CN1254342A - Pharmaceutically acceptable salts of 5 alpha-pregnan-3-beta, 16 alpha-diol-20-one 3-sulfate useful as progestins and CNS disorders - Google Patents
Pharmaceutically acceptable salts of 5 alpha-pregnan-3-beta, 16 alpha-diol-20-one 3-sulfate useful as progestins and CNS disorders Download PDFInfo
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- CN1254342A CN1254342A CN98804764A CN98804764A CN1254342A CN 1254342 A CN1254342 A CN 1254342A CN 98804764 A CN98804764 A CN 98804764A CN 98804764 A CN98804764 A CN 98804764A CN 1254342 A CN1254342 A CN 1254342A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention provides a pharmaceutically acceptable salt of 5 alpha-pregnan-3beta, 16alpha-diol-20-one 3-sulfate ester, which is useful as a progestational agent.
Description
Background technology of the present invention
Use pure basically and naturally occurring estrogen compositions that toxicity is low, PREMARIN (PREMAIN) for example, become osteoporosis/osteopenia disease of the women who alleviates menopausal syndrome, oestrogen deficiencies, and the preferred agents therapy of the symptom of other and hormone diseases associated.Through identifying that the estrogenic component in the naturally occurring estrogen compositions is generally oestrone, equilin, equilenin, 17-, the sulfuric ester of dihydroequilenin and 17-β-dihydroequilenin (United States Patent (USP) 2834712).Usually an alkali metal salt with organic acid or mineral acid cushions or stable estrogen compositions under the neutral pH basically of about 6.5-7.5.Urea also has been used as stablizer (United States Patent (USP) 3608077).US 4154820 has described the adding antioxidant and has stablized the synthetic conjugated estrogen, has also described with three (methylol) aminomethane (TRIS) control pH to stop hydrolysis.
A kind of compound of Miao Shuing in this manual, 5 alpha-pregnanes-3 β, the sodium salt of 16 salmefamols-20-one 3-sulphate ester are a small amount of components among the PREMARIN (PREMAIN).
Explanation of the present invention
The invention provides 5 alpha-pregnanes-3 β, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester as agent before pregnant.5 alpha-pregnanes-3 β, the structure of 16 salmefamols-20-one 3-sulphate ester sodium salt is shown in compound (5) among the diagram I.
5 alpha-pregnanes-3 β, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester includes but not limited to an alkali metal salt, alkaline earth salt, ammonium salt, contain the alkylammonium salt of 1-6 carbon atom or in each alkyl, contain the dialkyl ammonium salt of 1-6 carbon atom respectively, in each alkyl, contain the trialkyl ammonium salts of 1-6 carbon atom and the tetraalkylammonium salt that in each alkyl, contains 1-6 carbon atom respectively respectively.
An alkali metal salt comprises sodium salt and sylvite, special particular certain cancers.Alkaline earth salt comprises calcium salt and magnesium salts.Suitable alkyl comprises methyl, ethyl, propyl group, butyl, amyl group and hexyl, and preferred alkyl is methyl and ethyl.When having more than one alkyl, these alkyl can be identical or different.Preferred trialkyl ammonium salts is leptodactyline and triethyl ammonium salt.
Salt of the present invention preferably has the purity greater than 1%.
Because 5 alpha-pregnanes-3 β, the sodium salt of 16 salmefamols-20-one 3-sulphate ester is a small amount of component among the PREMARIN (conjugated Sterones), the present invention also provides purity to be preferably greater than 1% 5 alpha-pregnanes-3 β, the sodium salt of 16 salmefamols-20-one 3-sulphate ester.
The present invention also provides basically by 5 alpha-pregnanes-3 β, the compound that the sodium salt of 16 salmefamols-20-one 3-sulphate ester is formed; Basically by 5 alpha-pregnanes-3 β, the compound that the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester is formed.
The present invention also provides with 5 alpha-pregnanes-3 β, and the pharmacologically acceptable salt of 16 salmefamols-20-ketone or its 3-sulfuric ester is as the method for agent before pregnant.
The present invention also provides and has contained 5 alpha-pregnanes-3 β, the composition of the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester.The present invention especially provides and has contained at least 1% 5 alpha-pregnanes-3 β, the composition of the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester.On the one hand, the invention provides composition, wherein unique pregnant preceding agent is 5 alpha-pregnanes-3 β, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester.Embodiment of the present invention comprise composition, and wherein unique active compound is 5 alpha-pregnanes-3 β, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester.In these embodiments, composition can contain other vehicle and carrier, but does not contain other active substance.
The present invention also provides preparation 5 alpha-pregnanes-3 β, and the method for the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester comprises:
A) with 5 alpha-pregnanes-3 β, 16 salmefamols-20-one 3-sulphate ester changes into its pharmacologically acceptable salt,
B) with 5 alpha-pregnanes-3 β, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester changes into 5 alpha-pregnanes-3 β, the different pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester,
C) with 5 alpha-pregnanes-16 α, 17-epoxy-3 β-alcohol-20-ketone changes into 5 alpha-pregnanes-16 α, the pharmacologically acceptable salt of 17-epoxy-3 β-alcohol-20-one 3-sulphate ester, or
D) with protected 5 alpha-pregnanes-3 of 16-hydroxyl β, the pharmacologically acceptable salt deprotection of 16 salmefamols-20-one 3-sulphate ester.
5 alpha-pregnanes-3 β, 16 salmefamols-20-one 3-sulphate ester can be by with in the suitable alkali and change into its pharmacologically acceptable salt, and described alkali has, for example alkali-metal carbonate, the carbonate of alkaline-earth metal, or the carbonate of primary amine, secondary amine, tertiary amine or quaternary ammonium.An alkali metal salt or alkaline earth salt can prepare with suitable alkalimetal hydride such as sodium hydride, potassium hydride KH or lithium hydride.
5 alpha-pregnanes-3 β, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester can be by replacing, changing into different pharmacologically acceptable salts by the spent ion exchange resin processing or by replacement(metathesis)reaction (metastasis).Available highly basic is replaced weakly alkaline reaction and is transformed described salt, for example with suitable alkali such as oxyhydroxide amine salt is changed into an alkali metal salt or alkaline earth salt.For example, trialkyl amine salt such as triethyl amine salt can change into an alkali metal salt such as sodium salt by handling with alkali-metal oxyhydroxide such as aqueous sodium hydroxide solution.Also can replace by spent ion exchange resin.Use another kind of method, a kind of salt can change into another kind of salt by replacement(metathesis)reaction, for example, and alkaline earth salt such as the displacement of calcium salt available bases metal-salt.For example, can be with 5 alpha-pregnanes-3 β, the calcium salt of 16 salmefamols-20-one 3-sulphate ester is dissolved in the water, adds for example yellow soda ash then.Insoluble lime carbonate will be precipitated out, and obtains 5 alpha-pregnanes-3 β, the sodium salt of 16 salmefamols-20-one 3-sulphate ester.
5 alpha-pregnanes-3 β, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester can pass through 5 alpha-pregnanes-3 β, and 16 salmefamols-20-ketone directly changes into 5 alpha-pregnanes-3 β, the pharmacologically acceptable salt preparation of 16 salmefamols-20-one 3-sulphate ester.This conversion can be by with 5 alpha-pregnanes-3 β, and 16 salmefamols-20-ketone and suitable amine sulphur trioxide title complex for example trialkylamine sulfurous gas title complex (for example triethylamine sulphur trioxide title complex) react to provide corresponding trialkyl amine salt (for example triethyl amine salt) to realize.If need, can according to the method described above this salt be changed into another kind of salt of the present invention.An alkali metal salt or alkaline earth salt can prepare by following manner, handle 5 alpha-pregnanes-3 β with suitable alkalimetal hydride such as sodium hydride, potassium hydride KH or lithium hydride, the pharmacologically acceptable salt of 16 salmefamols-20-ketone adds trialkylamine sulphur trioxide title complex (for example triethylamine sulphur trioxide title complex) then and obtains corresponding trialkyl amine salt (for example triethyl amine salt) to generate corresponding alkoxide in position.If need, can according to the method described above this salt be changed into another kind of salt of the present invention.
In order to prepare required 5 alpha-pregnanes-3 β, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester, 16 hydroxyls may need protection.This protection can be by reaching with the ordinary method that finally can be sloughed with due care base that product is provided.Use another kind of method; can be by forming 16 α of raw material, the 17-epoxy derivative is protected described hydroxyl, prepares required 5 alpha-pregnanes-16 α with this derivative then; the pharmacologically acceptable salt of 17-epoxy-3 β-alcohol-20-one 3-sulphate ester, deprotection is to obtain required compound of the present invention again.
The present invention also provides 5 alpha-pregnanes-3 β by chemical process preparation, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester, Zhi Bei 5 alpha-pregnanes-3 β especially according to the method described above, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester.The present invention also provides 5 alpha-pregnanes-3 that can obtain in this way β, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester.
Compound of the present invention can be according to as preparation 5 alpha-pregnanes-3 β, and the method among the diagram I of the sodium salt of 16 salmefamols-20-one 3-sulphate ester is by the feedstock production that is easy to get.
For example, according to diagram I, handle 5 α-pregnant-16-alkene-3 β-alcohol-20-ketone (1) to obtain 5 alpha-pregnanes-16 α, 17-epoxy-3 β-alcohol-20-ketone (3) with hydrogen peroxide/sodium hydroxide.With 1 equivalent or many equivalents triethylamine: sulphur trioxide agent treated epoxide (3), to obtain 5 alpha-pregnanes-16 α, the triethyl ammonium salt (4) of 17-epoxy-3 β-alcohol-20-one 3-sulphate ester.Handle triethyl ammonium salt (4) with the chromous acetate that is dissolved in the acetic acid/water, handle with aqueous sodium hydroxide solution then, to obtain 5 alpha-pregnanes-3 β, the sodium salt of 16 salmefamols-20-one 3-sulphate ester.
Diagram I
Compound of the present invention is pregnant preceding agent, therefore can be used as oral contraceptive (masculinity and femininity), be used for hormone replacement therapy (especially uniting use), be used for the treatment of endometriosis damaged, optimum breast luteal phase and prostatosis and prostate gland and carcinoma of endometrium with oestrogenic hormon.Compound of the present invention can also be used to prevent epileptic seizures, strengthens cognitive ability, treatment Alzheimer's, dementia, vasomotor symptoms and other central nervous system disease relevant with menopause.Compound of the present invention can also be used to stimulate erythropoiesis.
Compound of the present invention can be separately uses as the special for treating agent, or can with other therapeutical agent such as other oestrogenic hormon, progestogen or and male sex hormone unite use.
Compound of the present invention can be prepared separately or prepare with the pharmaceutical carrier of administration, and wherein the ratio of activeconstituents and carrier is determined by the solubleness of compound and the medicine routine of chemical property, selected route of administration and standard.Pharmaceutical carrier can be solid or liquid.
Solid carrier can contain one or more seasoningss, lubricant, solubility promoter, suspension agent, weighting agent, slip agents, pressing aid agent, tackiness agent or tablet disintegrant; It can also be packaged material.In pulvis, carrier is the very thin solid of the branch that mixes with the very thin activeconstituents that divides.In tablet, activeconstituents mixes with suitable proportion with the carrier with required compressing tablet character, and is pressed into the tablet with desired shape and size.Pulvis and tablet preferably contain the activeconstituents up to 99%.Suitable solid carrier comprises, calcium phosphate for example, Magnesium Stearate, talcum powder, sugar, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidine, low melt wax, and ion exchange resin.
Liquid vehicle is used to prepare solution, suspension, emulsion, syrup, elixir and supercharging composition.Active ingredient solubilized or be suspended in pharmaceutically acceptable liquid vehicle, water for example, organic solvent, the mixture of the two, or in acceptable oil or the fat.Liquid vehicle can contain other suitable medicated premix, solubility promoter for example, emulsifying agent, buffer reagent, sanitas, sweetener, seasonings, suspension agent, thickening material, pigment, viscosity modifier, stablizer, or Osmolyte regulator.The suitable example that is used for the liquid vehicle of oral or parenterai administration comprises that (part contains above-mentioned additive to water, derivatived cellulose for example, the preferably carboxymethyl cellulose sodium solution), alcohol (comprising monohydroxy-alcohol and polyvalent alcohol such as ethylene glycol) and derivative thereof, lethicins, and oil (for example fractionated Oleum Cocois and peanut oil).For parenterai administration, carrier can also be an oily ester, for example ethyl oleate and Isopropyl myristate.Aseptic liquid vehicle is used in the composition of the sterile liquid form that is used for parenterai administration.Being used for the supercharging liquid carriers of such compositions can be halohydrocarbon or other pharmaceutically acceptable propelling agent.
The composition of liquid medicine of sterile solution or form of suspension can come administration by for example intramuscular, intraperitoneal or subcutaneous injection.Sterile solution can also intravenous administration.Compound of the present invention also can be with the form oral administration of liquid or solid composition.
Compound of the present invention can carry out rectum or vagina administration with the form of conventional suppository.Suck in by nose or in the segmental bronchus or when being blown into administration, compound of the present invention can be made into the aqueous solution or the partially aqueous solution that can use with aerosol form.Compound of the present invention can also carry out transdermal administration by the transdermal administration plaster that use contains active compound and carrier, wherein said carrier is an inert to active compound, skin is not had toxicity, and therapeutical agent is discharged to absorb in the blood flow by integumentary system.Carrier can be taked various ways, for example creme and ointment, paste, gel, and enclosed appts.Creme and ointment can be oil-in-water or water-in-oil-type viscous liquid or semi-solid emulsion.Comprise and be dispersed in the Vaseline that contains activeconstituents or the paste of the absorbent powder in the wetting ability Vaseline also is suitable for.Can use various enclosed apptss that activeconstituents is discharged in the blood flow, for example use contains active ingredient and contains or the not carrier-containing medicine storage device that is covered with semi-permeable membranes, or contains this medicine storage device of active ingredient matrix.Other enclosed appts can be understood in the literature.
Required dosage is along with the difference of the severity of used concrete composition, route of administration, already present symptom and the concrete individuality that will treat and change.According to the result who obtains in the standard pharmacological test method, the expectation per daily dose of active compound is 0.02 μ g/kg-750 μ g/kg.Usually, treatment will low low dose begin with specific activity compound optimal dose.Subsequently, increase dosage till reaching best effect in the case; According to the test of carrying out with the treatment individuality, the administration doctor can determine in oral, non-enteron aisle, the nose or the exact dosage desired of administration in the segmental bronchus.Pharmaceutical composition is preferably made formulation such as the tablet or the capsule of unitary dose.In the formulation of unitary dose, pharmaceutical composition is divided into the unitary dose that contains the appropriate amount activeconstituents again; The formulation of unitary dose can be a packaged composition, for example Bao Zhuan pulvis, bottle, ampoule, pre-syringe of filling or contain the sachet of liquid.The formulation of unitary dose can be for example capsule or tablet self, or the appropriate amount of the said composition of packaged form.
The method of preparation representation compound of the present invention is provided below.
Embodiment 15 alpha-pregnanes-16 α, 17-epoxy-3 β-alcohol-20-ketone (3)
(5.74g 17.3mmol) is dissolved in the sodium hydroxide of the hydrogen peroxide of 500ml methyl alcohol, 25ml 30% and 20ml 4N with 5 α-pregnant-16-alkene-3 β-alcohol-20-ketone (1).Solution was at room temperature stirred 20 hours.Solution is poured in the mixture of 2.5 premium on currency, 500ml methylene dichloride and 25ml acetate.The separate dichloromethane layer is used the 500ml water washing, uses anhydrous magnesium sulfate drying, filters and concentrates.The residuum that drying obtains has obtained being the title compound of white solid (6g, 98%).
1H NMR (300MHz, CDCl
3) δ 0.82 (s, 3H), 1.00 (s, 3H), 2.03 (s, 3H), 3.58 (m, 1H), 3.67 (bs, 1H) m/z (ES is just) 355 (M+Na
+), 687 (2M+Na
+), 5 alpha-pregnanes-16 α, the triethyl ammonium salt (4) of 17-epoxy-3 β-alcohol-20-ketone-3-sulfuric ester
With 5 alpha-pregnanes-16 α, (6.49g 19.6mmol) is dissolved in 100ml tetrahydrofuran (THF) and the sulphur trioxide 17-epoxy-3 β-alcohol-20-ketone (3).Adding ethamine title complex (4.4g, 24.2mmol).Mixture was at room temperature stirred 20 hours.Collect product with B, with tetrahydrofuran (THF) and ether washing, drying has obtained being the title compound of white solid (8.2g, 82%) successively.
1H NMR (300MHz, DMSO-d
6) δ 0.76 (s, 3H), 1.16 (s, 3H), 1.19 (t, 9H), 1.96 (s, 3H), 3.11 (q, 6H), 3.91 (s, 1H), 3.93 (1H) m/z (ES is negative), 411 (M-H) 5 alpha-pregnanes-3 β, the triethyl ammonium salt of 16 salmefamols-20-ketone-3-sulfuric ester
With 5 alpha-pregnanes-16 α, (7.8g 15.2mmol) is dissolved in 200ml acetate and the 60ml water triethyl ammonium salt of 17 epoxies-3 β-alcohol-20-one 3-sulphate ester.Add chromous acetate (newly making), mixture was at room temperature stirred 70 hours with 26g (0.5mol) chromium powder end.Vacuum is desolvated with removing, with residuum pulp in water.Use the sodium bicarbonate neutralise mixt, the sodium hydroxide with 4N alkalizes then.Mixture is passed through diatomite filtration.Use the n-butanol extraction aqueous solution.Butanol extraction liquid is also concentrated by diatomite filtration.By HPLC purified product (during with chromatography purification, having changed into triethyl ammonium salt) (Primesphere, C18-HC, 10 μ, 50 * 250mm, s#171320; Since 10/90, change to 30/70 4.5 ', change to 5/45 7 ', change to 60/40 11 ', change to 70/30 18 ', change to 90/10 (the acetate triethyl ammonium of MeOH/50mM 26 '; PH=7) flow velocity=70ml/ minute; UV=214nm; 1000 PSI), obtained to be the title compound of white solid (4.1g, 53%).
1H NMR (300MHz, DMSO-d
6) δ 0.52 (s, 3H), 0.75 (s, 3H), 1.14 (t, 9H), 2.08 (s, 3H), 2.42 (d, 1H), 2.97 (q, 6H), 3.93 (m, 1H), 4.49 (t, 1H); M/z (ES is negative) 413 (M-H) 5 alpha-pregnanes-3 β, the sodium salt (5) of 16 salmefamols-20-one 3-sulphate ester
With 5 alpha-pregnanes-3 β, (4g 7.8mmol) is dissolved in the 150ml distilled water triethyl ammonium salt of 16 salmefamols-20-ketone-3-sulfuric ester, and (Dowex 50 * 8, Na to allow solution pass through ion exchange column
+Type).With this ion exchange column of 100ml distillation washing.Concentrate eluant is dissolved in residuum in the ethanol.With the ethanolic soln vacuum concentration, collect solid with ether, to filter with B, drying has obtained being the title compound of white solid (3.2g, 94%).
1H NMR (300MHz, DMSO-d
6) δ 0.53 (s, 3H), 0.76 (s, 3H), 2.08 (s, 3H), 2.42 (s, 1H), 3.93 (m, 1H), 4.50 (s, 3Hm/z (ES is negative) 413 (M-H)
Claims (13)
1. compound, it is 5 alpha-pregnanes-3 β, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester.
2. according to the compound of claim 1, the pharmacologically acceptable salt of wherein said 3-sulfuric ester is an an alkali metal salt, alkaline earth salt, ammonium salt, the alkylammonium salt that contains 1-6 carbon atom, the dialkyl ammonium salt that contains 1-6 carbon atom in each alkyl respectively contains the tetraalkylammonium salt that contains 1-6 carbon atom in the trialkyl ammonium salts of 1-6 carbon atom or each alkyl respectively respectively in each alkyl.
3. purity is at least 1% 5 alpha-pregnanes-3 β, the sodium salt of 16 salmefamols-20-one 3-sulphate ester.
4. basically by 5 alpha-pregnanes-3 β, the compound that the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester is formed.
5. basically by 5 alpha-pregnanes-3 β, the compound that the sodium salt of 16 salmefamols-20-one 3-sulphate ester is formed.
6. a pharmaceutical composition contains 5 alpha-pregnanes-3 β, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester.
7. a pharmaceutical composition contains at least 1% 5 alpha-pregnanes-3 β, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester.
8. the method for treatment before providing Mammals pregnant comprises that the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester delivers medicine to described Mammals with 5 alpha-pregnanes-3 β of treatment significant quantity before pregnant.
9. the method for treatment or inhibition mammalian cancer, central nervous system disease, dementia or Alzheimer's comprises that the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester delivers medicine to described Mammals with 5 alpha-pregnanes-3 β of significant quantity before pregnant.
10. as the purposes of the arbitrary claim claimed compounds of claim 1-6 as medicine.
11. as the arbitrary claim claimed compounds of claim 1-6 preparation be used for providing to Mammals pregnant before the medicine of treatment, be used for the treatment of or the medicine of preventing cancer, central nervous system disease, dementia or Alzheimer's in purposes.
12. prepare 5 alpha-pregnanes-3 β, the method for the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester comprises:
A) with 5 alpha-pregnanes-3 β, 16 salmefamols-20-one 3-sulphate ester changes into its pharmacologically acceptable salt,
B) with 5 alpha-pregnanes-3 β, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester changes into 5 alpha-pregnanes-3 β, the different pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester,
C) with 5 alpha-pregnanes-16 α, 17-epoxy-3 β-alcohol-20-ketone changes into 5 alpha-pregnanes-16 α, the pharmacologically acceptable salt of 17-epoxy-3 β-alcohol-20-one 3-sulphate ester, or
D) with protected 5 alpha-pregnanes-3 of 16-hydroxyl β, the pharmacologically acceptable salt deprotection base of 16 salmefamols-20-one 3-sulphate ester.
13. the method claimed according to claim 12, wherein with 5 alpha-pregnanes-16 α, the pharmacologically acceptable salt of 17-epoxy-3 β-alcohol-20-one 3-sulphate ester changes into 5 alpha-pregnanes-3 β, the pharmacologically acceptable salt of 16 salmefamols-20-one 3-sulphate ester.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US85057197A | 1997-05-02 | 1997-05-02 | |
| US08/850571 | 1997-05-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1254342A true CN1254342A (en) | 2000-05-24 |
Family
ID=25308520
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98804764A Pending CN1254342A (en) | 1997-05-02 | 1998-04-28 | Pharmaceutically acceptable salts of 5 alpha-pregnan-3-beta, 16 alpha-diol-20-one 3-sulfate useful as progestins and CNS disorders |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0981538A1 (en) |
| JP (1) | JP2001527552A (en) |
| KR (1) | KR20010012180A (en) |
| CN (1) | CN1254342A (en) |
| AR (1) | AR012637A1 (en) |
| AU (1) | AU746326B2 (en) |
| BR (1) | BR9809435A (en) |
| CA (1) | CA2289096A1 (en) |
| WO (1) | WO1998050411A1 (en) |
| ZA (1) | ZA983706B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE0104423D0 (en) | 2001-12-27 | 2001-12-27 | Umecrine Ab | Pregnane steroids and their use in the treatment of CNS disorders |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3895103A (en) * | 1971-11-22 | 1975-07-15 | Alza Corp | Intrauterine contraceptive device containing certain pharmaceutically acceptable steroids |
-
1998
- 1998-04-28 CN CN98804764A patent/CN1254342A/en active Pending
- 1998-04-28 KR KR19997010129A patent/KR20010012180A/en not_active Application Discontinuation
- 1998-04-28 JP JP54815398A patent/JP2001527552A/en active Pending
- 1998-04-28 BR BR9809435-1A patent/BR9809435A/en not_active IP Right Cessation
- 1998-04-28 AU AU71645/98A patent/AU746326B2/en not_active Ceased
- 1998-04-28 WO PCT/US1998/008454 patent/WO1998050411A1/en not_active Application Discontinuation
- 1998-04-28 EP EP98918787A patent/EP0981538A1/en not_active Withdrawn
- 1998-04-28 CA CA002289096A patent/CA2289096A1/en not_active Abandoned
- 1998-04-30 ZA ZA9803706A patent/ZA983706B/en unknown
- 1998-04-30 AR ARP980102023A patent/AR012637A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA2289096A1 (en) | 1998-11-12 |
| EP0981538A1 (en) | 2000-03-01 |
| KR20010012180A (en) | 2001-02-15 |
| AU746326B2 (en) | 2002-04-18 |
| BR9809435A (en) | 2000-06-13 |
| JP2001527552A (en) | 2001-12-25 |
| WO1998050411A1 (en) | 1998-11-12 |
| ZA983706B (en) | 1999-11-01 |
| AR012637A1 (en) | 2000-11-08 |
| AU7164598A (en) | 1998-11-27 |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |