CN101659689B - Methylprednisolone derivative - Google Patents
Methylprednisolone derivative Download PDFInfo
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- CN101659689B CN101659689B CN 200810054276 CN200810054276A CN101659689B CN 101659689 B CN101659689 B CN 101659689B CN 200810054276 CN200810054276 CN 200810054276 CN 200810054276 A CN200810054276 A CN 200810054276A CN 101659689 B CN101659689 B CN 101659689B
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- VHRSUDSXCMQTMA-IETLARDKSA-N C[C@@H](CC(C(CC1)[C@](C)(C[C@@H]2O)[C@]1(C(CO)=O)O)C2[C@@]1(C)C=C2)C1=CC2=O Chemical compound C[C@@H](CC(C(CC1)[C@](C)(C[C@@H]2O)[C@]1(C(CO)=O)O)C2[C@@]1(C)C=C2)C1=CC2=O VHRSUDSXCMQTMA-IETLARDKSA-N 0.000 description 1
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Abstract
The invention discloses a novel compound (1) of a methylprednisolone derivative, a synthesis method thereof, and application of the compound (1) in preparing a medicament for diseases of human or mammals. R1 is H, C2-C16 acyl or -COCH2CH2COOH; R2 is a hydrocarbon group with less than 10 carbon atoms containing 1 to 2 heteroatoms, wherein the heteroatom is one or two of N, O and S. The invention also discloses a medicinal composition using the compound (1) as an active component.
Description
Technical field:
The present invention relates to a kind of medical compounds and synthetic method thereof and the application in the medicine of preparation treatment age-related macular degeneration.
Background technology:
Methylprednisolone (Methylprednisolone, CAS:83-43-2) be a kind of not halogen-containing glucocorticoid medicine of synthetic, China document " clinical application of methylprednisolone " (Yang Congrong etc., continue medical education, the 20th the 33rd phase of volume, 61～64) reported that methylprednisolone has pharmacological actions such as anti-inflammatory, immunosuppression, antianaphylaxis, antishock.The anti-inflammatory action of this medicine is stronger, is equivalent to 5 times of hydrocortisone, is 1.4 times of prednisone.In numerous glucocorticosteroids, the avidity of methylprednisolone and glucocorticoid receptor is the strongest, is 12 times of hydrocortisone, 23 times of prednisone.And mineralocorticoid sample effect (as water, sodium retention) is faint, is about 1/200 of Doca, and significantly less than prednisone, to the restraining effect of hypothalamus-hypophysis-hypothalamic pituitary adrenal axis a little less than, and this medicine itself namely exists with the activeconstituents form, onset is rapid.
Methylprednisolone and derivative thereof are widely used in respiratory tract disease, endocrine disturbance, rheumatism, collagen disease, hematologic disease, tetter, allergic state, nervous system disorders, gastrointestinal tract disease, organ transplantation etc. clinically owing to have pharmacological actions such as powerful anti-inflammatory, immunosuppression, antianaphylaxis, antishock.(Mursch K such as Mursch, Buhre W, Behnke-Mursch J, et al.Peroperative cardiovascular stability during brainstem surgery.The use ofhigh-dose methylprednisolone compared to dexamethasone.A retrospective analysis.AetaAnaesthesiol Seand, 2000,44:378-382) reported the renal toxicity of methylprednisolone, digestive tract hemorrhage, side effects such as withdrawal reaction may be lighter, and the incidence of the unstable event of cardiovascular systems is significantly less than dexamethasone (P＜0.05) when treating with it.(Pastenmak JJ such as Pastenmak, McCregor DG, Lanier WL.Effect of single-dosedexaemethasone on blood glucose concentration in patients undergoing craniotomy.J NeurosurgAnesthesiol, 2004,16:122-125) dexamethasone is than the easier blood sugar increasing that causes of methylprednisolone.
The derivative of methylprednisolone is mainly its pharmaceutically useful carboxylate, the methylprednisolone derivative of prior art is mainly methylprednisolone acetate, methylprednisolone aceponate, Urbason Solubile etc., because the introducing of different ester groups, methylprednisolone has shown different characteristics, and be used to prepare different preparations to treat different diseases, be made into suspension injection (trade(brand)name: DEPO-MEDROL) be used for joint cavity or injection of soft tissue with treatment rheumatism as methylprednisolone acetate, diseases such as rheumatoid arthritis, methylprednisolone aceponate are made into external preparation (trade(brand)name: ADVANTAN) be used for the treatment of skin inflammation, Urbason Solubile is made into lyophilized injectable powder (trade(brand)name: prednisolone Solu-Medrol) be used for muscle or intravenous injection.
Summary of the invention:
In the research to the methylprednisolone derivative, we have found the compound (1) as a kind of new methylprednisolone derivative
R wherein
1Be H, the acyl group of carbonatoms 2～16 or-COCH
2CH
2COOH; The acyl group of preferred C2～4, preferred especially ethanoyl, propionyl, butyryl radicals, isobutyryl ,-COCH
2CH
2COOH; R
2For containing 1-2 heteroatomic ten carbon with interior hydrocarbon group, heteroatoms is N, O, and one or both among the S, preferred but be not limited only to R
2A kind of in furyl, thienyl, pyrryl, imidazolyl, pyrazolyl, thiazolyl, pyranyl, pyridyl, miaow pyridine base, pyrazinyl, indyl, purine radicals, the benzopyranyl, more preferably R
2A kind of in furyl, thienyl, pyranyl, pyridyl, pyrazinyl, the indyl, preferred especially R
2A kind of in furyl, pyrryl, thienyl, the pyridyl, most preferably R
2Be α-Fu Nan base or α-thienyl.
The invention also discloses a kind of synthetic method of formula (1) compound:
With obtaining of compound (2), when R is-C (O) CH
2CH
2During COOH succsinic acid methylprednisolone (2.3) (CAS:2921-57-5), when R is-C (O) CH
2CH
2Succsinic acid methylprednisolone (2.3) during COOH; Work as R
1During for the acyl group of carbonatoms 2～16, can adopt among the Chinese patent application CN200710201633.9 that disclosed method makes among disclosed method or the Chinese patent application 200710059954.X.
Compound (2) is dissolved in the inert solvent, in the time of 0～25 ℃, adds excessive alkaline reagents, in the time of 0～25 ℃, slowly add excessive R then
2COCl stirs and carries out acylation reaction, and reaction finishes the excessive alkaline reagents of back neutralization, obtains formula (1) compound with conventional separation method as the method for separating with silica gel column chromatography.The weightmeasurement ratio of described formula (2) compound and inert solvent is 1:5～1:20, described inert solvent includes but are not limited to one or more in methylene dichloride, trichloromethane, ethylene dichloride, tetracol phenixin, triethylamine, acetonitrile, pyridine, the tetrahydrofuran (THF), in preferred especially methylene dichloride and the trichloromethane one or both, the preferred triethylamine of described alkaline reagents and/or pyridine, the mol ratio of described alkaline reagents and formula (1.2) compound is 3～6 times, described R
2The mol ratio of COCl and formula (2) compound is 2.5～4 times, also can directly adopt a large amount of alkaline reagentss such as pyridine, triethylamine as solvent when reaction.
Work as R
1During for H, the preparation of formula (1) compound: adopt R
1Prepared formula (1) compound carries out basic hydrolysis being dissolved in full during for the acyl group of carbonatoms 2～16 in the organic solvent, described organic solvent particular methanol and/or chloroform, and the preferred sodium hydroxide of described alkali and/or potassium hydroxide, temperature of reaction is-10 ℃～0 ℃
The invention also discloses the application of acceptable solvent compound in preparation treatment people or Mammals medicine on described formula (1) compound and the physiology thereof.
The invention also discloses the application of acceptable solvent compound in preparation treatment people or Mammals anti-inflammatory or Claritin on described formula (1) compound and the physiology thereof.Particularly preferably in preparation treatment people or mammal skin disease such as eczema, psoriasis, allergic dermatitis, neurodermatitis, itch and hypersensitivity reaction; Airway inflammation such as bronchial asthma, rhinallergosis, chronic obstructive pulmonary disease, interstitial pneumonia, pulmonary fibrosis; Eye inflammation such as conjunctivitis; Inflammatory bowel such as ulcerative colitis or Crohn disease; And the application in the medicine of diseases such as autoimmune disease such as rheumatic arthritis, rheumatoid arthritis, lupus erythematosus, pemphigus." treatment " of the present invention can extend to prevention and the diagnosis of disease.
The dosage of formula disclosed by the invention (I) compound in treatment people or mammalian diseases medicine is 0.2 μ g-50mg/kg/ days, preferred 1 μ g-2mg/kg/ days.During as treatment people's disease, people's body weight is generally calculated according to 50kg, so the dosage of human described in the present invention can calculate according to ABW, also can calculate according to above-mentioned dosage * 50.
The invention also discloses a kind of pharmaceutical composition, it is characterized in that containing described any one or a few compound and one or more the pharmaceutically useful auxiliary materials of formula (1) as activeconstituents.
Disclosed in this invention is that the pharmaceutical composition of activeconstituents includes but are not limited to the pharmaceutical composition that is applicable to oral administration, orally administering, sublingual administration, parenteral admin, part or rectal administration with formula (1) compound, is preferably the pharmaceutical composition of topical especially.
The pharmaceutical composition of described topical includes but are not limited to inhalation such as aerosol, powder inhalation, sprays; Nasal formulations such as nasal spray, nasal drop, external preparation comprise as ointment, ointment, gelifying agent, lotion, foaming agent, patch, powder; The orally administering preparation is as chewing the tablet that maybe can suck or pill, oral cavity sticking tablet; Local cavity preparation such as suppository, vaginal suppository, enema,retention; Ophthalmic preparation such as eye drops; And liposome or microcapsule formulation.Be preferably inhalation, nasal formulations and external preparation.
Described is that pharmaceutical composition dosage when treatment people or mammalian diseases of activeconstituents is counted 0.2 μ g-5mg/kg/ days with methylprednisolone, preferred 1 μ g-2mg/kg/ days with formula (1) compound.Described pharmaceutical composition is counted 0.2 μ g-5mg/kg/ days at the dosage for the treatment of people or Mammals supersensitivity, diseases associated with inflammation with formula (1) compound, preferred 1 μ g-2mg/kg/ days, described pharmaceutical composition adopts every day 1 time or more administering mode in use, preferred every day 1～3 time, also can adopt medication in many days administering mode once, dosage is the stack of Dan Tian.
When described be that the pharmaceutical composition of activeconstituents is when making inhalation, nasal formulations and being used for the treatment of people or Mammals airway inflammation airway inflammation such as bronchial asthma, rhinallergosis, chronic obstructive pulmonary disease, interstitial pneumonia, pulmonary fibrosis with formula (1) compound, described formula (1) compound dosage is counted 0.2 μ g/kg/ days to 20 μ g/kg/ days with methylprednisolone, use every day 1 to 4 time, preferred using dosage is counted 1 μ g/kg/ days to 10 μ g/kg/ days with methylprednisolone, use every day 1 time to 2 times, use 1 preferred especially every day.
When described described be the pharmaceutical composition of activeconstituents when being made as the aerosol of inhalation with formula (1) compound, described pharmaceutically acceptable auxiliaries is propellent and one or more low volatility component.
Described propellent can include but are not limited to one or more in freon hydrocarbon, fluorohydrocarbon class, pressurized gas, the ethers, comprise 1,1,1,2-Tetrafluoroethane (HFA134a) and 1,1,1.2,3,3,3-heptafluoro-propane (HFA227), Trichloromonofluoromethane (CCl3F), chlorodifluoromethane (CCl2F2), dichloro tetrafluoro ethane (CClF2-CClF2), propane (C3H8), Trimethylmethane (iso-C4H10), normal butane (n-C4H10), carbonic acid gas, nitrous oxide, nitrogen is preferably in the fluorohydrocarbon compounds one or more.Be preferably a kind of or its combination among HFA134a and the HFA227 especially.
Described low volatility component can include but are not limited to, one or more in solvent, latent solvent, suspending agent, stablizer, correctives, the sanitas.And also can be applicable to aerosol or the sprays of non-suction.
Described suitable latent solvent can be but be not limited only to ethanol or oleic acid, and preferably use ethanol, suitable solvent is glycerine, and propylene glycol or polyoxyethylene glycol preferably use glycerine.Solvent and latent solvent also can be referred to as thinner herein.
Described low volatiles can also be but be not limited only to following component, comprise other pure and mild glycol, for example alkanol, as sugar alcohol, glycofural (tetrahydrofuran base methyl alcohol) and the dipropylene glycol of decyl alcohol (decyl alcohol), Sorbitol Powder, mannitol, Saccharum lactis, maltose alcohol, comprise that vegetables oil, organic acid are as comprising dodecylic acid and saturated carboxylic acids such as tetradecanoic acid and stearic acid; Comprise Sorbic Acid, particularly unsaturated carboxylic acid such as oleic acid.The known stablizer that is applied to aerosol, sprays, suspending agent, correctives as asccharin, xitix, cyclamic acid, amino acid or aspartame; Alkane such as dodecane and octadecane; Terpenes such as menthol, eucalyptol, limonene; Sugar is as lactose, glucose, sucrose; Polysaccharide such as ethyl cellulose, dextran; Antioxidant such as Yoshinox BHT, Sodium Pyrosulfite, butylated hydroxyanisol; Polymkeric substance such as polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone; Amine such as thanomin, diethanolamine, trolamine; Steroid class such as cholesterol, cholesteryl ester.
Should be appreciated that because of known reason as the retention of activeconstituents in suction apparatus, the amount of every kind of activeconstituents that the patient sucks can be different from the amount of metering.Therefore the applicating ratio between the activeconstituents can be different from the ratio of metering.The ratio of preferably using is in the described metered proportions that indicates.
Of the present invention is the aerosol that the pharmaceutical composition of activeconstituents is made as inhalation with formula (1) compound; described powder inhalation is made up of dried powder; the method that obtains dried powder is for pulverizing activeconstituents of the present invention and pharmaceutical excipient with known breaking method such as mechanical disintegration or spray-dired mode; be preferably mid-diameter less than the micronized dried powder of 10 μ m; powder mass, preferred mid-diameter is from 0.1 to 5 μ m.As a kind of replacement, activeconstituents in small, broken bits can with one or more pharmaceutically useful non-active ingredients, as additive, diluent or carrier etc. form the form of mixtures of appointment.The composition that uses among the present invention can oneself knows by those skilled in the art method obtain these preferred forms.Add nonionogenic tenside when utilizing spray-drying process to reach median size in the carrier to increase flowability, preferred nonionic is poloxamer.Activeconstituents: the poloxamer weight ratio is 1:(0.01～5).The composition that uses among the present invention can oneself knows by those skilled in the art method obtain these preferred forms.
Described is that the pharmaceutical composition of activeconstituents is when making nasal formulations with formula (1) compound, described pharmaceutically acceptable auxiliaries can include but are not limited to pH regulator agent, carrier, osmotic pressure regulator, viscosity modifier,, suspending agent, antioxidant, tensio-active agent, stablizer, antibacterial sanitas etc. all be applicable in the pharmaceutical excipient of local nose administration one or more.
Described carrier can include but are not limited to one or more in water, propylene glycol, Xylo-Mucine, Vltra tears, hydroxypropylcellulose, whiteruss, vegetables oil, Vaseline, lanolin, the crosslinked polypropylene acid resin.When described pharmaceutical composition is made gelifying agent, described carrier contains water and crosslinked acrylic resin, and employed crosslinked polypropylene acid resin is preferably the carbomer resin, is preferably carbomer 934 especially, consumption is 0.1%～1% of pharmaceutical composition weight, preferred 0.2% to 0.5%.The consumption of water is 90% to 99% of pharmaceutical composition weight.
Described pH regulator agent can be enumerated but is not limited only to phosphoric acid and salt, boric acid and salt thereof, Citric Acid and salt thereof, acetic acid and salt thereof, tartrate and salt thereof, sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, tromethane etc.
Described suspending agent can include but are not limited to, asccharin, xitix, cyclamic acid, amino acid or aspartame; Alkane such as dodecane and octadecane; Terpenes such as menthol, eucalyptol, limonene; Sugar is as lactose, glucose, sucrose; In polysaccharide such as ethyl cellulose, the dextran one or more.
Described antioxidant can include but are not limited to Yoshinox BHT, Sodium Pyrosulfite, butylated hydroxyanisol; Amine such as thanomin, diethanolamine, trolamine; Steroid class such as cholesterol, cholesteryl ester.
Described osmotic pressure regulator to include but are not limited to osmotic pressure regulator and can enumerate but be not limited only to glycerine, propylene glycol, sodium-chlor, Repone K, Sorbitol Powder, N.F,USP MANNITOL one or more etc.
Described viscosity modifier can be enumerated but be not limited only to one or more of polyvinyl alcohol, carboxy vinyl polymer, Polyvinylpyrolidone (PVP), foregoing crosslinked polypropylene acid resin, Xylo-Mucine, Vltra tears, hydroxypropylcellulose, also can be used as viscosity modifier.
Described stablizer can include but are not limited to ethylenediamine tetraacetic acid (EDTA) and alkaline metal salt thereof, preferred disodium ethylene diamine tetraacetate.
Described tensio-active agent can be enumerated but be not limited only to tween-80, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene glycol-stearate, Macrogol 4000, Yelkin TTS, sucrose ester, Voranol EP 2001, the polyoxy stearate, one or more in polyoxyethylene, polyoxypropylene diols and the analogue thereof.
Described antibacterial sanitas can include but are not limited to, in the benzalkonium chloride, benzethonium chloride, Sorbic Acid, potassium sorbate, methyl p-hydroxybenzoate (Tegosept M), nipagin A (ethyl p-hydroxybenzoate) propylparaben (propylben), chlorobutanol one or more.
Propylene glycol in the described pharmaceutically useful auxiliary material, glycerine can also replace with other alcohols, available alcohols can include but are not limited to other alcohols and glycols, for example alkanol, as decyl alcohol (decyl alcohol), the sugar alcohol that comprises Sorbitol Powder, mannitol, Saccharum lactis, maltose alcohol, glycofural (tetrahydrofuran base methyl alcohol) and dipropylene glycol.
Described is that the pharmaceutical composition of activeconstituents is when making external preparation with formula (1) compound, preferably make ointment, described pharmaceutically acceptable auxiliaries includes but are not limited to the antioxidant for the described pharmaceutical composition of preservation, the pH buffer reagent, wetting Agent for Printing Inks, oil-phase component, antibiotic antiseptic, the water of surplus in addition.
Described oil-phase component comprises one or more in solid in the oil-phase component, consistency modifiers, the emulsifying agent.
Solid in the described oil-phase component includes but are not limited to one or more of stearic acid, paraffin, beeswax, higher alcohols, described higher alcohols is the monohydroxy-alcohol of 16～22 carbon atoms, preferred hexadecanol and/or stearyl alcohol, described consistency modifiers includes but are not limited to one or more in Vaseline, whiteruss, the vegetables oil, preferred Vaseline and/or Liquid Paraffin, described emulsifying agent, include but are not limited to the derivative of soap class emulsifying agent, Soxylat A 25-7, described higher alcohols also plays the effect of tensio-active agent simultaneously in emulsifiable paste.
It is described that the composition of the above pharmaceutical composition is not limited only to technical solution of the present invention, also comprise any composition that can be used for the pharmaceutical excipient of above-mentioned preparation, the composition of described pharmaceutical excipient can be with reference to disclosed scheme in " pharmaceutics " (the 5th edition, Cui Fude published in 2003).
Compare with the various derivatives that methylprednisolone of the prior art and its are known, new methylprednisolone derivative (1) provided by the invention, produced beyond thought effect when using in the part, with the suction methylprednisolone, methylprednisolone aceponate, methylprednisolone acetate relatively, sucking new methylprednisolone derivative (1) provided by the invention can obviously reduce rat and induce drawing the time of breathing heavily of asthma by histamine, show new methylprednisolone derivative (1) provided by the invention by the experimentation on animals to the mouse chronic dermatitis, the chronic dermatitis that can more effectively suppress mouse causes part that atrophy experiment shows new methylprednisolone derivative (1) provided by the invention by the mouse part in addition and causes the more existing methylprednisolone derivative of atrophy effect and have obviously and weaken.Show by above-mentioned pharmacological evaluation, compare with existing methylprednisolone derivative, the new methylprednisolone derivative (1) of gained of the present invention when local anti-inflammatory and antianaphylactic treatment, better effects if, the effect of caused whole body glucocorticosteroid is littler, more has superiority when treatment.
Embodiment:
Column chromatography separation method among the present invention:
The minimum 70cm of the length of chromatographic column, inner filling 254-silica gel, and the organism that will need to separate is dissolved in minimum chloroform entirely: among methyl alcohol=1:1, this solution absorption is placed on the top of silica gel in the chromatography column with minimum 254-silica gel, use the moving phase wash-out, connect the solution that obtains through column chromatography with several 10ml test tubes under the chromatography column, the control flow velocity is 10ml/3min, the solution of each test tube is analyzed with HPLC, the test tube solution that retention time is identical merges, the compound of getting principal point carries out recrystallization, obtains corresponding product.Wash-out moving phase adopts the mixed solvent of chloroform: methyl alcohol=1:1 (volume ratio).
Determine the method for principal point: the organism that will need to separate is analyzed with HPLC, and except the point of the peak area maximum of raw material point is defined as principal point, its retention time is the retention time of principal point.
Equipment: HP1084B liquid chromatograph, HP79850BLC terminal and UV detector
Column material: Hypersil C18,5 μ m, 150 * 4.6mm
Detect wavelength: 242nm
Moving phase: methyl alcohol: water=5.5:4.5
Column temperature: 45 ℃
Flow velocity: about 1.2ml/ branch
Embodiment 1-1:
The preparation of 6 Alpha-Methyls-prednisolone-17 Alpha-hydroxies-17-furoate (compound 1-a1)
Acidylate
Getting methylprednisolone acetate (2.2) 3g is dissolved in the 30ml methylene dichloride, the solution of gained is cooled to 0～5 ℃, and under this temperature, add the 6ml triethylamine, then under temperature is 5-10 ℃ condition, slowly add the 2.5ml furoyl chloride, under 5-10 ℃ condition, stir resultant mixture then, reaction 3h afterreaction liquid washing three times, each 20ml water transfers to 1-2 with concentrated hydrochloric acid with water layer pH during washing, and with the dichloromethane extraction water of 10ml * 3 time, organic phase merges, with sodium hydroxide solution pH is transferred to 5-6 and uses the washing of 200ml water, organic phase concentrates, and obtains enriched material.
Hydrolysis
The enriched material that acidylate is obtained is dissolved in methylene dichloride; the methyl alcohol that adds equivalent; logical N2 protection adds the 0.3g sodium hydroxide that is dissolved in methyl alcohol, after reacting completely under 0 ℃; reaction solution is neutralized to neutrality with Glacial acetic acid; wash three times, each 20ml water, and with the dichloromethane extraction water of 10ml * 3 time; organic phase merges, and concentrates.Adopt the column chromatography separation method to obtain 6 Alpha-Methyls-prednisolone-17 Alpha-hydroxies-17-furoate (compound 1-a1).
Ultimate analysis calculated value: C
27H
34O
7C69.21.% H6.88% O23.90%
Ultimate analysis measured value: C69.18% H6.92% O23.89%
13C-NMR(CDCl
3)：
| The position of C | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 13C-NMR | 154.3 | 128.6 | 185.9 | 125.0 | 173.9 | 33.3 | 35.4 | 26.1 |
| The position of C | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 |
| 13C-NMR | 59.4 | 36.1 | 68.8 | 39.7 | 41.2 | 50.1 | 23.8 | 22.0 |
| The position of C | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 |
| 13C-NMR | 98.1 | 16.9 | 19.2 | 212.1 | 66.2 | 157.8 | 143.9 | 116.8 |
| The position of C | 25 | 26 | 27 | 28 | 29 | 30 | 31 | 32 |
| 13C-NMR | 111.4 | 145.0 | 19.9 |
The preparation of embodiment 1-2:6 Alpha-Methyl-prednisolone-21-acetic ester-17 Alpha-hydroxies-17-furoate (compound 1-a2)
Getting methylprednisolone acetic ester (2.2) 3g is dissolved in the 30ml pyridine, the solution of gained is cooled to 0～5 ℃, then under temperature is 5-10 ℃ condition, slowly add the 2.5ml furoyl chloride, under 5-10 ℃ condition, stir resultant mixture then, reaction 3h afterreaction liquid washing three times, each 20ml water transfers to 1-2 with concentrated hydrochloric acid with water layer pH during washing, and with the dichloromethane extraction water of 10ml * 3 time, organic phase merges, with sodium hydroxide solution pH is transferred to 5-6 and uses the washing of 200ml water, organic phase concentrates, and adopts the column chromatography separation method to obtain 6 Alpha-Methyls-prednisolone-21-acetic ester-17 Alpha-hydroxies-17-furoate (compound 1-a2).
Ultimate analysis calculated value: C
29H
34O
8C68.22.% H6.71% O25.07%
Ultimate analysis measured value: C68.18% H6.72% O25.04%
13C-NMR(CDCl
3)：
| The position of C | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 13C-NMR | 154.4 | 128.6 | 185.9 | 125.0 | 173.9 | 33.2 | 35.4 | 26.1 |
| The position of C | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 |
| 13C-NMR | 59.4 | 36.1 | 68.6 | 39.7 | 41.2 | 50.2 | 23.8 | 22.0 |
| The position of C | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 |
| 13C-NMR | 98.1 | 16.9 | 19.2 | 211.0 | 67.6 | 158.0 | 144.1 | 116.8 |
| The position of C | 25 | 26 | 27 | 28 | 29 | 30 | 31 | 32 |
| 13C-NMR | 111.4 | 145.0 | 19.9 | 169.8 | 20.1 |
Embodiment 2-1:
The preparation of 6 Alpha-Methyls-prednisolone-17 Alpha-hydroxies-17-(2-thiophenic acid)-ester (compound 1-b1)
Acidylate
Getting methylprednisolone acetate (2.2) 3g is dissolved in the 30ml methylene dichloride, gained suspension is cooled to 0～5 ℃, and under this temperature, add the 6ml triethylamine, then under temperature is 5-10 ℃ condition, slowly add the 2.5ml2-thiophene chloride, under 5-10 ℃ condition, stir resultant mixture then, reaction 3h afterreaction liquid washing three times, each 20ml water transfers to 1-2 with concentrated hydrochloric acid with water layer pH during washing, and with the dichloromethane extraction water of 10ml * 3 time, organic phase merges, with sodium hydroxide solution pH is transferred to 5-6 and uses the washing of 200ml water, organic phase concentrates, and obtains enriched material.
Hydrolysis
The enriched material that acidylate is obtained is dissolved in the methylene dichloride, adds the methyl alcohol of equivalent, logical N
2Protection adds the 0.3g sodium hydroxide be dissolved in methyl alcohol, and after reacting completely under 0 ℃, reaction solution is neutralized to neutrality with Glacial acetic acid, wash three times, each 20ml water, and with the dichloromethane extraction water of 10ml * 3 time, the organic phase merging, concentrated.Adopt the column chromatography product separation to obtain 6 Alpha-Methyls-prednisolone-17 Alpha-hydroxies-17-(2-thiophenic acid)-ester (1-b1).
Ultimate analysis calculated value: C
27H
34O
6S C66.64% H7.04% O19.73% S6.59%
Ultimate analysis measured value: C66.67% H7.01% O19.75% S6.57%
13C-NMR(CDCl
3)：
| The position of C | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 13C-NMR | 154.3 | 128.2 | 185.9 | 124.8 | 173.9 | 33.3 | 35.4 | 26.2 |
| The position of C | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 |
| 13C-NMR | 59.4 | 36.2 | 68.8 | 39.7 | 41.2 | 50.1 | 23.9 | 22.1 |
| The position of C | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 |
| 13C-NMR | 100.3 | 16.9 | 19.2 | 211.0 | 66.1 | 160.0 | 134.1 | 134.1 |
| The position of C | 25 | 26 | 27 | 28 | 29 | 30 | 31 | 32 |
| 13C-NMR | 127.9 | 133.6 | 19.9 |
Embodiment 2-2:
The preparation of 6 Alpha-Methyls-prednisolone-21-succinate-17 Alpha-hydroxies-17-(2-thiophenic acid)-ester (compound 1-b2)
Acidylate
Getting compound 1-b13g is dissolved in the 30ml triethylamine, gained suspension is cooled to 0～5 ℃, then under temperature is 5-10 ℃ condition, slowly add the 3g succinyl oxide, at room temperature stir resultant mixture then, reaction 24h afterreaction liquid washing three times, each 20ml water, with concentrated hydrochloric acid water layer pH is transferred to 1-2 during washing, and with the dichloromethane extraction water of 10ml * 3 time, organic phase merges, and pH is transferred to 5-6 and with the washing of 200ml water with sodium hydroxide solution, organic phase concentrates, and adopts the column chromatography product separation to obtain 6 Alpha-Methyls-prednisolone-21-succinate-17 Alpha-hydroxies-17-(2-thiophenic acid)-ester (1-b2).
Ultimate analysis calculated value: C
31H
38O
9S C63.46% H6.53% O24.54% S5.47%
Ultimate analysis measured value: C66.45% H6.55% O24.51% S5.47%
13C-NMR(CDCl
3)：
| The position of C | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 13C-NMR | 154.3 | 128.2 | 185.9 | 124.8 | 173.9 | 33.4 | 35.4 | 26.2 |
| The position of C | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 |
| 13C-NMR | 59.4 | 36.2 | 68.9 | 39.7 | 41.2 | 50.2 | 23.9 | 22.6 |
| The position of C | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 |
| 13C-NMR | 100.7 | 16.9 | 19.2 | 211.1 | 68.1 | 160.1 | 134.1 | 134.0 |
| The position of C | 25 | 26 | 27 | 28 | 29 | 30 | 31 | 32 |
| 13C-NMR | 127.9 | 133.6 | 19.9 | 173.0 | 28.8 | 29.2 | 175.2 |
Embodiment 2-3:
The preparation of 6 Alpha-Methyls-prednisolone-21-cetylate-17 Alpha-hydroxies-17-(2-thiophenic acid)-ester (compound 1-b3)
The preparation of 6 Alpha-Methyls-prednisolone-21-cetylate makes according to disclosed method among the Chinese patent application 200710059954.X, and reaction formula is as follows:
Get 0.1mol methylprednisolone (2.1) and be dissolved in the pyridine (130ml), be cooled to 0 ℃ of dropping 0.12mol palmityl chloride (purchasing chemical industry Manufacturing Co., Ltd in close in Wuhan) and be dissolved in the solution that the 130ml chloroform forms, 1h finishes.Under 0 ℃, continue to stir 7h, add trash ice (150g), continue stirring 2h, reaction solution is poured in the 1mol sulphuric acid soln (600ml), chloroform extraction (125ml * 3), evaporated under reduced pressure obtains crude product.Acetone-water recrystallization obtains elaboration, content〉98%.
The above methylprednisolone that makes-21-cetylate (2.4) 5g is dissolved in the 30ml methylene dichloride, gained suspension is cooled to 0～5 ℃, and under this temperature, add the 6ml triethylamine, then under temperature is 5-10 ℃ condition, slowly add the 2.5ml2-thiophene chloride, under 5-10 ℃ condition, stir resultant mixture then, reaction 3h afterreaction liquid washing three times, each 20ml water, with concentrated hydrochloric acid water layer pH is transferred to 1-2 during washing, and with the dichloromethane extraction water of 10ml * 3 time, organic phase merges, with sodium hydroxide solution pH is transferred to 5-6 and uses the washing of 200ml water, organic phase concentrates, and adopts the column chromatography product separation to obtain 6 Alpha-Methyls-prednisolone-21-cetylate-17 Alpha-hydroxies-17-(2-thiophenic acid)-ester (1-b3).
Ultimate analysis calculated value: C
43H
62O
7S C71.43% H8.64% O15.49% S4.43%
Ultimate analysis measured value: C71.45% H8.59% O15.50% S4.45%
13C-NMR(CDCl
3)：
| The position of C | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 13C-NMR | 154.3 | 128.2 | 185.9 | 124.8 | 173.9 | 33.5 | 35.4 | 26.2 |
| The position of C | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 |
| 13C-NMR | 59.4 | 36.4 | 68.8 | 39.7 | 41.2 | 50.2 | 23.9 | 22.6 |
| The position of C | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 |
| 13C-NMR | 100.6 | 16.9 | 19.2 | 211.1 | 68.1 | 160.1 | 134.1 | 134.0 |
| The position of C | 25 | 26 | 27 | 28 | 29 | 30 | 31 | 32 |
| 13C-NMR | 127.9 | 133.6 | 19.9 | 172.9 | 33.4 | 24.9 | 29.0 | 29.4 |
| The position of C | 33 | 34 | 35 | 36 | 37 | 38 | 39 | 40 |
| 13C-NMR | 29.6 | 29.6 | 29.6 | 29.6 | 29.6 | 29.6 | 29.6 | 29.4 |
| The position of C | 41 | 42 | 43 | |||||
| 13C-NMR | 31.6 | 22.5 | 14.0 |
The preparation of embodiment 3 aerosols
Compound 1-a1 6.3g
Ethanol 750g
Glycerine 150g
HFA227 1500g
Preparation technology: the compound 1-a1 of recipe quantity is added in the ethanol and glycerine that stirs, stir, heat in warm water bath, make material dissolution, sand core funnel filters, the divided dose can, sealing-in dosage valve system, the HFA227 that pressurizes again respectively, namely, theoretical canned 1000 bottles, the can yield is more than 85%.Through 45-50 ℃ of water-bath leak detection 30 minutes, do not have and leak.Press for every bottle 100, whenever press and contain compound 1-a1 63 μ g (amounting to methylprednisolone 50 μ g).
The preparation of embodiment 4 eye drops
Compound 1-b1 0.05g (particle diameter 5～20 μ m)
Sodium-chlor 0.08g
SODIUM PHOSPHATE, MONOBASIC 0.65g
Sodium phosphate dibasic 0.5g
Benzalkonium chloride 0.01g
Vltra tears 0.2g
Tween-80 0.08g
Water for injection is to 100ml
Getting benzalkonium chloride is dissolved in recipe quantity 50% water for injection, be heated to 40-50 ℃, adding SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, tween-80 make dissolving, No. 4 sintered filter funnels filter conduct＜1〉liquid is stand-by, in addition Vltra tears is dissolved in the distilled water of recipe quantity 30, filter with the B that is lined with 200 order nylon cloths, be heated to 60-70 ℃, add compound 1-a and stir evenly, insulation 30min is cooled to 40-50 ℃, again with＜1〉the liquid merging, add the injection water to capacity, 200 order nylon mesh filter twice, packing, sterilize, seal.
The preparation of embodiment 5 powder inhalations
Compound 1-a2 675mg
Lactose 25000mg
Preparation technology: compound 1-a and lactose are mixed, with fluid energy mill medicine is carried out abundant micronization processes after, the can of medicine carrying powder to capsule, is got final product theoretical can 1000 capsules.Every capsules includes micronized compound 1-a2675 μ g (amounting to methylprednisolone 500 μ g), lactose 25mg.
The preparation of embodiment 6 powder inhalations
Compound 1-b1 650mg
Lactose 25000mg
Preparation technology: compound 1-b1 and lactose are mixed, with fluid energy mill medicine is carried out abundant micronization processes after, the can of medicine carrying powder to capsule, is got final product theoretical can 1000 capsules.Every capsules includes micronized compound 1-b1650 μ g (amounting to methylprednisolone 500 μ g), lactose 25mg.
The preparation of embodiment 7 ointments
Compound 1-a1 1g, white vaseline 30g, stearyl alcohol 120g, glyceryl monostearate 20g, whiteruss 10g, peregal A-2050g, glycerine 120g, EDTA-2Na2g, phenylcarbinol 5g, hydroxypropylcellulose, 3g, purified water 639g
By the accurate weighing of above proportioning, moisture is two portions: 380g and 259g, gets ready, and the emulsifiable paste process for preparation is as follows:
(1) oil phase preparation:, get white vaseline, stearyl alcohol, glyceryl monostearate, whiteruss, peregal A-20 places container, is heated to fusion, and temperature remains on 72 ± 2 ℃;
(2) water preparation: by the accurate weighing of above proportioning, get glycerine, EDTA-2Na and 380g water place container, heating, and temperature remains on 70 ± 2 ℃;
(3) close phase: pour the oil phase of step (1) preparation the aqueous phase of step (2) preparation into, stir, maintain the temperature at 75 ± 2 ℃, add phenylcarbinol;
(4) main ingredient suspension: compound 1-a1,259g water, polyethylene pyrrole network alkane ketone are placed container, and stirring or ultrasonic obtains the main ingredient suspension;
(5) the control temperature is at 60 ± 2 ℃, and the main ingredient suspension that obtains in the step (4) is added in the solution that step (3) obtains, and the limit edged stirs, and is cooled to cream.Obtain emulsifiable paste 1kg.
The preparation of embodiment 8 ointments
Compound 1-b1 1.3g, an amount of propylene glycol
The prescription of oil phase:
White vaseline 100g stearyl alcohol 30g Liquid Paraffin 50g glyceryl monostearate 20g
Peregal a-20 20g Tegosept M 0.5g propylben 0.05g alpha-tocopherol 1g
The prescription of water:
Disodium ethylene diamine tetraacetate (EDTA-2Na) 1g, glycerine 50g
Emulsifiable paste is buffered to the phosphate buffer distilled water of pH=6.5 to 1000g (in the emulsifiable paste gross weight)
Preparation:
(1) compound 1-b1 is dissolved in an amount of propylene glycol
(2) preparation of oil phase
The oil-phase component of getting recipe quantity is heated to 70 ℃, adds the Tegosept E that is dissolved in an amount of organic solvent, and the compound 1-b1 that will be dissolved into again in the propylene glycol joins in the oil phase, stirs while adding to evenly namely.
(3) preparation of water
The water-phase component that takes by weighing recipe quantity joins stirring and dissolving in the distilled water of recipe quantity,
(4) preparation of emulsifiable paste
Water is heated to 70 ± 10 ℃ of oil-phase components that will be heated to 70 ± 10 ℃ joins aqueous phase, stir while adding evenly to condensation namely.The compound 1-b1 that makes 0.1% (in methylprednisolone) is the emulsifiable paste of activeconstituents.
Pharmacology embodiment 1
Relatively methylprednisolone, methylprednisolone aceponate, methylprednisolone acetate, compound 1-a1, compound 1-a2, compound 1-b1 suck the influence that histamine is induced the rat asthma attack
1. laboratory animal: choose healthy childhood of rat, body weight 180～220g, male and female are not limit.
2 laboratory apparatuss: the bell glass of air compressor, aerosol shower nozzle, mercury manometer, base, 4L
3 experimental drugs: 2% Ovisot, 0.1% histamine phosphate, methylprednisolone powder inhalation, methylprednisolone acetate powder inhalation, methylprednisolone aceponate powder inhalation, compound 1-a1 powder inhalation, compound 1-a2 powder inhalation, compound 1-b1 powder inhalation, (above powder inhalation is all prepared by the method for embodiment 5)
4 data processing: adopt the check of t in groups of SAS system.
Three, experimental technique
Choose rat childhood, male and female all can, body weight is 180-220g, puts into the lens about 5 liters, sprays into 2% Ovisot and 15 seconds of 0.1% histamine phosphate's volume mixed solution with the pressure of 400mmHg.After spraying stops, observing drawing of rat and breathe heavily latent period (asthma namely takes place, breathe and be the devil, until the time that tic is fallen), draw and breathe heavily the phase of diving and to select for use greater than 120 seconds rat.Learn from else's experience to measure to draw and breathe heavily 120 of qualified rats in latent period, be equally divided into 6 groups latent period at random by drawing to breathe heavily, the A-F group is respectively methylprednisolone suction group, methylprednisolone acetate suction group, methylprednisolone aceponate suction group, compound 1-a1 suction group, compound 1-a2 suction group, compound 1-b1 suction group, behind the inhalation 30min, spraying gives 0.25% 2 hydrochloric acid histamine respectively, observes to give and draws the variation of breathing heavily latent period and tic incidence (draw when breathing heavily animal do not occur the person of falling in 6 minutes to breathe heavily latent period be 360s to draw) before and after the medicine
Four, experimental result: a few treated animal generation asthma, until the time that tic is fallen difference is arranged, see Table 1:
Table 1 pair histamine phosphate's spraying sucks the influence of inducing asthma attack
(n＝20，X±s，)
Show by this experiment, compound 1-a1, compound 1-a2 and compound 1-b all can the significant prolongation mouse be breathed heavily latent period drawing of bringing out by histamine phosphate, (P＜0.01), and existing several methylprednisolone derivative is compared, under Isodose, use the D of The compounds of this invention, E, draw after the administration that F is three groups and breathe heavily latent period and A, B, draw after the administration that C is three groups and breathe heavily latent period and compare respectively, all have significance (P＜0.05), illustrate that thus new methylprednisolone derivative provided by the invention compares with existing methylprednisolone derivative in treatment more significant effect is arranged during asthma.
Pharmacology embodiment 2
Laboratory animal: 70 of CXA-1 recombinant inbred strain small white mouses (Bengbu Medical College's animal center provides), body weight 18～22g, divide control group, experimental group A-F, adopting with methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, compound 1-a1, compound 1-a2, compound 1-b1 respectively is activeconstituents, coat experiment mice auris dextra inboard according to 0.1% emulsifiable paste (in methylprednisolone) that embodiment 8 methods make, every experiment mice coating same amount emulsifiable paste, and simultaneously at the emulsifiable paste matrix of left ear coating same amount in contrast.Control group two ears are coating substrate all.
Chronic dermatitis eczema Animal Model Making: adopt 7%DNCB (dinitrotoluene (DNT)) acetone soln 100 μ L to be coated with mouse back sensitization outward, being coated with 0.1%DNCB acetone soln 5 μ L outside after 5 days excites in the mouse right ear inboard, excite once every 72h, experimental group is exciting back 24h to begin coating first, every day, coating twice, and to be coated with dose identical at every turn.Excite back 72h to put to death mouse in the 5th, measure swelling degree and the incrustation rate of mouse right ear.Swelling degree=(auris dextra weight-left ear weight)/(left ear weight) * 100%.
Experimental data adopts spss to handle and carries out the t check
Experimental data sees the following form
(X±s，n＝10)
| Group | Swelling degree % | Incrustation rate % |
| Contrast | 151.2 | 70 |
| A | 135.4 | 50 |
| B | 132.1 | 40 |
| C | 125.1 | 30 |
| D | 105.2 | 10 |
| E | 107.5 | 10 |
| F | 110.7 | 10 |
Show through experiment, other methylprednisolone derivative is compared, compound provided by the invention is in the treatment to mouse chronic dermatitis Eczema Model, there were significant differences for the swelling degree of mouse ear and incrustation rate (P＜0.05), show that compound provided by the invention has and existing methylprednisolone derivative when being used for the treatment of the Mammals local inflammation, comparing to have significant curative effect.Especially with in the existing methylprednisolone derivative be considered to local antiinflammatory effect preferably and be made into the methylprednisolone aceponate of external preparation that (trade(brand)name: trade(brand)name: ADVANTAN) compare, also there is significant curative effect in the local antiinflammatory effect of compound provided by the invention.
Pharmacology embodiment 3 local actions cause atrophy effect contrast
Laboratory animal: 60 of white cavys childhood, body weight 300g ± 20g, be divided into experiment A-F group, be activeconstituents with methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, compound 1-a1, compound 1-a2, compound 1-b respectively, 0.1% emulsifiable paste that makes according to embodiment 8 methods is the medication of experiment A-F group.
Experimental technique: the zone of every guinea pig back left and right sides antimere being selected 3cm * 3cm, shave hair, the left side uses experimental group to be coated with the pastille emulsifiable paste, right side coating emulsifiable paste matrix, medication every day 2 times is coated with same amount at every turn, continuous use, after medication the 5th day with every group of cavy drug withdrawal, medication district, back and check plot skin are put to death and got respectively to cavy, measure the ratio of medication district skin thickness and check plot skin thickness to determine the skin atrophy degree.The results are shown in following table
Last table data declaration is compared with existing several methylprednisolone derivatives, and compound provided by the invention causes the skin atrophy effect when local application have remarkable reduction (P＜0.05).Can draw thus, use compound provided by the invention to be used for the treatment of local inflammation, side effect is littler, and medication is safer.
Claims (4)
1. compound as shown in the formula (1)
Work as R
2During for α-thienyl, R
1Be H.
2. the application of formula as claimed in claim 1 (1) compound in preparation people or Mammals anti-inflammatory or Claritin.
3. a pharmaceutical composition is characterized in that containing formula as claimed in claim 1 (1) compound and one or more pharmaceutically useful auxiliary materials as activeconstituents.
4. the pharmaceutical composition described in claim 3 is characterized in that described pharmaceutical composition can make inhalation, external preparation, local cavity preparation, ophthalmic preparation and microcapsule formulation.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4567172A (en) * | 1982-05-31 | 1986-01-28 | Ohta Seiyaku Kabushiki Kaisha | 6α-Methylprednisolone derivatives |
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2008
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4567172A (en) * | 1982-05-31 | 1986-01-28 | Ohta Seiyaku Kabushiki Kaisha | 6α-Methylprednisolone derivatives |
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