JP2002527448A - Pregnane glucuronide - Google Patents

Abstract

  (57) [Summary] The present invention relates to 5α-pregnane-3β, 20S, 21-triol.20-O-β-glucuronide and 5α-pregnane-3β, 20R-diol.20-O-β-glucuronide useful as progesterone agents, and pharmaceuticals thereof. To provide an acceptable salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to pregnane glucuronide useful as a progestational agent.

BACKGROUND OF THE INVENTION The use of substantially pure and low toxicity compositions of natural estrogens, such as premarin (conjugated equine estrogens), has been used in menopause, osteoporosis / osteopenia in women with estrogen deficiency, and others. Is becoming a preferred treatment for alleviating the symptoms of hormone-related disorders in children. The estrogen component of the natural estrogen composition has been generally identified as the sulfate of estrone, equilin, equilenin, 17-β-estradiol, dihydroequilenin, and 17-β-dihydroeculenin (U.S. Pat.No. 2,834,712). issue). Estrogen compositions are typically prepared using an alkali metal salt of an organic or inorganic acid to a substantially neutral pH of about 6.5.
Buffered or stabilized at ~ 7.5. Urea has also been used as a stabilizer (US Pat. No. 3,608,077). U.S. Pat.No. 4,897,086 states that failure to incorporate antioxidants to stabilize synthetic conjugated estrogens and to adjust pH using tris (hydroxymethyl) aminomethane (TRIS) to prevent hydrolysis has failed. 4,1
It is discussed in 54,820.

[0003] Two of the compounds described herein, namely 5α-pregnane-3β, 20S, 21
-Triol-20-O-β-glucuronide sodium salt and 5α-pregnane-
3β, 20R-diol.20-O-β-glucuronide sodium salt is a minor component of premarin (conjugated equine estrogen).

DISCLOSURE OF THE INVENTION According to the present invention, 5α-pregnane-3β, 20 useful as a progestational agent
S, 21-triol.20-O-β-glucuronide and 5α-pregnane-3β, 2
Provided are 0R-diol.20-O-β-glucuronide and pharmaceutically acceptable salts thereof. The preparation of pregnane glucuronides 7 and 12 is shown in Schemes I and II, respectively. In addition, glucuronide natural sodium salt form 8
And 13 are also shown.

[0005] Pharmaceutically acceptable salts of 5α-pregnan-3β, 20S, 21-triol.20-O-β-glucuronide and 5α-pregnan-3β, 20R-diol.20-O-β-glucuronide are naturally occurring. There is no limitation on the type, and alkali metal salts, alkaline earth metal salts, ammonium salts, alkylammonium salts having 1 to 6 carbon atoms, dialkylammonium salts having 1 to 6 carbon atoms per alkyl group, and each alkyl group Examples thereof include trialkylammonium salts having 1 to 6 carbon atoms, and other atoms or molecules having a positive charge.

[0006] 5α-pregnane-3β, 20S, 21-triol.20-O-β-glucuronide and 5α-pregnane-3β, 20R-diol.20-O-β-glucuronide are trace amounts of premarin (conjugated equine estrogen). As a component, the present invention also relates to 5α-pregnane-3β, 20S, 21-triol.20-O-β-glucuronide and 5α-pregnane-3β, 20R-diol.20-O with a purity of more than 1%. -β-glucuronide and pharmaceutically acceptable salts thereof are provided.

[0007] The present invention also provides substantially 5α-pregnane-3β, 20S, 21-triol.
A compound comprising 20-O-β-glucuronide or a pharmaceutically acceptable salt thereof, or 5α-pregnane-3β, 20R-diol.20-O-β-glucuronide or a pharmaceutically acceptable salt thereof is provided.

The present invention further provides a method of using a pharmaceutically acceptable salt of 5α-pregnane-3β, 20S, 21-triol glucuronide and 5α-pregnane-3β, 20R-diol glucuronide or a related glucuronide as a progesterone agent. I will provide a.

The raw materials used in this synthesis can be obtained from commercially available products or can be produced by using standard chemical methods.

The compound of the present invention comprises 5α-pregnane-3β, 20S, 21-triol.20-O
According to the method of Scheme I shown for -β-glucuronide (and the corresponding basic monosodium salt), or alternatively, 5α-pregnane-3β, 20R-diol.20
It can be prepared from readily available raw materials according to the method of Scheme II shown for the synthesis of -O-β-glucuronide (and the corresponding basic monosodium salt).

In Scheme I, pregnenolone-3-acetate 1 was used as a raw material. Purdy et al. [Journ of Medicinal Chemistry (Journ)
al of Medicinal Chemistry) 33 (6), 1572-1581 (1990)] and reacting 1 with lead tetraacetate in acetic acid to give 2. Hydrogenation of ₂ over PtO 2 in acetic acid gives compounds 3 and 4 in a ratio of about 3: 1. Subsequently, compound 3 is heated with an excess of acetobromoglucuronic acid methyl ester 5. Subsequently, the protected glucuronide is hydrolyzed with LiOH and reprotonated with acid to give the desired 20-
Glucuronic acid conjugate 7 is obtained. The free acid can be titrated with a slight excess of NaOH solution, thus giving the monosodium salt 8.

[0012]

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In Scheme II, compound 10 was reacted with acetobromoglucuronic acid methyl ester 5 and Ag ₂ CO ₃ to give protected conjugate 11. Subsequently, the substance was hydrolyzed and then protonated with an acid to obtain the deprotected glucuronic acid derivative 12. This material was then titrated with NaOH to give sodium glucuronate 13.

[0014]

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The compounds of the present invention are progestational agents and are therefore useful as oral contraceptives (for men and women), as well as for hormone replacement therapy (especially when used in combination with estrogen) and in utero. Membrane disease, luteal phase defect, benign chest and prostate disease,
And is useful in treating prostate and endometrial cancer. The compounds of the present invention also prevent seizures in epilepsy, enhance cognition, Alzheimer's disease, dementia,
It is useful for treating vasomotor symptoms associated with menopause, and other central nervous system disorders. The compounds of the present invention are further useful for stimulating erythropoiesis.

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

The compounds of the present invention can be formulated as such or using a pharmaceutical carrier for administration. The proportion will be determined by the solubility and chemistry of the compound, the route of administration chosen, and standard pharmacological practices. The pharmaceutical carrier may be either solid or liquid.

As the solid carrier, one or more of which can also act as a flavoring agent, lubricant, solubilizer, suspending agent, filler, flow agent, compression aid, binder or tablet disintegrant The above substances can be mentioned. It can also be an encapsulating material. In powders, the carrier is a finely divided solid, which is in turn mixed with the finely divided active component. In tablets, the active component is mixed with the 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, sugar, lactose,
Dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, 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 a pharmaceutically acceptable oil or fat. Liquid carriers may contain other suitable pharmaceutical excipients, for example, solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, coloring agents, viscosity modifiers, stabilizers. Agent or an osmotic pressure adjusting agent. Suitable examples of liquid carriers for oral and parenteral administration include water (additives as described above (e.g.,
Cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols (e.g., glycols) and their derivatives, lecithin, and oils (e.g.,
Fractionated coconut oil and peanut 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 compositions for parenteral administration. Liquid carriers for pressurized compositions can be halogenated hydrocarbons or other pharmaceutically acceptable propellants.

Liquid pharmaceutical compositions that 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 the invention may also be administered orally in the form of either a liquid or solid composition.

The compounds of the present invention may be administered rectally or vaginally in the form of a conventional suppository.
When administered by intranasal or intrabronchial inhalation or insufflation, the compounds of the invention may be formulated in aqueous or semi-aqueous solutions. These can then be utilized in the form of an aerosol. The compounds of the present invention may be administered transdermally by the use of a transdermal patch containing the active compound and a carrier. Provided that the carrier is inert to the active compound, non-toxic to the skin, and allows for delivery of the systemically absorbable drug into the blood stream through the skin. Such carriers may take any number of forms, such as creams and ointments, pastes, gels, and closures. Creams and ointments may be viscous liquids or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes made of absorbent powder dispersed in petrolatum or hydrophilic petrolatum containing the active ingredient are also suitable. The active ingredient may be released into the bloodstream using a variety of closures, such as semipermeable membranes that cover the reservoir containing the active ingredient, if desired with a carrier, or a matrix containing the active ingredient. . Other closure devices are known in the literature.

[0022] Dosage requirements vary with the particular composition employed, the route of administration, the severity of the symptoms being manifested, and the particular patient being treated. Based on the results obtained in standard pharmacological tests, the planned daily dose of active compound is from 0.02 μg / kg to 75
0 μg / kg. Treatment will generally be initiated with small dosages, which are less than the optimum dose of the compound. Then, until the optimal effect is obtained under such circumstances,
Increase dose. Precise dosages for oral, parenteral, nasal or intrabronchial administration will be determined by the administering physician based on experience with the individual patient being treated.
Preferably, the pharmaceutical composition is in unit dosage form, for example, provided as a tablet or capsule. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged composition, for example,
It can be a vial, ampoule, pre-filled syringe or liquid bag. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of such compositions in package form.

Hereinafter, production of a typical compound of the present invention will be described.

Example 1 Compound 2 (6.0 g, 14.4 mmol) in 0.2 L of pregnane-3β, 20R, 21-triol-3,21-diacetate 3 AcOH was converted to PtO ₂ (1.75 g, 7 It was treated with .7 mmol) was hydrogenated and the solution _{of H 2} under 40 psi. After 18 hours, the catalyst was filtered and the crude reaction mixture was concentrated and chromatographed on silica gel with EtOAc / hexane (1: 4) to give two products (3 and 4). The first product to elute is the major (desired) substance 3;
It was isolated as 2.40 g of a white solid. Melting point 164-166 ° C; ¹ H N
MR (CDCl ₃ ) 4.75 to 4.60 (m, 1H), 4.16 (dd, 1H, J = 11.4)
Hz, 2.2 Hz), 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, 1
H, J = 5.2 Hz), 1.82-0.88 (m, 21H), 0.83 (s, 3H), 0.76
(s, 3H), 0.68 (dt, 1H, J = 10.6 Hz); MS (+ ESI) 421 (M +
H) ⁺ ; IR (KBr) 3520,2920,2880,1740,1710 cm ^-1
.

Example 2 Pregnane-3β, 20R, 21-triol-3,20-diacetate 4 The second product 4 eluted is a by-product, which was isolated as 0.73 g of a white solid did. 189-191 ° C; ¹ H NMR (DMSO) 4.91 (dq, 1
H, J = 5.5 Hz, 2.2 Hz), 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 EI
420 (M +); IR (KBr) 3410, 2920, 1730, 1700 cm- ¹ .

Example 3 2,3,4-O-Triacetyl-1-O- (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).
g ₂ CO ₃ (4.3 g, 17.7 mmol) and glocuronyl bromide 5 [21085-7
2-3] (6.2 g, 15.7 mmol). After refluxing for 1.5 hours, an additional 0.5 hours.
Five equivalents of Ag ₂ CO ₃ and 0.5 equivalents of grocuronyl bromide were added. After a further 1.5 hours, the addition of the reagent was repeated, and after a further 1.5 hours, another cycle was repeated. The reaction was refluxed for a total of 5.5 hours. The reaction was cooled and the inorganic salts were filtered off.
Concentrate the filtrate and silica gel chromatography (3: 7, EtOAc / hexane)
And the fractions containing the product were concentrated and re-chromatographed under the same conditions to give 4.1 g of 6. This was triturated with MeOH to give 3.05 g of 6
Was obtained as a white solid. 180-183 ° C; MS (APCI) 754 (M
+ NH ₄ ⁺ ); ¹ H NMR (DMSO) 5.36 (t, 1 H, J = 9.6 Hz), 5.0
6 (d, 1H, J = 8.0 Hz), 4.91 (t, 1H, J = 9.8 Hz), 4.70 (dd,
1H, J = 9.5 Hz, 8.1 Hz), 4.63-4.50 (m, 1H), 4.47 (d, 1H)
, J = 10.0 Hz), 4.16 (d, 1H, J = 11.3 Hz), 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 4 5α-pregnane-3β, 20S, 21-triol.20-O-β-D-glucuronide 7 Compound 6 (3.76 g, 5.1 mmol) was dissolved in THF (25 mL), and H ₂ O (
(13 mL) in a solution consisting of LiOH (1.35 g, 56.1 mmol). To this solution was added MeOH (4 mL) and the reaction was heated to 75 ° C. for 2 hours. The solution was then cooled and concentrated. It took more _H 2 O 15 mL aqueous residue. Then, 2N HCl solution (43 mL) was added to the residue. Scratching the glass induced the formation of solids. Filtration provided 2.6 g of 7 as a white solid. Melting point 231 to 235 ° C .; ¹³ C NMR (75 MHz, MeO
D) (C = O missing) 102.6, 82.1, 77.6, 76.8, 75.3, 73.1, 71.9
, 63.6,57.6,56.1,51.5,49.9,46.3,43.6,40.3,39.0
, 38.3,36.9,36.7,33.5,32.2,30.0,25.9,25.4,22.3
, 12.8, 11.9; ¹ H NMR (300 MHz, MeOD) 4.54 (d, 1 H, J
= 7.7 Hz), 3.82-3.71 (m, 3H), 3.59-3.22 (m, 5H), 2.3
0 (d, 1H, J = 12.6 Hz), 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 (-) ESI 511 (MH) ^- ; IR (KBr)
3410, 2910, 2830, 1730, 1700 cm ^-1 .

Example 5 5α-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). Cloudy, NaO
Treated with aqueous H solution (6.4 mL, 0.5 N) and stirred for 5 minutes. Thus, all the ingredients went into solution. This solution is then mixed with 0.65 g of the product obtained in the previous experiment, the mixture is stripped on silica gel and column chromatography on silica gel (MeOH: CH ₂ Cl ₂ , 4: 6, then 5: 5). : 5). The product was then diluted with a 1: 1 mixture of MeOH and dioxane (60 mL total volume).
Triturated once to give 1.57 g of 8 as a white solid. Melting point 240-
244 ° C .; ¹³ C NMR (75 MHz, DMSO) (C = O missing) 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). H ₂ O 3
A solution of LiOH (0.27 g, 11.4 mmol) in mL 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, 100 mL of EtOAc,
An organic layer composed of 20 mL of CH ₂ Cl ₂ and 10 mL of MeOH and 60 mL of H ₂ O
And distributed. The organic layer was then washed with brine, dried over MgSO _4. The solution was concentrated and the resulting solid was triturated with ether to give 1.1 g of 9 as a white solid. Melting point 210-212 ° C; ¹ H NMR (DMSO) (3OH
4.43 (d, 1H, J = 4.6 Hz), 4.31 (t, 1H, J = 5.5 H)
z), 4.05 (d, 1H, J = 5.2 Hz), 3.16-3.05 (m, 1H), 2.10 (
d, 1H, J = 12.4 Hz), 1.65-0.78 (m, 21H), 0.75 (s, 3H),
0.68 (s, 3H), 0.65-0.54 (m, 1H); MS EI 336 M +; IR (
(KBr) 3400, 2930, 2880 cm ^-1 .

Example 7 1-O- (3β-acetoxy-pregnan-20-yl) -2,3,4-triacetyl-β-
D-glucuronic acid methyl ester 115α-pregnane-3β, 20β-diol-3-acetate 10 (3.0 g, 11.
0 mmol), glucuronide bromide 5 [21085-72-3] (5.5 g, 13.8 mmol)
) And Ag ₂ CO ₃ (4.5 g, 16.1 mmol) at room temperature, toluene (40 mL)
(The flask was protected from light with aluminum foil). After 18 hours, the reaction was diluted with CH ₂ Cl ₂ , filtered, concentrated, and chromatographed on silica gel (E
tOAc: Hex, 2: 8 then EtOAc: Hex, 4: 6) to give a solid. This was triturated with MeOH to give 3.0 g of 11 as a white solid. Mp ^{248~251 ℃; 1 H NMR (DMSO} ) 5.33 (t, 1H, J
= 9.6 Hz), 4.95-4.88 (m, 2H), 4.68 (dd, 1H, J = 9.5 Hz,
8.1 Hz), 4.62-4.49 (m, 1H), 4.44 (d, 1H, J = 10.0 Hz),
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)
3H), 1.77-1.64 (m, 2H), 1.63-1.10 (m, 14H), 0.99 (d,
3H, H, J = 5.8 Hz), 0.95-0.83 (m, 5H), 0.78 (s, 3H), 0.7.
66 (s, 3H), 0.65-0.58 (m, 1H); IR (KBr) 2930, 2900,
2830, 1750, 1730 cm ^-1 ; MS (+) ESI 696 (M + NH ₄ ) ⁺
.

Example 8 5α-pregnane-3β, 20R-diol.20-O-β-D-glucuronide 12 Compound 11 (2.5 g, 3.7 mmol) was added to THF (25 mL) and MeOH (1
Was dissolved in a solution of 5 mL), LiOH in the _{H 2 O (10mL) (0.9g} , 37.
(5 mmol). The reaction was heated at reflux for 1 hour. The reaction was cooled to room temperature and concentrated. The product was taken up in water (20 mL) and acidified with 2N aqueous HCl. A precipitate formed. This was filtered to give 1.5 g of 12 as a white solid. 255-260 ° C; ¹ H NMR (DMSO) (3H buried) 4.98 (d, 1
H, J = 3.8 Hz), 4.91 (d, 1H, J = 4.6 Hz), 4.42 (brs, 1H)
, 4.25 (d, 1H, J = 7.7 Hz), 3.71-3.62 (m, 1H), 3.58 (d,
1H, J = 9.7 Hz), 3.23-3.12 (m, 1H), 2.96-2.87 (m, 1H)
, 2.15 (d, 1H, J = 12.3 Hz), 1.67-1.46 (m, 5H), 1.45-0
.80 (m, 17H), 1.01 (d, 3H, J = 5.8 Hz), 0.74 (s, 3H), 0.
65 (s, 3H), 0.65-0.52 (m, 1H); IR (KBr) 3520, 3400,
2920, 2820, 2800, 1710 cm ^-1 ; MS (-) ESI 495 (M-
H) ^- .

Example 9 5α-Pregnane-3β, 20R-diol.20-O-β-D-glucuronide sodium salt 13 Suspension of compound 12 (1.5 g, 3.0 mmol) in MeOH (25 mL) The solution was treated with aqueous NaOH (0.5N, 6.0 mL, 3.0 mmol) and stirred for 5 minutes. In the meantime, everything went into solution. The solution was concentrated to dryness and the residue was
Trituration with H afforded 1.1 g of 13 as a white solid. Melting point 223-2
26 ° C. (decomposition); ¹ H NMR (DMSO) 7.26 (s, 1 H), 4.76 (d, 1 H, J
= 3.6 Hz), 4.67 (d, 1H, J = 3.6 Hz), 4.43 (d, 1H, J = about 4H)
z), 4.12 (d, 1H, J = 7.6 Hz), 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 = 12.4 Hz), 1.67-1.49 (m, 5H), 1.45-0.8
0 (m, 17H), 0.99 (d, 3H, J = 5.9 Hz), 0.76 (s, 3H), 0.75
(s, 3H), 0.65-0.53 (m, 1H); IR (KBr) 3400,2920,28
30,1610 cm- ¹ ; MS (-) ESI 495 (MH) ^- .

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/00 A61P 25/00 25/28 25/28 35/00 35/00 (81) Designated country EP ( AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM , AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU , CZ , DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ , TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Buck Din Trang United States 21221 Glenshannon Court, Baltimore, Maryland 21221, Apartment A (72) Inventor Michael David Collini, United States 19018 Davis Avenue, Clifton Heights, PA 251 F-term (reference) 4C086 AA01 AA03 AA04 EA19 MA01 MA02 MA04 NA05 NA14 ZA03 ZA15 ZA16 ZA51 ZB26 4C091 AA01 BB01 CC01 DD01 EE04 FF01 GG01 HH01 JJ03 KK01 LL01 MM03 NN01 PA02 PA09 PB02 QQ01 RR01

Claims (33)

[Claims] (1) 5α-pregnane-3β, 20S, 21-triol.20-O-
A compound which is β-D-glucuronide or a pharmaceutically acceptable salt thereof. 2. The pharmaceutically acceptable salt of the 20-glucuronide is an alkali metal salt, an alkaline earth metal salt, an ammonium salt, an alkylammonium salt having 1 to 6 carbon atoms, and 1 to 6 carbon atoms per alkyl group. The compound according to claim 1, which is a dialkylammonium salt or a trialkylammonium salt having 1 to 6 carbon atoms per alkyl group. 3. A compound which is 5α-pregnane-3β, 20R-diol.20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof. 4. The pharmaceutically acceptable salt of the 20-glucuronide is an alkali metal salt, an alkaline earth metal salt, an ammonium salt, an alkylammonium salt having 1 to 6 carbon atoms, and 1 to 6 carbon atoms per alkyl group. The compound according to claim 3, which is a dialkylammonium salt or a trialkylammonium salt having 1 to 6 carbon atoms per alkyl group. 5. 5α-pregnane-3β, 20S having a purity of at least 1%.
21-triol.20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof. 6. 5α-Pregnane-3β, 20R- having a purity of at least 1%.
Diol 20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof. 7. Substantially 5α-pregnane-3β, 20S, 21-triol.
A compound comprising 20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof. 8. Substantially 5α-pregnane-3β, 20R-diol.20-O-
A compound comprising β-D-glucuronide or a pharmaceutically acceptable salt thereof. 9. Substantially 5α-pregnane-3β, 20S, 21-triol.
A compound comprising 20-O-β-D-glucuronide sodium salt. 10. Substantially 5α-pregnane-3β, 20R-diol.20-
A compound comprising O-β-D-glucuronide sodium salt. 11. 5α-pregnane-3β, 20S, 21-triol.20-O
A pharmaceutical composition comprising -β-D-glucuronide or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier. 12. 5α-pregnane-3β, 20R-diol.20-O-β-D-
A pharmaceutical composition comprising glucuronide or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier. 13. The pharmaceutical composition according to claim 11, further comprising another drug selected from estrogen, progestogen and androgen. 14. The method according to claim 1, which comprises substantially 5α-pregnane-3β, 20S, 21-triol.20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof and at least one pharmaceutical carrier. 13. The pharmaceutical composition according to 12. 15. Substantially 5α-pregnane-3β, 20R-diol.20-
The pharmaceutical composition according to claim 12, comprising O-β-D-glucuronide or a pharmaceutically acceptable salt thereof and at least one pharmaceutical carrier. 16. 1% w / w or more than 5% w / v of 5α-pregnane-3β,
A pharmaceutical composition comprising 20S, 21-triol.20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof and at least one pharmaceutical carrier. 17. 1% w / w or more than 5% w / w of 5α-pregnane-3β,
A pharmaceutical composition comprising 20R-diol.20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof and at least one pharmaceutical carrier. 18. The use of 5α-pregnane-3β, for use in treating mammals.
20S, 21-triol.20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof. 19. A 5α-pregnane-3β, for use in treating mammals.
20R-diol.20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof. 20. 5α-pregnane for use as a progestational agent
3β, 20S, 21-triol.20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof. 21. 5α-pregnane for use as a progestational agent
3β, 20R-diol.20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof. 22. 5α-Pregnane-3β, 20S, 21-triol-20 for use in treating or inhibiting cancer, central nervous system disorders, dementia or Alzheimer's disease in a mammal in need thereof. -O-β-D-glucuronide or a pharmaceutically acceptable salt thereof. 23. 5α-Pregnane-3β, 20R-diol-20-O for use in treating or inhibiting cancer, central nervous system disorders, dementia or Alzheimer's disease in a mammal in need thereof. -β-D-glucuronide or a pharmaceutically acceptable salt thereof. 24. In the manufacture of a medicament for use as a progestational agent, or in treating or inhibiting a cancer, central nervous system disorder, dementia or Alzheimer's disease in a mammal in need thereof, or 5α-pregnane-3β, 20 in stimulating erythropoiesis in mammals in need thereof
Use of S, 21-triol.20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof. 25. in the manufacture of a medicament for use as a progestational agent, or in treating or inhibiting a cancer, central nervous system disorder, dementia or Alzheimer's disease in a mammal in need thereof, or 5α-pregnane-3β, 20 in stimulating erythropoiesis in mammals in need thereof
Use of R-diol.20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof. 26. A method of providing progesterone therapy to a mammal in need thereof, comprising the steps of: providing a progesterone effective amount of 5α-pregnane-3β, 20S, 21-.
Administering triol-20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof to said mammal. 27. A method of providing progesterone therapy to a mammal in need thereof, comprising the steps of: administering a progesterone effective amount of 5α-pregnane-3β, 20R-diol.20-O-β-D-glucuronide or a medicament thereof; Administering an acceptable salt to the mammal. 28. A method for treating or inhibiting cancer, central nervous system disorder, dementia or Alzheimer's disease in a mammal in need thereof, comprising an effective amount of 5α-.
A method comprising administering to the mammal pregnane-3β, 20S, 21-triol.20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof. 29. A method for treating or inhibiting cancer, central nervous system disorder, dementia or Alzheimer's disease in a mammal in need thereof, comprising: an effective amount of 5α-
A method comprising administering to the mammal pregnane-3β, 20R-diol.20-O-β-D-glucuronide or a pharmaceutically acceptable salt thereof. 30. 5α-pregnane-3β, 20S, 21-triol.20-O
A process for the preparation of -β-D-glucuronide or a pharmaceutically acceptable salt thereof, comprising reacting pregnenolone-3-acetate with lead tetraacetate in acetic acid to obtain a compound of the formula 2: Which is then hydrogenated in acetic acid over PtO ₂ to give compound 3: Which is subsequently converted to an excess of compound 5: Together with the compound of formula 6: And subsequently hydrolyzed and reprotonated with an acid to give 5α-pregnane-3β, 20S, 21-triol.20-O-β-D-glucuronide, The compound can be converted into a pharmaceutically acceptable salt thereof by the method described above. 31. A method for producing 5α-pregnane-3β, 20R-diol.20-O-β-glucuronide, which comprises the compound 10: To formula 5: And Ag ₂ CO ₃ to give a compound of formula 11: Which is subsequently hydrolyzed and reprotonated with an acid to give 5α-pregnane-3β, 20R-diol.20-O-β-glucuronide, optionally Which can be converted into a pharmaceutically acceptable salt thereof. 32. 5α-pregnane-3β, 20S, 21-triol.20-O
A method for producing monosodium salt of -β-glucuronide, comprising a slight excess of NaOH
A production method comprising titrating with a solution. 33. A method for producing 5α-pregnane-3β, 20R-diol.20-O-β-glucuronide monosodium salt, which comprises titrating with a slight excess of NaOH solution.