CN105585612A - Octapeptide modified dexamethasone, preparation, nano-structure and application thereof - Google Patents
Octapeptide modified dexamethasone, preparation, nano-structure and application thereof Download PDFInfo
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- CN105585612A CN105585612A CN201410562127.2A CN201410562127A CN105585612A CN 105585612 A CN105585612 A CN 105585612A CN 201410562127 A CN201410562127 A CN 201410562127A CN 105585612 A CN105585612 A CN 105585612A
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Abstract
The invention discloses octapeptide Lys(AA-Asp-Gly-Arg)-His-Gly-Glu modified dexamethasone shown as the formula, wherein the AA is L-Val or L-Phe. The invention also discloses a preparation method, a nano-structure thereof, and an inhibitory effect of the compound on mouse retroauricular cardiac transplantation immunological rejective reaction and xylene induced inflammation reaction, and further discloses that the compound does not generate osteoporosis and thrombus side effects like dexamethasone. Therefore, the octapeptide modified dexamethasone disclosed by the invention has definite application prospect in preparation of immunosuppressive and anti-inflammatory drugs. (formula of the compound).
Description
Technical field
The present invention relates to the dexamethasone that octapeptide Lys (AA-Asp-Gly-Arg)-His-Gly-Glu modifies, the AA in octapeptide isL-Val or L-Phe residue. Relate to their preparation method, relate to their nanostructured, relate to they to mouse ear after cardiac muscleThe inhibitory action of trnasplantion immunity rejection, relates to the inhibitory action that their paraxylene cause inflammatory reaction, further relates toThey can produce osteoporosis and thrombus side effect unlike dexamethasone. Thereby the present invention relates to following formula octapeptide modifyDexamethasone is in the application prospect of preparation immunosupress and anti-inflammatory drug. The invention belongs to biomedicine field.
Background technology
Replace waste and old organ by organ transplant, become the conventional therapy means of Clinical Surgery. Immunity row in organ transplantScolding reaction is the main factor of organ transplant failure. Accept the patient of organ transplant, the postoperative dexamethasone class sugar cortex of takingHormone immunity inhibitor is to avoid rejection and extend one of important measures of transplant organ time-to-live. Dexamethasone classGlucocorticoid is to treat rheumatic disease, autoimmunity disease and severe infections or inflammatory in clinical other important applicationDisease. Patient uses dexamethasone glucocoricoid for a long time, inevitably induced osteoporosis and thrombotic diseases. OrderBefore, unique way of reduction dexamethasone glucocoricoid side effect risk, is exactly drug withdrawal. The consequence of drug withdrawal is to reduce and treatEffect. The structure of transformation dexamethasone glucocoricoid, reduces or evades side effect, is that dexamethasone glucocoricoid grindsThe focus of studying carefully.
Inventor once modified cortin with RGD tetrapeptide, had prepared the compound of structure A. They are in 1.43 μ mol/kg agentUnder amount, can extend the suckling mouse myocardial viability time of transplanting. They,, under 25.5 μ mol/kg dosage, can suppress mouse inflammation. ItUnder 1.43 μ mol/kg dosage, can not bring out mouse suffer from osteoporosis. Not whether they under 1.43 μ mol/kg dosage,There is thrombosis risk, do not come to a conclusion at that time.
Inventor also once modified hydrocortisone and prednisolone with Urotoxin tripeptide, had prepared the compound of structure B. TheyUnder 7.5mmol/kg and 2.0mmol/kg dosage, can extend the suckling mouse myocardial viability time of transplanting respectively. Do not find themAnti-inflammatory activity. Whether they there is not osteoporosis and thrombosis wind under 7.5mmol/kg and 2.0mmol/kg dosageDanger, did not come to a conclusion at that time.
The structure that adopts new method transformation dexamethasone, further reduces dosage, not only eliminates osteoporosis side effect, andAnd eliminating thrombosis side effect, is the new technology that inventor makes great efforts development always. Through various combinations, inventor recognizesPeptide and steroidal five-membered ring are one of problems by the isolation of more than five atom. So inventor replaces succinyl base with acetyl group, systemFor the compound of following formula. Curative effect is not obviously improved.
Then, inventor takes RGD tetrapeptide to reverse the strategy on the side chain amino that is connected to L-Lys, has prepared the change of following formulaCompound. Although curative effect is not obviously improved, osteoporosis and thrombosis side effect all no longer occur.
Finally, inventor takes Urotoxin tripeptide His-Gly-Glu to reverse on the alpha-amido that is connected to the L-Lys of compound aboveStrategy, prepared compound of the present invention, reached reduction dosage, eliminate osteoporosis side effect and eliminate thrombusForm the triple targets of side effect. According to these research, inventor has proposed the present invention.
Summary of the invention
First technical problem that the present invention will solve is to propose the dexamethasone structure of the octapeptide modification of following formula. In formula, AA isL-Val and L-Phe residue.
Second technical problem that the present invention will solve is to provide and prepare octapeptide Lys (AA-Asp-Gly-Arg)-His-Gly-GluThe method of the dexamethasone (in formula, AA is L-Val or L-Phe residue) of modifying, this compound comprises three large steps:
1), in DMSO, the hydroxyl of 17 glycolyls of NaH catalysis dexamethasone and bromoacetate take off HBr, by 17Glycolyl is converted into carbethoxyl group methoxy acetyl group. In NaOH solution, 17 carbethoxyl group methoxy acetyl group are transformed againBe 17 carboxylic methoxy acetyl group;
2) connect peptide method according to the liquid phase of standard, progressively connect peptide, the full guard by the side chain amino of L-Boc-Lys with carboxylic end dissociativeRGDV or the carboxylic end coupling of RGDF, by the N end of the His-Gly-Glu of the carboxylic end of L-Lys and the free full guard of alpha-amidoCoupling, octapeptide Fmoc-Lys[AA-Asp (the OMe)-Gly-of preparation full guardArg (Tos)-Boc)]-His-Gly-Glu (OBzl)-OBzl, then in the DMF of 20% piperidines solution de-Fmoc to prepare N freeFull guard octapeptide Lys[AA-Asp (OMe)-Gly-Arg (Tos)-Boc)]-His-Gly-Glu (OBzl)-OBzl, in formula, AA isL-Val or L-Phe residue;
3) at HATU, under HOBt and NMM exist, in dry DMF, the dexamethasone-17-first step 1 being obtainedLys[AA-Asp (OMe)-Gly-Arg (Tos)-Boc that carboxylic acid and step 2 obtain)]-His-Gly-Glu (OBzl)-OBzl coupling,In trifluoroacetic acid, slough whole protecting groups with TFMS again, make the octapeptide of claim 1The dexamethasone (in formula, AA is L-Val or L-Phe residue) that Lys (AA-Asp-Gly-Arg)-His-Gly-Glu modifies.
The 3rd technical problem that the present invention will solve is to evaluate octapeptide Lys (AA-Asp-Gly-Arg)-His-Gly-Glu and modifyDexamethasone (in formula, AA is L-Val or L-Phe residue) extend after mouse ear and transplant the cardiac muscle time-to-live.
The 4th technical problem that the present invention will solve is to evaluate octapeptide Lys (AA-Asp-Gly-Arg)-His-Gly-Glu and modifyDexamethasone (in formula, AA is L-Val or L-Phe residue) suppress the activity of mouse inflammation.
The 5th technical problem that the present invention will solve is to evaluate octapeptide Lys (AA-Asp-Gly-Arg)-His-Gly-Glu and modifyDexamethasone (in formula, AA is L-Val or L-Phe residue) suppress rat suppository form activity.
The 6th technical problem that the present invention will solve is to evaluate octapeptide Lys (AA-Asp-Gly-Arg)-His-Gly-Glu and modifyDexamethasone (in formula, AA is L-Val or L-Phe residue) suppress mouse osteoporotic activity.
Brief description of the drawings
Dexamethasone that Fig. 1 octapeptide Lys (AA-Asp-Gly-Arg)-His-Gly-Glu modifies (in formula AA be L-Val orL-Phe residue) synthetic route .i) DMSO, BrCH2CO2C2H5，NaH；ii)MeOH，NaOH；iii)DCC，HOBt，NMM；iv)4NHCl/EtOAc，v/v)H2, Pt/C; Vi) HATU, HOBt, NMM; Vii) 20% piperidines/DMF; Viii)TFMSA，TFA。
Fig. 2 concentration is 1.43 × 10-6The dexamethasone that octapeptide Lys (AA-Asp-Gly-Arg)-His-Gly-Glu of M modifies(in formula, AA is L-Val or L-Phe residue) transmission electron microscope photo in the aqueous solution.
Fig. 3 compound on mouse ear after the impact of myocardium transplantation myocardial viability, n=10, oral administration, 0.1 μ mol/kg/day,Successive administration 15 days.
Detailed description of the invention
In order further to set forth the present invention, provide a series of embodiment below. These embodiment are illustrative completely, theyOnly be used for the present invention to be specifically described, do not should be understood to limitation of the present invention.
Embodiment 1 prepares Boc-Gly-Glu (OBzl)-OBzl
Take (30.0mmol) Boc-Gly5.294g, 4.353g (32.5mmol) HOBt, (THF) is molten for dry tetrahydrofuranSeparate, under ice bath, stir, drip wherein 7.406g (35.9mmol) DCC that THF dissolves, stir-activating is after 30 minutesAdd 15.572g (31.3mmol) TosHGlu (OBzl)-OBzl, NMM adjusts pH=8, room temperature reaction 12 hours, TLC(CH2Cl2/ MeOH=20/1), show that raw material point disappears. Remove by filter DCU, filtrate decompression is concentrated, and residue is with 200ML acetic acid ethyl dissolution, the ethyl acetate solution obtaining is used 50mL saturated sodium bicarbonate aqueous solution successively, the saturated chlorine of 50mLChange sodium water solution, the saturated aqueous potassium hydrogen sulfate of 50mL, 50mL saturated sodium-chloride water solution, 50mL saturated sodium bicarbonateThe aqueous solution, 50mL saturated sodium-chloride water solution is respectively washed 3 times, and ethyl acetate layer anhydrous sodium sulfate drying filters, and filtrate subtractsPress and concentrate, obtain 13.0g (88.4%) title compound.
Embodiment 2 prepares HClGly-Glu (OBzl)-OBzl
Under ice bath, add the second of the hydrogen chloride of 200mL4M to 13.0g (26.9mmol) Boc-Gly-Glu (OBzl)-OBzAcetoacetic ester solution, reacts after 2 hours TLC (CH2Cl2/ MeOH=20/1) show that raw material point disappears. Reduced pressure concentration. ResidualThing dissolves with anhydrous ethyl acetate, reduced pressure concentration. This operation repeats 3 times. Residue dissolves with absolute ether, reduced pressure concentration.This operation also repeats 3 times. Obtain 12.5g (96.1%) title compound.
Embodiment 3 prepares Boc-His (Boc)-Gly-Glu (OBzl)-OBzl
Take 1.400g (3.9mmol) Boc-His (Boc), 0.561g (4.0mmol) HOBt, dry tetrahydrofuran (THF)Dissolve, under ice bath, stir, drip wherein 0.975g (4.7mmol) DCC that THF dissolves, stir-activating is after 30 minutesAdd 2.0g (4.8mmol) HClGly-Glu (OBzl)-OBzl, NMM adjusts pH=8, room temperature reaction 12 hours,TLC(CH2Cl2/ MeOH=20/1), show that raw material point disappears. Remove by filter DCU, filtrate decompression is concentrated, and residue is used100mL acetic acid ethyl dissolution, the ethyl acetate solution obtaining is used saturated sodium bicarbonate 20mL saturated sodium bicarbonate water successivelySolution, saturated 20mL sodium-chloride water solution, the saturated aqueous potassium hydrogen sulfate of 20mL, 20mL saturated sodium-chloride water solution,20mL saturated sodium bicarbonate aqueous solution, 20mL saturated sodium-chloride water solution washing 3 times, ethyl acetate layer anhydrous sodium sulfateDry 30 minutes, to filter, filtrate decompression is concentrated, obtains 1.700g (60.7%) title compound.
Embodiment 4 prepares HClHis-Gly-Glu (OBzl)-OBzl
Under ice bath, adding 10mL concentration to 1.7g (2.4mmol) Boc-His (Boc)-Gly-Glu (OBzl)-OBzl is 4MThe ethyl acetate solution of hydrogen chloride, react after 2 hours TLC (CH2Cl2/ MeOH=20/1) show that raw material point disappears. SubtractPress concentrated. Residue dissolves with anhydrous ethyl acetate, reduced pressure concentration. This operation repeats 3 times. Residue is molten with absolute etherSeparate reduced pressure concentration. This operation also repeats 3 times, obtains 1.2g (92.3%) title compound.
Embodiment 5 prepares Fmoc-Lys (Boc)-His-Gly-Glu (OBzl)-OBzl
Take 20g (42.7mmol) Fmoc-Lys (Boc), 4.9g (36.2mmol) HOBt, (THF) is molten for dry tetrahydrofuranSeparate under ice bath and stir, drip wherein 9.6g (46.6mmol) DCC that THF dissolves, stir-activating added after 30 minutes20g (35.8mmol) HClHis-Gly-Glu (OBzl)-OBzl, NMM adjusts pH=8, room temperature reaction 12 hours, TLC(CH2Cl2/ MeOH=10/1) show that raw material point disappears. Remove by filter DCU, filtrate decompression is concentrated, residue 400mLAcetic acid ethyl dissolution, the ethyl acetate solution obtaining is used 100mL saturated sodium bicarbonate aqueous solution successively, the saturated chlorine of 100mLChange sodium water solution, the saturated aqueous potassium hydrogen sulfate of 100mL, 100mL saturated sodium-chloride water solution, 100mL unsaturated carbonate hydrogenSodium water solution, 100mL saturated sodium-chloride water solution washing 3 times, ethyl acetate layer is used anhydrous sodium sulfate drying 30 minutes, mixesSample, column chromatography purification, obtains 22g (63.2%) title compound. ESI-MS (m/z): 972.9[M+H]+。
Embodiment 6 prepares HClFmoc-Lys-His-Gly-Glu (OBzl)-OBzl
Under ice bath, add 500mL concentration to 22g (22.7mmol) Fmoc-Lys (Boc)-His-Gly-Glu (OBzl)-OBzlFor the ethyl acetate solution of the hydrogen chloride of 4M, react after 6 hours TLC (CH2Cl2/ MeOH=10/1) demonstration raw material pointDisappear. Reduced pressure concentration. Residue dissolves with anhydrous ethyl acetate, reduced pressure concentration. This operation repeats 3 times. Residue nothingWater ether dissolution, reduced pressure concentration. This operation also repeats 3 times, obtains 15.1g (93.8%) title compound. ESI-MS (m/z):872.9[M+H]+。
Embodiment 7 prepares Boc-Arg (Tos)-Gly-OBzl
Take 38.5g (90.0mmol) Boc-Arg (Tos), 12g (88.6mmol) HOBt, (THF) is molten for dry tetrahydrofuranSeparate, under ice bath, stir, drip wherein 22g (109.2mmol) DCC that THF dissolves, stir-activating added after 30 minutesEnter 22g (109.2mmol) HClGly-OBzl, NMM adjusts pH=8, room temperature reaction 12 hours, TLC (CH2Cl2/MeOH=20/1) show that raw material point disappears. Remove by filter DCU, filtrate decompression is concentrated, residue 500mL acetic acid ethyl dissolution,The ethyl acetate solution obtaining is used 100mL saturated sodium bicarbonate aqueous solution successively, 100mL saturated sodium-chloride water solution, 100The saturated aqueous potassium hydrogen sulfate of mL, 100mL saturated sodium-chloride water solution, 100mL saturated sodium bicarbonate aqueous solution, 100ML saturated sodium-chloride water solution washing 3 times, ethyl acetate layer is used anhydrous sodium sulfate drying 30 minutes, mixes sample, and column chromatography is pureChange, obtain 45g (87.8%) title compound.
Embodiment 8 prepares Boc-Arg (Tos)-Gly
With 200mL methyl alcohol dissolving 45g (78.3mmol) Boc-Arg (Tos) Gly-OBzl, add wherein 9gPd/C, anti-Should bottle be above installed by threeway, water pump is evacuated to vacuum, passes into hydrogen, again repeats to vacuumize, and ventilates 2 times, and room temperature reaction 12 is littleTime, TLC (CH2Cl2/ MeOH=20/1) show that raw material point disappears, filtering Pd/C, filtrate decompression is concentrated, obtains 31g (64.0%)Title compound.
Embodiment 9 prepares Boc-Asp (OMe)-Val-OBzl
Take 5g (20.2mmol) Boc-Asp (OMe), 2.7g (19.9mmol) HOBt, (THF) is molten for dry tetrahydrofuranSeparate, under ice bath, stir, drip wherein 5g (24.3mmol) DCC that THF dissolves, stir-activating added after 30 minutes8.3g (22.0mmol) TosHVal-OBzl, NMM adjusts pH=8, room temperature reaction 12 hours, TLC (CH2Cl2/MeOH=20/1) show that raw material point disappears. Remove by filter DCU, filtrate decompression is concentrated, residue 100mL acetic acid ethyl dissolution,The ethyl acetate solution obtaining is used 20mL saturated sodium bicarbonate aqueous solution successively, 20mL saturated sodium-chloride water solution, 20mLSaturated aqueous potassium hydrogen sulfate, 20mL saturated sodium-chloride water solution, 20mL saturated sodium bicarbonate aqueous solution, 20mL is saturatedSodium-chloride water solution washing 3 times, ethyl acetate layer is used anhydrous sodium sulfate drying 30 minutes, filters, and filtrate decompression is concentrated,8.1g (92.0%) title compound.
Embodiment 10 prepares HClAsp (OMe)-Val-OBzl
Under ice bath, adding 80mL concentration to 8.1g (18.6mmol) Boc-Asp (OMe) Val-OBzl is the hydrogen chloride of 4MEthyl acetate solution, react after 4 hours TLC (CH2Cl2/ MeOH=20/1) show that raw material point disappears, reduced pressure concentration.Residue dissolves with anhydrous ethyl acetate, reduced pressure concentration. This operation repeats 3 times. Residue dissolves with absolute ether, decompressionConcentrated. This operation also repeats 3 times, obtains 6.7g (97.1%) title compound.
Embodiment 11 prepares Boc-Asp (OMe)-Phe-OBzl
Take 3g (12.1mmol) Boc-Asp (OMe), 1.6g (11.8mmol) HOBt, (THF) is molten for dry tetrahydrofuranSeparate, under ice bath, stir, drip wherein 3g (14.6mmol) DCC that THF dissolves, stir-activating added 4 after 30 minutesG (13.7mmol) HClPhe-OBzl, NMM adjusts pH=8, room temperature reaction 12 hours, TLC (CH2Cl2/MeOH＝20/1)Show that raw material point disappears. Remove by filter DCU, filtrate decompression is concentrated, and residue 100mL acetic acid ethyl dissolution, obtainsEthyl acetate solution is used 20mL saturated sodium bicarbonate aqueous solution successively, 20mL saturated sodium-chloride water solution, the saturated sulphur of 20mLThe potassium hydrogen phthalate aqueous solution, 20mL saturated sodium-chloride water solution, 20mL saturated sodium bicarbonate aqueous solution, 20mL saturated sodium-chlorideSolution washing 3 times, ethyl acetate layer is used anhydrous sodium sulfate drying 30 minutes, filters, and filtrate decompression is concentrated, obtains 5.2g(88.1%) title compound.
Embodiment 12 prepares HClAsp (OMe)-Phe-OBzl
Under ice bath, adding 50mL concentration to 5.2g (10.7mmol) Boc-Asp (OMe) Phe-OBzl is the hydrogen chloride of 4MEthyl acetate solution, react after 4 hours TLC (CH2Cl2/ MeOH=20/1) show that raw material point disappears, reduced pressure concentration.Residue dissolves with anhydrous ethyl acetate, reduced pressure concentration. This operation repeats 3 times. Residue dissolves with absolute ether, decompressionConcentrated. This operation also repeats 3 times, obtains 4.3g (95.6%) title compound.
Embodiment 13 prepares Boc-Arg (Tos)-Gly-Asp (OMe)-Val-OBzl
Take 13g (26.8mmol) Boc-Arg (Tos) Gly, 3.6g (26.6mmol) HOBt, dry tetrahydrofuran (THF)Dissolve, under ice bath, stir, drip wherein 6.5g (31.6mmol) DCC that THF dissolves, stir-activating added after 30 minutesEnter 10.7g (28.6mmol) HClAsp (OMe) Val-OBzl, NMM adjusts pH=8, room temperature reaction 12 hours, TLC(CH2Cl2/ MeOH=20/1) show that raw material point disappears. Remove by filter DCU, filtrate decompression is concentrated, residue 400mLAcetic acid ethyl dissolution, the ethyl acetate solution obtaining is used 50mL saturated sodium bicarbonate aqueous solution successively, saturated 50mL chlorinationSodium water solution, the saturated aqueous potassium hydrogen sulfate of 50mL, 50mL saturated sodium-chloride water solution, 50mL saturated sodium bicarbonate waterSolution, 50mL saturated sodium-chloride water solution washing 3 times, ethyl acetate layer is used anhydrous sodium sulfate drying 30 minutes, filters,Filtrate decompression is concentrated, obtains 18.0g (83.7%) title compound.
Embodiment 14 prepares Boc-Arg (Tos)-Gly-Asp (OMe)-Phe-OBzl
Take 25g (51.5mmol) Boc-Arg (Tos) Gly, 5.5g (40.6mmol) HOBt, dry tetrahydrofuran (THF)Dissolve, under ice bath, stir, drip wherein 11g (53.4mmol) DCC that THF dissolves, stir-activating added after 30 minutesEnter 10.7g (40.4mmol) HClAsp (OMe) Phe-OBzl, NMM adjusts pH=8, room temperature reaction 12 hours, TLC(CH2Cl2/ MeOH=20/1) show that raw material point disappears. Remove by filter DCU, be evaporated to dry, residue 400mLAcetic acid ethyl dissolution, the ethyl acetate solution obtaining is used 50mL saturated sodium bicarbonate aqueous solution successively, saturated 50mL chlorinationSodium water solution, the saturated aqueous potassium hydrogen sulfate of 50mL, 50mL saturated sodium-chloride water solution, 50mL saturated sodium bicarbonate waterSolution, 50mL saturated sodium-chloride water solution washing 3 times, ethyl acetate layer is used anhydrous sodium sulfate drying 30 minutes, filters,Filtrate decompression is concentrated, obtains 30.2g (87.8%) title compound.
Embodiment 15 prepares Fmoc-Lys[Val-Asp (OMe)-Gly-Arg (Tos)-Boc] His-Gly-Glu (OBzl)-OBzl
Take 2.7g (3.8mmol) Boc-Arg (Tos)-Gly-Asp (OMe)-Val, 515mg (3.8mmol) HOBt, dryDry oxolane (THF) dissolves, and under ice bath, stirs, and drips wherein 1.75g (4.6mmol) and is dissolved in dry DMFHATU, stir-activating adds 3.5g (3.9mmol) HClFmoc-Lys-His-Gly-Glu (OBzl)-OBzl after 30 minutes,NMM adjusts pH=8, room temperature reaction 12 hours, TLC (CH2Cl2/ MeOH=5/1) show that raw material point disappears. Reduced pressure concentration,Residue 200mL acetic acid ethyl dissolution, the ethyl acetate solution obtaining is used 30mL saturated sodium bicarbonate aqueous solution successively,30mL saturated sodium-chloride water solution, the saturated aqueous potassium hydrogen sulfate of 30mL, 30mL saturated sodium-chloride water solution, 30mLSaturated sodium bicarbonate aqueous solution, 30mL saturated sodium-chloride water solution washing 3 times, ethyl acetate layer anhydrous sodium sulfate drying30 minutes, mix sample, column chromatography purification, obtains 2.2g (40.0%) title compound. ESI-MS (m/z): 1668.5[M+H]+。
Embodiment 16 prepares Fmoc-Lys[Phe-Asp (OMe)-Gly-Arg (Tos)-Boc] His-Gly-Glu (OBzl)-OBzl
Take 3.8g (5.0mmol) Boc-Arg (Tos)-Gly-Asp (OMe)-Phe, 676mg (5.0mmol) HOBt, dryDry oxolane (THF) dissolves, and under ice bath, stirs, and drips wherein 2.1g (5.5mmol) and be dissolved in the HATU of dry DMF,Stir-activating adds 4.5g (5.0mmol) HClFmoc-Lys-His-Gly-Glu (OBzl)-OBzl after 30 minutes, NMM adjustsPH=8, room temperature reaction 12 hours, TLC (CH2Cl2/ MeOH=5/1) show that raw material point disappears. Reduced pressure concentration, residueUse 200mL acetic acid ethyl dissolution, the ethyl acetate solution obtaining is used 30mL saturated sodium bicarbonate aqueous solution, 30mL successivelySaturated sodium-chloride water solution, the saturated aqueous potassium hydrogen sulfate of 30mL, 30mL saturated sodium-chloride water solution, 30mL saturated carbonAcid hydrogen sodium water solution, 30mL saturated sodium-chloride water solution washing 3 times, ethyl acetate layer is used anhydrous sodium sulfate drying 30 minutes,Mix sample, column chromatography purification, obtains 2.7g (33.8%) title compound. ESI-MS (m/z): 1716.8[M+H]+。
Embodiment 17 prepares 17-carbethoxyl group methoxy acetyl group dexamethasone
Take 20g (51.5mmol) dexamethasone 50mLDMSO and dissolve, be placed under ice bath and stir, take 1.3g(52.1mmol) NaH carefully adds in reaction bulb, measures 17mL bromoacetate and is added drop-wise in reaction bulb, room temperature reaction 2Hour, then in reaction bulb, adding 400mL ethyl acetate, the solution obtaining is washed 5 times with saturated sodium-chloride water solution, everyInferior 50mL, anhydrous sodium sulfate drying, filters, and filtrate decompression concentrates to obtain 15.1g (62.9%) title compound. Mp:225-226℃，(c＝0.1，CH3OH)，ESI-MS(m/z)：479.84[M+H]+，1HNMR(300MHz，CDCl3)：δ/ppm＝7.23-7.20(d，J＝9Hz，1H)，6.36-6.33(d，J＝9Hz，1H)，6.12(s，1H)，4.52(m，2H)，4.40-4.37(d，J＝9Hz，1H)，4.22(m，4H)，3.11(m，1H)，2.39(m，3H)，1.81(m，3H)，1.56(m，5H)，1.30(m，4H)，1.08(s，3H)，0.95-0.92(d，J＝9Hz，3H)。
Embodiment 18 prepares 17-carboxylic methoxy acetyl group dexamethasone
With 100mL methyl alcohol dissolving 15.1g (31.6mmol) 17-carbethoxyl group methoxy acetyl group dexamethasone, under ice bath, use2NNaOH regulates pH=12, reacts and maintains pH=12, TLC (CH after 15 hours under ice bath2Cl2/ EA=1/1) showRaw material point disappears. Reactant mixture is adjusted pH=7 with saturated aqueous potassium hydrogen sulfate, reduced pressure concentration, and residue steams with 200mLHeat up in a steamer water-soluble solution, adjust pH=2 with saturated aqueous potassium hydrogen sulfate, be extracted with ethyl acetate 3 times, each 60mL, merges acetic acidMethacrylate layer, with anhydrous sodium sulfate drying, reduced pressure concentration, the colourless powder obtaining washs with carbon dichloride, filters, and collects filter cake,Obtain 12.8g (90.1%) title compound. Mp232-233 DEG C, ESI-MS (m/z): 449.3[M-H]-,(c＝0.1，CH3OH)，1HNMR(300MHz，DMSO-d6)：δ/ppm＝7.31-7.28(d，J＝9Hz，1H)，6.23-6.20(d，J＝9Hz，1H)，6.01(s，1H)，5.30(m，1H)，5.04(s，1H)，4.45(m，2H)，4.19(m，1H)，4.03(s，2H)，2.91(m，1H)，2.61(m，1H)，2.34(m，2H)，2.16(m，2H)，1.75(m，1H)，1.61(m，1H)，1.49(s，3H)，1.33(m，1H)，1.08(m，1H)，0.87(s，3H)，0.80-0.77(d，J＝9Hz，3H)。
Embodiment 19 prepares dexamethasone-17-carbonyl methoxy acetyl group
-Lys[Val-Asp(OMe)-Gly-Arg(Tos)-Boc]-His-Gly-Glu(OBzl)-OBzl
Take 1.3g (2.9mmol) 17-carboxylic methoxy acetyl group dexamethasone, 270mg (2.0mmol) HOBt, is dissolved in nothingIn water DMF, under ice bath, stir, drip wherein the HATU that 1.1g (2.9mmol) dry DMF is dissolved, stir-activatingAfter 30 minutes, add 2.7g (2.0mmol) Lys[Val-Asp (OMe)-Gly-Arg (Tos)-Boc] His-Gly-Glu (OBzl)-OBzl, NMM adjusts pH=8, room temperature reaction 12 hours, TLC (CH2Cl2/ MeOH=5/1) show that raw material point disappears. IceBathe in downhill reaction liquid and add 200mL saturated sodium-chloride water solution, be extracted with ethyl acetate 3 times, each 50mL, mergesEthyl acetate layer, uses 30mL saturated sodium bicarbonate aqueous solution successively, 30mL saturated sodium-chloride water solution, the saturated sulphur of 30mLThe potassium hydrogen phthalate aqueous solution, 30mL saturated sodium-chloride water solution, 30mL saturated sodium bicarbonate aqueous solution, 30mL saturated sodium-chlorideThe each washing of the aqueous solution 3 times, anhydrous sodium sulfate drying, is evaporated to 1mL and mixes sample, column chromatography purification with chromatographic silica gel afterwards(CH2Cl2/ MeOH=15/1), obtain 1.217g (33.8%) title compound. Mp:144.3-147.0,(c＝0.1，CH3OH)，ESI-MS(m/z)：1779.8102[M+H]+，1HNMR(300MHz，DMSO-d6)：δ/ppm＝8.69(s，1H)，8.26(m，2H)，8.10(s，2H)，7.90(m，2H)，7.65(m，3H)，7.51(s，1H)，7.31(m，15H)，6.89(m，4H)，6.59，(s，1H)，6.23-6.20(d，J＝9Hz，1H)，6.01(s，1H)，5.38(s，1H)，5.13(s，2H)，5.06(m，4H)，4.68(m，2H)，4.45(m，2H)，4.29(m，2H)，4.17-4.14(d，J＝9Hz，1H)，4.05(m，1H)，3.93(m，4H)，3.72(m，3H)，3.56(s，4H)，2.94(m，4H)，2.60(m，2H)，2.34(s，5H)，2.12(m，3H)，1.95(m，2H)，1.62(m，7H)，1.28(m，17H)，0.89(m，3H)，0.80(m，6H)。
Embodiment 20 prepares dexamethasone-17-carbonyl methoxy acetyl group-Lys (Val-Asp-Gly-Arg)-His-Gly-Glu (5a)
Take 380mg (0.21mmol) dexamethasone-17-carbonyl methoxy acetyl group-Lys[Val-Asp (OMe)-Gly-Arg (Tos)-Boc]-His-Gly-Glu (OBzl)-OBzl is in 100mL eggplant bottle, under ice bathAdd trifluoroacetic acid 3mL, stir and add TFMS 1mL after 15 minutes, continue to stir 15 minutes, add 80mLAbsolute ether, separates out product, stirs 5 minutes, leaves standstill, and sedimentation precipitate, carefully pours out liquid. Residue adds diethyl etherWashing, carefully pours out liquid. The residue washing that adds diethyl ether, carefully pours out liquid. Residue removal of solvent under reduced pressure, residualStay thing to add 5mL distilled water and dissolve, the solution obtaining is adjusted pH to 7 with weak aqua ammonia, filters, and filtrate is de-with SephdexG10Salt, freeze-drying, obtains 102mg (35.9%) title compound. Mp:96.8-97.4,(c＝0.03，H2O)，ESI-MS(m/z)：1349.19[M+NH4]+，1HNMR(300MHz，DMSO-d6)：δ/ppm＝8.29(m，2H)，8.14(m，5H)，7.78(m，5H)，7.53(m，8H)，7.13-7.10(d，J＝9Hz，1H)，6.79(s，2H)，6.23-6.20(d，J＝9Hz，1H)，6.01(s，1H)，4.63(m，2H)，4.49(m，2H)，4.20(m，2H)，3.72(m，6H)，3.57(s，2H)，3.07(m，5H)，2.72(m，3H)，2.42(m，4H)，2.00(m，6H)，1.62(m，7H)，1.26(m，8H)，0.96(s，3H)，0.83(m，6H)。
Embodiment 21 prepares dexamethasone-17-carbonyl methoxy acetyl group
-Lys[Phe-Asp(OMe)-Gly-Arg(Tos)-Boc]His-Gly-Glu(OBzl)-OBzl
Take 1.0g (2.2mmol) 17-carboxylic methoxy acetyl group dexamethasone, 218mg (1.6mmol) HOBt, is dissolved in nothingWater DMF, stirs under ice bath, drips wherein the HATU that 857mg (2.3mmol) dry DMF is dissolved, stir-activatingAfter 30 minutes, add 2.2g (1.6mmol)Lys[Phe-Asp (OMe)-Gly-Arg (Tos)-Boc] His-Gly-Glu (OBzl)-OBzl, NMM adjusts pH=8, room temperature reaction12 hours, TLC (CH2Cl2/ MeOH=5/1) show that raw material point disappears. In ice bath downhill reaction liquid, add saturated sodium-chlorideSolution 200mL, ethyl acetate extraction 3 times, each 50mL, combined ethyl acetate layer, uses 30mL unsaturated carbonate hydrogen successivelySodium water solution, 30mL saturated sodium-chloride water solution, the saturated aqueous potassium hydrogen sulfate of 30mL, 30mL saturated sodium-chloride is water-solubleLiquid, 30mL saturated sodium bicarbonate aqueous solution, the each washing of 30mL saturated sodium-chloride water solution 3 times, anhydrous sodium sulfate drying,Be evaporated to 1mL and mix sample, column chromatography purification (CH with chromatographic silica gel afterwards2Cl2/ MeOH=15/1), obtain 873mg(30.1%) title compound. Mp:151.9-153.4,(c＝0.1，CH3OH)，ESI-MS(m/z)：1826.7932[M+H]+，1HNMR(300MHz，DMSO-d6)：δ/ppm＝8.70(s，1H)，8.28(m，2H)，8.14(m，4H)，7.87(m，4H)，7.64(m，3H)，7.51(s，1H)，7.28(m，20H)，6.89(m，4H)，6.60，(s，1H)，6.23-6.20(d，J＝9Hz，1H)，6.01(s，1H)，5.38(s，1H)，5.13(s，2H)，5.06(m，4H)，4.65(m，2H)，4.35(m，6H)，4.17-4.14(d，J＝9Hz，1H)，3.80(m，8H)，3.55(s，4H)，2.73(m，4H)，2.47(m，3H)，2.33(s，6H)，2.08(m，5H)，1.58(m，8H)，1.28(m，16H)，0.93(m，3H)。
Embodiment 22 prepares dexamethasone-17-carbonyl methoxy acetyl group-Lys (Phe-Asp-Gly-Arg)-His-Gly-Glu (5b)
Take 365mg (0.20mmol) dexamethasone-17-carbonyl methoxy acetyl group-Lys[Phe-Asp (OMe)-Gly-Arg (Tos)-Boc] His-Gly-Glu (OBzl)-OBzl is in 100mL eggplant bottle, under ice bathAdd trifluoroacetic acid 3mL, stir and add TFMS 1mL after 15 minutes, continue reaction and within 15 minutes, add 80mLAbsolute ether, separates out product, stirs and stops after 5 minutes, and standing, sedimentation precipitate, carefully pour out liquid. ResidueThe washing that adds diethyl ether, carefully pours out liquid. The residue washing that adds diethyl ether, carefully pours out liquid. Residue decompression is removed moltenAgent, residue adds 5mL distilled water and dissolves, and obtains solution weak aqua ammonia and adjusts pH to 7, filters filtrate SephdexG10Desalination, freeze-drying, obtains 91mg (33.0%) title compound. Mp:92.7-93.8,(c＝0.03，H2O)，ESI-MS(m/z)：1396.15[M+NH4]+，1HNMR(300MHz，DMSO-d6)：δ/ppm＝8.42(m，2H)，8.13(m，3H)，7.83(m，1H)，7.73(m，1H)，7.52(m，6H)，7.18(m，7H)，6.76(m，1H)，6.19-6.16(d，J＝9Hz，1H)，6.00(s，1H)，5.44(s，1H)，4.51(m，1H)，4.42(m，1H)，4.35(m，1H)，4.25(m，1H)，4.11(m，1H)，3.99(m，1H)，3.72(m，6H)，3.51(s，3H)，3.37(m，4H)，2.87(m，4H)，2.39(m，3H)，1.76(m，1H)，1.61(m，6H)，1.53(m，8H)，0.92(m，3H)。
Experimental example 1 is measured 5a, the transmission electron microscope photo of b
By 5a, it is 1.43 × 10 that b is made into concentration-6The aqueous solution of M, then drops in this solution on copper mesh, volatilizees after dry solventUnder JEM-1230 transmission electron microscope, observe nano shape. Mensuration shows, 5a, the nanosphere of b formation rule. AsRepresentative photo, Fig. 2 is that concentration is 1.43 × 10-6The 5a of M, the transmission electron microscope photo of b. Result shows, 5a, the nanometer of bStructure is the nanosphere that diameter is less than 100nn. Visible, 5a, the nanostructured of b is very beneficial for them and carries in vivo.
Experimental example 2 is evaluated 5a, the impact that b transplants mouse ear rear myocardium tissue
Acceptor mouse (Balb/c mouse, male, body weight 20 ± 2g) through 10% urethane (10mg/10g body weight) abdominal cavityInjecting anesthetic. 1% bromogeramine tincture auricle partly sterilised, holds eye scissors 1/3 place's work one and ear before auricle dorsal part center lineWide center line vertically locates to do the otch of a 3-4 millimeters long, does not damage auricle vein. Hold tweezers subcutaneous to have sharp ears direction blunt separationTissue, makes it into a tube chamber. New life is placed in to trash ice after one minute 75% for mouse (C57bl/6j24 hour suckling mouse)Alcohol skin degerming, cuts open chest and wins heart. Heart is placed in and in PBS liquid, beats 1-2 time with blood more than the emptying chambers of the heart. When transplanting,With blade, longitudinally cuing open and become large two halves such as basic grade for the heart, muscle fibre becomes an inclined-plane. Cardiac muscular tissue is transplanted and inserts acceptor mouseIn ear chamber, the isolated time of cardiac muscular tissue is no more than 2 minutes. With finger flicking part, make graft and the group around that is subject to mouseKnit and be adjacent to. Post-transplantation administration on the same day. Blank is physiological saline, 5a, b physiological saline solution, all oral administrations, agentAmount is 0.1 μ mol/kg/d, 0.2mL/20g body weight, successive administration 15 days, altogether administration 15 times. Within postoperative the 7th day, rise every dayRecord the electrocardiosignal of heart transplantation muscular tissue, when test exocardia electrograph, positive and negative electrode is placed in respectively heart transplant both sides, connectsEarth polar is connected to mouse hind leg.
Draw and transplant myocardium survival curve Fig. 3. Result shows, the 17th day after surgery 5a, and it is dead that b group just occurs transplanting cardiac muscle,Myocardial viability rate increases substantially than dexamethasone. This presentation of results, 5a under the dosage of 0.1 μ mol/kg/d, b is significantlySuppress the rejection of heart transplantation muscular tissue. With the once effective dose (1.43 of the compound of structure A openly of inventorμ mol/kg) to compare, effective dose of the present invention has reduced by 14 times. With the once compound of structure B openly of inventorEffective dose (2.0 with 7.0mmol/kg) is compared, and effective dose of the present invention has reduced by 2000 times and 7500 times. Obviously, originallyInvention has obtained the result of beyond thought inhibition heart transplantation muscular tissue rejection.
The scorching model evaluation 5a of experimental example 3 use mouse caused by dimethylbenzene xylene, the anti-inflammatory activity of b
Use the scorching model evaluation 5a of mouse caused by dimethylbenzene xylene, b anti-inflammatory activity. Dexamethasone and 5a, the equal single administration of b, dexamethasoneOral dose be 25.5 μ mol/kg, 5a, the oral dose of b is 2.55 μ mol/kg. Physiological saline is blank. ICRMale mice (body weight 20 ± 2g) is divided into blank group at random, positive group and administration group, 10 every group. Tranquillization one day,Operation room holding temperature is 22 DEG C, and experiment starts, and oral administration is after single-dose 30min, even toward the left auricle of mouseSmear 30 μ L dimethylbenzene, after 2h, disconnected mortar is put to death mouse, cuts left and right two ears, and the card punch of use 7mm is identical two earsCircular auricle is got in position, weighs, and obtains two ear swelling differences, as swelling, and swelling=left ear disk weight-right sideEar disk weight. Table 1 data declaration, 5a under 2.55 μ mol/kg dosage, b suppresses the inflammatory reaction of mouse effectively. WithInventor once disclosed the effective dose (25.5 μ mol/kg) of the compound of structure A and compared, and effective dose of the present invention reduces10 times. The compound that inventor once disclosed structure B does not have anti-inflammatory activity. Obviously, the present invention has obtained and has expected not
The result of the inflammation-inhibiting arriving. The impact of table 1 compound of the present invention on mice ear degree
N=10, oral administration, the variance t inspections such as two samples; A) P < 0.01 compared with physiological saline group; B) with physiological saline and dexamethasoneGroup is compared P < 0.01.
Experimental example 4 is evaluated 5a, the impact of b on mouse femur
Experimental example 2 small mouses disconnected mortar after transplanting the whole death of cardiac muscle is put to death, and gets femur and weighs and measure bone density. Table 3Data declaration, 5a under 0.1 μ mol/kg dosage, b can not cause that mouse produces osteoporosis. Once open with inventorThe compound of structure A does not cause that osteoporotic effective dose (1.43 μ mol/kg) compares, and effective dose of the present invention reduces10 times. The compound that inventor once disclosed structure B does not have anti-osteoporosis activity. Obviously, the present invention has obtained meaningThe result of unimaginable anti-osteoporosis.
Weight and the Effects of Density of table 2 compound of the present invention to femur
N=10, oral administration, successive administration 15 days, the variance t inspections such as two samples: a) compared with physiological saline group, P < 0.05; And physiology b)Salt solution group is compared P > 0.05, P < 0.05 compared with dexamethasone.
Experimental example 5 is evaluated 5a, and b is on thrombotic impact
Male SD rat is divided into group at random: blank is physiological saline, positive control is aspirin, dosage 167μ mol/kg; Administration group dexamethasone and 5a, b dosage is 0.99 μ mol/kg. After oral administration 30 minutes, urethane (20G/100mL, 7mL/kg) anesthesia. Separate right carotid and left jugular vein, the silk of the long prior precise weighing of a 6cmLine is placed in polyethylene pipe, intubate is full of to the normal saline solution of anti-coagulants liquaemin (0.42mg/mL, 0.42mg/kg)After, left side vein is inserted in one end, injects quantitative liquaemin anti-freezing, then inserts right side artery. Blood flow is flowed through from right side arteryPolyethylene pipe flows into left side vein, circulates 15 minutes. After 15min, take out silk thread, accurately weigh, calculate weightening finish, statisticsizationThe antithrombotic acitivity of compound. Result is listed table 3 in. The data declaration of table 3,5a under 0.99 μ mol/kg dosage, b is effectivelySuppress rat and form thrombus. The compound that inventor once disclosed structure A and B does not all have antithrombotic acitivity. Obviously, originallyInvention has obtained beyond thought antithrombotic result.
The antithrombotic acitivity of table 3 compound of the present invention
N=9, oral administration, 0.99 μ mol/kg, the variance t inspection .a such as two samples) P < 0.01 compared with physiological saline; B) P compared with physiological saline< 0.05; C) compare P < 0.01 with Dexamethasone group with physiological saline.
Claims (5)
1. the dexamethasone that the octapeptide Lys (AA-Asp-Gly-Arg) of following formula-His-Gly-Glu modifies,
Formula AA is L-Val or L-Phe residue.
2. the method for the dexamethasone that octapeptide Lys (the AA-Asp-Gly-Arg)-His-Gly-Glu of preparation claim 1 modifies,This compound comprises three large steps:
1), in DMSO, the hydroxyl of 17 glycolyls of NaH catalysis dexamethasone and bromoacetate take off HBr, by 17Glycolyl is converted into carbethoxyl group methoxy acetyl group. In NaOH solution, 17 carbethoxyl group methoxy acetyl group are transformed againBe 17 carboxylic methoxy acetyl group;
2) connect peptide method according to the liquid phase of standard, progressively connect peptide, the full guard by the side chain amino of L-Boc-Lys with carboxylic end dissociativeRGDV or the carboxylic end coupling of RGDF, by the N end of the His-Gly-Glu of the carboxylic end of L-Lys and the free full guard of alpha-amidoCoupling, octapeptide Fmoc-Lys[AA-Asp (OMe)-Gly-Arg (the Tos)-Boc of preparation full guard)]-His-Gly-Glu (OBzl)-OBzl, then in the DMF of 20% piperidines solution, de-Fmoc prepares the free full guard octapeptide of NLys[AA-Asp (OMe)-Gly-Arg (Tos)-Boc)]-His-Gly-Glu (OBzl)-OBzl, in formula, AA is L-Val or L-PheResidue;
3) at HATU, under HOBt and NMM exist, in dry DMF, the dexamethasone-17-carboxylic first step 1 being obtainedLys[AA-Asp (OMe)-Gly-Arg (Tos)-Boc that acid and step 2 obtain)]-His-Gly-Glu (OBzl)-OBzl coupling, thenIn trifluoroacetic acid, slough whole protecting groups with TFMS, make the octapeptide of claim 1The dexamethasone that Lys (AA-Asp-Gly-Arg)-His-Gly-Glu modifies.
3. the nanostructured of the dexamethasone that the octapeptide Lys (AA-Asp-Gly-Arg) of claim 1-His-Gly-Glu modifies.
4. the dexamethasone that the octapeptide Lys (AA-Asp-Gly-Arg) of claim 1-His-Gly-Glu modifies presses down in preparation immunityApplication in preparation, is characterized in that the immunodepressant that makes has overcome the loose and thrombus of spongy bone that dexamethasone causesSide effect.
5. the dexamethasone that the octapeptide Lys (AA-Asp-Gly-Arg) of claim 1-His-Gly-Glu modifies is being prepared antiinflammatoryIn application, it is characterized in that the antiinflammatory making has overcome the loose and thrombus side effect of spongy bone that dexamethasone causes.
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