, 1 Η) , 4.25 (d, 1 Η, J = 7.7 Hz), 3.71-3.62 (m, 1 Η), 3.58 (d, 1 Η, J 2 9.7 Ηζ), 3.23-3 · 12 (m, 1 Η), 2.96-2.87 (m, 1 Η), 2.15 (d, 1 Η, J = 12.3 Ηζ), 1.67-1.46 (m, 5 Η), L45-0.80 (m, 17 Η), 1.01 (d, 3 Η, J = 5.8 Ηζ), 0.74 (s, 3 Η), 0.65 (s, 3 Η), 0.65-0.52 (m, 1 Η): IR (KBr) 3520, 3400 , 2920, 2820, 28 () (), 171 () cm '; MS ㈠ ESI 495 (Μ-Η): Tube Example 9 5 --pregnane. 20 hydrazine 20-0- / 3 glucosamine Sodium ether salt 1 3 Compound 12 (1.5 g) in MeOH (25 ml) Mo ear 3. 0 mmol) was MNa0H (0,5H, 6.0 mL, 3.0 mmol) aqueous solution treatment, and when all material was stirred into the solution for 5 minutes. The solution was concentrated to dryness and the residue was triturated with EtOH to obtain 1 ♦ 1 g of a white solid 13: M = 223-226 ° C (^ m;! H NMR (DMSO) 7.26 (s, 1 H), 4.76 (d, 1 H, J = 3.6 Hz), 4.67 (d, 1 H, J = 3.6 Hz), 4.43 (d, 1 H, J = large 4 Hz), 4.12 (d, 1 H, J = 7.6 Hz), 3.78-3.71 (m, 1 H), 3.45-3.35 (m, 1 H), 3.17-3.03 (m, 3 H), 3.38-3.29 (m, 1 H), 2.17 (d, 1 H, J = 12.4 Hz), 1.67-1.49 (m, 5 H), 1.45-0.80 (m, 17 H), 0.99 (d, 3 H, J 5.9 Hz), 0.76 (s, 3 H), 0.75 (s , 3 H), 0.65-0.5l (m, 1 H); IR (KBr) 3400, 2920, 2830, 1610 cm'1; MS (-) ESI 495 (MH) *. (Please read the precautions on the back first #ipKthis page)

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Claims (1)

499435 Scope of patent application No. 88 1 17305 "Pregnane glucuronic acid" patent case (Amended in January 2011) Scope of patent application: 1. A compound of formula 7, Or a pharmaceutically acceptable salt thereof. 2. For example, the compound in the scope of patent application, wherein the pharmaceutically acceptable salts of 20-glucuronic acid are alkali metal salts, alkaline earth metal salts, ammonium salts, alkyl ammonium salts containing 1-6 carbon atoms, Or a dialkylammonium salt containing 1-6 carbon atoms in each alkyl group, or a trialkylammonium salt containing 1-6 carbon atoms in each alkyl group. 3. For example, the compound in the first scope of the patent application is 5 α-pregnane-3 cold, 20S, 21-triol 20-0-y5-D-glucuronide sodium salt. 4. A compound of formula 12 Or a pharmaceutically acceptable salt thereof. 499435 VI. Application for patent scope 5. For the compound in the scope of patent application for item 4, in which the pharmaceutically acceptable salts of 20-glucuronic acid are alkali metal salts, alkaline earth metal salts, ammonium salts, containing 1-6 carbon atoms An alkylammonium salt, or a dialkylammonium salt having 1-6 carbon atoms in each alkyl group, or a trialkylammonium salt having 1-6 carbon atoms in each alkyl group. 6. The compound according to item 4 of the scope of patent application, which is 5 α-pregnane-3 yS, 20R-triol 20-O- / 3-D-glucuronide sodium salt.