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CN1046735C - Steroids for treating menopausal complaints - Google Patents

Steroids for treating menopausal complaints Download PDF

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Publication number
CN1046735C
CN1046735C CN94191126A CN94191126A CN1046735C CN 1046735 C CN1046735 C CN 1046735C CN 94191126 A CN94191126 A CN 94191126A CN 94191126 A CN94191126 A CN 94191126A CN 1046735 C CN1046735 C CN 1046735C
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alkene
hydroxyl
methyl
female
alkyl
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CN1117735A (en
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H·J·J·卢贞
L·P·C·肖特
J·M·L·范德沃福-比特
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Akzo Nobel NV
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Akzo Nobel NV
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0081—Substituted in position 17 alfa and 17 beta
    • C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
    • C07J1/0096—Alkynyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J11/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J21/005—Ketals
    • C07J21/008—Ketals at position 17
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J33/005—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton spiro-condensed
    • C07J33/007—Cyclic thioketals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0044—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an estrane or gonane skeleton, including 18-substituted derivatives and derivatives where position 17-beta is substituted by a carbon atom not directly bonded to another carbon atom and not being part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Reproductive Health (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Toxicology (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A use of a steroid having general formula (I), wherein R1, R2, R3, R4 and R5 are defined as in the description, for the manufacture of a medicament for the treatment or prevention of menopausal complaints, especially osteoporosis.

Description

The steroide of treatment menopausal complaints
The present invention relates to use steroide preparation treatment or prevention menopausal complaints, the particularly medicine of treatment or preventing osteoporosis disease.
The of the present invention many steroides that are used for the treatment of menopausal complaints itself are known.
For example, 11 β-alkyl steroide is found in United States Patent (USP) 3,983,144.Has interesting antifertility activity according to describing these steroides.Have the protein stimulatory composite reactive, facilitate male property active other 11 β in active and pregnant early stage-alkyl steroid to be disclosed in United States Patent (USP) 3,325,520.The compound in relevant pregnant early stage that is used to control menstruation and ovulation is also shown in Australian patent application AL6614974, european patent application 0,145,493 and United States Patent (USP) 3,465,010.The steroide that has unsaturated alkyl on 11 of steroid class skeleton is found in United States Patent (USP) 4,292,251 (these patent disclosures uterine contraction and ovulation suppress active) and above-mentioned european patent application 0,145,493.
Have now found that the compound with formula I can be used for treatment or prevention menopausal complaints, particularly osteoporosis: R wherein 1Represent O, (H, OH), or two hydrogen atoms; R 2Be hydroxyl, can be by selectivity etherificate or esterification; R 3Be (2-6C) alkynyl, can be replaced by the hydroxyl selectivity; R 4Be CN or be selected from (1-6C) alkyl, (1-6C) alkoxyl group, (2-6C) alkenyl, (2-6C) alkynyl and (2-6C) one of the alkyl of alkylidene group, each said alkyl all can by halogen, hydroxyl or (1-6C) the alkoxyl group selectivity replace; R 5Be hydrogen or (1-6C) alkyl.
One of the most serious menopausal complaints is an osteoporosis, and this disease is attacked the women specially.The purpose of this invention is to provide a kind of can preventing osteoporosis disease, might strengthen sclerotin and and then the medicine of treatment climacteric syndrome.The effective constituent of these medicines and have strong estrogen activity and weak or non-existent androgenic activity.Preferred medicine further has favourable hemorrhage performance, can not bring out endometrial hyperplasia, and have favourable HDL/LDL (high/low density fat) ratio.
In an embodiment preferred, compound has formula I, wherein R 1Represent O or two hydrogen atoms; R 2It is hydroxyl; R 3It is ethynyl; R 4Be selected from methyl, (2-6C) alkynyl, (2-6C) alkylidene group and (2-6C) alkyl, (2-7C) alkoxyalkyl, (1-6C) alkoxyl group or (2-6C) one of alkenyl, they can be replaced by the halogen selectivity; R 5Be hydrogen or (1-6C) alkyl.
The preferred steroide that is to use with formula I, wherein: R 1Middle O; R 2It is hydroxyl; R 3It is ethynyl; R 4Be ethyl, 2-fluoro ethyl, ethynyl, (2-6C) alkenyl that can be replaced by the fluorine selectivity or (2-6C) alkylidene group that can be replaced by the fluorine selectivity; R 5Be hydrogen or methyl.In preferred embodiments, R 5Be hydrogen.
The preferred steroide that is to use with formula I, wherein: R 1Be O; R 2It is hydroxyl; R 3It is ethynyl; R 4Be ethyl or ethynyl; R 5Be hydrogen.
The invention still further relates to new steroide, wherein: R with formula I 1Represent O; R 2Be hydroxyl, alternative etherificate or esterification; R 3Be (2-6C) alkynyl, can be replaced by the hydroxyl selectivity; R 4Be CN, (2-6C) alkyl that can be replaced by the halogen selectivity or (2-6C) alkenyl that can be replaced by the halogen selectivity; R 5Be hydrogen or (1-6C) alkyl; Or R wherein 1Represent two hydrogen atoms; R 2Be can be by the hydroxyl of selectivity etherificate or esterification; R 3It is (2-6C) alkynyl that can be replaced by the hydroxyl selectivity; R 4Be CN or be selected from (2-6C) alkyl, (1-6C) alkoxyl group, (2-6C) alkynyl, (2-6C) alkynyl and (2-6C) one of the alkyl of alkylidene group, each said alkyl all can by halogen, hydroxyl or (1-6C) the alkoxyl group selectivity replace; R 5It is (1-6C) alkyl.
R wherein 1Be O; R 2It is hydroxyl; R 3It is ethynyl; R 4Be 2-fluoro ethyl or 2-fluorine ethynyl; And R 5The steroide that is the general formula 1 of hydrogen is preferred steroide.
Other preferred steroide is the steroide of general formula I, wherein R 1Represent two hydrogen atoms; R 2It is hydroxyl; R 3It is ethynyl; R 4Be (2-6C) alkyl, (2-6C) alkylidene group or (2-6C) alkenyl, each said group all can be replaced by the fluorine selectivity; R 5It is methyl.
At R 2Definition in, the OH base can be by etherificate or esterification.Term " etherificate " is meant hydroxyl by low alkyl group, preferably has the alkyl of 1-6 carbon atom, as etherificates such as methyl, ethyl, propyl group, sec-butyls.Term " esterification " is meant hydroxyl by low-grade alkane acidyl, preferably has the alkyloyl of 2-6 carbon atom, as esterifications such as ethanoyl, propionyls.Say that in principle need only ester group cleavable when taking this compound in the body, any ester all can be satisfied the demand.
(1-6C) alkyl in the formula I definition is side chain or the non-branched-chain alkyl with 1-6 carbon atom, as methyl, ethyl, propyl group, butyl, the tertiary butyl, amyl group and hexyl.Preferred alkyl is that methyl is (particularly for R 5) and ethyl (particularly for R 4).Term " (2-6C) alkyl " has synonymous except that methyl.
(2-6C) alkenyl is side chain or the non-branched-chain alkenyl with 2-6 carbon atom, as vinyl, 2-propenyl and 1,3-butadiene base.
(2-6C) alkynyl is side chain or non-the alkynyl group with 2-6 carbon atom, as ethynyl, proyl, butynyl etc.
(2-6C) alkylidene group is side chain or the non-branched alkylidene with 2-6 carbon atom, as ethylidene, propylidene, 2-methyl propylidene etc.
Term " halogen " used in the definition of formula I is meant fluorine, chlorine, bromine or iodine.Fluorine is preferred halogen.
Term " (1-6C) alkoxyl group " is meant that alkoxyl group, its moieties are (1-6C) alkyl as defined above.
Term " (2-7C) alkoxyalkyl " is meant (1-6C) alkyl as defined above that can be replaced by (1-6C) alkoxyl group as defined above, and the total number of carbon atoms is 2～7.
New compound of the present invention can be prepared as follows: the 11-ketone steroid of general formula II, R wherein 1Represent O; R 2Be can be by the hydroxyl of selectivity etherificate or esterification; R 3It is (2-6C) alkynyl that can be replaced by the hydroxyl selectivity; R 5Be hydrogen or (1-6C) alkyl; Or R wherein 1Represent two hydrogen atoms; R 2Be can be by the hydroxyl of selectivity etherificate or esterification; R 3It is (2-6C) alkynyl that can be replaced by the hydroxyl selectivity; R 5It is (1-6C) alkyl; Its active group is protected by selectivity, with formula R 4' R 4" CH-W Wei Tixi (Wei Tixi class) compound condensation, wherein R 4' R 4" C can form R 4Group, R 4Be can be by halogen, hydroxyl or (1-6C) (2-6C) alkylidene group as defined above of replacing of alkoxyl group selectivity, or with formula R 4The compound condensation of Li, wherein R 4 is by halogen, hydroxyl or (1-6C) alkoxyl group selectivity replacement (2-6C) alkyl or (2-6C) alkenyl; wherein reactive group can be protected by protecting group as known in the art and (be seen for example T.W.Green:ProtectiveGroups in Organic Synthesis; Wiley; NY; 1981), W is Wittig, Wittig-Horner or Petenson class part; carry out selective halogenation and dehydration or hydration subsequently, after this gained compound is converted into nitrile or with formula R 6The Wei Tixi of W (Wei Tixi class) compound condensation, wherein W has the connotation that provides previously, R 6Be hydrogen, halogen or (1-6C) alkyl independently, carry out hydroboration subsequently, after this carry out selective alkylation, halogenation or halogenation and deoxidation halogenation or (part) hydrogenation, then the protecting group that exists of selectively removing.
Suitable reagent has pseudo-ginseng base phosphorane such as R 4' R 4" CH-P (Hal) Ph 3Deng; Suitable Peterson reagent is, for example, and trimethyl silane reagent such as R 4' R 4" C (MgHal) Si (CH 3) 3, wherein Hal represents halogen such as chlorine or bromine.
Steroide of the present invention can be used for preventing and treating disease such as the menopausal complaints that brings out because of estrogen deficiency, and this point is confirmed in the osteoporosis that oestrogenic hormon brings out is measured.In this measures,, handled 1 month with test compound with the oophorectomize of young ripe Wistar female rats.After 1 month, blood sampling and according to people's such as Verhaeghe method (J.Endrocrinol., 120,143-151) measure bone undated parameter (bone is calcareous) in lithium-heparin blood plasma.When necrotomy, dissect right femur and use the X ray photodensitometry to measure the bone density of metaphysis terminal portions.Bone density (representing with the mm equivalent thickness of aluminium) represents that with the per-cent with respect to complete control group the bone density of complete control group is defined as 100%, and the bone density of oophorectomize control group is defined as 0%.
The calcareous value of bone is defined as 100% (oophorectomize group) and 0% (close set).Active compound can suppress bone to be upgraded, thereby the calcareous value of bone is lower than 100%.
The table I has provided the result of this mensuration.
Table 1
R 1 R 2 R 3 R 4 R 5 Dosage bone density bone calcareous (μ g) is (%) (%)
Reference: O OH C ≡ CH H H 1000 24 55
The present invention: O OH C ≡ CH C 2H 5 H O OH C≡CH CH 2Cl H O OH C≡CH CH 2OCH 3 H O OH C≡CH CH=CH 2 H O OH C≡CH C≡CH H O OH C≡CH C≡N H O OH C≡CH CH 2=CH CH 3O OH C≡CH OCH 3 H O OH C≡CH CH 3 H O OH C≡CH CH 2CH 2F H O OH C≡CH (E)=CHCH 3 H O OH C≡CH C≡N H O OH C≡CH C 2H 5 CH 3H2 OH C≡CH CH 3 H H2 OH C≡CH CH 2Cl H H2 OH C=CH CH 2Cl H H2 OH C≡CH CH=CH 2 CH 3H2 OH C≡CH C≡CH H 64 94 -117 10 57 -78 250 66 -45 100 48 -52 250 115 -117 1000 113 -35 1000 90 -80 1000 73 -46 125 81 500 93 -59 64 86 125 119 -66 250 115 1000 80 -54 10 43 -72 100 81 -112 1000 124 -80 32 66 -17
Compound of the present invention can for human body, be advisable with the per daily dose of every kg body weight 0.001-10mg through stomach or administered parenterally.Mix with auxiliary suitable on the medicine, for example as at authoritative reference, people such as Gennaro, Remington ' s Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, especially referring to the 8th part: pharmaceutical preparation and preparation thereof) described in, compound can be pressed into solid dosage unit, as nine doses, tablet or be processed into capsule or suppository.By appropriate liquid on the medicine, also compound can be made the injection formulations of solution, suspension, emulsion form or make sprays, for example nasal spray is used.In order to make dose unit, for example tablet can use conventional additive such as weighting agent, tinting material, polymeric binder etc.In general, any pharmaceutically acceptable additive of interferon activity compound function all can not use.
The suitable carrier that can be used in the composition comprises lactose, starch, derivatived cellulose etc., or their mixture that uses with sufficient quantity.
The present invention can further specify with the following example.Embodiment 1
In 0.5 ℃ to 115g (7 α, 11 α)-11-hydroxyl-7-methyl-female-4-alkene-3, drip 110ml 8N chromic acid in the 5L acetone soln of 17-diketone.Stir after 1 hour, add 50ml propyl alcohol-2,15 minute rear section enriched mixture and use the dilution of 3L water.After the stirred for several hour, filtering-depositing is dissolved in a spot of methylene dichloride and use dried over sodium sulfate, after evaporating organic solvent, obtains the 107g triketone again, promptly (7 α)-7-methyl female-4-alkene-3,11, the 17-triketone.Rf=0.54 (toluene-ethyl acetate 4-6V/V).
With 115g (7 α)-7-methyl female-4-alkene-3,11,17-triketone, 8g be right-toluenesulphonic acids and the mixture of 40ml dithioglycol in the 1l dehydrated alcohol refluxed 1 hour.After the cooling, with 1l water diluted mixture thing, and under cooling stirred for several hour.Filtering-depositing, and with 1N NaOH, water and cold methanol washing.Obtaining 134g (7 α)-3 after the drying, 3-ethylene dithiol generation-7-methyl is female-4-alkene-11,17-diketone, Rf=0.62 (toluene-ethyl acetate 8/2).
Will be by 36g (7 α)-3,3-ethylene dithiol generation-7-methyl is female-4-alkene-11, and 17-diketone, 300ml methylene dichloride, 85ml triethyl orthoformate, 70ml ethylene glycol and 2g be right-solution stirring that toluenesulphonic acids is formed 7 hours.Use 10% sodium carbonate solution purging compound then, drying, concentrate and, obtain 44g (7 α)-3 by behind the silicagel column, 3-ethylene dithiol generation-17,17-ethylenedioxy-7-methyl is female-4-alkene, Rf=0.65 (toluene-ethyl acetate 8/2).
9.2g potassium tert.-butoxide, the 34.8g first base three phenyl phosphonium bromides mixture in 260ml toluene was refluxed 1 hour.Add 7.8g (7 α)-3 then, in 3-ethylene dithiol generation-17,17-ethylenedioxy-7-methyl is female-4-alkene, and mixture was boiled 2 hours again.After the cooling reaction, washing, drying also concentrates.Resistates obtains 6.1g (7 α)-3 behind chromatography, 3-ethylene dithiol generation-17,17-ethylenedioxy-7-methyl isophthalic acid 1-methylene radical-female-4-alkene, Rf=0.77 (toluene-ethyl acetate 9/1).
With 6.1g (7 α)-3, the 3-ethylene dithiol is for-17, and the mixture of 17-ethylenedioxy-7-methyl isophthalic acid 1-methylene radical-female-4-alkene, 90ml acetone, 50ml tetrahydrofuran (THF) and 3ml 6N hydrochloric acid stirs under room temperature.Pass through after 1 hour to add 700ml 5% yellow soda ash diluted mixture thing, and stirred 1/2 hour.Filtering-depositing is also dry, obtains 5.4g (7 α)-3,3-ethylene dithiol generation-7-methyl isophthalic acid 1-methylene radical-female-4-alkene-17-ketone.Rf=0.74 (toluene-ethyl acetate 9/1).
With the 500ml dry thf solution of acetylene gas by the 50g potassium tert.-butoxide.After 2 hours, in 0 ℃ to wherein dripping 30g (7 α)-3, the 400ml tetrahydrofuran solution of 3-ethylene dithiol generation-7-methyl isophthalic acid 1-methylene radical-female-4-alkene-17-ketone.Behind the restir 1 hour, mixture is poured in 71 water, and stirred 1/2 hour.Filtering-depositing is also dry, obtains 31g (7 α, 17 α)-3, and pregnant-4-alkene-20-alkynes falls in 3-ethylene dithiol generation-17-hydroxyl-7-methyl isophthalic acid 1-methylene radical-19-.Rf-0.64 (toluene-ethyl acetate 9/1).
In-50 ℃, in the solution of 300ml liquid ammonia, drip 16g (7 α, 17 α)-3 to 8g sodium, the 75ml tetrahydrofuran solution of pregnant-4-alkene-20-alkynes-17-alcohol falls in 3-ethylene dithiol generation-7-methyl isophthalic acid 1-methylene radical-19-.Stir after 1 hour, remove excessive sodium by adding 10ml ethanol.After the vaporized ammonia, resistates is distributed between methylene dichloride and water.Separate organic layer, washing is also dry.The evaporating solvent layer, residue of chromatography obtains 5.4g (7 α, 17 α)-7-methyl isophthalic acid 1-methylene radical-17-and falls pregnant-4-alkene-20-alkynes-17-alcohol.Rf=0.59 (toluene-ethyl acetate 9/1).Embodiment 2
With 15g (7 α, 17 α)-3, the mixture that pregnant-4-alkene-20-alkynes-17-alcohol, 300ml methyl alcohol, 20ml water, 6g lime carbonate and 51ml methyl-iodide fall in 3-ethylene dithiol generation-7-methyl isophthalic acid 1-methylene radical-19-refluxed 6 hours.After filtering on the Hy-flow, filtrate is concentrated, be dissolved in the methylene dichloride washing, dry and evaporation.Obtain 6.5g (7 α, 17 α)-17-hydroxyl-7-methyl isophthalic acid 1-methylene radical-19-after the residue of chromatography and fall pregnant-4-alkene-20-alkynes-3-ketone.Rf=0.40 (toluene-ethyl acetate 9/1).Embodiment 3
In 0-5 ℃ 110g three trimethyl carbinol lithium aluminum hydride being added to 134g (7 α)-3 in batches, 3-ethylene dithiol generation-7-methyl is female-4-alkene-11, the 5L of 17-diketone is in tetrahydrofuran solution.Stir after 3 hours, mixture is poured in the 10l frozen water, and by adding the slight acidifying of 1l2N hydrochloric acid.Use the ethyl acetate extraction product.After dried over sodium sulfate, handle organism with ether, obtain pure basically (7 α, 17 β)-3 of 133g, 3-ethylene dithiol generation-17-hydroxyl-7-methyl is female-4-alkene-11-ketone.Rf=0.45 (toluene-ethyl acetate 6/4).
In 0 ℃ to 132g (7 α, 17 β)-3,3-ethylene dithiol generation-17-hydroxyl-7-methyl is female-add the 182ml trimethylsilyl chloride in the 800ml pyridine solution of 4-alkene-11-ketone.Stir after 1 hour, mixture is poured in the frozen water, and use the ethyl acetate extraction product.Behind washing, drying and evaporating solvent, with resistates and toluene coevaporation, handle with hexane then, obtain 137g (7 α, 17 β)-3,3-ethylene dithiol generation-7-methyl-17-trimethylsiloxy-female-4-alkene-11-ketone.Rf=0.63 (toluene-ethyl acetate 6/4).
In 0.5 ℃, in the 6L dry ether suspension of 334g methoxyl methyl triphenyl phosphonium chloride, drip 600ml 1.6M butyllithium.Stir after 1 hour, add 44.6g (7 α, 17 β)-3, the 1.5L diethyl ether solution of 3-ethylene dithiol generation-7-methyl-17-trimethylsiloxy-female-4-alkene-11-ketone, and stirred the mixture 24 hours.Washing and dry organic solution are distributed the resistates after the concentrated organic phase, and were stirred 15 minutes between hexane-methanol-water (1/0.7/0.3V/V/V).Dry and concentrated hexane phase obtains 47g (7 α, 17 β)-3,3-ethylene dithiol generation-11-methoxy methylene radical-7-methyl-17-trimethylsiloxy-female-4-alkene.Rf=0.50 (hexane-ethyl acetate 3/1).
To 265g (7 α, 17 β)-3, add the 80ml concentrated hydrochloric acid in the 800ml acetone soln of 3-ethylene dithiol generation-11-methoxy methylene radical-7-methyl-17-trimethyl silyl oxygen-female-4-alkene, and mixture is stirred under room temperature.After 1 hour, mixture is poured in the water, and used ethyl acetate extraction.Washing, dry and evaporate organic solvent after, resistates by silicagel column, and with methylene dichloride-acetone 9/1 wash-out, is obtained 63g (7 α, 11 β, 17 β)-3,3-ethylene dithiol generation-17-hydroxyl-7-methyl-female-4-alkene-11-carboxylic aldehyde.Rf=0) .38 (toluene-ethyl acetate 7/3).
To 55g (7 α, 11 β, 17 β)-3,3-ethylene dithiol generation-17-hydroxyl-7-methyl is female-add in the 1100ml dry thf solution of 4-alkene-11-carboxylic aldehyde and 165ml dihydropyrane 1.3g right-toluenesulphonic acids.Stir after 2 hours, mixture is poured in 5L 5% sodium hydrogen carbonate solution, and use the ethyl acetate extraction product.Separating (7 α, 11 β, 17 β)-3 after concentrating organic phase, 3-ethylene dithiol generation-17-tetrahydro-pyran oxy-7-methyl is female-4-alkene-11-carboxylic aldehyde.
With 1g (7 α, 11 β, 17 β)-3,3-ethylene dithiol generation-17-tetrahydro-pyran oxy-7-methyl is female-and 4-alkene-11-carboxylic aldehyde and the mixture of 2g oxammonium hydrochloride in the 12ml pyridine do 80 ℃ and stirred 1 hour.Then with its cooling, pour in the water and use ethyl acetate extraction.Through washing, dry and concentrate after, obtain 0.9g amorphous (7 α, 11 β, 17 β)-3,3-ethylene dithiol generation-17-tetrahydro-pyran oxy-7-methyl is female-4-alkene-11-carboxylic aldoxime.Rf=0.60 (toluene-ethyl acetate 8/2).
By with 0.8g (7 α, 17 β, 17 β)-3,3-ethylene dithiol generation-17-tetrahydro-pyran oxy-7-methyl is female-and 4-alkene-11-carboxylic aldoxime reacts in the 8ml diacetyl oxide and carried out the dehydrogenation of oxime in 45 minutes.Observing the 17-tetrahydropyranyl ethers is replaced by acetoxyl by way of parenthesis.Pour into reaction mixture in the 50ml frozen water and stirred 30 minutes.With 2N sodium hydroxide neutralization and with behind the ethyl acetate extraction, obtain 0.75g (7 α, 11 β, 17 β)-3,3-ethylene dithiol generation-17-acetoxyl group-7-methyl is female-4-alkene-11-nitrile.Rf=0.58 (toluene-ethyl acetate 9/1).
By with 0.75g (7 α, 11 β, 17 β)-3,3-ethylene dithiol generation-17-acetoxyl group-7-methyl is female-and 4-alkene-11-nitrile stirred 30 minutes saponification acetoxyl functional group in the mixture of 20ml tetrahydrofuran (THF) and 10ml water (containing 1g sodium hydroxide).With ethyl acetate dilution and extraction mixture.After the dry and evaporation, obtaining 0.50g (7 α, 11 β, 17 β)-3,3-ethylene dithiol generation-17-hydroxyl-7-methyl is female-4-alkene-11-nitrile.Rf=0.34 (toluene-ethyl acetate 9/1).
To 20g (7 α, 11 β, 17 β)-3,3-ethylene dithiol generation-17-hydroxyl-7-methyl is female-add the 20g sodium acetate in the 600ml dry dichloromethane solution of 4-alkene-11-nitrile, then add the 85g pyridinium chlorochromate.Stir after 3 hours, reaction proves completely.Remove excessive oxygenant by adding 40ml propyl alcohol-2.Go up filtering mixt in Hy-Flow.Concentrate and chromatography after, obtain 13g (7 α, 11 β)-3,3-ethylene dithiol generation-17-ketone-7-methyl is female-4-alkene-11-nitrile.Rf=0.75 (toluene-ethyl acetate 8/2).
In 0 ℃ with the 60ml dry thf solution of acetylene gas by the 10.5g potassium tert.-butoxide 1 hour.Dripping 9.3g (7 α, 11 β)-3 then, 3-ethylene dithiol generation-17-oxo-7-methyl is female-the 100ml tetrahydrofuran solution of 4-alkene-11-nitrile.After 0-5 ℃ is stirred 1 hour, mixture is poured in the 500ml saturated ammonium chloride solution, and used the ethyl acetate extraction product.Through washing, drying with after concentrating, obtain 9.5g (7 α, 11 β, 17 α)-3, pregnant-4-alkene-20-alkynes-11-nitrile falls in 3-ethylene dithiol generation-17-hydroxyl-7-methyl isophthalic acid 9-.Rf=0.28 (toluene-ethyl acetate 9/1).
With 6.5g (7 α, 11 β, 17 α)-3,3-ethylene dithiol generation-17-hydroxyl-7-methyl isophthalic acid 9-falls pregnant-4-alkene-20-alkynes-11-nitrile, 200ml methyl alcohol, 100ml tetrahydrofuran (THF), 2.4g lime carbonate, 8.5ml water and 35ml methanol mixture and refluxes a few hours, and add methyl alcohol every now and then, after initiator disappeared, cooling mixture filtered and concentrates.Resistates carries out silica gel column chromatography, obtains pure (7 α, 11 β, 17 the α)-17-hydroxyl-7-methyl-3-oxo-19-of 215g and falls pregnant-4-alkene-20-alkynes-11-nitrile.M.P.234℃。Rf=0.33 (toluene-ethyl acetate 7/3).Embodiment 4
3,3,17, the hydroboration of 11-methylene radical functional group carries out as follows in two (the ethylenedioxy)-11-methylene radical of 17--female-5-alkene:
In the 10ml dry thf solution of 2.18ml 10M hydroborons-dimethyl sulfoxide (DMSO) mixture, add the 2.7ml cyclooctadiene in 0 ℃.After refluxing again 1 hour, add 2.7g 3,3,17, the 30ml tetrahydrofuran solution of two (the ethylenedioxy)-11-methylene radical of 17--female-5-alkene.After stirring the mixture 16 hours, use 10ml 10% sodium hydroxide and 10ml 30% hydrogen peroxide treatment successively.Stir after 4 hours, mixture is poured in the water, and use the dichloromethane extraction product.After carrying out final purifying by chromatography, obtain 2g (11 β)-3,3,17, two (the ethylenedioxy)-11-(methylol) of 17--female-5-alkene.Rf=0.25 (toluene-ethyl acetate 1/1).
In the 200ml of 20g pyridinium chlorochromate methylene dichloride suspension, add 9.3g (11 β)-3,3,17, the 100ml dichloromethane solution of two (the ethylenedioxy)-11-(methylol) of 17--female-5-alkene.Stir after 1 hour, remove excessive oxygenant, use the ethyl acetate extraction product then by the 200ml aqueous solution that adds the 40g sodium bisulfite.After the dry and concentrated organic phase,, obtain 5.4g (11 β)-3,3,17, two (ethylenedioxy)-female-5-alkene-11-carboxylic aldehyde of 17-by the chromatography purification resistates.Rf=0.50 (hexane-ethyl acetate 1/l).
Hexane (44ml) drips of solution of 1.6M butyllithium is added in the 500ml ether suspension of 24.4g chloromethyl triphenyl phosphonium chloride.Stir after 15 minutes Dropwise 5 .4g (11 β)-3,3,17, the 30ml tetrahydrofuran solution of two (ethylenedioxy)-female-5-alkene-11-carboxylic aldehyde of 17-.After 12 hours, pour into mixture in the 0.5L water and isolate organic phase, washing, dry and concentrate.Obtain 3.7g E/Z (11 β)-3,3,17 after the residue of chromatography, two (the ethylenedioxy)-11-(2-chlorovinyl) of 17--female-5-alkene.Rf=0.4 (hexane-ethyl acetate 7/3).
In lithium amide suspension (in the 130ml liquid ammonia, making), add 3.6g (11 β)-3,3,17, the 30ml tetrahydrofuran solution of two (the ethylenedioxy)-11-(2-is fluoride-based) of 17--female-5-alkene in-45 ℃ by the 920mg lithium.Stir after 1 hour, remove excess reagent by adding 15g ammonium chloride, then vaporized ammonia.Resistates distributes between methylene dichloride and water.The organic phase drying, concentrate and chromatography after, produce 1.8g (11 β)-3,3,17, two (the ethylenedioxy)-11-ethynyls of 17--female-5-alkene; M.P.200 ℃.Rf=0.45 (hexane-ethyl acetate 7/3).
With 8g (11 β)-3,3,17, the 5ml 6N salt acid treatment of the mixture of two (the ethylenedioxy)-11-ethynyls of 17--female-5-alkene, 200ml acetone, 100ml methyl alcohol and 100ml tetrahydrofuran (THF), and stir and spend the night.After sodium bicarbonate was handled and concentrated, residue of chromatography obtained 5.1g (11 β)-11-ethynyl-female-4-alkene-3, the 17-diketone.Rf=0.48 (hexane-ethyl acetate 1/1).
The mixture of 2.7g potassium tert.-butoxide in the 12ml tetrahydrofuran (THF) and the 5ml trimethyl carbinol placed under the nitrogen environment, and blasted acetylene gas 1.5 hours in 0 ℃.Add 1.85g (11 β)-11-ethynyl-female-4-alkene-3 then, the 5ml tetrahydrofuran (THF) suspension of 17-diketone, and continue to stir 1 hour.Water (200ml) diluted mixture thing is used the neutralization of 2N hydrochloric acid and used ethyl acetate extraction, and is dry and concentrated.The residue of chromatography layer obtains 1.6g (11 β, 17 α)-11-ethynyl-17-hydroxyl-19-and falls pregnant-4-alkene-20-alkynes-3-ketone; M.P.168 ℃.Rf=0.60 (hexane-ethyl acetate 1/1).Embodiment 5
Dropwise 5 ml 1 in the 20ml tetrahydrofuran solution of 4ml borane methyl-sulfide (10M is in tetrahydrofuran (THF)), 5-ring-octadiene.Stir after 1 hour Dropwise 5 g 11 β-vinyl-3,3,17, two (ethylenedioxy)-female-5-alkene of 17-(can pass through selectivity Lindlar hydrogenation (11 β)-3,3,17, two (the ethylenedioxy)-11-ethynyls of 17--female-5-alkene obtains) the 25ml tetrahydrofuran solution.Behind the restir 1 hour, add 20ml 15% aqueous sodium hydroxide solution and 20ml 30% hydrogen peroxide.After the stirred overnight, use the ethyl acetate extraction product.Gained organism chromatography purification obtains 3.4g 11 β-(2-hydroxyethyl)-3,3,17, the two ethylenedioxies of 17--female-5-alkene; M.P.190 ℃.
In-30 ℃ to 5g 11 β-(2-hydroxyethyl)-3,3,17, add 500mg 2,6-two-tert .-butylpyridine and 800mg trifluoromethanesulfanhydride anhydride in the 7ml tetrahydrofuran solution of the two ethylenedioxies of 17--female-5-alkene.Again in-30 ℃ stir 15 minutes after, the tetrahydrofuran solution that adds 10ml 1M tetrabutylammonium, under room temperature, stirred the mixture 2 hours, pour into then in 30ml 10% sodium hydrogen carbonate solution, use the ethyl acetate extraction mixture then, and by the chromatography purification organism, obtain 600mg 11 β-(2-fluoro ethyl)-3,3,17, the two ethylenedioxies of 17--female-5-alkene; M.P.196 ℃.
To 580mg 11 β-(2-fluoro ethyl)-3,3,17, add 6ml 3M hydrochloric acid in the two ethylenedioxies of the 17--solution of female-5-alkene in 3ml acetone and 3ml tetrahydrofuran compound.Stir after 2 hours, add sodium bicarbonate and water, and use the ethyl acetate extraction product.Resistates behind the evaporating solvent is handled with diisopropyl ether, obtains 400mg 11 β-(2-fluoro ethyl)-female-4-alkene-3, the 17-diketone; M.P.85 ℃.
Acetylene gas is fed in the 5ml tetrahydrofuran (THF) and 1ml t-butanol solution of 0.7g potassium tert.-butoxide.After 15 minutes, add 400mg 11 β-(2-fluoro ethyl)-female-4-alkene-3, the 5ml tetrahydrofuran solution of 17-diketone.Behind the restir 15 minutes, solution is poured in the water, used the ethyl acetate extraction product.The isolating organism of institute produces 320mg (11 β, 17 α)-11-(2-fluoro ethyl)-17-hydroxyl-19-and falls pregnant-4-alkene-20-alkynes-3-ketone after handling through column chromatography purification with ether; M.P.212 ℃.Embodiment 6
In-50 ℃ of 2ml tetrahydrofuran solutions that in the 3ml tetrahydrofuran solution of diisopropylaminoethyl lithium (making), add 600mg difluoromethyl diphenyl phosphine oxide by 250mg Diisopropylamine and 1.6ml1.6M butyllithium-hexane solution.Stir after 15 minutes, add 800mg (11 β)-3,3,17,17-is two-the 3ml tetrahydrofuran solution of (ethylenedioxy)-female-5-alkene-11-carboxylic aldehyde, and mixture stirred under room temperature spend the night.Pour into reaction product in the water and use ethyl acetate extraction.Obtain 465mg 11 β-(2,2-difluoroethylene base)-3,3,17 behind the chromatography organism, 17-pair-(ethylenedioxy)-female-5-alkene; M.P.180-181 ℃.
With the solution of the above-mentioned product of 2ml4N salt acid treatment 430mg in 3ml acetone and 2ml tetrahydrofuran compound.Stir after 2 hours, use the solid sodium bicarbonate neutralise mixt, and use the ethyl acetate extraction product.The gained organism after the crystallization, produces 270mg 11 β-(2,2-difluoro ethylidene)-female-4-alkene-3, the 17-diketone in diisopropyl ether; M.P.150) ℃.
In the solution of 0.48g potassium tert.-butoxide in 5ml tetrahydrofuran (THF) and 0.5ml trimethyl carbinol mixture, feed acetylene gas.After 15 minutes, add 250mg 11 β-(2,2-difluoro ethylidene)-female-4-alkene-3, the 3ml tetrahydrofuran solution of 17-diketone, water makes the mixture quenching after 15 minutes, uses the ethyl acetate extraction product.Handle isolating organism with diisopropyl ether, obtain 160mg (11 β, 17 α)-11-(2,2-difluoroethylene base)-17-hydroxyl-19-and fall pregnant-4-alkene-20-alkynes-3-ketone; M.P.196 ℃.Embodiment 7
Separate 11 β-3,3,17 on silicagel column, the E/Z mixture of 17-pair-(ethylenedioxy)-11-(2-chlorovinyl)-female-4-alkene obtains pure E-isomer (m.p.143 ℃) and Z-isomer (m.p.182 ℃).Handle 3g (E) 11 β-3 with the 3ml concentrated hydrochloric acid, 3,17, the 20ml acetone soln of two (the ethylenedioxy)-11-(2-chlorovinyl) of 17--female-5-alkene 1 hour, neutralize with sodium hydrogen carbonate solution then, and use ethyl acetate extraction, obtain required diketone (11 β, E)-and 11-(2-chlorovinyl)-female-4-alkene-3,17-diketone (2.3g).
This product is dissolved in the 10ml tetrahydrofuran (THF), and drops to (ethinylation potassium is to make by acetylene gas being fed in the solution of 2.9g potassium tert.-butoxide in the above-mentioned trimethyl carbinol-tetrahydrofuran compound) in the solution of ethinylation potassium in 14ml tetrahydrofuran (THF) and 3ml trimethyl carbinol mixture.Stir after 1/2 hour, the water chilled mixture, and use the ethyl acetate extraction product.Organism produces 1.9g (11 β, E, 17 α)-11-(2-chlorovinyl-19-falls pregnant-4-alkene-20-alkynes-3-ketone behind chromatography purification; M.P.180 ℃ of embodiment 8
Similarly, can make following product:
R 1 R 2 R 3 R 4 R 5 M.p.(℃)
O O O O O O O O O O O O O O O O OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C 2H 5 (E)CHCH 3 C≡CH (E)CHC 4H 9 C 2H 5 CH 3 CN CH 2OCH 3 CH 3 C≡CH CH=CH 2 CN CH=C(CH 3) 2 (Z)CH=CHF CH 2CH 2F n-C 3H 7 H H CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 H H CH 3 H H H CH 3 H 217 213 268 230 222 219 234 amorphous 221 165 223 208 212 215 151 208
R 1 R 2 R 3 R 4 R 5 M.p.(℃)
O O O O O O O O O O H 2 H 2 H 2 H 2 H 2 H 2 H 2 H 2 H 2 BOH BOH BOH BOH BOH BOH BOH BOH BOH BOH BOH BOH BOH BOH BOH BOH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH CH=CF 2 (E)CH=CHCH 3 (Z)CH=CHCH 3 (E)=CH-CH 3 CH 2CH 2F CH=CF 2 (E)CH=CHCl (Z)CH=CHCl (E)=CH-CH 2F (E)=CH-CH 2F C≡CH (E)CHC 4H 9 CN C 2H 5 CH 3 CH 2OCH 3 CH 3 C≡CH C=CH 2 (E)CHCH 3 (E)CHC 4H 9 C≡CH C 2H 5 CH 3 CN CH 3 CH 2OCH 3 CH2 CH=C(CH 3) 2 (Z)CH=CHF CH 2CH 2F n-C 3H 7 CH=CF 2 (E)CH=CHCH 3 (Z)CH=CHCH 3 CH 3 H H CH 3 H H H H H CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 H H CH 3 H H CH 3 CH 3 CH 3 CH 3 H CH 3 CH 3 H H CH 3 H CH 3 H H 169 168 169 235 212 196 180 186 116 120 172 120 119 134 107 98 135 145 172 217 133 151 243 183 amorphous 194 164 79 185 109 158 112 90
R 1 R 2 R 3 R 4 R 5 M.p.(℃)
BOH BOH BOH BOH BOH BOH BOH OH OH OH OH OH OH OH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH C≡CH (E)=CH-CH 3 CH 2CH 2F CH=CF 2 (E)CH=CHCl (Z)CH=CHCl (E)=CH-CH 2F (E)=CH-CH 2F CH 3 H H H H H CH 3 124 95 135 amorphous amorphous
Embodiment 9
Preparation has the tablet of following composition:
(11 β, 17 α)-17-hydroxyl-11-ethyl-19-
Pregnant-4-alkene-20-alkynes-3-ketone 2.5mg falls
Starch 10mg
Palmitinic acid ascorbigen ester 0.2mg
Magnesium Stearate 0.5mg
The lactose capacity is to 100mg
Prepare basic granules by mixing lactose and partial starch.Remaining starch and water are mixed into pulpous state and add in the mixture.With their granulations and dry.These basic granuleses are mixed with palmitinic acid ascorbigen ester and activeconstituents, and screening with the Magnesium Stearate thorough mixing, is made tablet then.Embodiment 10
Fall pregnant-4-alkene-20-alkynes-3-ketone as activeconstituents with (11 β, 17 α)-11-ethynyl-17-hydroxyl-19-, prepare the tablet that has same composition with embodiment 9.Embodiment 11
In the following manner, with (7 α, 11 β, 17 α)-and 11-methylene radical-17-hydroxyl-7-methyl isophthalic acid 9-falls pregnant-4-alkene-20-alkynes and prepares the tablet that has same composition with embodiment 9 as activeconstituents: at first activeconstituents mixed with 10% lactose and palmitinic acid ascorbigen ester, then this mixture is mixed with lactose, starch and starch slurry, drying composite divides with the Magnesium Stearate skin and to mix and make tablet.Embodiment 12
Preparation has the capsule of following composition:
That (11 β, 17 α)-11-ethyl-17-hydroxyl-19-falls is pregnant-
-4-alkene-20-alkynes-3-ketone 2.5mg
Starch 10mg
Palmitinic acid ascorbigen ester 0.2mg
Magnesium Stearate 0.5mg
The Microcrystalline Cellulose capacity is to 100mg
By embodiment 9 described modes said components is mixed with each other, granulation is also inserted in the gelatine capsule.

Claims (7)

1. the steroide that has a formula I is used for the treatment of or prevents application in the medicine of menopausal complaints in preparation:
Figure C9419112600021
R wherein 1Represent O, (H, OH), or two hydrogen atoms; R 2Be hydroxyl, can be by selectivity etherificate or esterification; R 3It is (2-6C) alkynyl; R 1Be CN or be selected from (1-6C) alkyl, (1-6C) alkoxyl group, (2-6C) alkenyl, (2-6C) alkynyl and (2-6C) one of the alkyl of alkylidene group, each said alkyl all can by halogen, hydroxyl or (1-6C) the alkoxyl group selectivity replace; R 5Be hydrogen or (1-6C) alkyl.
2. according to the application of claim 1, wherein menopausal complaints is an osteoporosis.
3. require 1 or 2 application according to profit, wherein steroide has formula I, wherein: R 1Represent O or two hydrogen atoms; R 2It is hydroxyl; R 3It is ethynyl; R 4Be selected from methyl, (2-6C) alkynyl, (2-6C) alkylidene group and (2-6C) alkyl, (2-7C) alkoxyalkyl, (1-6C) alkoxyl group or (2-6C) one of alkenyl, they can be replaced by the halogen selectivity; R 5Be hydrogen or (1-6C) alkyl.
4. according to the application of claim 1 or 2, wherein steroide has formula I, wherein: R 1Be O; R 2It is hydroxyl; R 3It is ethynyl; R 4Be ethyl, 2-fluoro ethyl, ethynyl, (2-6C) alkenyl that can be replaced by the fluorine selectivity or (2-6C) alkylidene group that can be replaced by the fluorine selectivity; R 5Be hydrogen or methyl.
5. according to the application of claim 1 or 2, wherein steroide has formula I, wherein: R 1Be O; R 2It is hydroxyl; R 3It is ethynyl; R 4Be ethyl or ethynyl; R 5Be hydrogen.
6. pharmaceutical composition, said composition comprise that (11 β, 17 α)-11-ethyl-17-hydroxyl-19-falls pregnant-4-alkene-20-alkynes-3-ketone is as active compound and pharmaceutically acceptable auxiliary.
7. the steroide of formula I, wherein R 1Expression O; R 2It is hydroxyl; R 3It is ethynyl; R 4It is (E)-ethylidene; R 5It is methyl.
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