CN1330659A - Pregnane glucuronides compound - Google Patents
Pregnane glucuronides compound Download PDFInfo
- Publication number
- CN1330659A CN1330659A CN99814413A CN99814413A CN1330659A CN 1330659 A CN1330659 A CN 1330659A CN 99814413 A CN99814413 A CN 99814413A CN 99814413 A CN99814413 A CN 99814413A CN 1330659 A CN1330659 A CN 1330659A
- Authority
- CN
- China
- Prior art keywords
- glucuronide
- alpha
- pregnanes
- pharmacologically acceptable
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 Pregnane glucuronides compound Chemical class 0.000 title claims description 10
- 229930182480 glucuronide Natural products 0.000 title description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- 239000000583 progesterone congener Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 206010012289 Dementia Diseases 0.000 claims description 7
- 208000015114 central nervous system disease Diseases 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 159000000000 sodium salts Chemical class 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 229940126214 compound 3 Drugs 0.000 claims description 5
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 230000001076 estrogenic effect Effects 0.000 claims description 4
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- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 3
- 150000003863 ammonium salts Chemical class 0.000 claims description 3
- 125000005131 dialkylammonium group Chemical group 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 125000005208 trialkylammonium group Chemical group 0.000 claims description 3
- 229940125773 compound 10 Drugs 0.000 claims description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 2
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 claims description 2
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
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- 239000005556 hormone Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- GWTNLHGTLIBHHZ-SVNGYHJRSA-N methyl (2s,3s,4s,5r,6r)-3,4,5-triacetyloxy-6-bromooxane-2-carboxylate Chemical compound COC(=O)[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O GWTNLHGTLIBHHZ-SVNGYHJRSA-N 0.000 description 2
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- RYWZPRVUQHMJFF-BZSNNMDCSA-N (13s,14s,17s)-13-methyl-11,12,14,15,16,17-hexahydrocyclopenta[a]phenanthrene-3,17-diol Chemical compound OC1=CC=C2C(CC[C@]3([C@H]4CC[C@@H]3O)C)=C4C=CC2=C1 RYWZPRVUQHMJFF-BZSNNMDCSA-N 0.000 description 1
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
-
- C—CHEMISTRY; METALLURGY
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- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
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- C—CHEMISTRY; METALLURGY
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- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0007—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa
- C07J5/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa not substituted in position 16
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Abstract
This invention provides 5 alpha -pregnane-3 beta , (20S), 21-triol, 20-O- beta -glucuronide and 5 alpha -pregnane-3 beta ,20R-diol, 20-O- beta -glucuronide and pharmaceutically acceptalbe salts thereof which are useful as progestational agents.
Description
Background of invention
Use substantially pure and hypotoxic natural estrogen composition such as conjugated estrogens (PREMARIN) (the pregnant Sterones of mating type) and become a kind of menopausal syndrome, osteoporosis and/or osteopenia syndrome and diseases related preferred medical therapy of alleviating among the estrogen deficiency women of other hormones already.It is sulfuric ester, equilin, equilenin, 17-, dihydroequilenin and the 17-β-dihydroequilenin (United States Patent (USP) 2834712) of oestrone that estrogenic component in the natural estrogen composition generally is accredited as.Estrogen compositions normally cushions under the basic neutral pH of about 6.5-7.5 with alkali-metal organic or inorganic hydrochlorate or is stable.Urea also can be used as stablizer and uses (United States Patent (USP) 3608077).In United States Patent (USP) 4154820, inquired into and sneaked into that oxidation inhibitor is stablized synthetic premarin compounds and with the imbalance of three (methylol) aminomethane (TRIS) regulation and control pH to prevent that water from separating.
Two kinds of compound 5 alpha-pregnanes-3 β of the present invention, (20S), 21 triol 20-O-β-glucuronide sodium salts and 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-glucuronide sodium salt are the submembers of conjugated estrogens (the pregnant Sterones of mating type).
Detailed Description Of The Invention
According to the present invention, 5 alpha-pregnanes-3 β as progestational agents is provided, (20S), 21-triol, 20-O-β-glucuronide and 5 alpha-pregnanes-3 β, 20R-glycol, 20-O-β-glucuronide and pharmaceutically acceptable salt thereof.Synthetic route I and II express the preparation method of pregnane glucuronide 7 and 12.In addition, route 8 and 13 also demonstrates the form that glucuronide is converted into natural sodium salt.
5 alpha-pregnanes-3 β, (20S) 21-triol 20-O-β-glucuronide and 5 alpha-pregnanes-3 β, the pharmacologically acceptable salt of 20R-glycol 20-O-β-glucuronide is not limited to natural form, and comprise an alkali metal salt, alkaline earth salt, ammonium salt, contain in the alkylammonium salt of 1-6 carbon atom or each alkyl and contain the dialkyl ammonium salt of 1-6 carbon atom and trialkyl ammonium salts and any other atom that has positive charge or the molecule that each alkyl contains 1-6 carbon atom.
Because 5 alpha-pregnanes-3 β, (20S), 21-triol 20-O-β-glucuronide and 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-glucuronide is the submember of conjugated estrogens (the pregnant Sterones of mating type), so the present invention also provides purity greater than 1% 5 alpha-pregnanes-3 β, (20S), 21-triol 20-O-β-glucuronide or its pharmacologically acceptable salt or 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-glucuronide or its pharmacologically acceptable salt.
The present invention further provides substantially by 5 alpha-pregnanes-3 β, (20S), 21-triol 20-O-β-glucuronide or its pharmacologically acceptable salt or 5 alpha-pregnanes-3 β, the compound that 20R-glycol 20-O-β-glucuronide or its pharmacologically acceptable salt are formed.
The present invention further provides with 5 alpha-pregnanes-3 β, (20S), 21-triol glucuronide and 5 alpha-pregnanes-3 β, the pharmacologically acceptable salt of 20R-glycol glucuronide or relevant glucuronide is as progestational agents.
Used starting raw material or can buy during this is synthetic perhaps can utilize the standard chemical process preparation.
Compound of the present invention is made 5 alpha-pregnanes-3 β by the starting raw material that is easy to buy according to method shown in the synthetic route I, (20S), 21-triol 20-O-β-glucuronide (with corresponding single sodium salt), or according to synthetic 5 alpha-pregnanes-3 β of method shown in the synthetic route II, 20R-glycol 20-O-β-glucuronide (with corresponding single sodium salt).
In synthetic route I, use Vitarrine 3-acetic ester 1 as starting raw material.1 with lead tetra-acetate in acetic acid according to people such as Purdy at " journal of medicinal chemistry " 33 (6), method described in the 1572-1581 (1990) reaction generates 2.Compound 2 is used PtO
2Hydrogenation generation ratio is about 3: 1 compound 3 and 4 in acetic acid.Compound 3 is subsequently with excessive normal acetobromoglucose aldehydic acid methyl esters 5 heating.The protection glucuronide is again with the LiOH saponification and with the required 20-glucuronide counterpart 7 of sour protonated once more generation.Generate a sodium salt 8 with excess NaOH titration free acid slightly.
In synthetic route II, compound 10 and acetobromoglucose aldehydic acid methyl esters 5 and Ag
2CO
3Reaction generates the counterpart 11 of protection.This material is with after saponification and with sour protonated generation deprotection glucuronic acid derivative 12.After this this material generates glucuronide sodium 13 with the NaOH titration.Synthetic route II
Therefore compound of the present invention is a progestational agents, and is applicable to oral contraception (masculinity and femininity), Hormone Replacement Therapy (especially when with the oestrogenic hormon combined utilization), endometriosis, luteal phase damaged, optimum mammary gland and prostatosis and prostate gland and treatment of endometrial cancer.Also effectively anti-epileptic outbreak of compound of the present invention, the power of deepening the understanding, treatment Alzheimer's, dementia, vasomotion syndrome and other central nervous system disease relevant with menopause.Compound of the present invention can further promote erythropoiesis effectively.
Compound of the present invention can singly be used as unique therapeutical agent, or can with other drug such as other oestrogenic hormon, progesterone or male hormone combined utilization.
Compound of the present invention can be prepared separately or be used for administration with the pharmaceutical carrier preparation, and its ratio depends on solubleness and chemical property, selected route of administration and the practice of standard pharmacology of this compound.Pharmaceutical carrier can be solid or liquid.
Solid-state carrier can comprise that one or more also can serve as the material of correctives, lubricant, solubilizing agent, suspending agent, weighting agent, glidant, compression aid, tackiness agent or tablet disintegrant; It can be a coating material.In powder, carrier is a micronizing solid, and it can mix with micronised active ingredient.In tablet, activeconstituents mixes with suitable proportion with the carrier with necessary compression property and is compressed to anticipated shape and size.Powder and tablet preferably contain the activeconstituents up to 99%.The solid-state carrier that is suitable for comprises, for example: calcium phosphate, Magnesium Stearate, talcum, sucrose, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidine, low melt wax and ion exchange resin.
Liquid carrier is used to prepare solution, suspension, emulsion, syrup, elixir and pressurized compositions.Can be in pharmaceutically acceptable liquid carrier with activeconstituents dissolving or DL, as water, organic solvent, both mixtures or acceptable oil or fat.Described liquid carrier can contain other suitable pharmacy additives such as solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweeting agent, correctives, suspending agent, thickening material, tinting material, viscosity modifier, stablizer or smell conditioning agent.Oral and suitable liquid carrier example administered parenterally comprises that (part contains above-mentioned additive to water, derivatived cellulose for example, the preferably carboxymethyl cellulose sodium solution), alcohol (comprises monohydroxy-alcohol and polyvalent alcohol, dibasic alcohol for example) and derivative, Yelkin TTS class and oil (for example fractionated cocounut oil and peanut oil).For administered parenterally, carrier also can be grease such as ethyl oleate and Isopropyl myristate.The sterilization liquid carrier is fit to make with sterilising liq the composition of administered parenterally.The used liquid carrier of pressurized compositions can be halohydrocarbon or other pharmaceutically acceptable propellents.
The composition of liquid medicine that becomes sterile solution or suspension can be used for for example intramuscular, intraperitoneal or subcutaneous injection.Sterile solution also can intravenous administration.Compound of the present invention can also be with the administration of liquid or solid composition forms oral administration.
Compound of the present invention can be with the form per rectum or the intravaginal administration of conventional suppository.In order to suck in the intranasal or in the segmental bronchus or to be blown into administration, compound of the present invention can be formulated as the solution of moisture or partially aqueous, and it can use with aerosol form subsequently.Contain active compound and active compound is inertia and to the transdermal patch of the nontoxic carrier of skin by application, compound of the present invention also can percutaneous dosing, and through skin with drug release so that system absorbs in the blood.Carrier can be any amount of form, as creme or ointment, paste, gel and enclosed appts.Creme and ointment can be the semi-solid emulsion of thick liquid or oil-in-water or water-in-oil-type.Comprise that the absorption powder is dispersed in the oil or the paste in the hydrophilic petroleum that contain activeconstituents and also is suitable for.Can activeconstituents be discharged in the blood with different enclosed apptss, for example cover contain that activeconstituents bank cocoa has can DNAcarrier free semi-permeable membranes or contain the matrix of activeconstituents.Other enclosed apptss openly in the literature.
Dosage requires to change with the concrete object that the seriousness of used particular composition, route of administration, present symptom and quilt are treated.Based on the result who obtains in standard pharmacology test method, the expectation per daily dose of active compound should be 0.02 μ g/kg-750 μ g/kg.Normally with low dose of begin treatment less than this compound optimal dose.After this increase dosage until the best effect that reaches under this situation; The exact dosage desired Ying You doctor in charge of administration is based on being decided by the experience of treatment individual subject in oral, parenteral, intranasal or the segmental bronchus.Preferred this pharmaceutical composition is a unit dosage, for example becomes tablet or capsule.In above-mentioned formulation, composition further is subdivided into the unitary dose that contains an amount of activeconstituents; Unit dosage can be packaged in the composition, for example packs powder, bottled dose, ampoule, pre-filled syringe or contains the anther sac of liquid.Unit dosage can for example be capsule or tablet itself, maybe can be to have any this type of the composition of proper amt in packaged form.
The preparation method of representation compound of the present invention is provided below.
Embodiment 1 pregnane-3 β, 20R, 21-triol 3,21-diacetate 3
In 0.2L AcOH, use PtO
2(1.75g, (6.0g is 14.4mmol) and at the H of 40PSI 7.7mmol) to handle compound 2
2Following this solution of hydrogenation.After 18 hours, filtering catalyst concentrates crude product mixture, with EtOAc/ hexane (1: 4) chromatography, generates two kinds of products (3 and 4) on silica gel.First product of wash-out is main (required) material 3, isolates the white solid of 2.40g:
Mp＝164-166℃；
1H?NMR(CDCl
3)4.75-4.60(m，1H)，4.16(dd，1H，J＝11.4Hz，2.2Hz)，3.94-3.87(m，1H)，3.81-3.73(m，1H)，2.10(s，3H)，2.10-2.05(m，1H)，2.02(s，3H)，1.84(d，1H，J＝5.2Hz)，1.82-0.88(m，21H)，0.83(s，3H)，0.76(s，3H)，0.68(dt，1H，J＝10.6Hz)；MS(+ESI)421(M＋H)
+；IR(KBr)3520，2920，2880，1740，1710cm
-1.
Embodiment 2 pregnane-3 β, 20R, 21-33,20-diacetate 4
Second product 4 of wash-out is a secondary product, isolates the 0.73g white solid:
Mp＝189-191℃；
1H?NMR(DMSO)4.91(dq，1H，J＝5.5Hz，2.2Hz)，4.74-4.63(m，1H)，3.81-3.74(m，1H)，3.57-3.49(m，1H)，2.09(s，3H)，2.02(s，3H)，1.91(dd，1H，J＝7.2Hz，5.0Hz)，1.85-0.83(m，22H)，0.82(s，3H)，0.72-0.61(m，1H)，0.65(s，3H)；MS?EI420(M+)；IR(KBr)3410，2920，1730，1700cm
-1.
Embodiment 32,3,4-0-triacetyl-1-0-(3 β, 21-diacetoxy-5 alpha-pregnanes-20S-yl)-β-D-glucuronic acid methyl esters 6
(6.6g 15.7mmol) is dissolved in CHCl with compound 3
3(125mL) and use Ag
2CO
3(4.3g is 15.7mmol) with glucuronide bromide 5[21085-72-3] (6.2g 15.7mmol) handles.Reflux after 1.5 hours, add other 0.5 normal Ag
2CO
3With 0.5 normal glucuronide bromide.After 1.5 hours, so add mentioned reagent once more and carry out repeating again in 1.5 hours aforesaid operations again.This reaction was refluxed 5.5 hours altogether.Should react cooling and filtering inorganic salt.Concentrated filtrate and on silica gel chromatography (3: 7 EtOAc/ hexanes), concentrate the fraction that contains product, chromatography again generates 6 of 4.1g under the same conditions, and it obtains 6 white solids of 3.05g with the MeOH development: Mp=180-183 ℃; MS (APCI) 754 (M+NH4
+);
1H NMR (DMSO) 5.36 (t, 1H, J=9.6Hz), 5.06 (d, 1H, J=8.0Hz), 4.91 (t, 1H, J=9.8Hz), 4.70 (dd, 1H, J=9.5Hz, 8.1Hz), 4.63-4.50 (m, 1H), 4.47 (d, 1H, J=10.0Hz), 4.16 (d, 1H, J=11.3Hz), 3.92-3.75 (m, 2H), 3.63 (s, 3H), 2.16-2.07 (m, 1H), 2.04 (s, 3H), 1.99 (s, 3H), 1.97 (s, 3H), 1.95 (s, 3H), 1.93 (s, 3H), 1.78-1.63 (m, 3H), 1.62-1.39 (m, 6H), and 1.36-1.10 (m, 8H), 1.06-0.85 (m, 5H), 0.79 (s, 3H), 0.68 (s, 3H).
Embodiment 45 alpha-pregnanes-3 β, 20S.21-triol 20-O-B-D-glucuronide 7
(3.76g 5.1mmol) is dissolved in THF (25m1) neutralization with being present in H with compound 6
2LiOH (1.35g, 56.1mmol) solution-treated among the O (13mL).In this solution, add MeOH (4mL) and this is reflected at 75 ℃ and heated 2 hours down.With this solution of postcooling and concentrated.The H that aqueous residue is added other 15ml
2Among the O.In this resistates, add 2N HCl solution (43ml).Cause solid formation by scraping to clean the windows.Filtration obtains 7 of 2.6g, and it is a white solid.Mp=231-235 ℃;
13C NMR (75MHz, MeOD) (C=O disappearance), 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;
1H NMR (300MHz, and MeOD) 4.54 (d, 1H, J=7.7Hz), 3.82-3.71 (m, 3H), 3 59-3.22 (m, 5H), 2.30 (d, 1H, J=12.6Hz), 1.75-1.66 (m, 6H), and 1.53-1.18 (m, 9H), 1.17-0.88 (m, 6H), 0.83 (s, 3H), 0.78 (s, 3H), and 0.70-0.58 (m, 1H); MS (-) ESI511 (M-H)
-IR (KBr) 3410,2910,2830,1730,1700cm
-1.
Embodiment 55 alpha-pregnanes-3 β, 20S, 21-triol 20-O-β-D-glucuronide sodium salt 8
(1.57g 1.7mmol) is suspended among the MeOH (20mL) and (6.4mL, aqueous solution 0.5N) is handled, and stirs 5 minutes so that whole starting raw material is dissolved in the solution with NaOH with compound 7.This solution mixes with the 0.65g product in preceding-step subsequently, and mixture stripping (stripped) carries out column chromatography (MeOH: CH to silica gel and on silica gel
2Cl
2, 4: 6,5: 5 subsequently).This after product is with 1: the mixture of 1MeOH and diox (cumulative volume equals 60ml) development, generate 8 of 1.57g, and it is a white solid:
Mp=240-244 ℃;
13CNMR (75MHz, DMSO) (C=O disappearance), 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
2O), 2920,2870,1610cm
-1.
Embodiment 6 pregnane-3 β, 20S, 21-triol 9
(1.6g 3.8mmol) is dissolved among the THF (8ml) with compound 3.Add and be present in 3mlH
2LiOH in the O water (0.27g, solution 11.4mmol).In order to make this solution produce a phase, in reaction mixture, add the MeOH of 1ml.Reflux after 30 minutes, handle this reaction mixture and make it at organic layer and 60ml H with the AcOH of 1.1mL
2Distribute between the O water, organic layer has 100ml EtOAc, 20mLCH
2Cl
2, 10mlMeOH forms.Subsequently with this organic layer of salt water washing and use MgSO
4Dry.Concentrate this solution, the gained solid is developed with ether, obtain 1.1 9 be white solid:
Mp=210-212 ℃;
1H NMR (DMSO) (disappearance of 3OH proton) 4.43 (d, 1H, J=4.6Hz), 4.31 (t, 1H, J=5.5Hz), 4.05 (d, 1H, J=5.2Hz), and 3.16-3.05 (m, 1H), 2.10 (d, 1H, J=12.4Hz), 1.65-0.78 (m, 21H), 0.75 (s, 3H), 0.68 (s, 3H), and 0.65-0.54 (m, 1H); MS EI336 M+; IR (KBr) 3400,2930,2880cm
-1.
Embodiment 71-0-(3 β-acetoxyl group-pregnane-20-yl)-2,3,4-triacetyl-β-D-glucuronide methyl esters 11
Under the room temperature with 5 alpha-pregnanes-3 β, 20 beta-diol 3-acetic ester 10 (3.0g, 11.0mmol), glucuronyl-bromide 5[21085-72-3] (5.5g, 13.8mmol) and Ag
2CO
3(4.5g 16.1mmol) stirs (not being subjected to illumination with the protection foil flask) in toluene (40ml).After 18 hours, use CH
2Cl
2Dilute this reaction, filter, concentrate and on silica gel chromatography (EtOAc: Hex, 2: 8, EtOAc: Hex subsequently, 4: 6), generate solid, obtain 11 of 3.0g with the MeOH development, it is white solid: Mp=248-251 ℃;
1H NMR (DMSO) 5.33 (t, 1H, J=9.6Hz), 4.95-4.88 (m, 2H), 4.68 (dd, 1H, J=9.5Hz, 8.1Hz), 4.62-4.49 (m, 1H), 4.44 (d, 1H, J=10.0Hz), 3.71-3.65 (m, 1H), 3.63 (s, 3H), 2.11 (d, 1H, J=12.6 Hz), 1.98 (s, 3H), 1.97 (s, 3H), 1.96 (s, 3H), 1.95 (s, 3H), and 1.77-1.64 (m, 2H), 1.63-1.10 (m, 14H), 0.99 (d, 3H, J=5.8Hz), 0.95-0.83 (m, 5H), 0.78 (s, 3H), 0.66 (s, 3H), 0.65-0.58 (m, 1H); IR (KBr) 2930,2900,2830,1750,1730cm
-1MS (+) ESI696 (M+NH
4)
+.
Embodiment 85 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide 12
(2.5g 3.7mmol) is dissolved in THF (25ml) and MeOH (15ml) neutralization with being present in H with compound 11
2LiOH (0.9g, 37.5mmol) solution-treated among the O (10mL).This is reflected at the heating down 1 hour that refluxes.Make this reaction be cooled to room temperature, concentrate.Product placed water (20ml) and with 2N HCl acidified aqueous solution.Filter the precipitation that generates, obtain 12 of 1.5g, it is a white solid:
Mp=255-260 °;
1H NMR (DMSO) (3H covers) 4.98 (d, 1H, J=3.8Hz), 4.91 (d, 1H, J=4.6Hz), 4.42 (brs, 1H), 4.25 (d, 1H, J=7.7Hz), 3.71-3.62 (m, 1H), 3.58 (d, 1H, J=9.7Hz), 3.23-3.12 (m, 1H), 2.96-2.87 (m, 1H), 2.15 (d, 1H, J=12.3Hz), 1.67-1.46 (m, 5 H), 1.45-0.80 (m, 17H), 1.01 (d, 3H, J=5.8Hz), 0.74 (s, 3H), 0.65 (s, 3H), 0.65-0.52 (m, 1H); IR (KBr) 3520,3400,2920,2820,2800,1710cm
-1MS (-) ESI495 (M-H)
-.
Embodiment 95 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide 13
(1.5g, 3.0mmol) (3.0mmol) handle, and stirred 5 minutes for 0.5N, 6.0ml, and all things enter solution by the aqueous solution with NaOH for the suspension in MeOH (25mL) with compound 12.To doing, resistates obtains 13 of 1.1g with the EtOH development with this solution concentration, and it is white solid: Mp=223-226 ℃ (dec);
1H NMR (DMSO) 7.26 (s, 1H), 4.76 (d, 1H, J=3.6Hz), 4.67 (d, 1H, J=3.6Hz), 4.43 (d, 1H, J=approx4Hz), 4.12 (d, 1H, J=7.6Hz), 3.78-3.71 (m, 1H), 3.45-3.35 (m, 1H), 3.17-3.03 (m, 3H), 3.38-3.29 (m, 1H), 2.17 (d, 1H, J=12.4Hz), and 1.67-1.49 (m, 5H), 1.45-0.80 (m, 17H), 0.99 (d, 3H, J=5.9Hz), 0.76 (s, 3H), 0.75 (s, 3H), and 0.65-0.53 (m, 1H); IR (KBr) 3400,2920,2830,1610cm
-1MS (-) ESI495 (M-H)
-.
Claims (33)
1. compound, it is 5 alpha-pregnanes-3 β, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.
2. the compound of claim 1, the pharmacologically acceptable salt of wherein said 20-glucuronide is an an alkali metal salt, alkaline earth salt, ammonium salt, the alkylammonium salt that contains 1-6 carbon atom, or contain the dialkyl ammonium salt of 1-6 carbon atom in each alkyl, or contain the trialkyl ammonium salts of 1-6 carbon atom in each alkyl.
3. compound, it is 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.
4. the compound of claim 3, the pharmacologically acceptable salt of wherein said 20-glucuronide is an an alkali metal salt, alkaline earth salt, ammonium salt, the alkylammonium salt that contains 1-6 carbon atom, or contain the dialkyl ammonium salt of 1-6 carbon atom in each alkyl, or contain the trialkyl ammonium salts of 1-6 carbon atom in each alkyl.
5.5 alpha-pregnane-3 β, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, its purity is at least one of percentage.
6.5 alpha-pregnane-3 β, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, its purity is at least one of percentage.
7. one kind mainly by 5 alpha-pregnanes-3 β, 20S, the compound that 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt are formed.
8. one kind mainly by 5 alpha-pregnanes-3 β, the compound that 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt are formed.
9. one kind mainly by 5 alpha-pregnanes-3 β, 20S, the compound that 21-triol 20-O-β-D-glucuronide sodium salt is formed.
10. one kind mainly by 5 alpha-pregnanes-3 β, the compound that 20R-glycol 20-O-β-D-glucuronide sodium salt is formed.
11. one kind contains 5 alpha-pregnanes-3 β, 20S, the pharmaceutical composition of 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.
12. one kind contains 5 alpha-pregnanes-3 β, the pharmaceutical composition of 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.
13., wherein further contain other and be selected from oestrogenic hormon, progestogen and androgenic medicine according to claim 11 or 12 described pharmaceutical compositions.
14. according to the pharmaceutical composition of claim 12, it is mainly by 5 alpha-pregnanes-3 β, 20S, and 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt and at least a pharmaceutical carrier are formed.
15. according to the pharmaceutical composition of claim 12, it is mainly by 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt and at least a pharmaceutical carrier are formed.
16. a pharmaceutical composition wherein contains 5 alpha-pregnanes-3 β greater than 1%w/w or w/v, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt and at least a pharmaceutical carrier.
17. a pharmaceutical composition wherein contains 5 alpha-pregnanes-3 β greater than 1%w/w or w/v, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt and at least a pharmaceutical carrier.
18. 5 alpha-pregnanes-3 β, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, it is used for the treatment of Mammals.
19. 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, it is used for the treatment of Mammals.
20. 5 alpha-pregnanes-3 β, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, it is as progestational agents.
21. 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, it is as progestational agents.
22. 5 alpha-pregnanes-3 β, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, it is used in the Mammals treatment of needs or suppresses cancer, central nervous system disorder, dementia or Alzheimer's.
23. 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, it is used in the Mammals treatment of needs or suppresses cancer, central nervous system disorder, dementia or Alzheimer's.
24. 5 alpha-pregnanes-3 β, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt are used as progestational agents or in treatment or suppress in cancer, central nervous system disorder, dementia or the Alzheimer's or promote application in the erythropoietic medicine in the Mammals of preparation at needs.
25. 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt are used as progestational agents in the Mammals of preparation at needs or in treatment or suppress in cancer, central nervous system disorder, dementia or the Alzheimer's or promote application in the erythropoietic medicine.
26. a method of the progestogenic treatment being provided for the Mammals that needs, it comprises 5 alpha-pregnanes-3 β that uses the progestogenic significant quantity, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.
27. a method of the progestogenic treatment being provided for the Mammals that needs, it comprises 5 alpha-pregnanes-3 β that uses the progestogenic significant quantity, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.
28. method for the treatment of or suppressing cancer, central nervous system disorder, dementia or Alzheimer's in the Mammals that needs, it comprises 5 alpha-pregnanes-3 β to this administration significant quantity, 20S, 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.
29. method for the treatment of or suppressing cancer, central nervous system disorder, dementia or Alzheimer's in the Mammals that needs, it comprises 5 alpha-pregnanes-3 β to this administration significant quantity, 20R-glycol 20-O-β-D-glucuronide or its pharmacologically acceptable salt.
30. prepare 5 alpha-pregnanes-3 β, (20S), the method for 21-triol 20-O-β-D-glucuronide or its pharmacologically acceptable salt, it comprises makes Vitarrine 3-acetic ester and lead tetra-acetate react the compound of the formula that obtains 2 in acetic acid:
Use PtO subsequently
2Hydrogenation in acetic acid obtains compound 3:
Itself so with 5 heating of superstoichiometric compound:
Obtain the compound of formula 6:
With after saponification and protonated again with acid, obtain 5 alpha-pregnanes-3 β, (20S), and 21-triol 20-O-β-D-glucuronide, and this compound can optionally be converted into its pharmacologically acceptable salt.
31. prepare 5 alpha-pregnanes-3 β, the method for 20R-glycol 20-O-β-D-glucuronide, it comprises compound 10:
Compound and Ag with formula 5
2CO
3Reaction:
The compound of production 11:
With after saponification and protonated again with acid, obtain 5 alpha-pregnanes-3 β, 20R-glycol 20-O-β-D-glucuronide can optionally be converted into its pharmacologically acceptable salt according to claim and this compound.
32. 5 alpha-pregnanes-3 β, (20S), the preparation method of 21-triol 20-O-β-D-glucuronide one sodium salt, it comprises with excess NaOH solution development slightly.
33. 5 alpha-pregnanes-3 β, the preparation method of 20R-glycol 20-O-β-D-glucuronide one sodium salt, it comprises with excess NaOH solution development slightly.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US17034298A | 1998-10-13 | 1998-10-13 | |
| US09/170342 | 1998-10-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1330659A true CN1330659A (en) | 2002-01-09 |
Family
ID=22619512
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99814413A Pending CN1330659A (en) | 1998-10-13 | 1999-10-07 | Pregnane glucuronides compound |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP1121376A1 (en) |
| JP (1) | JP2002527448A (en) |
| KR (1) | KR20010080102A (en) |
| CN (1) | CN1330659A (en) |
| AR (1) | AR020778A1 (en) |
| AU (1) | AU751708B2 (en) |
| BR (1) | BR9914521A (en) |
| CA (1) | CA2346693A1 (en) |
| CZ (1) | CZ20011343A3 (en) |
| EA (1) | EA200100437A1 (en) |
| HU (1) | HUP0103992A3 (en) |
| IL (1) | IL142441A0 (en) |
| NO (1) | NO20011825L (en) |
| PL (1) | PL347270A1 (en) |
| TW (1) | TW499435B (en) |
| WO (1) | WO2000021977A1 (en) |
| ZA (1) | ZA200103012B (en) |
Families Citing this family (2)
| 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 |
| KR100440607B1 (en) * | 2001-12-28 | 2004-07-15 | 주식회사 엘컴사이언스 | Pregnan glycoside compounds and preventives and remedies of neurodegenerative disease containing them as active ingredients |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2029011B (en) * | 1978-09-01 | 1983-02-02 | Coulson W | Use of a synthetic bifunctional ligand for the immunimetric determination of the concentration ratio of two solutes |
-
1999
- 1999-10-07 CA CA002346693A patent/CA2346693A1/en not_active Abandoned
- 1999-10-07 CN CN99814413A patent/CN1330659A/en active Pending
- 1999-10-07 KR KR1020017004572A patent/KR20010080102A/en not_active Application Discontinuation
- 1999-10-07 EA EA200100437A patent/EA200100437A1/en unknown
- 1999-10-07 CZ CZ20011343A patent/CZ20011343A3/en unknown
- 1999-10-07 WO PCT/US1999/023467 patent/WO2000021977A1/en not_active Application Discontinuation
- 1999-10-07 JP JP2000575882A patent/JP2002527448A/en active Pending
- 1999-10-07 TW TW088117305A patent/TW499435B/en active
- 1999-10-07 AU AU65115/99A patent/AU751708B2/en not_active Ceased
- 1999-10-07 BR BR9914521-9A patent/BR9914521A/en not_active IP Right Cessation
- 1999-10-07 EP EP99953101A patent/EP1121376A1/en not_active Withdrawn
- 1999-10-07 PL PL99347270A patent/PL347270A1/en not_active Application Discontinuation
- 1999-10-07 IL IL14244199A patent/IL142441A0/en unknown
- 1999-10-07 HU HU0103992A patent/HUP0103992A3/en unknown
- 1999-10-12 AR ARP990105144A patent/AR020778A1/en unknown
-
2001
- 2001-04-10 NO NO20011825A patent/NO20011825L/en not_active Application Discontinuation
- 2001-04-11 ZA ZA200103012A patent/ZA200103012B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EA200100437A1 (en) | 2001-10-22 |
| TW499435B (en) | 2002-08-21 |
| CZ20011343A3 (en) | 2002-04-17 |
| EP1121376A1 (en) | 2001-08-08 |
| NO20011825L (en) | 2001-06-05 |
| WO2000021977A1 (en) | 2000-04-20 |
| CA2346693A1 (en) | 2000-04-20 |
| BR9914521A (en) | 2001-06-26 |
| AU751708B2 (en) | 2002-08-22 |
| AU6511599A (en) | 2000-05-01 |
| KR20010080102A (en) | 2001-08-22 |
| HUP0103992A2 (en) | 2002-04-29 |
| IL142441A0 (en) | 2002-03-10 |
| AR020778A1 (en) | 2002-05-29 |
| PL347270A1 (en) | 2002-03-25 |
| NO20011825D0 (en) | 2001-04-10 |
| ZA200103012B (en) | 2002-07-11 |
| JP2002527448A (en) | 2002-08-27 |
| HUP0103992A3 (en) | 2002-12-28 |
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