CN105504013B - Octapeptide modified dexamethasone, preparation, nanostructure and application thereof - Google Patents
Octapeptide modified dexamethasone, preparation, nanostructure and application thereof Download PDFInfo
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Abstract
The invention discloses an octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone with the following formula, wherein AA in the octapeptide is L-Val or L-Phe. Discloses a preparation method thereof, discloses a nano structure thereof, discloses an inhibition effect thereof on myocardial graft immune rejection reaction after mouse ear, discloses an inhibition effect thereof on inflammatory reaction caused by dimethylbenzene, and further discloses that the side effects of osteoporosis and thrombus are not generated like dexamethasone.
Description
Technical Field
The invention relates to octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone, wherein AA in the octapeptide is L-Val or L-Phe residue. Relates to a preparation method thereof, relates to a nano structure thereof, relates to an inhibition effect thereof on myocardial graft immune rejection reaction after mouse ear, relates to an inhibition effect thereof on inflammatory reaction caused by dimethylbenzene, and further relates to the side effect that the nano structure thereof does not generate osteoporosis and thrombus like dexamethasone. Therefore, the invention relates to the application prospect of octapeptide modified dexamethasone in preparing immunosuppressive and anti-inflammatory drugs. The invention belongs to the field of biological medicine.
Background
The replacement of waste organs by organ transplantation has become a routine treatment for clinical surgery. Immune rejection in organ transplantation is the most important factor in organ transplantation failure. Patients receiving organ transplantation take dexamethasone glucocorticoid immunosuppressant after operation, which is one of the important measures for avoiding rejection reaction and prolonging the survival time of transplanted organs. An additional important clinical application of dexamethasone glucocorticoids is the treatment of rheumatic diseases, autoimmune diseases and severe infections or inflammatory diseases. Patients take dexamethasone glucocorticoid for a long time, and osteoporosis and thrombotic diseases are inevitably induced. At present, the only method for reducing the side effect risk of dexamethasone glucocorticoids is to stop taking the medicine. The consequence of discontinuation is a decrease in efficacy. The structure of the dexamethasone glucocorticoid is modified, and the side effect is reduced or avoided, so that the method is a hotspot for researching the dexamethasone glucocorticoid.
The inventors have modified corticosteroids with RGD tetrapeptides to prepare compounds of structure A. They can prolong the survival time of the myocardium of transplanted suckling mice under the dosage of 1.43 mu mol/kg. They can inhibit the inflammation of mice at the dose of 25.5 mu mol/kg. They do not induce osteoporosis in mice at the dose of 1.43. mu. mol/kg. Whether there is no risk of thrombosis at a dose of 1.43. mu. mol/kg, was not concluded.
Structure A. RGD tetrapeptide modified corticoids, once disclosed by the inventors
The inventors have also modified hydrocortisone and prednisolone with the uremic tripeptide to prepare compounds of structure B. They can prolong the survival time of transplanted myocardium of suckling mouse at 7.5mmol/kg and 2.0mmol/kg respectively. Their anti-inflammatory activity was not found. Whether they are free of osteoporosis and thrombotic risk at doses of 7.5mmol/kg and 2.0mmol/kg, when not stated.
Structure B. Nicotoxin tripeptide modified hydrocortisone and prednisolone that the inventors have also disclosed
The structure of dexamethasone is modified by adopting a new method, the dosage of the dexamethasone is further reduced, the side effect of osteoporosis and the side effect of thrombosis are eliminated, and the dexamethasone injection is a new technology which is developed by the inventor all the time. Through various combinations, the inventors recognized that separation of the peptide from the steroidal five-membered ring by more than five atoms is one of the problems. Thus, the inventors have prepared a compound of the following formula by substituting acetyl for succinyl. The curative effect is not obviously improved.
Next, the inventors prepared a compound of the following formula by adopting a strategy of reversing the attachment of RGD tetrapeptide to the side chain amino group of L-Lys. Although the efficacy was not significantly improved, neither osteoporosis nor thrombotic side effects occurred.
Finally, the inventors have prepared the compound of the present invention by adopting a strategy of inverting α -amino group of L-Lys linked to the above compound by the uremic toxin tripeptide Glu-Asp-Gly, achieving the triple objectives of reducing the dosage, eliminating the side effect of osteoporosis and eliminating the side effect of thrombosis.
Disclosure of Invention
The first technical problem to be solved by the invention is to provide an octapeptide modified dexamethasone structure shown in the formula. In which AA is a residue of L-Val and L-Phe.
The second technical problem to be solved by the invention is to provide a method for preparing octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone, wherein the compound comprises three steps:
1) in DMSO, NaH catalyzes the de-HBr reaction between the hydroxyl group of the 17-position hydroxyacetyl group of dexamethasone and ethyl bromoacetate, and converts the 17-position hydroxyacetyl group into ethoxycarbonylmethoxyacetyl group. Then converting the 17-position ethoxycarbonyl methoxyacetyl into 17-position carboxymethoxyacetyl in NaOH solution;
2) stepwise peptide attachment according to standard liquid phase peptide attachment procedure, coupling the side chain amino group of L-Boc-Lys to the carboxy-terminus of carboxy-free fully protected RGDV or RGDF, coupling the carboxy-terminus of L-Lys to the N-terminus of α -amino free fully protected Glu-Asp-Gly, preparing fully protected octapeptide Fmoc-Lys [ AA-Asp (OMe) -Gly-Arg (tos) -Boc) ] -Glu (OBzl) -Asp (OBzl) -Gly-OBzl, followed by Fmoc elimination in 20% piperidine DMF solution to prepare N free fully protected octapeptide Lys [ AA-Asp (OMe) -Gly-Arg (tos) -Boc) ] -Glu (OBzl) -Asp (OBzl) -Gly-OBzl, wherein AA is L-Val or L-Phe residue;
3) coupling dexamethasone-17-carboxylic acid obtained in step 1 with Lys [ AA-Asp (OMe) -Gly-Arg (tos) -Boc) ] -Glu (OBzl) -Asp (OBzl) -Gly-OBzl obtained in step 2 in anhydrous DMF in the presence of HATU, HOBt and NMM, and removing all protecting groups with trifluoromethanesulfonic acid in trifluoroacetic acid to obtain octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone of claim 1 (wherein AA is L-Val or L-Phe residue).
The third technical problem to be solved by the invention is to evaluate that octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone (wherein AA is L-Val or L-Phe residue) prolongs survival time of transplanted myocardium after ears of mice.
The fourth technical problem to be solved by the invention is to evaluate the activity of the octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone (wherein AA is L-Val or L-Phe residue) for inhibiting the inflammation of the mice.
The fifth technical problem to be solved by the invention is to evaluate the activity of the octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone (wherein AA is L-Val or L-Phe residue) for inhibiting the thrombosis of rats.
The sixth technical problem to be solved by the invention is to evaluate the activity of the octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone (wherein AA is L-Val or L-Phe residue) for inhibiting the osteoporosis of mice.
Drawings
FIG. 1 Synthesis of the octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone (wherein AA is L-Val or L-Phe residue.) I) DMSO, BrCH2CO2C2H5，NaH；ii)MeOH，NaOH；iii)DCC，HOBt，NMM；iV)4N HCl/EtOAc，v/v)H2Pt/C; vi) HATU, HOBt, NMM; vii) 20% piperidine/DMF; viii) TFMSA, TFA.
FIG. 2 the concentration is 1.43X 10-6And (3) a transmission electron microscope photo of the M octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone (wherein AA is L-Val or L-Phe residue) in an aqueous solution.
Figure 3 effect of compound on myocardial survival following myocardial transplantation in mice ears, n 10, orally administered, 0.1 μmol/kg/day for 15 consecutive days.
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 preparation of Boc-Asp (OBzl) -Gly-OBzl
17.6g (54.2mmol) of Boc-Asp (OBzl), 7.3g (53.9mmol) of HOBt were weighed, dissolved in dry Tetrahydrofuran (THF), stirred in ice bath, 13.4g (65.0mmol) of DCC dissolved in THF was added dropwise thereto, stirred and activated for 30 minutes, 12.0g (59.6mmol) of HCl-Gly-OBzl was added thereto, NMM was adjusted to pH 8, and the reaction was carried out at room temperature for 12 hours, TLC (CH)2Cl2MeOH 20/1) showed the disappearance of the starting point. DCU was removed by filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in 200mL of ethyl acetate, and the obtained ethyl acetate solution was sequentially washed with 50mL of a saturated aqueous sodium bicarbonate solution, 50mL of a saturated aqueous sodium chloride solution, and 50mL of a saturated aqueous potassium hydrogen sulfate solutionThe solution, 50mL of a saturated aqueous solution of sodium chloride, 50mL of a saturated aqueous solution of sodium hydrogencarbonate and 50mL of a saturated aqueous solution of sodium chloride were each washed 3 times, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 24.0g (93.8%) of the title compound.
EXAMPLE 2 preparation of HCl. Asp (OBzl) -Gly-OBzl
To 24.0g (50.8mmol) of Boc-Asp (OBzl) Gly-OBzl was added 200mL of 4M hydrogen chloride in ethyl acetate under ice-bath, and after 2 hours of reaction, TLC (CH)2Cl2MeOH 20/1) showed the disappearance of the starting point. Concentrating under reduced pressure. The residue was dissolved in anhydrous ethyl acetate and concentrated under reduced pressure. This operation was repeated 3 times. The residue was dissolved in anhydrous ether and concentrated under reduced pressure. This operation was also repeated 3 times. 19.6g (93.3%) of the title compound are obtained.
EXAMPLE 3 preparation of Boc-Glu (OBzl) -Asp (OBzl) -Gly-OBzl
3.9g (11.6mmol) of Boc-Glu (OBzl), 1.65g (12.2mmol) of HOBt were weighed, dissolved in dry Tetrahydrofuran (THF), stirred in ice bath, 2.86g (13.9mmol) of DCC dissolved in THF were added dropwise thereto, stirred and activated for 30 minutes, 5.7g (13.9mmol) of HCl & Asp (OBzl) Gly-OBzl were added, NMM was adjusted to pH 8, and the mixture was reacted at room temperature for 12 hours, TLC (CH) was performed2Cl2MeOH 20/1) indicating the disappearance of the starting material dot. DCU was removed by filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in 200mL of ethyl acetate, the obtained ethyl acetate solution was washed with 50mL of a saturated aqueous sodium bicarbonate solution, a saturated 50mL of an aqueous sodium chloride solution, 50mL of a saturated aqueous potassium hydrogensulfate solution, 50mL of a saturated aqueous sodium chloride solution, 50mL of a saturated aqueous sodium bicarbonate solution, and 50mL of a saturated aqueous sodium chloride solution in this order for 3 times, the ethyl acetate layer was dried over anhydrous sodium sulfate for 30 minutes, and the filtrate was concentrated under reduced pressure to obtain 6.3g (78.8%) of the title compound.
EXAMPLE 4 preparation of HCl. Glu (OBzl) -Asp (OBzl) -Gly-OBzl
To 6.3g (9.1mmol) of Boc-Glu (OBzl) Asp (OBzl) Gly-OBzl was added 100mL of a 4M solution of hydrogen chloride in ethyl acetate under ice-bath, and after 2 hours of reaction, TLC (CH)2Cl2MeOH 20/1) showed the disappearance of the starting point. Concentrating under reduced pressure. The residue was dissolved in anhydrous ethyl acetate and concentrated under reduced pressure. This operation was repeated 3 times. The residue was extracted with anhydrous diethyl etherDissolving, and concentrating under reduced pressure. This operation was also repeated 3 times to give 5.5g (96.5%) of the title compound.
EXAMPLE 5 preparation of Fmoc-Lys (Boc) -Glu (OBzl) -Asp (OBzl) -Gly-OBzl
22.5g (48.0mmol) of Fmoc-Lys (Boc), 6.5g (48.0mmol) of HOBt were weighed, dried Tetrahydrofuran (THF) was dissolved, stirring was performed in ice bath, 12g (58.3mmol) of DCC dissolved in THF was added dropwise thereto, after stirring and activation for 30 minutes, 30g (48.0mmol) of HCl & Glu (OBzl) Asp (OBzl) Gly-OBzl was added, NMM was adjusted to pH 8, reaction was performed at room temperature for 12 hours, and TLC (CH)2Cl2MeOH 10/1) showed the disappearance of the starting point. DCU was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 400mL of ethyl acetate, and the obtained ethyl acetate solution was washed with 100mL of a saturated aqueous sodium bicarbonate solution, 100mL of a saturated aqueous sodium chloride solution, 100mL of a saturated aqueous potassium hydrogen sulfate solution, 100mL of a saturated aqueous sodium chloride solution, 100mL of a saturated aqueous sodium bicarbonate solution, and 100mL of a saturated aqueous sodium chloride solution in this order for 3 times, and the ethyl acetate layer was dried over anhydrous sodium sulfate for 30 minutes, sampled, and purified by column chromatography to obtain 42.1g (84.2%) of the title compound. ESI-MS (m/z): 1040.9[ M + H]+。
EXAMPLE 6 preparation of HCl. Fmoc-Lys-Glu (OBzl-) Asp (OBzl) -Gly-OBzl
42.1g (40.5mmol) Fmoc-Lys (Boc) Glu (OBzl) Asp (OBzl) Gly-OBzl was added with ice bath to 500mL of 4M hydrogen chloride in ethyl acetate, reacted for 6 hours, followed by TLC (CH)2Cl2MeOH 10/1) showed the disappearance of the starting point. Concentrating under reduced pressure. The residue was dissolved in anhydrous ethyl acetate and concentrated under reduced pressure. This operation was repeated 3 times. The residue was dissolved in anhydrous ether and concentrated under reduced pressure. This procedure was also repeated 3 times to give 38g (96.2%) of the title compound. ESI-MS (m/z): 941.2[ M + H]+
EXAMPLE 7 preparation of Boc-Arg (tos) -Gly-OBzl
38.5g (90.0mmol) of Boc-Arg (tos), 12g (88.6mmol) of HOBt were weighed, dried Tetrahydrofuran (THF) was dissolved, stirred in ice bath, 22g (109.2mmol) of DCC dissolved in THF was added dropwise thereto, stirred and activated for 30 minutes, 22g (109.2mmol) of HCl. Gly-OBzl was added, NMM was adjusted to pH 8, and the reaction was carried out at room temperature for 12 hours, TLC (CH-O-B-H-H2Cl2MeOH 20/1) showed the disappearance of the starting point. Filtering to remove DCU, filteringThe solution was concentrated under reduced pressure, and the residue was dissolved in 500mL of ethyl acetate, and the resulting ethyl acetate solution was washed with 100mL of a saturated aqueous sodium bicarbonate solution, 100mL of a saturated aqueous sodium chloride solution, 100mL of a saturated aqueous potassium hydrogen sulfate solution, 100mL of a saturated aqueous sodium chloride solution, 100mL of a saturated aqueous sodium bicarbonate solution, and 100mL of a saturated aqueous sodium chloride solution in this order for 3 times, and the ethyl acetate layer was dried over anhydrous sodium sulfate for 30 minutes, stirred, and purified by column chromatography to give 45g (87.8%) of the title compound.
EXAMPLE 8 preparation of Boc-Arg (tos) -Gly
Dissolving 45g (78.3mmol) of Boc-Arg (tos) Gly-OBzl in 200mL of methanol, adding 9g of Pd/C, installing a tee joint on a reaction bottle, pumping vacuum by a water pump, introducing hydrogen, repeatedly pumping vacuum again, introducing gas for 2 times, reacting at room temperature for 12 hours, and TLC (CH)2Cl2MeOH 20/1) showed the disappearance of the starting material spot, Pd/C was filtered off, and the filtrate was concentrated under reduced pressure to give 31g (64.0%) of the title compound.
EXAMPLE 9 preparation of Boc-Asp (OMe) -Val-OBzl
5g (20.2mmol) of Boc-Asp (OMe), 2.7g (19.9mmol) of HOBt were weighed, dried and dissolved in Tetrahydrofuran (THF), stirred in ice bath, 5g (24.3mmol) of DCC dissolved in THF was added dropwise thereto, stirred and activated for 30 minutes, 8.3g (22.0mmol) of TosH.Val-OBzl was added, NMM was adjusted to pH 8, and the reaction was carried out at room temperature for 12 hours, TLC (CH)2Cl2MeOH 20/1) showed the disappearance of the starting point. DCU was removed by filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in 100mL of ethyl acetate, the obtained ethyl acetate solution was washed with 20mL of a saturated aqueous sodium bicarbonate solution, 20mL of a saturated aqueous sodium chloride solution, 20mL of a saturated aqueous potassium hydrogen sulfate solution, 20mL of a saturated aqueous sodium chloride solution, 20mL of a saturated aqueous sodium bicarbonate solution, and 20mL of a saturated aqueous sodium chloride solution in this order for 3 times, the ethyl acetate layer was dried over anhydrous sodium sulfate for 30 minutes, and the filtrate was concentrated under reduced pressure to obtain 8.1g (92.0%) of the title compound.
EXAMPLE 10 preparation of HCl Asp (OMe) -Val-OBzl
To 8.1g (18.6mmol) of Boc-Asp (OMe) Val-OBzl was added 80mL of 4M hydrogen chloride in ethyl acetate under ice-bath, and after 4 hours of reaction, TLC (CH)2Cl2MeOH 20/1) showed the disappearance of the starting material dot and was concentrated under reduced pressure. Anhydrous residue for useDissolving with ethyl acetate, and concentrating under reduced pressure. This operation was repeated 3 times. The residue was dissolved in anhydrous ether and concentrated under reduced pressure. This operation was also repeated 3 times to give 6.7g (97.1%) of the title compound.
EXAMPLE 11 preparation of Boc-Asp (OMe) -Phe-OBzl
3g (12.1mmol) of Boc-Asp (OMe), 1.6g (11.8mmol) of HOBt were weighed, dissolved in dry Tetrahydrofuran (THF), stirred in ice bath, 3g (14.6mmol) of DCC dissolved in THF were added dropwise thereto, after stirring for 30 minutes activation, 4g (13.7mmol) of HCl Phe-OBzl were added, NMM was adjusted to pH 8, and the reaction was carried out at room temperature for 12 hours, TLC (CH)2Cl2MeOH 20/1) showed the disappearance of the starting point. DCU was removed by filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in 100mL of ethyl acetate, the obtained ethyl acetate solution was washed with 20mL of a saturated aqueous sodium bicarbonate solution, 20mL of a saturated aqueous sodium chloride solution, 20mL of a saturated aqueous potassium hydrogen sulfate solution, 20mL of a saturated aqueous sodium chloride solution, 20mL of a saturated aqueous sodium bicarbonate solution, and 20mL of a saturated aqueous sodium chloride solution in this order for 3 times, the ethyl acetate layer was dried over anhydrous sodium sulfate for 30 minutes, and the filtrate was concentrated under reduced pressure to obtain 5.2g (88.1%) of the title compound.
EXAMPLE 12 preparation of HCl. Asp (OMe) -Phe-OBzl
5.2g (10.7mmol) Boc-Asp (OMe) Phe-OBzl were added with ice bath 50mL of 4M hydrogen chloride in ethyl acetate and reacted for 4 hours, followed by TLC (CH)2Cl2MeOH 20/1) showed the disappearance of the starting material dot and was concentrated under reduced pressure. The residue was dissolved in anhydrous ethyl acetate and concentrated under reduced pressure. This operation was repeated 3 times. The residue was dissolved in anhydrous ether and concentrated under reduced pressure. This operation was also repeated 3 times to give 4.3g (95.6%) of the title compound.
EXAMPLE 13 preparation of Boc-Arg (tos) -Gly-Asp (OMe) -Val-OBzl
13g (26.8mmol) of Boc-Arg (tos) Gly, 3.6g (26.6mmol) of HOBt were weighed, dried Tetrahydrofuran (THF) was dissolved, stirring was performed in ice bath, 6.5g (31.6mmol) of DCC dissolved in THF was added dropwise thereto, stirring was performed for 30 minutes to activate the mixture, 10.7g (28.6mmol) of HCl & Asp (OMe) Val-OBzl was added thereto, NMM was adjusted to pH 8, reaction was performed at room temperature for 12 hours, and TLC (CH)2Cl2MeOH 20/1) showed the disappearance of the starting point. DCU was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 400mL of ethyl acetateThe ethyl acetate layer was washed with 50mL of a saturated aqueous sodium bicarbonate solution, 50mL of a saturated aqueous sodium chloride solution, 50mL of a saturated aqueous potassium hydrogen sulfate solution, 50mL of a saturated aqueous sodium chloride solution, 50mL of a saturated aqueous sodium bicarbonate solution, and 50mL of a saturated aqueous sodium chloride solution in this order for 3 times, and the ethyl acetate layer was dried over anhydrous sodium sulfate for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain 18.0g (83.7%) of the title compound.
EXAMPLE 14 preparation of Boc-Arg (tos) -Gly-Asp (OMe) -Phe-OBzl
25g (51.5mmol) of Boc-Arg (tos) Gly, 5.5g (40.6mmol) of HOBt, dried Tetrahydrofuran (THF) were dissolved and stirred in ice bath, 11g (53.4mmol) of DCC dissolved in THF was added dropwise thereto, after stirring and activation for 30 minutes, 10.7g (40.4mmol) of HCl & Asp (OMe) Phe-OBzl was added, NMM was adjusted to pH 8, and the reaction was carried out at room temperature for 12 hours and TLC (CH)2Cl2MeOH 20/1) showed the disappearance of the starting point. DCU was removed by filtration, concentrated to dryness under reduced pressure, and the residue was dissolved in 400mL of ethyl acetate, and the resulting ethyl acetate solution was washed 3 times with 50mL of a saturated aqueous sodium bicarbonate solution, a saturated 50mL of an aqueous sodium chloride solution, 50mL of a saturated aqueous potassium hydrogen sulfate solution, 50mL of a saturated aqueous sodium chloride solution, 50mL of a saturated aqueous sodium bicarbonate solution, and 50mL of a saturated aqueous sodium chloride solution in this order, and the ethyl acetate layer was dried over anhydrous sodium sulfate for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure to give 30.2g (87.8%) of the title compound.
Example 15 preparation
Fmoc-Lys[Val-Asp-(OMe)-Gly-Arg(Tos)-Boc]-Glu(OBzl)-Asp(OBzl)-Gly-OBzl
4g (5.6mmol) Boc-Arg (tos) GlyAsp (OMe) Val, 780mg (5.8mmol) HOBt were weighed, dried Tetrahydrofuran (THF) was dissolved, stirred in ice bath, 2.6g (6.4mmol) HATU dissolved in anhydrous DMF was added dropwise thereto, stirred and activated for 30 minutes, 5.6g (5.7mmol) HCl. Fmoc-Lys-Glu (OBzl) Asp (OBzl) Gly-OBzl was added, NMM was adjusted to pH 8, and the reaction was carried out at room temperature for 12 hours, TLC (CH) was performed2Cl2MeOH 5/1) showed the disappearance of the starting point. Concentrated under reduced pressure, the residue was dissolved in 200mL of ethyl acetate, and the resulting ethyl acetate solution was successively diluted with 30mL of a saturated aqueous sodium bicarbonate solution, 30mL of a saturated aqueous sodium chloride solution, 30mL of a saturated aqueous potassium hydrogen sulfate solution, 30mL of a saturated aqueous sodium chloride solution, and 30mL of a saturated aqueous sodium bicarbonate solution30mL of a saturated aqueous solution of sodium chloride was washed 3 times, and the ethyl acetate layer was dried over anhydrous sodium sulfate for 30 minutes, stirred and purified by column chromatography to give 7.9g (85.9%) of the title compound. ESI-MS (m/z): 1636.5[ M + H]+。
Example 16 preparation
Fmoc-Lys[Phe-Asp(OMe)-Gly-Arg(Tos)-Boc]-Glu(OBzl)-Asp(OBzl)-Gly-OBzl
1.6g (2.1mmol) Boc-Arg (tos) GlyAsp (OMe) Phe, 285mg (2.1mmol) HOBt, dried Tetrahydrofuran (THF) were dissolved and stirred in ice bath, 1g (2.6mmol) HATU dissolved in DMF was added dropwise thereto, after stirring for activation for 30 minutes, 2.1g (2.2mmol) HCl. Fmoc-LysGlu (OBzl) Asp (OBzl) Gly-OBzl, NMM adjusted pH 8, and reacted at room temperature for 12 hours, TLC (CH) was added2Cl2MeOH 5/1) showed the disappearance of the starting point. Concentrated to dryness under reduced pressure, the residue was dissolved in 200mL of ethyl acetate, the resulting ethyl acetate solution was washed with 30mL of a saturated aqueous sodium bicarbonate solution, 30mL of a saturated aqueous sodium chloride solution, 30mL of a saturated aqueous potassium hydrogen sulfate solution, 30mL of a saturated aqueous sodium chloride solution, 30mL of a saturated aqueous sodium bicarbonate solution, and 30mL of a saturated aqueous sodium chloride solution in this order for 3 times, and the ethyl acetate layer was dried over anhydrous sodium sulfate for 30 minutes, stirred, and purified by column chromatography to give 2.1g (60.0%) of the title compound. ESI-MS (m/z): 1684.5[ M + H]+。
EXAMPLE 17 preparation of 17-ethoxycarbonylmethoxyacetyldexamethasone
20g (51.5mmol) of dexamethasone was weighed and dissolved in 50mL of DMSO, the mixture was stirred in an ice bath, 1.3g (52.1mmol) of NaH was carefully added to the reaction flask, 17mL of ethyl bromoacetate was added dropwise to the reaction flask, the reaction was carried out at room temperature for 2 hours, 400mL of ethyl acetate was added to the reaction flask, the resulting solution was washed 5 times with saturated aqueous sodium chloride solution, 50mL each time, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 15.1g (62.9%) of the title compound. And Mp: 225-226 deg.c,
(c＝0.1，CH3OH)，ESI-MS(m/z)：479.84[M+H]+，1H NMR(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)。
EXAMPLE 18 preparation of 17-Carboxymethoxyacetyldexamethasone
15.1g (31.6mmol) of 17-ethoxycarbonylmethoxyacetyldexamethasone were dissolved in 100mL of methanol, the pH was adjusted to 12 with 2N NaOH in ice bath, the reaction was carried out in ice bath while maintaining the pH at 12, and TLC (CH) was carried out after 15 hours2Cl2/EA-1/1) shows the disappearance of the starting material point. The reaction mixture was adjusted to pH 7 with saturated aqueous potassium hydrogensulfate solution, concentrated under reduced pressure, the residue was dissolved in 200mL of distilled water, adjusted to pH 2 with saturated aqueous potassium hydrogensulfate solution, extracted 3 times with ethyl acetate, each 60mL, the ethyl acetate layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting colorless powder was washed with carbon dichloride, filtered, and the cake was collected to obtain 12.8g (90.1%) of the title compound. Mp 232-: 449.3[ M-H ]]-，
(c＝0.1，CH3OH)，1H NMR(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)。
EXAMPLE 19 preparation of dexamethasone-17-Carboxyacetyl-Lys [ Val-Asp (OMe) -Gly-Arg (tos) -Boc ] -Glu (OBzl) -Asp (OBzl) -GlyOBzl
Dissolving 1.1g (2.4mmol) 17-carboxymethoxyacetyldexamethasone and 240mg (1.8mmol) HOBt in anhydrous DMF, adding 941mg (2.5mmol) HATU dissolved in anhydrous DMF dropwise with stirring in ice bath, stirring for 30min, adding 2.5g (1.8mmol) Lys [ Phe-Asp (OMe) -Gly-Arg (tos) -Boc]-glu (OBzl) -asp (OBzl) -Gly-OBzl, pH 8 adjusted with NMM, reaction at room temperature for 12 hours, TLC (CH)2Cl2MeOH 5/1) showed raw material point disappearedAnd (6) losing. Adding 200mL of saturated aqueous sodium chloride solution into the reaction solution under ice bath, extracting with ethyl acetate for 3 times (50 mL each time), combining ethyl acetate layers, washing with 30mL of saturated aqueous sodium bicarbonate solution, 30mL of saturated aqueous sodium chloride solution, 30mL of saturated aqueous potassium hydrogen sulfate solution, 30mL of saturated aqueous sodium chloride solution, 30mL of saturated aqueous sodium bicarbonate solution, 30mL of saturated aqueous sodium chloride solution for 3 times, drying over anhydrous sodium sulfate, concentrating under reduced pressure to 1mL, mixing with silica gel for chromatography, and purifying by column Chromatography (CH)2Cl2MeOH 15/1) to yield 1.6g (48.8%) of the title compound. And Mp: 137-140 deg.c,
(c＝0.1，CH3OH)，ESI-MS(m/z)：1845.8543[M+H]+，1H NMR(300MHz，DMSO-d6)：8.64-8.61(d，J＝9Hz，1H)，8.21(m，3H)，8.14(m，1H)，7.88(m，1H)，7.78(m，1H)，7.64(d，J＝9Hz，3H)，7.35(m，16H)，6.93-9.90(d，J＝9Hz，1H)，6.57(s，1H)，6.23-6.20(d，J＝9Hz，1H)，6.01(s，1H)，5.17(s，2H)，5.09(s，2H)，5.06(s，1H)，4.69(m，4H)，4.28(m，7H)，4.04(s，1H)，3.91(s，4H)，3.71(m，3H)，3.56(s，4H)，3.05(m，4H)，2.63(m，2H)，2.40(m，8H)，1.93(m，7H)，1.60(m，7H)，1.25(m，17H)，0.88(m，3H)，0.80(m，6H)。
EXAMPLE 20 preparation of dexamethasone-17-Carbonylmethoxyacetyl-Lys (Val-Asp-Gly-Arg) -Glu-Asp-Gly (5a)
285mg (0.15mmol) dexamethasone-17-carbomethoxyacetyl-Lys- [ Val-Asp (OMe) -Gly-Arg (tos) -Boc were weighed]-glu (obzl) -asp (obzl) -GlyOBzl in a 100mL eggplant flask, adding 3mL trifluoroacetic acid under ice bath, stirring for 15 minutes, adding 1mL trifluoromethanesulfonic acid, continuing stirring for 15 minutes, adding 80mL anhydrous ether to precipitate the product, stirring for 5 minutes, standing, settling the precipitate, and carefully pouring off the liquid. The residue was washed with ether and the liquid carefully decanted. The residue was washed with ether and the liquid carefully decanted. The residue was freed of the solvent under reduced pressure, dissolved in 5mL of distilled water, the solution obtained was adjusted to pH 7 with dilute ammonia, filtered, the filtrate was desalted with Sephdex G10 and lyophilized to give 111mg (55.0%) of the title compound. Mp：107-108℃，
(c＝0.03，H2O)，ESI-MS(m/z)：1303.5982[M+H]+，1H NMR(300MHz，DMSO-d6)：δ/ppm＝8.72(m，1H)，8.51(m，3H)，8.25(m，1H)，7.94(s，1H)，7.28-7.25(d，J＝9Hz，1H)，6.61(s，2H)，6.28(s，1H)，6.23-6.20(d，J＝9Hz，1H)，6.02(s，1H)，5.36(s，1H)，5.08(m，1H)，4.62(m，2H)，4.28(m，2H)，4.13(m，2H)，3.75(m，6H)，3.58(s，3H)，3.45(m，2H)，3.02(m，5H)，2.74(m，4H)，2.22(m，6H)，1.72(m，7H)，1.52(m，8H)，0.95(s，3H)，0.81(m，6H)。
EXAMPLE 21 preparation of dexamethasone-17-carbomethoxyacetyl
-Lys[Phe-Asp(OMe)-Gly-Arg(Tos)-Boc]-Glu(OBzl)-Asp(OBzl)-Gly-OBzl
1.3g (2.9mmol) of 17-carboxymethoxyacetyldexamethasone and 278mg (2.1mmol) of HOBt are dissolved in anhydrous DMF, stirred in ice bath, 1.1g (2.9mmol) of HATU dissolved in anhydrous DMF is added dropwise thereto, after stirring for 30 minutes 3.0g (2.1mmol) of Lys [ Phe-Asp (OMe) -Gly-Arg (tos) -Boc]-glu (OBzl) -asp (OBzl) -Gly-OBzl, pH 8 adjusted with NMM, reaction at room temperature for 12 hours, TLC (CH)2Cl2MeOH 5/1) showed the disappearance of the starting point. Adding saturated sodium chloride solution 200mL into the reaction solution under ice bath, extracting with ethyl acetate for 3 times, 50mL each time, combining ethyl acetate layers, washing with 30mL saturated sodium bicarbonate aqueous solution, 30mL saturated sodium chloride aqueous solution, 30mL saturated potassium bisulfate aqueous solution, 30mL saturated sodium chloride aqueous solution, 30mL saturated sodium bicarbonate aqueous solution, 30mL saturated sodium chloride aqueous solution for 3 times, drying with anhydrous sodium sulfate, concentrating under reduced pressure to 1mL, mixing with silica gel chromatography, and purifying by column Chromatography (CH)2Cl2MeOH 15/1) to yield 2.1g (53.7%) of the title compound. And Mp: 136.8-140.0,
(c＝0.1，CH3OH)，ESI-MS(m/z)：1893.8525[M+H]+，1H NMR(300MHz，DMSO-d6)：δ/ppm＝8.65-8.62(d，J＝9Hz，1H)，8.20(m，6H)，7.96-7.93(d，J＝9Hz，1H)，7.78(s，3H)，7.65-7.62(d，J＝9Hz，3H)，7.27(m，25H)，6.95(m，2H)，6.77(s，1H)，6.56，(s，1H)，6.24-6.21(d，J＝9Hz，1H)，6.01(s，1H)，5.28(s，1H)，5.17(s，2H)，5.09(m，4H)，4.66(m，3H)，4.31(m，7H)，4.16(m，2H)，3.92(s，4H)，3.70(m，2H)，3.56(s，4H)，2.75(m，10H)，2.34(m，8H)，1.99(m，9H)，1.38(m，17H)，0.88(s，3H)。
EXAMPLE 22 preparation of dexamethasone-17-carbomethoxyacetyl-Lys (Phe-Asp-Gly-Arg) -Glu-Asp-Gly (5b)
Weighing dexamethasone-17-carbo-methoxyacetyl-Lys [ Phe-Asp (OMe) -Gly-Arg (tos) -Boc]In a 100mL eggplant flask, 3mL of trifluoroacetic acid was added in an ice bath to 100mL of Glu (OBzl) -Asp (OBzl) -Gly-OBzl 526mg (0.28mmol), 1mL of trifluoromethanesulfonic acid was added after stirring for 15 minutes, 80mL of dehydrated ether was added after continuing the reaction for 15 minutes to precipitate the product, stirring was stopped after 5 minutes, the precipitate was allowed to stand and settled, and the liquid was carefully poured out. The residue was washed with ether and the liquid carefully decanted. The residue was washed with ether and the liquid carefully decanted. The residue was freed of the solvent under reduced pressure, dissolved in 5mL of distilled water to give a solution which was adjusted to pH 7 with dilute ammonia, filtered, the filtrate was desalted with Sephdex G10 and lyophilized to give 142mg (37.8%) of the title compound. And Mp: 96.7-97.3,
(c＝0.03，H2O)，ESI-MS(m/z)：1355.27[M+H]+，1H NMR(300MHz，DMSO-d6)：δ/ppm＝8.26(m，1H)，7.62(m，4H)，7.23(m，9H)，6.22-6.19(d，J＝9Hz，1H)，6.01(s，1H)，5.37(s，1H)，4.58(m，1H)，4.25(m，3H)，3.76(m，9H)，3.00(m，10H)，2.62(m，3H)，2.34(m，4H)，2.12(m，6H)，1.65(m，8H)，1.17(m，3H)，0.91(m，3H)。
experimental example 1 Transmission Electron micrograph of measured 5a, b
5a and b are prepared into the concentration of 1.43 multiplied by 10-6An aqueous solution of M, wherein the concentration of M,the solution was then dropped onto a copper mesh and the nano-morphology was observed under a JEM-1230 Transmission Electron microscope after evaporation of the dry solvent. The assay showed that 5a, b formed regular nanospheres. As a representative photograph, FIG. 2 shows the concentration of 1.43X 10-6Transmission electron micrographs of 5a, b of M. The results show that the nanostructures of 5a, b are nanospheres with a diameter of less than 100 nm. It can be seen that the nanostructures of 5a, b are very advantageous for their delivery in vivo.
Experimental example 2 evaluation of the effects of 5a, b on transplantation of myocardial tissue behind mouse ear
Recipient mice (Balb/c mice, male, 20 + -2 g in weight) were anesthetized by intraperitoneal injection of 10% urethane (10mg/10g in weight). 1% benzalkonium bromide tincture of auricle is topically sterilized, and an ophthalmic scissors is used to make a 3-4 mm long incision at 1/3 front of dorsal midline of auricle, and perpendicular to the midline of auricle, without damaging auricle vein. The subcutaneous tissue is bluntly separated towards the ear tip by holding forceps to form a lumen. Newborn mice (C57bl/6j24 h suckling mice) were placed in crushed ice for one minute, skin-sterilized with 75% alcohol, and hearts were removed by cutting open the chest. The heart was placed in PBS to beat 1-2 times to empty the heart chamber of the residual blood. When transplanting, the heart is cut into two halves with same size by a blade, and the muscle fiber forms a slope. The myocardial tissue is transplanted and filled into the ear cavity of a receptor mouse, and the in vitro time of the myocardial tissue does not exceed 2 minutes. The graft was tightly attached to the peripheral tissues of the mouse by pressing the part gently with a finger. Administration was performed on the day after transplantation. Blank control is physiological saline, 5a, b are dissolved by physiological saline and are orally administered, the dosage is 0.1 mu mol/kg/d, 0.2mL/20g body weight, and the administration is continuously carried out for 15 days and 15 times in total. Recording electrocardiosignals of the transplanted myocardial tissue every day from the 7 th day after operation, and respectively arranging positive and negative electrodes on two sides of the transplanted heart when testing the ectopic electrocardiogram, wherein the grounding electrode is connected with the hind limb of the mouse.
A graph 3 of survival of transplanted myocardium is plotted. The results show that the death of transplanted myocardium only occurs in the 5a and b groups at the 17 th day after operation, and the survival rate of myocardium is greatly improved compared with dexamethasone. The results indicate that 5a, b significantly inhibited rejection of transplanted myocardial tissue at a dose of 0.1. mu. mol/kg/d. The effective dose of the present invention is reduced by a factor of 14 compared to the inventors once disclosed an effective dose of the compound of structure A (1.43. mu. mol/kg). The effective dose of the present invention is reduced by a factor of 2000 and 7500 compared to the effective dose (2.0 and 7.0mmol/kg) that the inventors have previously disclosed for compounds of structure B. It is apparent that the present invention achieves unexpected results in suppressing rejection of transplanted myocardial tissue.
Experimental example 3 evaluation of anti-inflammatory Activity of 5a, b Using a mouse xylene-induced inflammation model
The anti-inflammatory activity of 5a, b was evaluated using a mouse xylene-induced inflammation model. Dexamethasone and 5a and b were administered in one dose, dexamethasone was administered at 25.5 μmol/kg per oral dose, and dexamethasone was administered at 2.55 μmol/kg per oral dose for both 5a and b. Saline was a blank control. ICR male mice (weight 20 + -2 g) were randomly divided into a blank control group, a positive group and a dosing group, 10 mice per group. The test is carried out orally, 30min after single administration, 30 mu L of dimethylbenzene is evenly smeared on the left auricle of the mouse, the mouse is killed by breaking the mortar after 2h, the left ear and the right ear are cut off, a round ear piece is taken at the same position of the two ears by a hole puncher with the thickness of 7mm, the round ear piece is weighed, the swelling difference value of the two ears is obtained and is used as the swelling degree, and the swelling degree is equal to the weight of the left ear piece-the weight of the right ear piece.
The data in Table 1 demonstrate that 5a, b effectively inhibited the inflammatory response in mice at a dose of 2.55. mu. mol/kg. The effective dose of the present invention is reduced by a factor of 10 compared to the inventors' previous disclosure of an effective dose of a compound of structure A (25.5. mu. mol/kg). The inventors have disclosed that the compounds of structure B have no anti-inflammatory activity. It is apparent that the present invention achieves unexpected results in inhibiting inflammation.
TABLE 1 Effect of the Compounds of the invention on the degree of ear swelling in mice
n is 10, oral administration, double-sample equal variance t test; a) p is less than 0.01 compared with the normal saline group; b) compared with the normal saline and the dexamethasone group, the P is less than 0.01.
Experimental example 4 evaluation of the effects of 5a, b on mouse femurs
In Experimental example 2, after the transplanted myocardium had died completely, the mouse was sacrificed by dislocation, and the femur was weighed and the bone density was measured. The data in Table 3 show that 5a, b did not cause osteoporosis in mice at the 0.1 μmol/kg dose. The effective dose of the present invention is reduced by a factor of 10 compared to the effective dose (1.43 μmol/kg) at which the inventors have previously disclosed that the compound of structure A does not cause osteoporosis. The inventors have previously disclosed that compounds of structure B have no anti-osteoporosis activity. It is apparent that the present invention achieves unexpected results against osteoporosis.
Table 2 weight and density effects of the compounds of the invention on femur
n-10, oral administration, continuous administration for 15 days, double-sample equal variance t test: a) compared with the normal saline group, P is less than 0.05; b) p is more than 0.05 compared with the normal saline group, and P is less than 0.05 compared with dexamethasone.
Experimental example 5 evaluation of the Effect of 5a, b on thrombosis
Male SD rats were randomly divided into groups: the blank control is physiological saline, the positive control is aspirin, and the dosage is 167 mu mol/kg; dexamethasone and 5a and b are dosed at 0.99 mu mol/kg in the administration group. After 30 minutes of oral administration, urethane (20 g/100mL, 7mL/kg) was anesthetized. The right carotid artery and the left jugular vein were separated, a 6cm long silk thread precisely weighed in advance was placed in a polyethylene tube, the cannula was filled with a physiological saline solution of heparin sodium (0.42mg/mL, 0.42mg/kg) as an anticoagulant, and after one end was inserted into the left vein, a fixed amount of heparin sodium was injected for anticoagulation, and then inserted into the right artery. Blood flow from the right artery through the polyethylene tube into the left vein circulates for 15 minutes. And taking out the silk thread after 15min, accurately weighing, calculating weight gain, and counting the antithrombotic activity of the compound. The results are shown in Table 3. The data in Table 3 demonstrate that 5a, b effectively inhibited thrombosis in rats at a dose of 0.99. mu. mol/kg. The inventors have previously disclosed that neither of the compounds of structures a and B have antithrombotic activity. It is apparent that the present invention achieves unexpected antithrombotic results.
TABLE 3 antithrombotic Activity of the Compounds of the invention
n-9, oral administration, 0.99 μmol/kg, two-sample equal variance t test, a) P < 0.01 compared to saline; b) compared with normal saline, P is less than 0.05; c) compared with the normal saline and the dexamethasone group, the P is less than 0.01.
Claims (5)
1. Octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone of the formula,
in which AA is a L-Val or L-Phe residue.
2. A process for the preparation of the octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone of claim 1, comprising three major steps:
1) in DMSO, NaH catalyzes hydroxyl of 17-position hydroxyacetyl of dexamethasone and ethyl bromoacetate to remove HBr, the 17-position hydroxyacetyl is converted into ethoxycarbonylmethoxyacetyl, and the 17-position ethoxycarbonylmethoxyacetyl is converted into 17-position carboxymethoxyacetyl in NaOH solution;
2) stepwise peptide attachment according to standard liquid phase peptide attachment procedure, coupling the side chain amino group of L-Boc-Lys to the carboxy-terminus of carboxy-free fully protected RGDV or RGDF, coupling the carboxy-terminus of L-Lys to the N-terminus of α -amino free fully protected Glu-Asp-Gly, preparing fully protected octapeptide Fmoc-Lys [ AA-Asp (OMe) -Gly-Arg (tos) -Boc) ] -Glu (OBzl) -Asp (OBzl) -Gly-OBzl, followed by Fmoc elimination in 20% piperidine DMF solution to prepare N free fully protected octapeptide Lys [ AA-Asp (OMe) -Gly-Arg (tos) -Boc) ] -Glu (OBzl) -Asp (OBzl) -Gly-OBzl, wherein AA is L-Val or L-Phe residue;
3) coupling dexamethasone-17-carboxylic acid obtained in step 1 with Lys [ AA-Asp (OMe) -Gly-Arg (tos) -Boc) ] -Glu (OBzl) -Asp (OBzl) -Gly-OBzl obtained in step 2 in anhydrous DMF in the presence of HATU, HOBt and NMM, and removing all protecting groups with trifluoromethanesulfonic acid in trifluoroacetic acid to obtain octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone of claim 1.
3. Nanospheres of the octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone of claim 1.
4. Use of the octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone according to claim 1 in the preparation of an immunosuppressant, characterised in that the immunosuppressant prepared overcomes the side effects of dexamethasone induced osteoporosis and thrombosis.
5. Use of the octapeptide Lys (AA-Asp-Gly-Arg) -Glu-Asp-Gly modified dexamethasone according to claim 1 in the preparation of an anti-inflammatory agent, characterised in that the anti-inflammatory agent prepared overcomes the side effects of osteoporosis and thrombosis caused by dexamethasone.
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